key: cord- - gun ep authors: celi, giuseppe; guarascio, dario; simonazzi, annamaria title: a fragile and divided european union meets covid- : further disintegration or ‘hamiltonian moment’? date: - - journal: j doi: . /s - - - sha: doc_id: cord_uid: gun ep despite being symmetric in its very nature, the covid- shock is affecting european economies in a very asymmetric way, threatening to deepen the divide between core and peripheral countries even more. it is not covid- itself, however, but the contradictions within the eu’s growth model and institutional architecture that would be to blame for such an outcome. the dramatic impact of the economic crisis brought on by the pandemic and the threat that it poses to eurozone survival seem to have forced a reluctant germany into action: a minor step, but an important signal. this note analyses the crossroads currently facing europe—the risk of disintegration vis-a-vis the opportunity for a ‘hamiltonian moment’—discussing possible future scenarios in the light of past developments. like viruses, crises too can rapidly change their dna: the financial crisis of changed from international to regional, from financial to real, eventually turning into an existential threat to the whole european integration project. in the institutional context of the eurozone (ez), the financial crisis soon developed into a sovereign debt crisis, dragging the banks along with it. in the austerity environment that followed, the southern periphery (sp) never completely recovered the losses in output, employment, and fiscal sustainability. thus, the "symmetric" coronavirus shock hit countries that were in highly asymmetric conditions. in fact, not all the countries of the union have the resources needed to intervene in support of their economy, prompting concern that countries with the deepest pockets might be getting an unfair advantage in the eu's single market. far from triggering mutual protection, the covid- crisis seems to be paving the way for the same mistakes that followed the financial crisis. the centrifugal forces threatening disintegration of the european monetary union (emu) seem to have been defused, albeit only in part and only in extremis, at least for the time being. however, the survival of the union depends not only on responding to the severe financial problems caused by the epidemic, but also means addressing the long-term, structural problems that led to the increasing divergences among her members. as chancellor merkel herself acknowledged, "it is in nobody's interest for germany alone to be strong after the crisis". convergence is essential to put the union on a more solid basis so as to guarantee its long-term sustainability. what policies and what reforms should be implemented to pursue this objective? and are they economically and politically feasible? trying to answer these questions, we shall briefly review the institutional and structural causes of the increasing divergence between core and sp, shedding light on three momentous events: the creation of the monetary union, the financial crisis and the covid- shock. the first decade following the introduction of the emu saw continuity in the process of europeanisation embarked upon as from the formation of the common market, based on financial liberalization and market globalization. as argued in celi et al. ( celi et al. ( , , europeanisation meant eu-wide application of a policy of deregulation of goods, labour and capital markets that affected the timing, shape and direction of the european integration process, halting the process of convergence between the core and the sp of the eu. the more developed core (centred on germany) increased its productive and technological capacity; the sp, caught between product competition within the eu and cost competition from emerging economies in the international markets, saw a decline in its manufacturing capacity. with the fall of the soviet union and the entry of the former socialist countries of central and eastern europe in the eu, the eastern periphery (ep) became a key gear of germany's manufacturing matrix (stehrer and stollinger ) . a huge flow of direct investments, primarily in the automotive sector, transformed the economies merkel: germany must help other eu states get back on their feet, euractiv.com with reuters mag https ://www.eurac tiv.com/secti on/econo my-jobs/news/merke l-germa ny-must-help-other -eustate s-get-back-on-their -feet/. these diverging trends are likely to increase as a result of the slow, small and asymmetric response that europe is giving to the ongoing pandemic-driven economic crisis, as confirmed by the macroeconomic evidence provided in this forum by heimberger et al. of the visegrad pact (poland, hungry, slovakia, and check republic) into an essential source of intermediate goods (medium and medium-high quality) for the german industry. a well-qualified, extremely cheap workforce, generous subsidies and tax breaks, as well as geographical proximity and historical links, are among the determining factors of the increasingly tight links between the core and its ep. the impressive growth in manufacturing capacity in the east led to a restructuring in the hierarchical organization of the supply chains across europe: the weaker suppliers in the south were displaced by their cheaper competitors in the east, while the highly specialised suppliers of components in the industrial regions of the south maintained, and even increased, their close links with the german producers. the crowding-out of the less dynamic firms in the sp did not take the form of efficiencyenhancing market selection but rather a generalized reduction of production capacity, contributing to fuel a well-documented (see, among the others, guarascio and simonazzi ; dosi et al. ) process of 'poor tertiarisation' of the sp. on the other hand, the ep's industrial miracle was created by foreign, mostly german, direct investment, with the automotive sector taking the lion's share. so far, we have seen no comparable development of other productive sectors, nor has the automotive sector created spill-over effects in the rest of the economy (krzywdzinski ). on the contrary, the surge in the production of components for the automotive sector has partly displaced other productions, leading to an increasing 'mono-specialization' of these economies. despite a growing shortage of skilled labour, wages have remained modest. threats of production shifting further east, to romania, turkey, or to north africa, (pavlinek et al. ) are reflected in the adoption of a wage containment policy at home, driving young people with high educational qualifications to emigrate, and weakening the countries' skills base. with domestic demand subdued, the high growth rates recorded by these countries are entirely led by the growth in exports of local production by foreign multinationals (i.e., the so-called "integrated peripheral markets"). while their intensive specialisation in the automotive industry makes them totally dependent on the health of the german automotive industry, the foreign control of production decisions, innovation processes and markets makes it extremely difficult to undertake an independent, less unbalanced development path (celi et al. ) . to conclude, the two peripheries-the southern one, made up of the mediterranean economies, and the eastern one, with the prominent role of the visegrad countries-suffer from different fragilities, which descend from their common, albeit diverse, economic and financial dependence on the core. however, the core itself is dependent for its growth on the pattern of specialisation within the eu: the southern markets providing an outlet for its increasing surplus of manufactures, the eastern countries supplying cheap inputs for its industries. this combination of structural divergence and economic interdependence lies behind the fragility of the union as well as of the improbability of its disintegration given the high costs it would entail for core and peripheries alike. in the first period of the emu ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) , the core-sp structural divergence was partly hidden by massive financial flows to the periphery. the financial crisis, and the ensuing international liquidity crunch, prompted a "sudden stop" of capital flows and a collapse in demand and imports. at that point, the structural and institutional flaws of the emu became evident: the reaction to the crisis aggravated the divergence. with the blame for the crisis put squarely on borrowers, austerity policies were advocated (or imposed) to ensure debtor countries' public and private solvency. with austerity killing demand, growth and imports in the sp, germany, which had built most of its huge trade surplus between and by exporting to the periphery, had to find new outlets for its goods. special international conditionsnamely, china's huge growth, which gobbled up german capital goods and highquality durable consumer products (particularly cars), and the vigorous american recovery-supported germany's ability to redirect its trade flows, expand its market shares outside the emu, and make a speedy return to its pre-crisis production levels. the united kingdom, the united states, but above all china, became the most important markets for german exports. the rapid recovery of the german economy pulled the ep along with it: the visegrad countries recorded unparalleled growth in europe. with the abrupt change in the international scenario in , germany's (and the entire emu's) mercantilist strategy was up against the ropes. the brexit referendum, trump's election, and the u-turn in chinese economic policy inaugurated a phase of retreat in international trade. trade with the uk began to suffer due to the increasing uncertainty in future trade relations. when the united states took action to reduce the external deficit, china and germany, the countries with the largest trade surpluses vis-à-vis the united states, were caught in the crosshairs. trade tensions between the us and china put further pressure on international trade. the export-led growth model that had so far supported germany's leadership began to creak. the change in world trade took its toll on german (and eu) growth rates. from the second quarter of , the slowdown in german exports hit industrial production and the gdp, widening the growth gap with china and the usa and dragging the whole emu along with it ( fig. ) . as the escalation of trade disputes affected relations between the united states and germany (and by extension the eu), the negative effects on europe's (exportled) growth intensified. in the last quarter of , just a few months before the outbreak of covid- in the eu, germany's growth rate zeroed. income growth estimates for the rest of europe were consequently reduced. the pandemic arrived in europe from the south: italy was the first country to suffer the contagion. its abrupt, dramatic effects exposed the fragility of the periphery and the crippling effects of austerity policies. since , across the board cuts in social spending had hit the entire range, from health to education, from social assistance to social investment. figures , and show the evolution of the share of public expenditure on education and health (divided between general expenditure and hospitals) relative to gdp in the emu, germany and the sp between and . many hospitals had been closed, the number of beds reduced, medical and nursing staff cut back (for a detailed analysis of the impact that austerity policies had on the italian health care system, see prante et al. ). it is not surprising that the death toll was higher where intensive care facilities were scarcer. on the eve of the covid crisis, public health accounted for . percent of the social product in italy and spain, and almost % in germany, where per capita healthcare spending did not suffer cuts due to austerity (though it was not completely spared self-imposed restrictions). the covid- exposed another aspect of the 'divisive' union (celi et al. ) : different capacities to respond to the pandemic crisis. economic ideology shares with austerity the responsibility for the scant endowment of medical equipment and health staff. efficiency, understood as cost reduction, has been taken as the guiding principle. the obsession with competitiveness and reliance solely on the export-led growth model accounts for the almost exclusive emphasis on "tradable" sectors, to the detriment of "non-tradable" sectors (housing, health, education, welfare services in general), considered of lesser importance for international competition. this means that, in the era of austerity, these items have been the first to be sacrificed, in debtor and creditor countries alike. chazan ( ) reports that for years, politicians and health economists in germany have complained that the country has too many hospitals, with the bertelsmann foundation recommending halving the number of hospital, from to fewer than (chazan ). only such a radical consolidation-the bertelsmann study arguedwould "improve patient care and mitigate the shortage of doctors and nursing staff". the pandemic succeeded in transforming this "oversupply" into an asset. the same logic of pursuing the lowest cost guided the international location of production, which displaced domestic production and weakened production capacity in the sp. from a regional (european) point of view, this process resulted in a reorganisation of production and trade relations between core, ep and sp. on a global scale, core and peripheries entered into very long and complex gvcs that proved extremely vulnerable in the face of the interruptions prompted by the pandemic. personal protective equipment, respirators, medicines: the emergency has made it clear what it means to lose the capacity to produce domestically, both in quantity and quality, what is urgently needed, bringing the problem of self-sufficiency back to the attention of economists and policymakers. there is no such thing as a symmetric shock. in addition to the grim toll of victims and the incredible pressure on the health systems of all countries, the lockdown of activities to reduce contagion meant a tremendous plunge in production and incomes and enormous pressure on public finances all over the world. however, the lockdown is expected to affect economies differently. the central and eastern european countries have been less affected by covid than the western european countries: not trusting the resilience of their fragile health systems, they have had to rely on rigid social distancing (walker and smith ) . even within this group of countries there are differences: thanks to their more robust health systems, the czech republic and slovenia were less constrained by rigid social distancing and able to start economic recovery earlier. moreover, due to their strong productive links with austria-a country relatively less affected by the pandemic which came out of the lockdown earlier-and their favourable positioning in the development of digital economy (wiiw ) , their economic outlook is rather better. conversely, it will be tougher for the economies, like those of the sp, which are more dependent on services-tourism and hospitality in particular (fig. ) -and for cee countries and southern regions that rely to a greater extent on production of intermediate products for final producers, since the latter can better defend themselves from fall in demand by cutting down orders to their suppliers (the so-called "whip effect"). policies have also differed widely across countries and regions. while all the central banks of the developed world promptly intervened to provide almost unlimited . although the stability pact has been temporarily suspended, there are obvious differences in how much member states can spend, depending on their fiscal space. member states are making use of the new flexibility granted by the ec on state aid rules, strictly enforced beforehand to ensure fair competition within the internal market (rios ) . germany, which accounts for about a quarter of the eu's gdp, accounts for more than half ( %) of the emergency coronavirus state aid approved by the ec, prompting concerns that countries with the deepest pockets might be getting an unfair advantage by such a sudden (and temporary) abandonment of one of the common market's key pillar (france and italy each account for % of the total). an eu official, speaking on condition of anonymity, observed that "if you look at the scale of what germany in particular, but also some others, are doing-any notion of level playing field or single market integrity has gone out of the window." these concerns underpin the ailing south's demand for a joint eu financial plan. in the absence of a prompt and massive common effort, the sp will pay the highest price to the health crisis. indeed, the different firepower will entail a still greater asymmetry in the economic and power relations between the various member states. the ecb, alone among the eurozone institutions, is doing as much as it can to avoid breakdown of the emu. to address the covid- crisis, it launched a new asset purchasing programme: the eurosystem's balance sheet shot up from billion euros on february to billion by st may . despite this massive monetary injection ( billion in two months) the spread on italian bonds, which had fallen in mid-march following the ecb's announcements, again rose very rapidly, fluctuating in response to political developments. indeed, as tooze and schularick ( ) point out, if, in the crisis, the liquidity injected into the system by the ecb was enough to prevent deflagration of the banking system, the current crisis would require a coordinated fiscal policy of enormous proportions. despite some recent moves (inaugurated by a merkel-macron agreement), this still does not seem to be looming on the horizon. the newly released 'next generation' (ng) plan, based on the - budget, celebrated by some as a "hamiltonian moment", has yet to qualify as forerunner of an eu-wide up-to-the-challenge fiscal capacity. first of all, it is meant to be temporary and, moreover, it is too little, too late. the plan should mobilize billion euros, in the form of grants and in loans. quote reported by the website euractiv.com. the eurosystem balance sheet (the network of european central banks, guided by the ecb) rose from billion euros at the beginning of to billion euros by the end of ; that is, from barely % to almost % of the euro zone gdp ( billion euros). the ng plan money will be spent over the - period. with an even subdivision over the period, the package amounts to an annual . % of the eu's gdp, over four years. several parties, including most recently the president of the ecb, christine lagarde, are urging the ec to review the pact before its temporary suspension expires on december , . apart from the fact that these are gross figures-once the member states' contributions to the eu budget are subtracted, the net amount received by the neediest countries is much smaller-their disbursement will not start before , will be distributed over a -year period, with amounts that grow over time, and, as stated in the ec's "proposal for a regulation" the financial contribution will "be paid in instalments once the member state has satisfactorily implemented the relevant milestones and targets identified in relation to the implementation of the recovery and resilience plan" (ec , art. . .a). as darvas ( ) emphasizes, the incorporation of the ng plan into the eu's next multiannual budget would take advantage of a well-established framework, 'already subject to various checks and balances'. on the other hand, ng resources risk to be trapped in a 'slow-moving machine'. in order to be financed, ng-related projects need to be designed, approved and implemented as part of a process that can take several years. as a result, the timing of disbursements is just the opposite of what would be required to respond to the urgency imposed by the current situation and, even more so, by the expected collapse of incomes that the european economies are going to face. however, the commission expects that barely . % of the total new firepower for grants would be spent in - , when the recovery needs will be greatest (darvas ) . far from being a tool to counter the immediate effects of the crisis, the ng plan is more similar to the juncker plan, and shares all its weaknesses. it is highly unlikely that countries like italy, severely hit by the pandemic and in persistent financial distress, will be able to afford to refrain from asking for other funds (namely, esm, sure and others for a total amount of about billion euros) which could be paid out immediately, subject to the usual conditionality. the merkel-macron agreement has been hailed as the first step towards a more supportive union. behind the good intentions, there are the concrete interests of both france and germany for the survival of the emu: they look with growing concern at the rise of euroscepticism in the sp. the french economy has been hit hard by the pandemic, and was already in difficulty before. gdp forecasts for vary widely, but all agree in estimating a fall in the french gdp of much the same proportions as in the case of italy. on the other hand, germany was, together with the netherlands, the main beneficiary of the creation of the euro, and italy and france were the main losers (gasparotti and kullas ) . as chancellor merkel told the german lawmakers, "it is essential for germany, as an export nation, that its eu partners also do well". indeed, the history of the eu has taught that excessive german surpluses are deleterious for the south of the eurozone. greater government action, retreat from hyper-globalism, and lower growth rates predate the pandemic. the covid- crisis has given yet more voice to calls for protectionist and "beggar thy neighbours" types of policies. it has led countries to prioritize resilience and autonomy in production over cost savings and efficiency through global outsourcing. the same powerful german production platform, so disproportionately export-oriented and dependent on imports of intermediate goods, finds itself vulnerable to a type of shock (the covid- pandemic) that disrupts gvcs and threatens to change the existing economic order through permanent disruption of the patterns of demand and production. although transition from an industrial platform designed for export to one for the internal market (a sort of transition from a war to a peace economy) is a formidable challenge, this transformation would benefit germany itself, considering the winds of trade war and the growing uncertainty about the future developments of the global value chains. the european countries are at a crossroad between either letting the union dissolve or radically reforming it. today's darkened geopolitical environment requires europe to act as a whole. however, the emu will remain fragile as long as it chooses to continue to delegate control over its policies to market surveillance. a true "hamiltonian moment", which involves adopting a common fiscal policy in support of the common monetary policy is a matter of urgency. we still have a long way to go. divisions between member countries marked by opposition between debtors and "frugal" creditors, as well intra-country political struggles and conflicting interests, have-even in the face of this dramatic crisisled to the paralysis of the european institutions, with the one exception of the ecb. faced with what she sees as a serious threat to the eu's survival, the german chancellor (and the commission's president ursula von der leyen) have been driven to action. however, as we argued in sect. , little can be expected from the ng plan for immediate support. the ability of the sp to emerge from the crisis will increasingly depend on its ability to take advantage of the greater flexibility of eu rules for an efficient use of industrial policy, helping companies and the whole economy to respond to the challenge posed by social and technological innovation, the restructuring of production and the reorganization and shortening of gvcs. the pandemic will have significant repercussions on the international organization of production and gvcs (on this point, see also the contributions to this forum by strange and coveri et al.) . indeed, the countries initially most affected by covid (china, korea, italy) are among the most important suppliers of intermediate goods at the international level. studies on the propagation of economic shocks triggered by natural disasters (such as the earthquake that hit japan in ) along the value chains (boehm et al. ; inoue and todo ) found significant supplier substitution effects. anecdotal evidence signals numerous cases of supplier substitution in some countries as a result of the coronavirus (baldwin and tomiura ). the extent of these effects depends on the degree of complexity of the production chains, which affects the degree of input substitutability. propagation effects also depend on the presence of "hub" companies interconnected with a large number of supplier and customer firms (inoue and todo ) . future developments are uncertain, depending on the relative strength of two opposite effects. on the one hand, greater coordination afforded by digitalisation of production networks could favour substitution effects (especially in cases where value chains are less regionalised and the search for new suppliers is more difficult) (zhenwei quiang et al. ). on the other hand, processes of reshoring and shortening of value chains could occur, especially where production chains are less complex or automation is more advanced. the second possibility could represent an opportunity to reverse the processes of deindustrialization that have impoverished, above all, the productive fabric of the peripheral countries. a third perspective, probably utopian, could contemplate coordination of coalitions of producers across eu member states. in a situation of strong productive complementarities between countries, the fortunes of the producers (workers and firms) in one country are bound to those in the other. this would call for a coordinated industrial policy at the european level aiming at ensuring a balanced development of the economies of its members through their integration in the european production networks. in emergency situations where production activities are reduced or temporarily suspended (as in the case of coronavirus shock), bilateral agreements (mediated by governments) between producers in different countries should aim at stabilizing employment levels and pre-existing supply contracts between firms through "mutualisation" of the required financial effort. after all, having surprisingly spoken out in favor of the eurobonds, the ceo of volkswagen herbert diess could-at one remove-be also supportive of such a project! 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/ . /. thinking ahead about the trade impact of covid- input linkages and the transmission of shocks: firm-level evidence from the tōhoku earthquake crisis in the european monetary union. a core-periphery perspective unravelling the roots of the emu crisis. structural divides, uneven recoveries and possible ways out un'unione divisiva. una prospettiva centro-periferia della crisi europea germany's oversupply of hospital beds aids pandemic fight, the financial times next generation eu: % of grants will have to wait until neodualism in the italian business firms: training, organizational capabilities, and productivity distributions proposal for a regulation of the european parliament and of the council establishing a recovery and resilience facility germany gains most from relaxed eu state aid rules re-prima -tranc he- -milia rdi- f -a - ea-b d-c d b b_previ ew.shtml ?reaso n=unaut henti cated &cat= &cid= &pids=po&credi ts= &origi n=https % a% f% fwww .corri ere. it% fint ernat ional % fpre mium% f _giugn o_ % frec overy -plan-tutti -ostac oli-fondi -europ eiralle ntato re-prima -tranc he- -milia rdi years of the euro: winners and losers. an empirical study, cep study a polarized country in a polarized europe: an industrial policy for italy's renaissance firm-level propagation of shocks through supply-chain networks globalisation, decarbonisation and technological change: challenges for the german and cee automotive supplier industry foreign direct investment and the development of the automotive industry in eastern and southern europe decades of tight fiscal policy have left the health care system in italy ill-prepared to fight the covid- outbreak eu countries use looser state aid rules to uphold troubled firms the central european manufacturin core: what is driving regional production sharing? (no. / - ) the shock of coronavirus could split europe-unless nations share the burden. the guardian why has eastern europe suffered less from coronavirus than the west? the vienna institute for international economic studies foreign direct investment and global value chains in the wake of covid- : lead firms of gcv acknowledgements open access funding provided by università di foggia within the crui-care agreement. key: cord- -upwe cpj authors: sullivan, kathleen e.; bassiri, hamid; bousfiha, ahmed a.; costa-carvalho, beatriz t.; freeman, alexandra f.; hagin, david; lau, yu l.; lionakis, michail s.; moreira, ileana; pinto, jorge a.; de moraes-pinto, m. isabel; rawat, amit; reda, shereen m.; reyes, saul oswaldo lugo; seppänen, mikko; tang, mimi l. k. title: emerging infections and pertinent infections related to travel for patients with primary immunodeficiencies date: - - journal: j clin immunol doi: . /s - - - sha: doc_id: cord_uid: upwe cpj in today’s global economy and affordable vacation travel, it is increasingly important that visitors to another country and their physician be familiar with emerging infections, infections unique to a specific geographic region, and risks related to the process of travel. this is never more important than for patients with primary immunodeficiency disorders (pidd). a recent review addressing common causes of fever in travelers provides important information for the general population thwaites and day (n engl j med : - , ). this review covers critical infectious and management concerns specifically related to travel for patients with pidd. this review will discuss the context of the changing landscape of infections, highlight specific infections of concern, and profile distinct infection phenotypes in patients who are immune compromised. the organization of this review will address the environment driving emerging infections and several concerns unique to patients with pidd. the first section addresses general considerations, the second section profiles specific infections organized according to mechanism of transmission, and the third section focuses on unique phenotypes and unique susceptibilities in patients with pidds. this review does not address most parasitic diseases. reference tables provide easily accessible information on a broader range of infections than is described in the text. . this review covers critical infectious and management concerns specifically related to travel for patients with pidd. this review will discuss the context of the changing landscape of infections, highlight specific infections of concern, and profile distinct infection phenotypes in patients who are immune compromised. the organization of this review will address the environment driving emerging infections and several concerns unique to patients with pidd. the first section addresses general considerations, the second section profiles specific infections organized according to mechanism of transmission, and the third section focuses on unique phenotypes and unique susceptibilities in patients with pidds. this review does not address most parasitic diseases. reference tables provide easily accessible information on a broader range of infections than is described in the text. physician be familiar with emerging infections, infections unique to a specific geographic region, and risks related to the process of travel. this is never more important than for patients with primary immunodeficiency disorders (pidd). a recent review addressing common causes of fever in travelers provides important information for the general population [ ] . this review covers critical infectious and management concerns specifically related to travel for patients with pidd. this review will discuss the context of the changing landscape of infections, highlight specific infections of concern, and profile distinct infection phenotypes in patients who are immune compromised. the organization of this review will address the environment driving emerging infections and several concerns unique to patients with pidd. the first section addresses general considerations, the second section profiles specific infections organized according to mechanism of transmission, and the third section focuses on unique phenotypes and unique susceptibilities in patients with pidds. this review does not address most parasitic diseases. reference tables provide easily accessible information on a broader range of infections than is described in the text. emerging infectious diseases are a result of a convergence of numerous factors and comprise complex interactions among multiple variables. some of those factors are human movement, land use change, encroachment and wildlife translocation, rapid transport, and climate change. several studies demonstrate that for a pathogen to persist in a population, a minimal host population size that is specific for the type of pathogen and host population. of particular relevance to emerging infections is the pattern of rapid population growth. in the tropics, before wwii, most regional ecosystems consisted of few large cities and scattered human settlements separated by large areas of cropland, pastureland, or undisturbed forest. today, the pattern is the opposite: many large cities have developed with only patches of undisturbed forest or grassland. domestic vectors have therefore expanded their population with increasing urbanization and this markedly impacts the interactions between vectors and pathogens [ ] . human activities such as deforestation, use of pesticides, pollution, etc. lead to the loss of predators that naturally regulate rodent and insect populations. this contributes to emerging zoonotic diseases and explains why they occur more frequently in areas recently settled. in today's global economy and affordable vacation travel, it is increasingly important that visitors to another country and their the southern, with a reduction in the number of cold days per year, changes in rainfall (more winter precipitation and summer droughts) [ ] , and together these changes increase the risk of several vector-borne diseases in new areas. climate change involves not only global warming but also changes in precipitation, wind, humidity, and the location and frequency of extreme weather events like floods, droughts, or heat waves. changes in climate produce changes in pathogens, vectors, hosts, and their living environment. increases in precipitation can increase mosquitoes for example, but heavy rainfalls may cause flooding that temporarily eliminates larval habitats and decreases mosquitoes. flooding may force rodents to look for new habitats in houses and increase the opportunities of vector-human interactions, as occurs for example in the case of epidemic leptospirosis. humidity is another very important factor of climate change in the development of vector-borne diseases. mosquitoes and ticks do not survive well in dry conditions. therefore, weather impacts infectious pathogen distribution in complex ways that are not predictable by the forecast. extreme weather events can precipitate outbreaks of infection. an increase in the frequency and intensity of natural disasters like hurricanes and tsunamis, in relation to the el niño/southern oscillation phenomenon, may result in more flooded grasslands, which favor the breeding of aedes and culex mosquitoes [ ] , and impact water sanitation fostering outbreaks such as cholera. flooded areas can displace rodents leading to plague. tornados and other severe weather can stir up soil leading to infections with soil fungi leading to episodic outbreaks of invasive fungal disease such as mucormycosis such as apophysomyces trapeziformis [ ] . malaria is a common disease that can vary dramatically depending on weather, and extreme weather can alter the very landscape, providing new bodies of water to support larval development. if the melting of glaciers and the polar ice caps bring coastal cities underwater, or if overpopulation and waste cause drinkable water shortages in certain regions of the world, we can expect mass migrations. these could change the patterns of infection and drive outbreaks. migrants traversing tropical forests, or feeding with meat from game or carcasses, are but two scenarios that could be envisioned for the emergence of zoonotic infectious diseases [ ] . several predictive models have been developed to evaluate the impact of climate change on the emerging infectious diseases: climex, dymex, miasma models. nevertheless, it remains difficult to predict when and where pathogen behavior will deviate from its typical pattern. climate change primarily affects vector-borne diseases by increasing rates of reproduction and biting and by shortening the incubation period of the pathogen they carry. ticks have gained spread from the mediterranean basin to northern and eastern europe, as well as appearing at higher altitudes. increased survival, density, and activity have also been reported following shorter, milder winters. climate change has also resulted in more days of activity per year for mosquitoes. as temperatures rise, more parasites are viable within regions ranging from the mediterranean and tropical zones, up to the balkans, russia, scandinavia, and the uk. for some ticks and fleas, temperatures over °c with relative humidity of over % are optimal for their proliferation and activity throughout the year [ , , ] . for example, dengue fever is usually limited to a tropical latitude and a low altitude, since mosquito eggs and larvae lose viability with sustained low temperatures. during unusually warm summers, however, dengue has been reported as high up as m above sea level. warmer temperatures also result in smaller adult mosquitoes, which need to bite more frequently to feed themselves and be able to lay eggs, thus increasing the rate of transmission [ ] . in contrast, the incidence of malaria has followed mixed patterns of increase and decrease along recent decades, and computer models have failed to predict the spread. the explanation for this is, in part, that climate change also results in diminished survival of the vectors (warming over °c affects the survival of both parasites and vectors), and in part, that the effect of climate change is non-linear and complex [ ] . the frequency of emerging vector-borne infections varies per changes in land use, human activity, intervention maneuvers to eradicate the vector or prevent transmission to humans, drug treatment, and vaccines. both ecologic and economic changes may bring together rodents and humans. hunting activities may change vector distribution and large-scale animal movements can impact disease distribution. impoverishment of cities and overcrowding in slums, but also reforestation, golf club development, and the urbanization of rural suburbs facilitate exposure to ticks and rodents [ ] . many patients with pidd require immunoglobulin replacement. immunoglobulin products have been demonstrated to improve outcomes in hepatitis a and measles [ , ] . at least some neutralizing antibody is present directed to rsv and group b streptococci [ , ] . this raises three distinct issues for patients: ( ) difficulty in the diagnosis of infections in travelers because locally produced immunoglobulin may have antibody titers to local infections that are not typical for other countries, ( ) safety concerns about locally produced immunoglobulin, if the patient resides in the location long enough to require immunoglobulin from a local provider, ( ) the decision to use locally produced immunoglobulin products to provide superior prevention of infection compared to the patient's usual product. there are limited data on each of these subjects. serologic diagnostic testing in patients on immunoglobulin therapy will be addressed below in terms of issues related to lack of specific antibody produced by the patient (potentially) after infection. the converse can also be an issue. patients arriving from countries with significant occurrences of infections unusual in their current country may have igg antibodies to those infections simply through their immunoglobulin product and not reflecting a true infectious event in the patient. this can lead to diagnostic confusion when serologic testing demonstrates the presence of antibodies due to the infusion product. patients will often ask if immunoglobulin products from other countries are held to the same rigorous standards as their home country. today, commercially produced immunoglobulin is safe and tightly regulated. all commercially produced immunoglobulin around the world has one of the time-tested viral inactivation procedures such as nanofiltration, caprylate absorption, pasteurization, solvent/detergent, vapor heating, and low ph treatment. these procedures uniformly inactivate enveloped viruses. many emerging viruses are specifically tested for their ability to withstand the purification process. much has been learned since the transmission of hepatitis c viruses through immunoglobulin products in the early s [ ] . nevertheless, vigilance is important. in , counterfeit immunoglobulin was identified. therefore, patients should ensure that they receive only brand name products while traveling. the subject of whether a patient's interests would be best served by using a local immunoglobulin product, with antibodies to pathogens that are prevalent in the community, or have their home physician ship their usual product, for which the patient has a known tolerance is hotly debated. patients with a history of intolerance to immunoglobulin products should not switch unless necessary. however, there are compelling reasons to consider a locally produced product when patients are in a foreign country for an extended period. it is known that antibodies to west nile virus have tracked with the distribution of the virus as it has emerged in several areas [ , ] . titers in products using donors from the usa have higher neutralizing titers to west nile virus than those using donors from europe, although there is a -fold difference in titers between lots from the usa [ ] . similarly, protective antibodies to concerning pathogens may be optimal in locally produced immunoglobulin. it is critical to inquire where the plasma source is derived. in most countries, the utilized immunoglobulin is produced in europe or the usa. having a different name does not ensure that the plasma pool comes from a different country. most lots of immunoglobulin are produced from to , plasma donors. the infrastructure to support such an endeavor is not easy to establish in each geographic area. serologic testing is commonly used for the diagnosis of infection. this approach relies upon detection or quantitation of antibodies made by the host against specific pathogens. the presence of igm antibodies against a specific pathogen indicates recent infection, while igg antibodies against a specific pathogen indicate past infection. importantly, serologic testing can only be applied for the diagnosis of infection if the host can mount a specific antibody response to the pathogen. conversely, serology cannot be relied upon to diagnose infection in the setting of immune deficiency where there is impairment of the specific antibody response, such as in the case of primary antibody deficiencies, cellular immune deficiencies, combined immune deficiencies, and other secondary immune deficiencies affecting t and/or b cell function. in these situations, the causative pathogen must be identified by alternate means such as culture of the organism, antigen detection, or molecular approaches (nucleic acid hybridization, nucleic acid sequencing, or oligonucleotide probe arrays). molecular approaches are particularly relevant for the diagnosis of infection in patients with pidd. signal and target amplification techniques can be coupled with nucleic acid hybridization or probe assays to allow detection of pathogen dna or rna that is present in very small amounts in clinical samples. in patients with pidd, vaccines could play an important role in preventing infections with vaccine-preventable diseases. even pidd patients may generate some protective responses [ , ] . the decision to immunize such patients or not depends on the type and severity of pidd as well as the type of vaccine to be administered (live or inactivated) ( table ). in general, inactivated vaccines are safe for pidd patients while immunization with live attenuated vaccines is a known hazard to patients with serious immunodeficiencies of t cell, b cell, and phagocytic cell origin (table ). in less severe pidd, the vaccine can induce adequate protection as in healthy individuals or the efficacy may be reduced [ ] [ ] [ ] . of note, immunoglobulin replacement therapy induces passive immune protection to some vaccine-preventable infections, such as measles, mumps, rubella (mmr), and varicella. in addition, live viral vaccines have greatly reduced efficacy while on immunoglobulin replacement. therefore, vaccine administration in patients receiving regular immunoglobulin replacement treatment should be withheld until at least to months (depending on dose) after cessation of such treatment, if cessation and vaccination are safe. in addition, pidd patients who have received hematopoietic stem cell transplantation but have incomplete immune reconstitution or are under immunosuppression should not receive live attenuated vaccines. in general, the decision of administering live viral vaccines should be made by clinical immunology experts [ ] . in developing countries where polio is still endemic and oral polio vaccine is essential for eradicating the disease, it is of utmost importance that all pidd patients and family members should not receive live oral polio (opv) because of the reported prolonged excretion of the virus for months and even years [ ] . in addition, vaccine-associated paralytic polio is a real risk for some with pidd. these patients and family members should receive inactivated polio vaccine (ipv) instead of opv. similarly, the hazards of administering bacillus calmette-guerin (bcg) vaccine to pidd patients have been documented. in a series of bcg, vaccinated severe combined immunodeficiency (scid) patients from centers in countries, % of scid patients developed disseminated bcg infection and had the worst outcome [ ] . patients with chronic granulomatous disease vaccinated with bcg also developed local and disseminated bcg infection. recently, vaccine strains of rubella virus were found to be associated with skin granulomas in pidd patients [ ] [ ] [ ] . siblings and household contacts of patients with suspected or diagnosed pidds should receive all the national immunization scheduled vaccines. ipv should be substituted for op in families where an antibody-deficient patient exists. yearly influenza vaccination of family members is recommended in order to reduce the risk of household-social transmission [ , , ] . diseases where routine vaccination has reduced incidence can occasionally experience a resurgence in times of economic hardship with reduced attention to vaccination. diphtheria is currently seen in venezuela for this reason. war and disruption of health infrastructure are other common reasons for resurgence in vaccine-preventable diseases. in other settings, antivaccination sentiment has led to outbreaks of diphtheria, measles, and mumps. an additional consideration is that not all countries provide the same level of vaccination, and therefore, vaccine-preventable illness can still be seen regionally. these outbreaks represent a significant risk to patients with pidd. a universal consideration for patients with pidd is the concern about antibiotic resistance, which varies dramatically around the world. for certain high impact infections, the emerging antibiotic resistance patterns will be discussed below. antimicrobial resistance occurs naturally, but misuse and overuse of antimicrobials are accelerating this process. in nearly every country, antibiotics are overused and misused in people and animals leading to antibiotic resistance in every country. key resistance patterns to common bacteria include emergence of carbapenem-resistant klebsiella pneumoniae around the world with high frequency of resistance (due to different mechanisms) in the mediterranean, with greece, italy, and turkey having endemic spread of this pathogen [ ] . carbapenem-resistant strains among other genera of enterobacteriaceae have also been recognized. they are particularly common in greece, but have been found widely distributed [ ] . the new delhi metallo-beta-lactamasemediated resistance, which is endemic in the indian subcontinent but becoming increasingly spread worldwide, is a growing concern [ , ] . as a common cause of urinary tract infections, colistin is the only recourse when carbapenemresistant enterobacteriaceae, and colistin resistance has recently emerged in small outbreaks throughout the world [ ] . in these cases, the infection is essentially untreatable. fluoroquinolone-resistant escherichia coli, a common cause of urinary tract infections, now accounts for over half of the isolates in some asian countries [ , ] . t he emergence of resistance to antibiotics in grampositive pathogens has become a major international problem as there are fewer, or even sometimes no effective, antimicrobial agents available for infections caused by these bacteria. methicillin-resistant staphylococcus aureus is common in many countries and in fact has spawned a nomenclature recognized by the general public: mrsa. several studies have reported resistance to the newer antimicrobial agents like linezolid, vancomycin, teicoplanin, and daptomycin [ ] . thus far, these isolates appear to be uncommon and have been found in < % of isolates in brazil, china, ireland, and italy, with nearly undetectable rates elsewhere. vancomycinresistant enterococcus (vre) is growing in frequency and can now be a cause of primary bacteremia in immunocompromised individuals [ ] . a key message is that antibiotic resistance is increasing (generally) and travelers should be alerted to resistance to commonly encountered organisms, and if antibiotic prophylaxis is required, their prophylaxis is adjusted. neisseria gonorrhoeae is a specific organism for which resistance has become especially problematic. it has progressively developed resistance to virtually all antimicrobial agents since introduction of sulfonamides in mid- s. the current treatment guidelines recommend dual antimicrobial therapy (ceftriaxone - mg × plus azithromycin - g × ) as first-line regimen [ , ] . although dual therapy is very effective, development of concomitant ceftriaxone and azithromycin resistance is likely to emerge [ ] . the risk of untreatable n. gonorrhoeae demands better global antimicrobial surveillance system, clinical trials on combined therapy of existing drugs as well as novel agents in monotherapy, and development of a gonococcal vaccine. for pidd patients, guidance on barrier methods for the prevention of sexually transmitted diseases should be a part of any pre-travel counseling. mycobacteria tuberculosis (mtb) is an age-old pathogen with emerging resistance. drug-resistant tb, fueled by the hiv epidemic, is a global threat. in , who estimated , new cases of multidrug-resistant tb (mdr-tb) and an additional , new cases of rifampin-resistant tb (rr-tb) who would also require mdr-tb treatment. treatment of mdr-tb and mycobacterium bovis disease is beyond the scope of this text and reader is referred to recent who mdr treatment guidelines [ ] . regions of the world with > % mdr tb include regions of azerbaijan, kazakhstan, russia, uzbekistan, china, georgia, and eastern europe. extensively drug-resistant tb (xdr tb) refers to mtb resistant to isoniazid, rifampin, any fluoroquinolone and at least one second-line drug. xdr tb has been reported in countries. on average, % of patients with mdr tb have xdr tb. as is true for all types of mtb, xdr tb is contagious and small outbreaks related to person-person transmission have been reported. non-tuberculous mycobacteria (ntm) cause significant systemic infections in patients with defects of the il- / ifnγ/stat axis as well as in gata deficiency and can cause significant pulmonary infections in pidd patients with bronchiectasis. compared to tb, ntm is acquired from the environment and not from person-to-person transmission; therefore, acquisition of antibiotic-resistant strains is less common. however, in these individuals with pidd, ntm disease is often chronic and can be difficult to eradicate, and resistance can then easily develop during therapy. using combination of antibiotics is essential, and consultation with those familiar with treatment of treatment refractory ntm disease is recommended. aspergillus species are ubiquitous inhaled molds with worldwide distribution that cause opportunistic infections in immunocompromised patients [ ] . aspergillosis also occurs in pidds associated with quantitative and/or qualitative phagocyte defects; it develops most frequently in chronic granulomatous disease (cgd) patients (prevalence,~ %), while it is seen less often in patients with gata deficiency, card deficiency, and congenital neutropenia syndromes [ , ] . upon inhalation, aspergillus species cause invasive pulmonary disease in susceptible hosts with the exception of card deficiency, where aspergillosis has a predilection for extrapulmonary tissues with sparing of the lungs [ ] . diagnosis is established by fungal culture and/or histopathology showing acute-angle septate hyphae and/or detection of galactomannan, an aspergillus cell wall component released during invasive infection, in serum or bronchoalveolar lavage fluid [ ] . while azole-susceptible aspergillus fumigatus is still the most common infecting species in pidd patients, the emergence of azole-resistant a. fumigatus and nonfumigatus aspergillus species underscores the importance of a high index of suspicion in patients who do not respond to front-line voriconazole treatment [ ] . the advent of fungal molecular diagnostics has demonstrated that patients with pidds are more prone to infections by uncommon low-virulence aspergillus species with intrinsic resistance to azole antifungal agents that do not infect patients with iatrogenic immunosuppression. these primarily include aspergillus viridinutans, aspergillus tanneri, and neosartorya udagawae, which pose major diagnostic and therapeutic challenges due to their impaired sporulation and propensity for contiguous and distant tissue spread, respectively. in addition, acquired azole resistance in a. fumigatus can be seen in patients on long-term exposure to azole drugs used as treatment and/or prophylaxis [ ] . azole resistance in these strains is predominantly caused by point mutations in the lanosterol α-demethylase gene that encodes the cyp a protein, the primary target of azole drugs. importantly, infection by azole-resistant a. fumigatus strains without prior exposure of patients to azole antifungals has recently emerged as an important global health concern due to the widespread use of sterol demethylase inhibitor fungicides in agriculture that results in cross-resistance with the triazole antifungals used in clinical practice [ ] [ ] [ ] . fungicide-driven azole-resistant environmental aspergillus strains were first observed in the netherlands in and have since then been documented in other parts of europe, south and north america, the middle east, australia, africa, and asia. the prevalence of these azole-resistant aspergillus strains among clinical aspergillus strains recovered from patients in european countries was reported to be . %, while alarmingly in some areas > % of recovered strains exhibited azole resistance [ ] . the emergence of such aspergillus environmental strains poses serious threats to the treatment of immunosuppressed patients. mortality rates as high as % have been seen due to delays in diagnosis and suboptimal treatment with azole antifungals [ ] . although no prospective data exist for the treatment of patients with such resistant fungi, the use of amphotericin b-and echinocandin-based regimens are preferred over azoles [ ] . in the absence of azoles, the lack of alternative oral antifungal agents is particularly challenging for pidd patients such as those with cgd who require long-term suppressive antifungal treatment. candida species are commensal yeast fungi that colonize the mucosal surfaces of~ % of healthy individuals [ ] . when perturbations in immunity and/or microbiota occur, candida causes opportunistic mucosal or systemic infections that depend on clearly segregated immune responses for host defense. specifically, t cells of the th program are critical for mucosal and phagocytes for systemic immunity [ ] . indeed, a proportion of patients with cgd and complete myeloperoxidase deficiency develop systemic, but not mucosal candidiasis [ ] , whereas patients with monogenic syndromes of chronic mucocutaneous candidiasis due to mutations in the il- signaling pathway (il ra, il rc, il f, act ) or in other genes that adversely affect th differentiation (rorc, stat , stat , aire, dock , stk , irf ) do not develop systemic candidiasis. the only known pidd to date that results in combined mucosal and systemic candida infection susceptibility is card deficiency. systemic candidiasis in card -deficient patients has a predilection for the central nervous system, associated with brain-specific impaired recruitment and effector function of neutrophils [ ] [ ] [ ] . diagnosis of candida infections is established by culture. azole-susceptible candida albicans is still the most common infecting species in pidd patients; however, emergence of azole-resistant c. albicans is not uncommon during chronic azole use, making long-term therapy challenging due to lack of alternative oral antifungal treatment options [ ] . beyond c. albicans, non-albicans candida species can rarely infect pidd patients, some of which have intrinsic resistance to azole antifungals, including candida glabrata and candida krusei [ ] . most recently, candida auris has emerged as a global public health concern due to its resistance to antifungal drugs, high virulence potential, propensity for health careassociated horizontal transmission and outbreaks in health care settings, persistence in the human skin and hospital environment, inherent resilience to antiseptics, and misidentification by routine biochemical methods as other yeasts (most often candida haemulonii, but also candida famata, rhodotorula glutinis, or saccharomyces cerevisiae). c. auris was first recovered from the ear canal of a patient in japan in and has since then been reported to cause life-threatening infections and hospital outbreaks in europe, asia, africa, the middle east, and south and north america [ ] [ ] [ ] [ ] . most of the reported strains of c. auris have intrinsic resistance to fluconazole and other triazole antifungal agents, while a significant proportion of strains has elevated minimum inhibitory concentrations to amphotericin b and echinocandins, with some strains reportedly resistant to all three classes of azoles, polyenes, and echinocandins [ ] . avoidance of azole antifungals is important in c. auris-infected patients, and echinocandinor amphotericin b-based regimens are preferred, guided by strain-specific in vitro susceptibility patterns. this section on vector-borne infections is a major focus of this review because the infections are often more severe in immunocompromised individuals and because there are mitigation strategies that should be considered even in the absence of defined medical treatments for infection. prevention of mosquito bites depends somewhat on the endemic species but there are generalizations. the use of a mosquito repellant such as deet, oil of lemon eucalyptus, ir , or picaridin is as important as using long sleeves and long pants while in an affected area. deet and picaridin are safe in pregnancy, and some data support their greater efficacy [ ] . air conditioning and fans tend to keep mosquitoes away but netting at night is essential in mosquito-prone areas. light-colored clothing is less attractive to mosquitoes than dark clothing, and scented detergents and use of dryer sheets tend to attract mosquitoes, hence should be avoided. aedes species prefer to bite indoors and thrive in urban areas with small puddles of water. they bite most frequently around dawn and dusk. anopheles species have very similar behaviors. culex mosquitoes, in contrast, bite primarily at night. tick and fly bite prevention is focused on physical and chemical prevention. for ticks, physical inspection for biting ticks should also be incorporated. arthropod-borne viruses (arboviruses) are transmitted to humans through the bites of infected insects: mosquitoes, ticks, sand flies, or midges. some arboviruses can be transmitted through blood transfusion, organ transplantation, perinatal transmission, consumption of unpasteurized dairy products, or breastfeeding. there are > arboviruses causing human disease. most arboviral infections are asymptomatic. infectious manifestations range from mild febrile illness to severe encephalitis. arboviral infections are often categorized into two primary groups: neuroinvasive disease and non-neuroinvasive disease. tables and list the encephalitigenic viruses and the febrile/hemorrhagic disease causing viruses. in this section, we will highlight west nile virus, the most common of the encephalitogenic arboviruses. west nile virus is a single-stranded mosquito-borne rna virus of the family flaviviridae. the natural transmission cycle of the virus occurs in culex mosquitoes and birds. humans and horses are dead-end hosts for the virus. the most common mode of transmission to humans is through the bite of infected mosquitoes. other less common modes of transmission include blood transfusions, organ transplantations, occupational exposure in laboratories and mother-to-child transmission during pregnancy, childbirth, and breastfeeding. west nile virus has been diagnosed in > people in the usa with slightly more than half having neuroinvasive disease. since , > , people in the usa have been infected. it is also common in africa, europe, and asia [ ] . infection with west nile virus is asymptomatic in most individuals [ , ] . the incubation period lasts for to days. however, it can be significantly longer in immunocompromised hosts. clinical manifestations following infection develop in - % of those infected and include fever, headache, myalgia, arthralgia, vomiting, and rash. severe neuroinvasive disease leading to meningitis, encephalitis, and flaccid paralysis develops in less than % of infected individuals. the overall case fatality is approximately % which is a disproportionately high mortality in patients with encephalitis and myelitis. diagnosis of west nile virus rests on demonstration of specific antibody responses especially specific igm antibodies in the serum or csf of infected individuals by enzyme immunoassays. plaque reduction neutralization tests can differentiate cross-reactive antibodies. detection of virus in csf, blood, or tissue specimens by culture or pcr is particularly useful in immunosuppressed individuals who may have impaired serological responses. west nile virus has been reported in the context of both primary and secondary immunodeficiency. severe neurological manifestations have been reported in hiv-positive individuals, individuals receiving immunosuppressive therapy including rituximab, and individuals with pidd. infection with wnv has been reported in individuals with common variable immunodeficiency, idiopathic cd lymphopenia, gata deficiency, and a case of probable good's syndrome [ ] [ ] [ ] . individuals with antibody defects, neutropenias, and impaired t cell responses are potentially at an increased risk of severe manifestations of wnv disease including severe neurological involvement. this section highlights the four important non-neuroinvasive arboviruses based on current geographical distribution: dengue, yellow fever, zika, and chikungunya (table ) . approximately countries/territories have reported local transmission for both chikungunya and dengue viruses [ ] . dengue is due to infection with one of four dengue virus serotypes, transmitted by a mosquito (typically aedes aegypti). this febrile illness affects all ages with symptoms appearing - days after the infective bite. symptoms range from mild to high fever, with severe headache, musculoskeletal pain, and rash. severe dengue (also known as dengue hemorrhagic fever) occurs in . - % of cases and is characterized by fever, abdominal pain, persistent vomiting, bleeding, and breathing difficulty and is a potentially lethal complication [ ] . paradoxically, the main risk factor for dengue hemorrhagic fever is pre-existing antibodies. early clinical diagnosis and comprehensive management by experienced clinicians increase survival. dengue is ubiquitous throughout the tropics with the highest infection rates in the americas and asia. dengue is now endemic in countries, causing up to million infections a year and , deaths, mainly among children. over half of the world's population inhabits areas at risk for dengue infection [ ] . the presence of a. aegypti in over countries potentially puts almost the whole world at risk of becoming infected with this virus. pcr is widely used as serologic methods to diagnose dengue. immunity to one serotype does not confer protection against the other three serotypes, and heterologous antibody may be a risk factor for hemorrhagic dengue [ ] . the natural history of dengue has been studied in hiv patients where hiv did not appear to increase severity. there have been no reports of patients with pidd having dengue; however, dengue infection after solid transplantation has been reported [ ] [ ] [ ] [ ] with some patients having severe complications suggesting that t cell compromise in pidd could be a risk for severe disease. there are no antiviral medications utilized for dengue virus. care of patients with hemorrhagic disease requires meticulous approach to fluids and coagulation status. one dengue vaccine has been registered in several countries (cyd-tdv) for individuals from to (or ) years old. it is a live attenuated recombinant tetravalent vaccine with backbone of the attenuated yellow fever d virus genome with the prm and e genes that encode the proteins from the four wild-type dengue viruses. the who has suggested its use in regions where seroprevalence of dengue virus of any serotype is % or greater, but has not recommended it to hiv-infected, immunocompromised individuals, nor pregnant or lactating women [ ] . most people infected with the yellow fever virus have no illness. symptoms of yellow fever include sudden onset of fever, chills, headache, musculoskeletal pain, nausea, vomiting, fatigue, and weakness. the incubation period is typically - days, and symptoms may appear after return from travel. most people improve after the initial presentation, but % of cases progress to develop a more severe form of the disease, usually after a day of presumed recovery. the severe form is characterized by high fever, jaundice, bleeding, and eventually shock and failure of multiple organs [ ] . yellow fever virus is an rna virus that belongs to the genus flavivirus. it is transmitted from mosquitoes after biting an infected primate. it is widely distributed in the equatorial tropics [ ] . aedes species of mosquitoes are primarily responsible for transmission. large epidemics of yellow fever occur when the infection enters heavily populated areas with a high mosquito density and where most people have little or no immunity. west africa has undergone a large-scale vaccination campaign with impressive results and yellow fever is now uncommon in west africa [ ] . serologic testing for yellow fever is the diagnostic standard. pcr can be performed on tissue samples. there are no published studies of yellow fever in immunocompromised people, but the elderly, very young, people with autoimmune disease, or who are post-thymectomy are at risk from the attenuated vaccine strain. thus, it seems likely that any immunodeficiency would be associated with more severe wildtype disease. currently, no specific antiviral drug for yellow fever exists. treatment of dehydration, liver and kidney failure, and fever improves outcomes. the yellow fever vaccine is highly effective; however, immunodeficient patients should not receive it. infection with zika virus is often asymptomatic. it represents a mild infection for those who have any symptoms [ ] . the zika virus has been detected in urine, semen, and saliva of infected individuals, and transmission from transfusion and sexual relations has been reported. it is also detectable in breast milk, but breastfeeding-associated transmission has not been reported so far [ ] [ ] [ ] . contact with highly infectious body fluids from patients with severe zika infection has also been suggested as a possible mode of transmission [ ] . of tremendous importance is the presence of prolonged shedding of zika virus in a congenitally infected newborn [ ] . the main public health risk of zika virus is microcephaly in newborns from infected mothers [ ] . zika virus is capable of infecting human neural progenitor cells in vitro. infection results in disruption of cell cycle, increased cell death, and attenuated neuron growth [ ] . zika is not thought to be a major risk for people with pidd (based on the experience with hiv patients, but our recognition of zika is very recent. there is no known specific treatment for zika; however, there is an important effort to develop a vaccine. chikungunya fever is an acute febrile illness caused by the alphavirus, chikungunya virus. the incubation period is usually - days after the bite of an infected aedes mosquito. there is abrupt onset of high fever, and the fevers can be biphasic [ , ] . severe polyarthraligias develop after the onset of fever. the joint pains can affect any joint, but the pattern is usually symmetric and a true acute arthritis is not uncommon. the proportion of infected people with rash has varied across studies. when seen, the rash appears after the fever as a truncal maculopapular type of rash [ ] . cervical adenopathy is another common feature of infection. death is uncommon in chikungunya, but serious complications such as myocarditis have been seen. over half of the patients report continued joint symptoms year after acute illness and % have long-term joint symptoms [ ] . chikungunya originated in central/east africa. in forests, the virus circulates in aedes mosquitoes and non-human primates. in urban centers, the virus circulates between humans and mosquitoes similar to the pattern of dengue. there have been periodic urban outbreaks in asia and africa since with an acceleration in spread since [ ] . an important consideration is the periodic outbreaks with high attack rates in naïve populations. areas at risk currently are east africa, central africa, la reunion, india, and southeast asia. diagnostic testing utilizes pcr or serology. the threat to immunodeficient patients is not entirely clear. there are a few provocative cases where the immunocompromised appears to have been associated with fewer joint symptoms, but there were two patients, medically immune compromised, who had very severe disease [ , ] . this suggests that the presentation may be atypical and the course may be severe in immunodeficient people. treatment is supportive, although chloroquine, acyclovir, ribavirin, interferon-ɑ, and steroids have limited preclinical data to support clinical trials. babesia microti (the main species in the usa) infection can be asymptomatic, but many people develop fever, chills, headache, myalgias, anorexia, nausea, or fatigue [ ] . babesiosis often causes hemolytic anemia. b. microti is spread by ixodes scapularis ticks in the usa and babesia divergens (the main species in europe) is spread by ixodes ricinus. symptoms begin - weeks after a bite from an infected tick with b. divergens having a higher mortality rate and greater symptomatology compared to b. microti. the main geographic areas involved are the coastal eastern usa and cattle breeding areas throughout europe. the diagnosis is usually by inspection of a blood smear or through serology. a pcr test has just been developed. immunodeficiency, asplenia, and older age are recognized risk factors for severe disease and even death [ ] [ ] [ ] . thus, congenital asplenia would be considered a major risk for severe disease. a combination of atovaquone and azithromycin is generally used for therapy, although clindamycin and quinine have been used with success. patients with severe illness have been treated with exchange transfusions. five different types of plasmodium (plasmodium falciparum, plasmodium vivax, plasmodium ovale, plasmodium malariae, and plasmodium knowelsi) infect humans. malaria is transmitted primarily by female anopheles mosquitoes. symptoms vary depending on the type of plasmodium involved but usually include high fever, chills, and headache. in some cases, the illness can progress to severe anemia, kidney and respiratory failure, and death. the incubation period typically ranges from to days for p. falciparum, to days for p. vivax and p. ovale, and to days for p. malariae. in p. vivax and p. ovale infections, relapses can occur months or even years without symptoms. p. vivax and p. ovale have dormant liver stage parasites that must be specifically eradicated through medical therapy. malaria has been a global health concern throughout history and is a leading cause of death and disease across many tropical and subtropical countries. over the last years, new control measures have reduced malaria by over half [ ] . the democratic republic of the congo and nigeria account for over % of the estimated total of malaria deaths globally. high rates of malaria are seen in india as well. nevertheless, malaria exists in most tropical regions of the americas, africa, and asia [ ] . the diagnosis of malaria depends on the demonstration of parasites in the blood, usually by microscopy. the threat to immunodeficient patients is not entirely clear, but patients with hiv seem to have no additional burden of disease other than an increase in placental malaria, suggesting that t cells are not central to the defense of malaria [ , ] . asplenia is a known risk factor for severe malaria [ ] . antibodies appear to be both protective and pathologic [ , ] . treatment and prophylaxis depend on the region of the world because the parasites and resistance are highly variable and highly dynamic. therefore, it is best to consult an infectious disease specialist familiar with the prophylaxis before travel and for treatment of acute cases. leishmaniasis is due to infection with an obligate macrophage intracellular protozoa of the genus leishmania. it causes a spectrum of disease ranging from a cutaneous ulcer to mucosal disease and the most severe form, visceral leishmaniasis (vl). the liver, spleen, and bone marrow are major sites of parasite growth and disease pathology in vl [ ] . purely cutaneous leishmaniasis is most often caused by leishmania major, leishmania. tropica, leishmania aethiopica, leishmania infantum, and parasites belonging to the leishmania mexicana complex, the leishmania braziliensis complex, and the leishmania guyanensis complex. mucocutaneous disease is most often due to l. braziliensis complex, leishmania panamensis, leishmania amazonensis, and rarely by leishmania guyanensis. vl is most often caused by leishmania donovani and leishmania infantum (previously l. chagasi) [ ] . cutaneous leishmaniasis can have many variations but is most often an ulcer that develops after an indolent papule. the incubation period ranges from weeks to months. the ulcer usually heals within months to years, and there can be mild adenopathy. mucocutaneous leishmaniasis follows a cutaneous ulcer and is only caused by l. braziliensis parasites. oral and respiratory mucosa are most often involved with granulomatous lesions that may be extremely destructive. vl is associated with fever, lymphadenopathy, hepatosplenomegaly, wasting, hypoalbuminemia, and pancytopenia. this picture evolves over months to years. there can be secondary immune deficiency due to the pancytopenia. the epidemiology has changed dramatically and has been impacted by climate change [ ] . the sand flies that spread the parasite are affected by temperature and rainfall. in most endemic regions, leishmania has a patchy distribution due to micro-ecologic factors. poverty has been demonstrated to be a major risk factor for leishmaniasis [ ] . it has been estimated that up to half a million new cases of vl occur every year, but the majority are in resource-poor countries such as bangladesh, nepal, india, sudan, ethiopia, and brazil. emergence of resistance to antimony-based drugs has also led to a major resurgence of disease. the primary reservoir for leishmania is forest rodents, but dogs are increasingly important. the growing spread of leishmania is due to a combination of factors, and now countries have reported cases. immunodeficient patients are more susceptible to infection, and relapse occurs more frequently [ ] . the risk of developing vl is estimated to be between and times higher in hiv-infected than in non-hiv-infected individuals [ ] , and these patients have higher rates of treatment failure with the illness often taking a prolonged chronic course and higher mortality rates [ ] . a similar picture has been seen in patients with vl-infected post-kidney transplantation [ ] . dendritic cells, t cells, and the generation of reactive oxygen species have been shown to be essential for parasite control [ ] [ ] [ ] . pidd with impaired il- production have been associated with severe disease [ ] . a patient with cd l deficiency, associated with poor il- production, had chronic leishmania and died in spite of aggressive treatment. vl has been reported in cgd patients [ ] . six cgd patients were infected by leishmania, and they developed hemophagocytic syndrome with a poor outcome for one of them [ ] . the diagnosis of leishmaniasis is usually by visual inspection for parasites. immunofluorescence microscopy, direct agglutination, skin test, and pcr have been used. treatment is long-term and difficult. emerging resistance to first-line treatment is increasingly problematic. pentavalent antimonials are the mainstay of treatment in most countries, but liposomal amphotericin is widely used where resistance occurs. newer drugs with more favorable side effect profiles have been used in certain geographic settings: miltefosine, paromycin, and sitamaquine. rickettsiae are small gram-negative bacteria. they are obligate intracellular parasites, and the primary target in humans appears to be endothelial cells with subsequent thrombosis and clinical presentation of vasculitis [ ] . the rickettsiaceae family, originally defined by non-specific phenotypic characteristics, was reclassified into different strains and subspecies based on gene sequencing and genetic phylogeny ( table ). the clinical presentation of rickettsial disease can vary, but the classic triad of fever, rash, and headache still provides major clues for the diagnosis [ ] [ ] [ ] . however, rash is not an obligatory sign, and the incidence of rash can range between % for rickettsia conorii infection,~ % for rickettsia rickettsii, % for rickettsia africae, and less than % in the case of anaplasma phagocytophilum infection. therefore, fever in patients with exposure to a potential vector should raise a concern for a rickettsial disease, especially if there is also evidence of rash, inoculation eschar, or localized lymphadenopathy. additional supporting laboratory findings can include neutropenia, thrombocytopenia, and increase in liver transaminases. the geographic distributions of rickettsioses and ehrlichioses are mostly dependent on their vector distribution [ ] . as such, louse-borne and flea-borne are worldwide, reflecting the worldwide distribution of lice and fleas, with a tendency to parasite poor people in cold places and, characteristically, during wars. ticks, on the other hand, depend on their environment and most do not have a worldwide distribution. with the exception of the dog tick, vector for r. conorii in asia and north africa, r. rickettsii in the usa, rickettsia massiiae and erhlichia canis worldwide, most other tick-borne diseases are restricted to areas of the world correlating with the distribution of their vector [ ] . for that reason, it should be anticipated that climate and environmental changes will affect vector distribution and its reservoir host and, hence, the geography and epidemiology of tick-borne diseases [ , , ] . diagnosis presents a challenge, as it is extremely difficult to grow these organisms in culture. immunohistochemistry and pcr can be helpful. the severity of rickettsial disease varies with the causative agent and the host. r. rickettsii, rickettsia prowazekii, and orienta tsutsugamushi are considered most pathogenic. as for host factors, although severe and fatal cases have been described in healthy immunocompetent hosts [ , ] , there is evidence to suggest that children under the age of [ ] and immunocompromised hosts either secondary to hematologic malignancies, immunosuppressant treatment for organ transplantation, or hiv infection are at a greater risk to develop more severe disease with higher case fatality rates [ , ] . all rickettsiaceae are intracellular pathogens, and one could expect an increased risk for severe disease in pidds with abnormal t cell function. five to days of doxycycline is the preferred treatment for non-pregnant adults and children. treatment should not be delayed while awaiting diagnostic testing [ ] and can be given to children despite a minimal risk for dental staining. alternative treatments include azithromycin for mild disease [ ] and chloramphenicol for pregnant women. anaplasma is an intracellular bacterium that infects wild and domestic mammals, including man. a. phagocytophilum was formerly known as human granulocytotropic ehrlighiosis but is now known as human granulocytotropic anaplasmosis [ ] . e. chaffeensis infects monocytes and causes human monocytic ehrlichiosis [ ] . anaplasma and ehrlichia have historically cycled within non-human enzootic hosts, and man has become infected through increasing interactions with the environment. ehrlichia and anaplasma are transmitted by ixodes species of ticks, and their ranges include the eastern usa, south central usa, and scattered regions of europe, as far north as sweden. these infections have not been seen in humans in the southern hemisphere, but there are reports of organisms being identified [ ] . a less common mode of transmission is through transfusions. the symptoms of ehrlichia and anaplasma infections are similar [ ] . abrupt onset of an influenza-like illness occurs about days after a tick bite. ehrlichia can cause a mild rash ( % of adults and % of children), but rash is uncommon in anaplasma infections. highly suggestive laboratory features are leukopenia and thrombocytopenia. mortality in the general populations appears to be < %, but icu admission is not uncommon. hemophagocytosis has been described with anaplasma [ ] and ehrlichia [ ] . both infections are more severe in any setting of immune compromised, including asplenia [ , ] . the diagnosis is typically made by pcr, and doxycycline is the recommended treatment. intracellular inclusions can be seen on cbc smears (more often in anaplasma than ehrlichia). an uncommon but well described facet of these infections is that the tick vector can also transmit borrelia burgdorferi and babesia microti, and simultaneous infection with multiple organisms can occur. c. burnetii is a highly pleomorphic gram-negative coccobacillus and the causative agent of q fever. q fever is a zoonosis, and the most common reservoirs are cattle, sheep, and goats but many other animals can be infected by c. burnetii [ , ] . when infected, these domestic animals can shed the organism in urine, feces, milk, and especially birth products. the pathogen survives within the phagolysosome of host cells, and a spore stage has been described. this spore stage explains the ability of c. burnetii to survive in unfavorable environmental conditions, and it can be an environmental risk for months to years after shedding from an infected animal. q fever is considered an occupational disease affecting people with direct contact with infected animals; however, indirect contact through exposure to contaminated animal products has also been described to cause disease outbreaks. humans are infected by inhalation of contaminated aerosols. following an average incubation period of days, infected patients can present with severe headache, fever, chills, fatigue, and myalgia. other signs and symptoms depend on the organs involved. in contrast to rickettsial diseases described above, rash rarely occurs in the early stages of the disease. c. burnetii can cause a range of clinical symptoms. a self-limited febrile illness is probably the most common form of q fever. pneumonia, either atypical or severe, is also common and can be a part of acute q fever syndrome. in contrast, a variety of manifestations can be recognized in chronic q fever, including endocarditis, endovascular infection, osteomyelitis, hepatitis, interstitial pulmonary fibrosis, prolonged fever, and purpuric vasculitic rash. q fever diagnosis is based on serologic testing with indirect immunofluorescence being the best for differentiating between acute and chronic q fever (high antiphase i antigen titer). the treatment of choice for acute q fever is doxycycline, with co-trimoxazole, chloramphenicol, or rifampin being an accepted alternative. there is no agreement on the treatment for q fever endocarditis, and a combination of doxycycline with either fluoroquinolone or hydroxychloroquine is recommended. there is also controversy regarding the duration of treatment, ranging from years to indefinite treatment. old evidence suggests that q fever is more common in immunocompromised patients. a french study showed higher incidence of antibodies to c. burnetii in hiv positive compared to hiv-negative patients ( . vs . %). in addition, out of hospitalized patients were hiv positive ( . %), suggesting a more frequent symptomatic disease [ ] . a smaller similar study performed in central africa failed to show increased incidence of seropositivity in hivpositive patients [ ] . two case reports describe severe disease in immunocompromised patients. the first was a case of fatal q fever disease in an -year-old male with cgd [ ] . the patient was treated with broad spectrum antibiotics, but without coverage for q fever. the second case was a -yearold asplenic male who presented with fever, jaundice, and encephalopathy and was diagnosed with acute q fever [ ] . the patient was successfully treated, but the two case reports could suggest susceptibility in cases of phagocytic disorders. the bartonellaceae are fastidious, facultative intracellular gram-negative bacilli (table ). most species infect primarily non-human animals, and in most cases, human are considered incidental hosts. the documented common human pathogens include bartonella bacilliformis, bartonella henselae, and bartonella quintana, and it is believed that humans are the primary mammalian reservoir of b. quintana. infection occurs through inoculation of bartonella-infected arthropod feces into breaks in the skin. the epidemiology of bartonella infection in humans follows the distribution of the vector. as such, infection with b. bacilliformis follows the distribution of the sand fly vector (lutzomya) and is confined to the andes mountain in peru, ecuador, and colombia at heights of between and m. the human body louse pediculus humanus is the vector of b. quintana, which explains the global distribution of this pathogen and worldwide outbreaks of trench fever, mostly in conditions of poor sanitation and upon exposure to body lice. trench fever was responsible for over a million infections during world war i. fever, either abrupt or indolent in onset, with a maculopapular rash, conjunctivitis, headache, myalgias (most often affecting legs), and splenomegaly was described. urban b. quintana infections occur most often among homeless and have a distinct clinical picture with fever as the most common manifestation. endocarditis occurs in many [ ] . bartonella henselae is globally endemic, and domestic cats are a major reservoir. the major arthropod vector of b. henselae is the cat flea, which is responsible for cat-to-cat transmission. human infection, called cat scratch disease, is assumed to involve inoculation of bartonella-infected flea feces into the skin during a cat scratch. b. henselae causes primarily adenopathy and neurologic symptoms [ ] . b. bacilliformis causes a condition with two phases: the acute phase with fever, anemia, and transient immunosuppression followed by nodular dermal eruption [ ] . recently appreciated are the ongoing systemic features during the eruptive phase such as arthralgias, adenopathy, and anorexia [ ] . diagnosis of bartonella-associated diseases can be achieved by direct examination of clinical material, bacteriologic culture methods, serologic and immunocytochemical studies, pcr-based assay, or combination of these methods. bartonella infection can present differently in immunocompromised hosts [ ] . in addition to higher prevalence of bartonella infection in hiv patients [ ] , both b. quintana and b. henselae can induce neovascular proliferation which might involve the skin, lymph nodes, and a variety of internal organs including the liver, spleen, bone, brain, lung, bowels, etc. these neovascular lesions, known as bacillary angiomatosis/peliosis (ba/bp), were initially described in hiv-infected patients with advanced disease and was later described in other immunocompromised hosts secondary to immunosuppressant treatment for solid organ transplantation or hematologic malignancy [ ] [ ] [ ] [ ] . cutaneous ba lesions can vary in presentation and can be subcutaneous, dermal nodules, single or multiple papule that can be flesh colored, red, or purple. lesions may ulcerate and bleed. they can change in number and size (millimeters to centimeters; few to hundreds) and can involve mucosal surfaces or deeper soft tissues. similar variation can be seen with visceral involvement. histologically, lesions consist of lobular proliferation of small blood vessels and neutrophilic predominant cell infiltration. the term bacilliary peliosis is used to describe bloodfilled cystic spaces mostly involving the liver, spleen, and lymph node. pathogenic bacteria can be isolated from vascular lesions. while both pathogens were associated with cutaneous lesions, only b. henselae was associated with visceral bp [ ] . based on hiv literature, it is reasonable to expect an unusual presentation of bartonella infection especially in pidds involving t cell dysfunction. bartonella infection was described as a cause for hepatitis in a single cd l deficiency patient [ ] . in addition, since cases of granulomatous disease due to bartonella infection [ ] [ ] [ ] have been described, it should be considered in the differential diagnosis of pidd with granulomatous inflammation. borrelia spp. the genus borrelia belongs to the spirochaetaceae family. it includes b. burgdorferi which causes lyme disease and species that cause relapsing fever. the latter are further divided into tick-borne species and louse-borne species. louse-borne relapsing fever (lbrf) is caused only by borrelia recurrentis and is spread by human body louse. the disease was epidemic in the early twentieth century, and it is estimated that more than , died of lbrf during world war ii. with sanitation improvement lbrf is now found only in the horn of africa and among homeless people in europe. more recently, cases of lbrf in refugees and migrants were described [ , ] . tick-borne relapsing fever (tbrf) is caused by a group of pathogens which are maintained by and survive in softticks (orinthodoros genus). each tbrf borrelia species depends on one specific species of soft-body tick. except for australia and antarctica, tbrf species can be found in all continents. the animal reservoir includes small animals and rodents. since the spirochetes persist in the tick salivary gland, disease transmission occurs when humans intrude the tick's environment. tick bites are painless, and history of a tick bite is often missing. therefore, a history of potential exposure can be valuable. the major clinical symptom is relapsing fever. after a median incubation period of days, patients present with febrile episode that can last - days, followed by afebrile period of - days. patients with tbrf can have up to febrile relapses, while lbrf is usually associated with only one relapse. other symptoms include myalgia, arthralgia headaches, and vomiting, and physical findings include lymphadenopathy and splenomegaly with rash occurring only in third of the patients. a range of neurologic complications as well as systemic inflammatory response syndrome also have been described [ ] . diagnosis is based on identifying the spirochetes on blood smear. sensitivity of blood smear is higher during febrile period (about %), and a negative blood smear does not exclude rf. in lbrf, the spirochete load can be low and specific stains can be helpful. other diagnostic methods include serologic testing, pcr, and mouse inoculation. doxycycline, tetracycline, and penicillin are the preferred treatment, with most patients treated with - days of doxycycline. jarisch-herxheimer reactions with high fever and leukopenia occur in half of the patients following the first antibiotic dose and can develop into a severe reaction with hypotension, respiratory distress, and death [ ] . without treatment, tbrf carries a mortality rate of up to % with even higher % mortality rate for untreated lbrf. two cases of meningoencephalitis with borrelia miyamotoi in heavily treated immunocompromised patients have been described [ , ] . lyme borreliosis is the most common vector-borne disease in the northern hemisphere caused by a group of at least genospecies. lyme disease is a multisystem illness affecting the skin, joints, nervous system, and heart. human infection is caused mainly by three species: b. burgdorferi is the most common cause in north america but also found in europe, and borrelia afzelii and borrelia garinii which cause the disease in europe and asia. emerging infections in the mid-western usa with borrelia mayonii cause a condition similar to lyme disease. most tick species do not carry borrelia species. the vectors of all borrelia species are the ixodid tick species; this includes the deer tick, i. scapularis, in the northeast and midwest of the usa, ixodes pacificus in the west, the sheep tick, ixodes ricinus, in europe and the taiga tick, ixodes persulcatus, in asia. the ixodid tick demonstrates a complex vector ecology with preferences for different hosts in different geographical regions and at different stages of its development. more than different species, including deer, rodents, birds, and reptiles, have been described. infection rates also show seasonal variation with highest rates during lyme disease follows several stages starting with localized disease at the site of inoculation, followed by dissemination stage and, later, persistent infection [ ] . however, an individual patient can show highly variable disease progression with different patterns of organ involvement and disease severity. erythema migrans (em) is often seen at the site of the tick bite after - days of incubation. regional lymphadenopathy can be seen. secondary skin lesions represent hematogenous dissemination. at this stage, constitutional symptoms of general fatigue, fever and headaches, migratory musculoskeletal pain, conjunctivitis, and cardiac involvement occur. in total, % of untreated patients can develop frank neurologic manifestations of meningitis, encephalitis, and variable forms of neuritis with fluctuating symptoms. persistence can occur in untreated (on inadequately) patients. antibiotic refractory arthritis is well described. however, even without treatment, intermittent or persistent attacks usually resolve completely within several years. co-infection with a. phagocytophilum and b. microti can cause diagnostic confusion [ , ] . the diagnosis of lyme disease is established based on clinical symptoms, history of potential exposure, and serologic studies. although positive culture can confirm the diagnosis, it can usually be obtained only from early em lesions. pcr testing is superior to cultures and can be performed on joint fluid samples [ ] . cdc recommendations for the diagnosis of lyme disease are based on serology which might be impossible in pidd patients with abnormal humoral response. cdc guidelines require both an elisa (or comparable test) to be positive and a western blot ( out of bands ( , , or kd) on the igm or out of bands on the igg ( , , , , , , , , , kd) . most lyme manifestations can be treated with oral antibiotics, while patients with neurologic abnormalities and some patient with lyme arthritis require intravenous therapy [ ] . doxycycline is the treatment of choice for early and disseminated disease, with amoxicillin as the second-line choice. jarisch-herxheimer-like reactions can appear in the first h in about % of the patients. for patients with clear neurologic symptoms, - weeks of iv ceftriaxone is the most commonly used therapy. few cases of neuroborreliosis and hiv have been described with a good response to treatment. descriptions of lyme disease in pidd patients are lacking. zoonoses are infectious diseases that pass between animals and humans and span the spectrum of pathogens including viruses, bacteria, fungi, and parasites. zoonoses are very common and range from mild such as certain forms of tinea to lifethreatening infections such as rabies. some of the zoonoses that are vector-borne will be covered in other sections. risk mitigation strategies for zoonoses include patient education, proactive advice about risk scenarios, and avoidance of infected animals. several zoonoses are associated with contact with mammals such as rodents or domestic farm animals through direct contact or through contact with their feces. for instance, hantavirus infections are often associated with exposures to mouse droppings when staying in cabins in the western usa. occupational exposures can occur with buffalopox or parapoxvirus (causing orf infection) through direct contact with buffalo and goats/sheep, respectively [ ] [ ] [ ] [ ] . in general, there are very few cases of pidd with zoonotic infections acquired from mammals. however, there are a few special considerations. for instance, lymphocytic choriomeningitis virus is acquired through exposure to house mice primarily, with hamsters being a less common source of infection. both domestic and wild mice can carry the infection without exhibiting symptoms. although infection is rare, there have been severe cases in patients with t/ nk cell dysfunction, such as a case in xlp and cases in solid organ transplant recipients [ ] . therefore, in patients with severe t/nk defects, consideration should be given to whether small rodents are appropriate household pets. tularemia is a disease of animals and humans caused by the bacterium francisella tularensis. rabbits, hares, and rodents are the main reservoirs. humans become infected through direct contact, ingestion of contaminated water, or inhalation of organisms. ticks and deer flies can also transmit the disease through bites. fever is universal, but other features depend on the mode of transmission. a patient with cgd had a complex course suggesting myeloid defects are a risk for more severe disease [ ] . rabies is an almost universally fatal infection caused by contact with oral secretions from infected mammals, typically raccoons, bats, or foxes, and there is no suggestion that pidd or immune compromised modifies the prognosis. for individuals with high-risk exposures, such as those working with wildlife or traveling in endemic areas, pre-exposure prophylaxis is given with vaccination, and if an exposure occurs, rabiesspecific immunoglobulin is provided as well as vaccination. however, for those with humoral immunodeficiencies who cannot respond to the typical pre-exposure vaccination, there needs to be counsel on the additional risk without vaccination. in table , several of the bacterial and viral zoonoses are summarized with their typical endemic areas, which is somewhat limited by diagnostic abilities and reporting, as well as the typical clinical scenarios, known cases in immunodeficiency and an approach to diagnosis and therapy. nipah virus causes a range of infectious phenotypes ranging from asymptomatic infection to acute respiratory distress and encephalitis. nipah virus was identified in on pig farms in malaysia, leading to identification of human cases, including human deaths and the culling of one million pigs [ ] . the natural host is the fruit bat: pteropodidae pteropus. symptoms of infection from the malaysian outbreak were primarily encephalitic in humans, but later, outbreaks have caused respiratory illness, increasing the likelihood of human-to-human transmission. fever, headache, cough, abdominal pain, nausea, vomiting, weakness, problems with swallowing, and blurred vision were common. seizures were seen in % and coma in %. relapses of encephalitis have been described [ ] . increasing infections due to nipah virus is thought to be due to an increasing overlap between bat habitats and pig sties in malaysia. all outbreaks thus far have been in india, bangladesh, or malaysia. the diagnosis of nipah virus relies on pcr of fluid samples, serology in convalescent samples, and immunofluorescence of tissue. there have been no infections of immune compromised patients reported. therapy is largely supportive, although preliminary reports of ribavirin use have been encouraging. a vaccine is under development. severe acute respiratory syndrome coronavirus (sars-cov) and the middle east respiratory syndrome coronavirus (mers-cov) are two zoonotic coronaviruses. the sars pandemic in - resulted in reported cases in countries. no further sars cases were reported after the pandemic except isolated cases linked to laboratory accidents. patients usually presented with fever and respiratory symptoms, but occasionally had diarrhea and vomiting. about - % of sars patients required mechanical ventilation, with a case fatality rate of about % [ ] [ ] [ ] . mers was first noted in saudi arabia in , and countries around the arabian peninsula are now endemic for mers-cov. patients usually present with fever, cough, chills, sore throat, myalgia, and arthralgia rapidly progressing to pneumonia with over % of patients requiring intensive care. about one-third of patients present with diarrhea and vomiting, and acute renal impairment is a striking feature of mers. risk factors for poor outcome include diabetes, hypertension, and renal and lung disease. cases have been exported to at least countries with travel occasionally causing cluster of secondary outbreaks. one such example is the mers-cov outbreak involving patients in south korea, and the median incubation period was estimated to be days with a range of to days [ ] . at the end of , there were confirmed mers with a % mortality rate [ ] [ ] [ ] . bats are the natural reservoirs of both sars-cov and mers-cov. sars-cov crossed the species barrier into palm civets and other animals in live animal markets in china, which then infected human, while a mers-cov ancestral virus crossed species barrier into dromedary camels. abundant circulation of mers-cov in camels results in continuous zoonotic transmission of this virus to human, while sars-cov was not found to circulate in the intermediate reservoirs, explaining sars being a one-off outbreak and mers a continuing zoonotic disease [ ] . aerosolgenerating procedures such as intubation were associated with increased viral transmission of both covs resulting in nosocomial outbreaks [ ] . super-spreaders are responsible for large and prolonged outbreaks [ ] . the diagnosis for sars and mers include both serological tests and pcr assays that can quantify viral loads [ ] . functional genetic polymorphisms leading to low serum mannose binding lectin (mbl) are associated with susceptibility to but not severity of sars in both southern and northern chinese [ ] [ ] [ ] . mbl was shown to bind to sars-cov and inhibit the infectivity [ ] , suggesting its role as first-line defense against sars-cov. although no patients with primary immunodeficiency infected with sars-cov or mers-cov were identified, likely due to the limited number of such infections, patients with t cell defect and type interferon pathway defects could suffer a more severe disease course [ , ] . virus-based and host-based treatment strategies are largely experimental with uncertain benefits. ribavirin, type interferons, small molecules, and monoclonal antibodies that block covs entry have been explored [ ] . passive immunotherapy and multiple candidate vaccines have been tested in various animal models. convalescent plasma immunotherapy has been considered, but clinical trials are lacking in mers [ ] , while for sars a systematic review concluded convalescent serum may reduce mortality and appear safe [ ] . the filoviridae family contains three known genera, the ebolaviruses, marburgviruses, and cuevavirus. ebolavirus and marburgvirus cause hemorrhagic fever syndromes in primates and humans, with high fatality rates. cuevavirus infects only bats. the ebolavirus genus contains five species, with two of the species (zaire ebolavirus and sudan ebolavirus) being responsible for the majority of cases of human disease, while marburgviruses contain two species (marburg virus and ravn virus). filoviruses are capable of replicating in a number of cell types (with the exception of neurons and lymphocytes). upon entry into the body of the host (via breaks in the skin, parenterally, or through mucosal surfaces), filoviruses employ a variety of mechanisms to evade the activity of the immune system [ ] . the incubation period (interval from infection to onset of symptoms) varies from to days. symptoms begin abruptly, with high fever, severe headache, malaise, myalgia, diarrhea, nausea, and vomiting. a rash can occur between and days after onset of symptoms. hemorrhagic manifestations occur between and days, and fatal cases usually have some form of active bleeding. in an outbreak setting, the symptoms are unmistakable but confusion with malaria can occur early in the disease or in sporadic cases. since their original descriptions in and , respectively, for marburg and ebola, there have been a number of sporadic cases and several major outbreaks. the largest marburg virus outbreak occurred in angola in (with a fatality rate of > %), while the largest ebola epidemic happened between and in west africa (sierra leone, guinea, and liberia) and claiming over , lives (fatality rate > %). although not definitively proven in the case of ebola, bats are believed to be the natural animal reservoir for these viruses [ , ] . these viruses are transmitted via contact with blood or body fluids from an infected host; notably, certain body fluids can harbor virus for weeks to months after resolution of disease. given the recent outbreak in west africa, there has been renewed interest in understanding the pathogenesis of filovirus infections and possible therapies. literature regarding how the pathogenesis of disease may be altered in patients with pidd is lacking. however, the assumption is that in the absence of an intact cellular and/or humoral immune response, the patient with a pidd may be at increased risk of mortality in the setting where mortality is already high. these viruses induce apoptosis of lymphocytes and macrophages, and there is therefore a profound secondary immune compromised [ , ] . filoviruses can be detected in multiple body fluids via pcr. although practiced for decades, a study in guinea in failed to show a decrease in mortality among patients receiving convalescent plasma from previously infected donors [ ] . a number of additional compounds (e.g., tkm-ebola, bcx , and gs- ) and biologics (zmapp) have been shown to offer protection in animal models of ebola, but to date, no controlled and appropriately powered clinical trials have addressed their efficacy in humans. finally, a number of vaccines for ebola are undergoing clinical studies (including four in phase iii trials). importantly, in late , the rvsv-zebov vaccine was shown to have displayed high efficacy in protecting immunized adults during the guinea ebola outbreak, and the data also suggested that the vaccine may even offer bherd immunity^to unimmunized persons in proximity to recipients of the vaccine [ , ] . hepatitis e virus is a single-strand rna virus of the hepeviridae family. it is an important zoonotic disease in asia and africa, and fecal-oral spread is the usual route of transmission [ ] . handling of pig or boar meat is a risk factor, and - % of pig livers sold in grocery stores in japan and the usa are infected [ , ] . swine represent the major reservoir, although antibodies to the virus have been found in many species [ ] . the incubation period is weeks to months, and viremia disappears with the onset of symptoms. the mortality rate is - % and can reach % in pregnancy [ ] . acute hepatitis usually resolves but can lead to liver failure in severe cases. patients with hepatitis e posttransplant have had severe courses in some cases [ ] . in immune compromised patients, the course can become chronic [ ] [ ] [ ] . in these cases, cirrhosis develops. the diagnosis is by serology or pcr, and the treatment is supportive. prevention modalities for infections transmitted by humans are conceptually different than infection prevention for vector-borne infections. hand hygiene is extremely important, and avoidance of clearly infected people can be helpful. recognition of infections with fecal-oral transmission and the importance of water purity are critical for patients with pidd. in contrast, infections transmitted by aerosols require prevention strategies related to droplet precautions. in outbreak scenarios, if the risk to the patient is high, specific chemoprophylaxis may be considered. influenza viruses type a and b cause annual epidemic influenza, while type c causes sporadic mild influenza-like illness. patients present with sudden onset of fever, chills, and myalgia, followed by sore throat and cough. other less common features include diarrhea, acute myositis, and encephalopathy [ , ] . co-infection with bacteria such as pneumococci results in more severe disease [ , ] . influenza pandemics occur yearly around the world. influenza viruses infect to % of the global population, resulting in~ , deaths annually [ ] . the viruses circulate in asia continuously and seed the temperate zones, beginning with oceania, north america, and europe, then later seeding into south america [ ] . diagnosis of influenza includes direct/ indirect immunofluorescent antibody staining for antigens in nasopharyngeal aspirates and pcr. a patient with compound heterozygous null mutations of the gene encoding irf , a transcription factor for amplifying ifn-α/β, was reported to have life-threatening influenza during primary infection [ ] . fatal influenza-associated encephalopathy in both chinese and japanese children has been reported to be associated with genetic variants of thermolabile carnitine palmitoyltransferase ii [ ] . patients with scid will have prolonged viral shedding [ ] . severe pandemic influenza a virus (h n ) infection has been associated with igg and igg subclass deficiency [ , ] . in addition, influenza infection can be more severe in pidd patients with underlying lung disease, such as bronchiectasis, and antibiotic coverage of chronic colonizing bacteria (such as pseudomonas) in this setting may be helpful. inactivated seasonal influenza vaccine should be given to pidd patients even those with humoral deficiencies as their t cell response to influenza could be normal and offer protective immunity against severe influenza [ , ] . antiviral drugs include neuraminidase inhibitors (oseltamivir and zanamir) and adamantanes (amantadine and rimantadine), but resistance to adamantanes is widespread. measles is a single-stranded, negative-sense, enveloped (nonsegmented) rna virus of the genus morbillivirus. measles is highly communicable, transmitted by droplets, and less commonly by airborne spread. patients present with fever, cough, coryza conjunctivitis rash, and koplik spots. complications include pneumonia, acute encephalitis, and subacute sclerosing panencephalitis (sspe) [ ] . diagnosis of measles includes serological tests, virus isolation, and pcr. in an outbreak, the clinical features may be sufficient for diagnosis. measles vaccine has caused severe measles in children with stat and ifn-α/β receptor deficiency [ , ] , demonstrating the importance of type interferon pathway in controlling measles. immune compromised of nearly any type is associated with severe disease and higher mortality [ ] . t cell deficiency states are the most strongly associated with the development of giant cell pneumonia and inclusion body encephalitis, the most feared complications of measles. sspe is a slow encephalitis due to persistence of replication defective measles virus in the cns. it is most frequently seen when young infants are infected with measles and - years later, sspe becomes evident. there are case reports supporting the immune compromised as increasing the risk of sspe [ ] . treatment of sspe with ribavirin has shown some improvement, but the prognosis in general with sspe is very grave. patients with cgd have defective memory b cell compartment, resulting in lower measle-specific antibody levels and antibody-secreting cell numbers, but severe disease has not been reported [ ] . pidd patients may harbor the virus latently for longer than usual, leading to complications at the time of transplant [ ] . specific antiviral therapy is lacking, but ribavirin has been given to severely ill and immunocompromised children. for measles post-exposure prophylaxis, intravenous immunoglobulin (ivig) is recommended for severely immunocompromised patients without evidence of measles immunity [ ] . this would likely include patients with scid and hypogammaglobulinemia who are not yet on regular ivig. measles vaccine, given in a two-dose regimen, has brought down incidence enormously worldwide and the who is planning for eradication globally. enteroviruses (evs) are among the most common viruses infecting humans worldwide. evs are small non-enveloped, single-stranded rna viruses of the picornaviridae family. human evs are categorized into seven species that include hundreds of serotypes, such as polioviruses (pv), coxsackie viruses a, and b (cv-a and b), echoviruses, and human rhinoviruses (hrvs). of these species, many important serotypes are known to infect human such as pv - , cv-a , cv-b , ev-a , ev-d , and hrv (table ) . non-polio enteroviruses (npevs) have a worldwide distribution. infants and young children have higher incidence of infection and a more severe course of illness than adults. the mode of transmission is mainly through fecal-oral and respiratory routes. infection occurs all around the year in tropical and subtropical regions, while in temperate climates the peak incidence of infection is during summer and fall months [ ] . npevs are associated with diverse clinical manifestations ranging from mild febrile illness to severe, potentially fatal conditions. most cases are asymptomatic or have mild symptoms including fever with or without rash; symptoms of hand, foot, and mouth disease; herpangina; acute hemorrhagic conjunctivitis; upper respiratory infection; and gastroenteritis. more severe symptoms occur in infants and young children [ , ] . acute flaccid paralysis [ ] , neonatal enteroviral sepsis [ ] , myocarditis/pericarditis [ , ] , hepatitis, pancreatitis, pneumonia, and atypical hemolytic uremic syndrome [ ] are severe manifestations seen in immunocompetent people. chronic infections have been seen in immunocompromised patients [ ] . each virus may produce one or more of the aforementioned manifestations; however, some serotypes are often associated with particular features ( table ) . the definitive diagnosis of npev infection relies on pcr or virus isolation from the cerebrospinal fluid, blood, stools, urine, or throat swab [ , ] . treatment of npevs is mainly supportive since most infections are self-limited. high doses of intravenous immunoglobulin (ivig) are recommended in patients with severe symptoms. the efficacy of some new antiviral drugs (pleconaril, vapendavir, and pocapavir) is still under investigation [ ] . no vaccine has been licensed yet for npevs. however, phase clinical trials of inactivated monovalent ev-a vaccines manufactured in china showed high efficacy against ev-a in infants and young children [ ] . patients with a variety of pidds are unusually susceptible to ev [ ] . the most susceptible groups are patients with primary antibody deficiency such as xla, cvid, and hyper-igm syndrome (higms) as well as those having scid and major histocompatibility class ii deficiency [ , ] . the most severe form of infection has been described in patients with xla due to the profound deficiency of immunoglobulins essential for viral neutralization during infection. affected patients usually present with indolent but relentlessly progressive non-necrotizing meningoencephalitis. regression of cognitive skills, flaccid quadriplegia, and deafness has been described. the reported non-neurologic presentations in xla include septicemia, dermatomyositis-like disease, hepatitis, and/or arthritis [ , ] . the incidence of npev meningoencephalitis in large registries of xla cases is - % [ ] . unpublished data from the kuwait national pidd registry, which includes pidd patients, showed that nine patients had documented npev infections and two died from these infections. the two deaths were seen in scid patients (personal communication with prof. waleed al-herz, md). in addition, npev meningoencephalitis and/or septicemia were reported in few cases with either primary b cell deficiency such as b cell linker (blink) protein deficiency [ ] or acquired b cell deficiency following the administration of anti-cd (rituximab) [ , ] . in all reports, better outcome was attributed to the early administration of high doses of ivig during npev viremia [ ] . npev infection in pidd diseases remains a major threat to patients. also, the possible prolonged viral excretion and the emergence of resistant strains runs the risk of spreading infection to the surrounding community. oral polio vaccine (opv) consists of a mixture of three live attenuated poliovirus serotypes. opv induces production of neutralizing antibodies against all three serotypes, in addition to a local intestinal immune response. opv can result in vaccine-associated paralysis (vap) secondary to reversion of the vaccine strain to the neurovirulent wild-type strain. an example for such an event was demonstrated by the - outbreak in the dominican republic and haiti [ ] , believed to be driven at least in part by undervaccination of the population, which allowed the spread of the reverted vaccine strain [ ] . although rare, patients with pidd have a higher risk to develop vap. reports have shown that pidd patients with antibody deficiency can have prolonged viral replication which can persist for years and therefore theoretically increase the risk for a spontaneous reversion within the immunodeficient host [ ] [ ] [ ] [ ] . cases of vap were shown in patients with antibody deficiency and combined immunodeficiency syndromes [ , , ] . therefore, opv is contraindicated in patients with pidd, and this contraindication extends to their household contacts [ ] . beyond the obvious risk for the pidd patient, prolonged virus shedding also increase the risk for spreading vaccine-derived paralytic strain in the general population. bacterial infections have molded human behavior and altered societies over human history. today, largely ignored due to antibiotic susceptibility, they continue to cause misery and disease around the world. three infections are highlighted, and additional commonly encountered infections are listed in table . pertussis is a respiratory infection caused by bordetella pertussis that begins after a -to -day incubation period as a minor upper respiratory infection that progresses with cough. initially intermittent, it evolves into paroxysmal coughing spells usually followed by vomiting in infants and young children. it lasts to weeks and can have many complications such as syncope, weight loss, rib fracture, and pneumonia. infants under months are more severely affected, developing pneumonia, pulmonary hypertension, hypoxia, subdural bleeding, and seizures. death can occur, especially in young infants [ , ] . adults typically have a prolonged cough with fewer complications [ ] . it is transmitted via aerosolized droplets during close contact. people are most contagious during the catarrhal stage and the first half of the paroxysmal phase, totaling to weeks [ ] . the introduction of whole-cell pertussis vaccine (dpt) in the s in the usa reduced the incidence of the disease from , cases to around cases per year in the s. a resurgence in was associated with the substitution of the whole-cell vaccine by the acellular pertussis vaccine (dtap) [ ] . new strategies such as boosters with acellular pertussis for adolescents and adults with tdap and use of tdap during pregnancy seem to be effective in partially reducing the incidence of the disease [ ] ; however, pertussis cases in the usa remain higher than the s. the lack of persistence of antibody in the adult population means adults not only represent a reservoir for the disease but also do not provide sufficient titers to immunoglobulin products prepared from adult plasma pools. a relatively recent requirement in some countries is vaccination of adults every years to maintain immunity. this should, over time, improve titers in immunoglobulin products. culture of specimens obtained by nasopharyngeal swabs is the gold standard of laboratory diagnosis due to the % specificity, but polymerase chain reaction (pcr) is gaining prominence due to its higher sensitivity and speed of results; serodiagnosis can be used in the late stages of the disease [ ] . filamentous hemagglutinin (fha) and pertussis toxin (pt) antibodies were detected at peak measurements in pidd patients on regular ivig, although some of them had pt antibodies below the protective level as trough measurements [ ] . severe pertussis cases have not been reported in pidd patients, but severe disease has been seen in malignancies [ ] . antimicrobials such as azithromycin, erythromycin, and clarithromycin, if given during the catarrhal stage, may ameliorate the disease and shorten the contagious period. to avoid cases of pertussis, it is also worth emphasizing the importance of good vaccine coverage rate among the whole population, but especially among healthcare workers and family members of patients with pidd. neisseria meningitidis the onset of neisserial meningitis is associated with sore throat, headache, drowsiness, fever, irritability, and neck stiffness [ , ] . purpuric lesions are very characteristic. this pathogen can also present with sepsis which has a % mortality rate as opposed to % mortality with a meningitic presentation. this bacterium can also cause a chronic condition referred to as chronic meningococcemia. this condition is characterized by intermittent fevers lasting week to - months [ ] . a non-purpuric rash is common which may evolve into purpura. arthritis, similar to that seen with gonococcus, is common. meningococcal disease primarily affects children under years of age. n. meningitidis is a global pathogen [ ] . there are serogroups, but the majority of invasive meningococcal infections are caused by organisms from the a, b, c, x, y, or w serogroups. the annual number of invasive disease cases worldwide is estimated to be at least . million, with , deaths related to invasive meningococcal disease. serogroups b and c are responsible for most infections in europe. serogroup a has historically been the major organism in africa; mass vaccination has led to some improvement, but the emergence of group x disease is worrisome. the hajj in the middle east has seen epidemics of w- , and vaccination is now required for hajj travelers. b and c serogroups are the most common through the americas. n. meningitidis cases occur at a rate of about case per , people throughout the world [ ] , but across the sahel of africa and in china, epidemics can lead to case rates of per , [ ] . the bacterium is a natural human commensal, with carriage rates of about %. diagnosis can be by clinical examination in epidemics or by gram stain and culture. complement-deficient individuals have an increased risk of neisserial disease, but not necessarily increased mortality. hiv is associated with increased disease, suggesting that t cells are also important for defense. thirdgeneration cephalosporins are typically used for treatment. penicillin, ampicillin, aztreonam, and chloramphenicol are alternatives. there is great inter-individual variability in the development of tb disease. roughly, % of infected individuals develop clinical disease within years of infection (mostly during childhood). about % became latently infected without clinical disease, and the remaining to % develop pulmonary tb later in life, either from reactivation of latent infection or reinfection. molecular epidemiology studies from high burden areas suggest more disease results from recent transmission than from reactivation of latent tb, particularly in people living with hiv [ ] . acquired or inherited host factors may at least partially account for the variable disease course, resulting in increased susceptibility to mycobacteria infections [ ] . pidd associated with tb and ntm infections include t cell deficiencies, gata deficiency, cgd, anhidrotic ectodermal dysplasia with immunodeficiency, x-linked (xl) recessive cd ligand deficiency, autosomal recessive (ar) stat deficiency, ar irf deficiency, and ar tyk deficiency. in addition, a group of disorders with a strong susceptibility to ntm, named mendelian susceptibility to mycobacterial diseases (msmd), have been recognized since the s. these are rare inborn errors of ifn-γ signaling pathway that present with isolated predisposition to infections caused by weakly virulent mycobacteria such as bcg vaccine and environmental ntm, in otherwise healthy patients. the genetic defects involve impairment in the production of interferons (ar il rβ , ar il p , autosomal dominant (ad) irf , ar isg , xl recessive nemo) or response to interferons (ifn-γr, ad stat , ad irf , cgd) [ ] . an acquired form exits: adults with ntm infection in thailand and taiwan were found to have high-titer anti-interferongamma antibody [ ] . these individuals from southeast asia were found to have hla-drb * / : and dqb * : / : . patients suspected of having pulmonary tb should have acid-fast bacilli (afb) smear microscopy and culture performed in three sputum samples. pcr for mtb can be performed [ ] . the use of rapid tests facilitates early diagnosis, and the who has recently recommended their use. the only recommended rapid test for detection of tb with and without rifampicin resistance is the xpert mtb/rif assay (cepheid, sunnyvale, ca). the who recommends the xpert test for those suspected of having drug-resistant tb or in hiv; however, culture is still the mainstay and is not replaced by the xpert test. tb skin testing (mantoux testing) uses a purified protein derivative injected under the skin. its advantages are that it can be used for large-scale screening and it is cost effective. skin testing does have several disadvantages when used as a diagnostic test. reading the induration requires training and immunodeficiencies can alter the magnitude of the induration. immunosuppressed patients (hiv, organ transplant) are considered positive if the induration is ≥ mm. some immunodeficiencies may completely ablate the response. other causes of false-negative tests are malnutrition, concurrent infection, recent live viral vaccine administration, renal failure, malignancy, medical stress, very elderly, young infants, or with a very recent infection with mtb. conversely, the results may be falsely positive if bcg has been administered. interferon gamma release assays can be used in any setting where skin testing would be done but are considered superior in settings where the patient has had bcg vaccination and, in some cases, where skin testing has been sown to have high false-negative rates. in general, tb treatment for patients with impaired immune response, including pidd, hiv infection, and immunosuppressive therapy, is based on the standard -month regimen consisting of a -month intensive phase of isoniazid, rifampin, pyrazinamide, and ethambutol, followed by months of isoniazid and rifampin. decisions regarding treatment duration can be individualized, taking into account disease severity, organs involved, and response to treatment. significant pharmacological interaction can occur between rifampin-based mtb regimens and immunosuppressive drugs, such as calcineurin inhibitors or rapamycin, requiring strict monitoring of drug plasma concentrations [ ] . therapy for ntm is complex with highly variable drug resistance patterns and a need for biological augmentation to effectively clear the organism. aspergillus fumigatus (see above), cryptococcus gattii, histoplasma capsulatum, coccidioides immitis (or c. posadasii), blastomyces dermatitidis, paracoccidioides brasiliensis, emmonsia pasteuriana, and penicillium (talaromyces) marneffei are environmental fungi that are endemic in certain parts of the world (table ). with the exception of penicillium marneffei and emmonsia pasteuriana that only cause disease in profoundly immune compromised individuals, these fungi can cause infection in healthy individuals, ranging from mild, self-limited pulmonary disease to infection that requires antifungal therapy for eradication. on the other hand, patients with acquired defects in cell-mediated immunity such as those infected with hiv, and patients with specific monogenic disorders, particularly those involving the il- / ifn-γ/stat signaling pathways, scid, and gata depends on underlying state of immunosuppression and magnitude of environmental exposure icl idiopathic cd lymphocytopenia, aids acquired immune deficiency syndrome, stat signal transducer and activator of transcription , gata gata binding protein , scid severe combined immunodeficiency, cvid common variable immune deficiency, pidd primary immunodeficiency, il rb , interleukin- receptor subunit beta , ifngr gamma interferon receptor deficiency, are at high risk of developing life-threatening disseminated infections by these endemic fungi following environmental exposure [ , [ ] [ ] [ ] [ ] [ ] . diagnosis relies on culture of the corresponding fungus, histopathological demonstration of the fungus-specific characteristic morphologies, and/or surrogate serological and fungal antigen tests. treatment of clinical disease (as opposed to colonization) typically involves an initial induction phase with amphotericin b, followed by long-term azole maintenance therapy and secondary prophylaxis, and prognosis varies significantly depending on the fungal pathogen and underlying pidd. melioidosis is caused by b. pseudomallei, a gram-negative bacteria found in soil and water, in tropical climates of southeast asia and northern australia [ , ] . melioidosis is an emerging, potentially fatal disease ( % mortality). b. pseudomallei can be transmitted by inhalation, ingestion, or direct contact (through open skin) with contaminated soil or water. animals (sheep, goats, swine, horses, cats, dogs, and cattle) are also susceptible to infection and cases of zoonotic transmission through direct contact of skin lesions with infected animal meat or milk have been described [ ] . b. pseudomallei infections are endemic in northern australia and southeast asia. approximately % of reported infections occur during the rainy seasons. cases have also been reported in south pacific, africa, india, and the middle east. in temperate areas, infection is extremely rare and is predominantly imported by travellers or immigrants [ ] . the incubation period of melioidosis is variable from day to years, although common symptoms develop between and weeks after exposure. melioidosis presents most frequently in adults - years of age, but can occur in all ages, with one study reporting % of cases occurred in children [ ] . in australia, the average annual incidence in - was reported as . cases per , people [ ] . the incidence in indigenous australians was higher at . cases per , . a case-cluster in an australian community was associated with post-cyclonic flooding. a recent review suggests that b. pseudomallei is increasingly prevalent in the americas, with a mortality rate of % [ ] . infection in healthy individuals is uncommon, and more than % of cases occur in the setting of underlying conditions such as chronic renal disease, diabetes, chronic lung disease, and alcoholism. a recent review of melioidosis in travelers found that % of cases were acquired in thailand. symptoms usually started at days (range - days) after leaving the endemic area. traveller infections were less often associated with predisposing risk factors ( . %), diabetes mellitus being the most common ( %). melioidosis in travelers had lower mortality ( %) than infection in autochthonous cases in southeast asia [ ] . pneumonia (~ - %) is the most common presentation in adults. there is usually high fever, headache, anorexia, and myalgia. b. pseudomallei infection may also present as localized skin infection, septicemia, or disseminated infection. localized infection results in an ulcer, nodule, or skin abscess. this usually occurs from the bacterium breaching through a break in the skin. patients with renal disease and diabetes are more susceptible to sepsis. in disseminated infection, abscesses may develop in the liver, spleen, lung, and prostate. in children, primary cutaneous melioidosis is the commonest presentation ( %). bacteremia is less common in children than in adults, but brainstem encephalitis has been reported [ ] . difficulties in laboratory diagnosis of melioidosis may delay treatment and affect disease outcomes [ ] . diagnosis of melioidosis is primarily by isolation of the organism. identification of b. pseudomallei can be difficult in clinical microbiology laboratories, especially in non-endemic areas where clinical suspicion is low. although various serological tests have been developed, they are generally unstandardized bin house^assays with low sensitivities and specificities. pcr assays have been applied to clinical and environmental specimens but are not widely available and sensitivity remains to be evaluated. cases of melioidosis have been reported in patients with acquired or inherited immune deficiency. melioidosis was the presenting complaint in several patients with cgd. bacteremic melioidosis was recently reported in two patients with prolonged neutropenia, who succumbed despite appropriate antibiotics [ ] . it is likely that there is increased susceptibility in situations where innate or adaptive immunity is compromised. treatment is with intravenous antimicrobial therapy for - days, followed by - months of oral antimicrobial therapy. intravenous therapy with ceftazidime or meropenem is usually effective. oral therapy may continue with trimethoprim-sulfamethoxazole or doxycycline. free-living amoebas (fla) are protozoa found worldwide that do not require hosts to survive. fla do not employ vectors for transmission and are not well adapted to parasitism in humans. however, there are four genera/species that can cause human disease: naegleria (n. fowleri), acanthamoeba (multiple species), balamuthia (b. mandrillaris), and sappinia (s. pedata). all of these amoebae are capable of inducing cns disease in humans, but acanthamoeba species also cause various extra-cns infections, especially in immunocompromised hosts. the fla that are pathogenic in humans are reviewed below. naegleria are a diverse group of fla flagellate protozoans with a large number of distinct species. only one species, n. fowleri, has been shown to cause infection in humans. n. fowleri has a multi-stage life cycle with amoeboid and trophozoite-infective forms as well as a cyst form [ ] . n. fowleri is found commonly in warm freshwater around the world including lakes, rivers, and hot springs. humans become can become infected when swimming or diving in contaminated water. in rare circumstances, infections have also been attributed to exposure from contaminated tap water sources when utilized for religious cleansing of the nose or irrigation of the sinuses. thus, tap water should not be used for nasal and sinus irrigation. it is not possible to become infected from drinking contaminated water or from contact with an infected person, and the amoeba is not found in salt water. after entry to the nasal cavity, the amoeba travels through the cribiform plate to the olfactory bulbs and migrates to the cerebellum, resulting in primary amoebic meningoencephalitis (pam), a rapidly fatal brain infection characterized by the destruction of brain tissue. in its initial presentation, pam can mimic bacterial meningitis, further delaying accurate diagnosis and initiation of therapies that may save the patient. overall, n. fowleri infections are rare. worldwide, most cases are reported in the usa, australia, and europe; however, in developing countries, it is suspected that a large number of cases go unreported. between and , there were only infections reported in the usa with of the cases attributed to contaminated recreational water, infections following nasal irrigation with contaminated tap water, and case where a person was infected following use of a backyard slipn-slide utilizing contaminated tap water [ ] . the fatality rate associated with n. fowleri infection is over %, and between and , only of the infected persons in the usa have survived infection. initial symptoms of pam start to days after infection and can include headache, fever, nausea, or vomiting [ ] . progressive symptoms can include stiff neck, confusion, lack of attention, loss of balance, seizures, and hallucinations. cardiac arrhythmias have also been observed. the infection progresses rapidly after initial onset and causes death within to days after exposure (mean of . days). since infection often progresses rapidly to death, there is often insufficient time to mount a robust immune response. however, both the innate (neutrophils, macrophages, and complement system) and the adaptive (both t and b cells) arms of the immune system have been shown to participate in the immune response to n. fowleri [ ] . patients with pam have csf with elevated pressure that is often cloudy or hemorrhagic, with neutrophil-predominant pleiocytosis, elevated protein levels, and very low glucose. wet mounts from centrifuged csf will show motile mono-nucleated trophozoites measuring~ - μm in size. additionally, trophozoites can be identified with giemsa and wright stains of csf smears combined with an enflagellation test [ ] . confirmation can be achieved via a variety of timeconsuming methods including an immunofluorescence assay [ ] , culture of csf [ ] , or pcr-based methods [ ] . the optimal therapy for n. fowleri pam is still debated. the use of intravenous amphotericin b and fluconazole followed by oral administration of rifampin resulted in survival of a year-old child with pam [ ] . another child was shown to survive following intravenous and intrathecal amphotericin b and miconazole as well as oral rifampin [ ] . most recently, an adolescent girl was successfully treated with the combination of azithromycin, rifampin, fluconazole, and miltefosine [ ] . prevention is critical for this highly fatal infection and warning pidd patients not to use tap water for nasal irrigation is important. since its original description in , over cases of b. mandrillaris infections have been described worldwidewith most cases occurring in south america and the usa. balamuthia are found in soil, and acquisition of disease has been associated with agricultural activities, dirt-biking, gardening, and swimming in contaminated water sources. b. mandrillaris is thought to enter the body of the host through breaks in the skin and or via inhalation. the organism is believed to access the cns through hematogenous spread, resulting in a chronic, insidious, but often fatal granulomatous amoebic encephalitis (gae), which has been documented in both immunocompetent and immunocompromised hosts [ , ] . the incubation period from exposure to development of clinical symptoms is not well established and experts believe that this may occur between months and years. finally, an alternative mode of transmission via solid organ transplantation has also gained attention [ ] [ ] [ ] . in many cases, gae is diagnosed post-mortem, due to delayed diagnosis or unawareness of the clinical entity. following infection by b. mandrillaris, two clinical patterns of presentation have been described. in the first pattern, patients initially develop a skin lesion that may resemble a painless plaque that may evolve into subcutaneous nodules and rarely ulcerations [ ] . these patients may develop neurologic manifestations weeks to months later. histopathologic examination of these lesions typically reveals granulomatous reactions in the reticular dermis, associated with lymphocytic and plasma cell infiltrates as well as multinucleated giant cells, without distinct epidermal changes. skin lesions will harbor trophozoites, but these are scarce and often easily overlooked as they resemble histiocytes. it is believed that early diagnosis of b. mandrillaris infections in those presenting with skin lesions may prevent subsequent development of cns disease, but there have also been cases in which patients presenting with skin lesions have progressed to developing gae despite treatment. in the second pattern, patients present with cns involvement without a previously recognized skin lesion. patients presenting with gae may initially display fever, malaise, headache, nausea and vomiting, and frank lethargy. later, these symptoms evolve into visual abnormalities, cranial nerve palsies, seizures, focal paresis; as intracranial pressure builds, coma, and eventually death with tonsilar or uncal herniation ensue within - weeks [ ] . upon infection with b. mandrillaris, brain endothelial cells produce the proinflammatory cytokine il- , thereby initiating an inflammatory response [ ] . moreover, the amoebic trophozoites infiltrate blood vessel walls. degradative enzymes, vessel wall infiltration, and the host inflammatory responses result in tissue necrosis and infarctions in the cerebral hemispheres, cerebellum, and the brainstem. in a mouse model of b. mandrillaris infection, cd + t cells were shown to be protective [ ] , suggesting that patients with lowered number or dysfunction in cd + t cells may be more susceptible to disease by this amoeba. however, b. mandrillaris infections have been described in a variety of human hosts [ ] , ranging from the young, healthy, and presumably immunocompetent to the elderly, and those with hiv, chronic corticosteroid exposure, on post-transplant immunosuppression and even patients with cvid. as such, further research is necessary to fully delineate the susceptibility of pidd patients. in patients who develop the characteristic skin lesions, recognition, testing, and treatment for b. mandrillaris may prevent subsequent gae. as such, obtaining tissue and looking for granulomas and trophozoites is quite helpful. skin biopsies can be stained via immunofluorescence or immunoperoxidase techniques to identify b. mandrillaris [ ] . additionally, a pcr technique that identifies mitochondrial s ribosomal rna from b. mandrillaris is also available through the cdc [ ] . in patients in whom the diagnosis is confirmed via skin biopsy, wide resection and medical treatment appears to prevent development of cns disease in at least a proportion of patients. in patients presenting with cns involvement, lumbar punctures reveal csf with lymphocytic pleiocytosis, low-to-normal glucose, and mildly to significantly elevated protein levels. trophozoites are not typically found in the csf, but pcr analysis may be performed. ct or mr imaging may show multiple nodules with ring enhancement; some of these nodules may also contain focal areas of hemorrhage. biopsies of brain tissues typically reveal granulomas and foamy macrophages and multinucleated giant cells surrounded by lymphocytic infiltrates. additionally, there will be areas of necrosis filled with neutrophils, multinucleated giant cells, and lymphocytes, with balamuthia trophozoites and cysts interspersed with macrophages [ ] . as with the skin biopsies, immunofluorescent and immunoperoxidase stains may aid diagnosis and should be performed. unfortunately, the optimal medical management of cns disease is unknown. in the usa, a few patients have been successfully treated with a combination of fluconazole, flucytosine, pentamidine, a macrolide antibiotic (either clarithromycin or azithromycin), and one of the following agents: liposomal amphotericin b, miltefosine, sulfadiazine, or thoridazine [ ] [ ] [ ] ; others in peru have been treated successfully with fluconazole (or itraconazole), albendazole, and miltefosine [ ] . based on these case reports, most experts recommend treatment with a combination of medications (along with partial or complete resection of nodules) for a prolonged period of time to prevent further deterioration and death [ ] [ ] [ ] [ ] . acanthamoeba spp. the genus acanthamoeba contains at least morphologically distinct species that live in a diverse array of habitats, including soil, salt, brackish, and fresh water. acanthamoeba spp. have also been found in humidifiers, heating and cooling unit components, jacuzzis, hot water tanks, bathrooms and drains, eye wash stations and dentistry irrigation systems, and more. acanthamoeba spp. have been isolated from reptiles, birds, and other non-human mammals, suggesting a broad distribution in the environment. acanthamoeba trophozoites feed on bacteria, but have also recently been shown to harbor a number of bacteria (including legionella and burkholderia spp., e. coli, listeria monocytogenes, vibrio cholerae, mycobacteria spp., chlamydophila, and others) and at least one virus (mimivirus) as endosymbionts. acanthamoeba infections in humans can present in a variety of ways. of primary importance are cns infections. like b. mandrillaris, acanthamoeba spp. can induce gae (described above). there is a high predilection for gae in those with hiv/aids, patients on chemotherapy, and those receiving broad spectrum antibiotics [ ] . acanthamoeba are rarely found in csf, but some case reports indicate isolation of amoebae by culturing csf on bacterized agar plates. similar to gae seen with b. mandrillaris, cns histopathology may reveal edema, multiple areas of necrosis and hemorrhage, and occasional findings of angitis and blood vessel cuffing by inflammatory cells, as well as occasional trophozoites or cysts. cns disease treatment is not standardized, but several patients have been successfully treated with pentamidine, fluconazole, flucytosine, sulfadiazine, as well as miltefosine. acanthamoeba can rarely cause cutaneous infections; these lesions, like gae, are also predominantly seen in immunocompromised hosts. these lesions can start as nodules or papules on the lower extremities and develop into necrotic ulcers. histopathologic examination may reveal granulomatous dermal lesions in immunocompetent hosts, with histiocytes, as well as neutrophils and plasmacytes; trophozoites are typically visible [ , ] . the optimal management of cutaneous disease is not known, but typically involves combinational therapy with topical (e.g., chlorhexidine, gluconate, or ketoconazole) and systemic (miltefosine, sulfadiazine, flucytosine, liposomal amphotericin b, azole antifungals, etc.) drugs. additionally, nasopharyngeal and sinus infections have been seen in people with severe compromise in immunity [ , ] . patients typically present with purulent nasal discharge, and examination may reveal erosion of the nasal septum. nasopharyngeal disease can present concomitantly with cutaneous disease. treatment of nasopharyngeal or sinus disease is difficult and involves surgical debridement and combinations of systemic drugs. disseminated disease is also seen in immunocompromised hosts and typically involves concomitant pulmonary and cutaneous disease in the presence or absence of cns infection. keratitis readily occurs in immunocompetent hosts-with the major risk factor being contact lens wearing without proper adherence to recommended cleansing protocols. this infection less commonly presents as a result of direct inoculation with trauma. one of the most common reasons for contact lens wearers to acquire disease is due to the use of non-sterile tap water in preparing contact lens saline solutions [ ] , although contaminated solutions from manufacturers have also been identified. patients will have pain and photophobia. physical exam reveals conjunctival injection and epithelial abnormalities (including pseudodendritic lesions) and stromal infiltrates [ ] . the proper diagnosis can be made by staining corneal scrapings with calcofluor or wright-giemsa stains and examined by confocal microscopy, culture, or pcr analysis. prompt therapy with a combination of polyhexamethylene biguanide (or biguanide-chlorhexidine) and propamidine or hexamidine [ , ] is indicated, but misdiagnosis and delayed therapy are common. more severe cases may also require debridement. the use of topical steroids before administration of combinational therapy may result in worse outcomes and should be avoided; however, if scleritis ensues, it may be necessary to use immunosuppressants to reduce the need for enucleation. severe and/or refractory cases may result in the need for cornea transplantation. phenotypes seen in pidd like hsv- and candida [ ] . patients with ifnar deficiency seem highly susceptible to cns disease caused by mmr vaccine, an otherwise extremely rare phenomenon [ ] . recently, a case of noroviral cns disease was described associated with a novel, yet unpublished pidd, suggesting that some pidds may lead to susceptibility of the cns to viruses that normally do not exhibit neurotropism (casanova jl, personal communication) . this again favors metagenomic approaches in the study of cns sequelae in pidd patients. in pidds, the cns is also more vulnerable to virally induced immunodysregulation [ ] . conditions like primary hemophagocytic lymphohistiocytosis (hlh) may present as isolated cns disease or relapse only in the cns [ ] [ ] [ ] . almost % all human malignancies are associated with chronic infections by hbv, hcv, hpv, ebv, hhv /kshv, htlv-i, hiv- , hiv- , jcv, merkel cell polyomavirus (mcpv), helicobacter pylori, schistosomes, or liver flukes [ ] . accordingly, pidd patients' malignancies are often associated with chronic infections. mcpv-associated merkel cell carcinoma has now been described in gata and tmc (ever ) deficiencies as well as other forms of pidd [ , [ ] [ ] [ ] [ ] [ ] . large follow-up cohorts are needed to refute or confirm associations between novel pidds and malignancies, such as hyperactivating pik cd and ovarian dysgerminoma or gata deficiency and leiomyosarcoma [ , ] . recently, hymenolepis nana was found to have driven malignant transformation in an hiv patient. likely, other novel pidd-and pathogen-associated malignancies will be found in the future by those with an open and inquisitive mind [ ] . understanding the specific infection susceptibility for each pidd allows not only a better understanding of host defense, but also allows the clinician to collaborate with the microbiology laboratory to make definitive diagnoses and provide the best therapy. reviewing all of the infections for each pidd is not within the scope of this article, but there are several infections that are unique for specific pidds and require special attention from the microbiology laboratory. three examples are provided below. g. bethesdensis is a gram-negative bacterium that was identified to cause disease in patients with cgd in [ ] . g. bethesdensis is a member of the methylotroph group of bacteria, which are able to use single-carbon organic compounds as their only source of energy. they are widespread in the environment, but are rare human pathogens, and infections with g. bethesdensis have been limited thus far to patients with cgd. the organism was first detected in an adult patient with indolent and recurrent necrotizing lymphadenitis [ ] . subsequently, g. bethesdensis was isolated from nine patients with cgd, primarily causing lymphadenitis, but there have been two fatalities [ ] . treatment has been most effective with intravenous ceftriaxone. the microbiology laboratory should be alerted when there is concern for g. bethesdensis infection to allow for proper culture media. charcoal yeast extract (cye) agar and lowenstein jensen (lj) media are appropriate culture media. mycoplasma and ureaplasma spp. as molecular techniques are becoming more widely used to detect pathogens, the spectrum of infections that were previously only detected through serologic assays and research laboratories will increase. this is important especially for patients with pidd who have unique susceptibility to infection and may not have the ability to mount a serologic response. examples of infections in this group are those caused by mycoplasma and ureaplasma [ , ] . these pathogens have been known to cause osteoarticular infections for those with antibody deficiency, such as xla and cvid. recently, mycoplasma orale, typically an oral commensal, has been isolated from two patients with defects in the activated pi k delta syndrome, as chronic lymphadenitis in one and chronic splenic abscess in the other (sm holland personal communication). defects in pi kcd and pi kr are frequently associated with hypogammaglobulinemia and therefore would fit in the pattern of mycoplasma infections in those with humoral immunodeficiency. mycoplasma orale has also previously been reported as causing bone disease in a patient with cvid [ ] . in patients with xla, helicobacter, camplyobacter, and the related flexispira bacteria that are typically isolated to the gi tract can disseminate and often lead to chronic bacteremia, ulcers, and bone infections [ ] [ ] [ ] . xla patients have higher susceptibility than other humoral pidd and are thought to be due to the role that igm is playing in controlling the dissemination of these pathogens and potentially iga in providing mucosal immunity. these bacteria can be fastidious to grow, and therefore, when there is suspicion, identification needs collaboration with the microbiology laboratory. for instance, the blood culture media may allow growth (although with a longer incubation period), but then the organisms may need molecular techniques for identification, such as s sequencing, as they will not grow on the agar plates. treatment is often difficult, requiring combination antimicrobials for prolonged periods (such as year), and relapse is common. this review provides an important perspective for practicing immunologists, namely that we are a part of a global community as are our patients. this overview of emerging infections and infectious concerns for travelers serves as a foundation for practical considerations for clinicians and patients. using prevalence data, an estimation of the number of infected patients with pidd (table ) can be developed [ , , [ ] [ ] [ ] [ ] . thus, the concerns addressed in this review are not theoretical but impact a considerable number of patients already. the landscape of emerging infections is by its nature highly dynamic. during the 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malignant transformation of hymenolepis nana in a human host granulibacter bethesdensis gen. nov., sp. nov., a distinctive pathogenic acetic acid bacterium in the family acetobacteraceae methylotroph infections and chronic granulomatous disease osteoarticular infectious complications in patients with primary immunodeficiencies increased susceptibility to mycoplasma infection in patients with hypogammaglobulinemia disseminated mycoplasma orale infection in a patient with common variable immunodeficiency syndrome relapsing campylobacter jejuni systemic infections in a child with x-linked agammaglobulinemia bacteremia and skin/bone infections in two patients with x-linked agammaglobulinemia caused by an unusual organism related to flexispira/helicobacter species successful approach to treatment of helicobacter bilis infection in x-linked agammaglobulinemia prevalence and morbidity of primary immunodeficiency diseases, united states epidemiological characteristics of spotted fever in israel over years complications of bacille calmette-guerin (bcg) vaccination and immunotherapy and their management acknowledgements the authors would like to thank thomas krell for information regarding ivig safety and david peden for recognizing global warming as central to medical knowledge. conflict of interest the authors declared that they have no conflict of interest. pidds display wide genetic and phenotypic heterogeneity [ ] . similar disease phenotypes may be caused by multiple genes, while patients' phenotypes caused by the same gene and even by the same mutations vary between individuals. importantly, after a novel pidd has been described, subsequent reports often reveal a wider variation in associated infections and cellular findings, often without clear genotype-phenotype correlations [ ] [ ] [ ] [ ] [ ] . variation may be caused by mechanisms such as other contributing genes or geographical variation in infectious exposures. geographic differences seem most pronounced in intracellular and often chronic infections. while the numbers of described pidd patients increase, at first seemingly rarely pidd-associated infections turn out to be found in a significant subset of pidd patients [ ] [ ] [ ] . for example, patients with cd l deficiency living in endemic areas display susceptibility to bartonellosis and paracoccidioidomycosis, infections not described in european and us cohorts [ , , ] .often, an infectious phenotype previously only described in secondary immunodeficiencies may reveal the possibility of an underlying primary immunodeficiency [ , , ] . increasing numbers of genetic defects causing early-onset, severe, and recurrent susceptibility to commonly circulating pathogens like pneumococci, tuberculosis, herpes simplex, and influenza viruses as well as endemic protozoans like trypanosomes and fungi are being recognized, and thus, infections with unusual pathogens require a high index of suspicion for pidd [ ] . in contrast, pidds may also manifest as suspected infection but sterile inflammation. for example, in inflammatory lesions like granulomas and necrotizing fasciitis where no clear pathogens are found, one needs to rule out aberrant host responses due to pidd [ ] .chronic viral and fungal infections may also display novel phenotypes never or rarely seen in secondary immunodefic i e n c i e s . i n f e c t i o n s l i k e d e r m a t o p h y t o s i s a n d phaeohyphomycosis deeply infiltrating the skin and lymph nodes, occasionally extending to bones and central nervous system (cns) as well as predisposition to primary cns candidiasis and extrapulmonary aspergillus slowly revealed the full phenotypic spectrum of card deficiency [ , , ] . chronic skin ulcers caused by hsv- and severe molluscum contagiosum suggest dock deficiency or gain-of-function mutations of stat [ , ] . chronic mucocutaneous candidiasis has revealed a large group of monogenic diseases (il ra, il rc, il f, stat (gof), rorx, act ), which may also be associated with recurrent bacterial infections or syndromic features [ ] . while novel diseases by newly described viruses are being discovered, one needs awareness to suspect these in pidd patients [ ] .interestingly, most novel forms of infectious disease in pidd patients have been described either in easily accessible sites like the skin or in immunologically privileged, normally sterile sites like the cns. this suggests that with the increasing use of invasive sampling and sensitive metagenomic approaches, we might find more novel infectious phenotypes. pathogens highly suggestive of certain pidds, like chronic enteroviral cns infections in xla patients are reviewed above. in hypomorphic mutations, cns seems to be especially vulnerable to chronically active and/or recurrent novel infectious bsmoldering^focal encephalitis lesions by pathogens key: cord- -trbge authors: gaubert, philippe title: fate of the mongooses and the genet (carnivora) in mediterranean europe: none native, all invasive? date: - - journal: problematic wildlife doi: . / - - - - _ sha: doc_id: cord_uid: trbge the mediterranean basin (mb), connected by cultural exchanges since prehistoric times, provides an outstanding framework to study species introductions, notably in mammals. carnivores are among the most successful mammalian invaders. as such, a number of middle-sized representatives (“mesocarnivores”) such as the domestic cat and mongooses have been pinpointed for their deleterious impact on the native fauna. in the mb, three species of mongooses (herpestidae) and one genet (viverridae) are or have recently been recorded and none of them has been considered native: the indian grey mongoose herpestes edwardsii, the small indian mongoose h. auropunctatus, the egyptian mongoose h. ichneumon, and the common genet genetta genetta. in order to clarify the history of introduction and status of the mongooses and genet in europe, i review various bodies of evidence including ( ) their natural history and relationships with humans in their native ranges, ( ) their history of introduction in europe, ( ) the enlightenments—and sometimes contradictions—brought by recent genetic analyses on their dispersal histories, and ( ) their range dynamics and ecological interactions with the european fauna. the species of herpestids and viverrids present in europe fall into three categories: ( ) introduced and spreading (g. genetta, h. auropunctatus), ( ) introduced and extinct (h. edwardsii), and ( ) natural disperser and spreading (h. ichneumon). in view of the reviewed evidence, there is weak support for a deleterious impact of the mongooses and genet on the european fauna (except possibly on the herpetofauna of small adriatic islands in the case of h. auropunctatus), notably in comparison with genuine invasive species such as the black rat and the domestic cat. rather than inefficient control programs such as those targeting h. ichneumon in portugal and h. auropunctatus in croatia, we suggest that a greater attention is focused on the restoration of large carnivores (the natural regulators of mesocarnivore populations), mesocarnivore communities and natural habitats, to contribute to a more sustainable way of “managing” the mongooses and genet in europe. introductions are considered as a component of the mediterranean bio-cultural heritage (gippoliti and amori ) . human-mediated introductions since the end of the würmian glaciations ( - kyr ago) have deeply impacted current patterns of biodiversity in the mb (vigne et al. ). these led to dramatic levels of endemic extinction, at the same time counterbalanced by the establishment of various allochthonous taxa (masseti ). the intensity of introductions signifi cantly increased from the fi rst millennium bc , following massive human migrations from eastern to western borders of the mediterranean sea that opened several dozens of potential routes to the humanmediated dispersal of species across the mb (ciolek ) . historical introductions had motives mostly related to agricultural practices (domestication, pest control) but also to more "esthetic" and political considerations, including entertainment, cultural exchanges and pet trade (hughes ; morales et al. ) . more recent introductions (twentieth to twenty-fi rst centuries) of mammals still originated from such motives (e.g., delibes ) . thus, the long history of introductions in the mb has resulted in serial faunal turnovers involving local extinctions of endemic fauna and serial establishments of introduced species, with new "invaders" regularly entering the native fauna (cuttelod et al. ) . assessing the impact of such introductions on the mediterranean fauna is politically and economically crucial, but has proven a diffi cult task that may deserve a "case-by-case" (i.e., taxonomically and/or geographically) approach . by focusing on a group of afro-asian small carnivores present in southern europe, we intend to provide an exhaustive reassessment of their status that shall clarify their ecological impact in the mb. carnivores are among the most successful mammalian invaders, with species such as the domestic cat ( felis silvestris catus ) and dog ( canis lupus familiaris ), the american mink ( neovison vison ), and the small indian mongoose ( herpestes auropunctatus ; see below) each established in more than countries or islands around the world (clout and russell ) . middle-sized representatives (" mesocarnivores ") such as those above-mentioned have been pinpointed for their deleterious impacts on the native communities of carnivores and their preys (bonesi and palazon ) , notably in the context of endemic fauna (medina et al. ). in the mb, mustelids (martens, weasels, badgers) seem to have been the earliest carnivores transported on islands (masseti ) . this pattern is congruent with the earliest molecular estimate of transportation of weasels ca. kya (lebarbenchon et al. ) . however, given their natural, circum-mediterranean distribution at the pleistocene period , it is unclear whether all the mustelids present on mediterranean islands were introduced or natural dispersers (masseti ) . a contrario , the establishment of another lineage of small carnivores including mongooses ( herpestidae ) and genets ( viverridae ) in europe has traditionally been considered as more recent. four species of herpestids and viverrids are or have recently been recorded from mediterranean europe and none of them has been considered native: the indian grey mongoose herpestes edwardsii , the small indian mongoose h. auropunctatus , the egyptian mongoose h. ichneumon , and the common genet genetta genetta (long ) . those species are medium-sized predators naturally distributed in the tropical and subtropical zones of the old world. they were supposedly introduced in europe at various historical times, from the middle age to the twentieth century. because such small carnivores actively predate on species that can have a deleterious role in agriculture (e.g., rodents) or be directly harmful to humans (e.g., snakes), and also because they are commensal and can be kept as pets, they were good candidates to be spread through mediterranean's trading and political networks. although the introductions of the indian grey and small indian mongooses in europe are quite well documented, the introduction history of the egyptian mongoose and the common genet has remained highly speculative. importantly, it is unclear whether those four carnivores have or had deleterious impacts on the native european fauna, and how their niches/ranges in the mb are characterized. despite such lack of empirical data, local control operations-notably targeting mongooses in portugal and croatia-have been attempted with various levels of "success" (hays and conant ; barun et al. ; beja et al. ). in order to clarify their history of introduction and their status within the european fauna , i will ( ) briefl y review the natural history of the afro-asian herpestids and viverrids present in the mb and their relationships with humans in their native ranges, ( ) review their history of introduction, and for the lesser known species the speculations that have surrounded the factors promoting their possible introduction in europe, ( ) detail the recent enlightenments-and sometimes contradictions-brought by genetic analyses (mostly phylogeography) as to the dispersal histories of those small carnivores, and ( ) summarize their range dynamics and ecological interactions with the european fauna. in view of the reviewed evidence, i will then conclude on the expected "invasiveness" of those species in europe and will eventually open a prospective on the strategies that could be adopted to improve our understanding of small carnivores' establishments in the mb. the indian grey mongoose occurs in the indian subcontinent and at the eastern fringe of the middle east ( fig. . ). it seems preferentially commensal with humans as it is often recorded near human settlements in central india where it frequently scavenges on carrion. the species is most common in disturbed areas, in dry secondary forests and thorn forests. it is generally diurnal, goes solitary or by mating pair and mainly feeds on small mammals, insects and reptiles (santiapillai et al. ; choudhury et al. ) . litter size is - and there are - litters a year (gilchrist et al. ). the small indian mongoose ranges from the eastern fringe of the middle east to the indian subcontinent and southern china (veron et al. ; gilchrist et al. ) (fig. . ). the species is found in a variety of open habitats and tolerates a large degree of habitat conversion (notably in its introduced range). it seems quite resistant to persecution and is still recorded from intensely hunted and cultivated areas (wozencraft et al. ). it goes solitary or by pair and feeds during both day and night on a wide range of items including arthropods, small mammals, birds, reptiles, frogs and crustaceans. mean litter size is (range = - ) and there are - litters a year (gilchrist et al. ). because they are natural predators of snakes , mongooses can be very popular animals in asia, in contrast with them being viewed as pests in most parts of their introduced ranges. it is, in fact, mainly for this reason (snake killing, but also rodentkilling) that asian mongooses have been introduced in various parts of the world (hays and conant ) . archaeological evidence from harappan sites (western indian subcontinent; fourth to fi rst millennia bc ) supports the idea that mongooses frequented human habitations, possibly as semidomesticated animals (lodrick ) . the " brahmin and the mongoose " is a famous folktale from india that is another token of the good consideration that the mongoose benefi ts there. it describes the impulsive killing of a loyal mongoose that had protected a baby from snakes, and thus is a warning against hasty actions (emeneau ) . in india, the mongoose is also associated to opulence and generally represents the god of wealth in the buddhist iconography (lodrick ) . small indian mongooses were possibly introduced during the second or fi rst millennium bc in eastern arabia and bahrain (uerpmann ) and were found buried in the temple of saar (dobney and jaques ) where they were probably linked to religious rituals. as of today, the small indian and the indian grey mongooses are frequently captured and sold as pets, notably in india and nepal. in central india, people consider the two species of mongooses to be sacred (wozencraft et al. ; choudhury et al. ) . another use is made by the jogi tribes in pakistan, whom capture the small indian mongoose for stage fi ghts with cobras (gilchrist et al. ). the egyptian mongoose is widely distributed in northern and sub-saharan africa and the coastal near east, avoiding deserts, high rainfall forest areas and the southern african steppe ( fig. . ) . it primarily occurs in habitats having dense understory vegetation, but is also frequent in cultivated zones. the species is generally solitary, although pairs and families of - individuals can be observed. it is mostly diurnal and has an opportunistic, omnivorous diet including small mammals, birds, small red arrows indicate introductions on several adriatic islands arthropods, amphibians, reptiles, fi sh, gastropods, carrion, fungi, fruit and other plant material. mean litter size is estimated to be . (range = - ), and there is usually a single litter per year (palomares ) . ichneumon is derived from the ancient greek for "tracker," possibly originating from the mongoose's supposed ability to track crocodile dens and feed on their eggs. in addition to this ancient belief related to the sacred crocodiles, its capacity of preying on snakes made the egyptian mongoose played an important part in the bestiary of the pharaonic egypt. representations of the species can be found on the walls of tombs and temples in thebes and saqqara as early as the period of the old kingdom ( - bc ). the egyptian mongoose was associated to several deities including atum, re and horus. it was also sacred to mafdet, the goddess providing protection from snakebite, and mummifi ed egyptian mongooses were discovered inside bronze statues of the lion-headed goddess uto. a legend relates the defeat of the thunder snake apophis by the mongoose as the surrogate of the god letopolis, refl ecting again the representation of the species as a benefi cial snakekiller. in ancient egypt and later in the arabic culture (as late as nineth century ad ), the egyptian mongoose was believed to alter its size between day and night, becoming very small at night (as a shrew or a mouse) and being able to kill snakes by suddenly increasing its size if captured (stuart ) . depictions of mongooses hold by their tail or on a leash suggest that the species was tamed in ancient egypt, possibly as a household pet, biocontrol agent, or hunting animal. egyptian mongooses were kept in temples as votive offerings until the greco-roman times. however, they seem not to have been domesticated or bred in captivity (osborn and osbornova ) . the status of the species is said to have moved from benefi cial to pest once the domestic fowl, on which it can prey, was introduced in egypt (osborn and osbornova ). more likely, the arising of the domestic cat as the preferred household pet and biocontrol agent against rodents all around the mb together with the spread of monotheist religions should have brought forward the discredit on the egyptian mongoose. there is, to date, no concrete evidence for the domestication or taming of h. ichneumon by post-roman north african cultures, although the discovery of a tibia from punic sardinia ca. fi fth to fourth century bc shows that episodic, historical translocations of the species might have occurred as early as the carthaginian period (campanella and wilkens ) . the common genet has a wide distribution in northern and sub-saharan africa and is also present in southern peninsular arabia ( fig. . ) . it avoids deserts, rainforests, dense woodlands and woodland-moist savannah mosaics, and is mostly found in open savannahs, oak forests and bushy areas with woody or rocky shelters. the species has a predisposition to live in the vicinity of human settlements . it is solitary and nocturnal, and is a generalist feeder consuming small mammals, arthropods, birds, eggs, reptiles, amphibians, fi sh, fruits, mushrooms and garbage. mean litter size is - . (range = - ), and there seems to be a single litter per year (delibes and gaubert ) . remains of common genets associated to hunting sites were found in the late pleistocene of northern africa (ouchaou and amani ) . although possible associations between common genets and humans have been the subject of numerous speculations, the archaeological and historical evidence is scarce. the species was pictured in swamp scenes climbing papyrus stems -often in association with the egyptian mongoose-on the walls of tombs and temples of ancient egypt (ca. - bc ). the common genet was seldom represented in later periods (i.e., the xviiith dynasty: - bc ). no mummies of the species have ever the upper left inset shows the potential range of the species (in red ) in southwestern europe (gaubert et al. ; delibes and gaubert ) : , portugal; , spain, , france; , ibiza isl.; , mallorca + cabrera isl been found in egypt. the assertions of a large number of authors as to the use of the species as a tamed " pre-cat " in egypt and later in northern africa are not based on any concrete evidence (see osborn and osbornova ) . there has been some confusion around which species of mongooses were introduced worldwide. the supposed introductions of the indian grey and the egyptian mongooses in various parts of the world (malaysia, japan, mauritius, antilles isl., madagascar) are most probably confusions with other (asian) mongooses, including h. auropunctatus (gilchrist et al. ; choudhury et al. ) . the history of introduction of the small indian mongoose in italy is relatively well documented. probably in , the owner of a hotel in san felice circeo (central italy) released a few mongooses-acquired from the giardino zoologico di roma-in her park with the aim of removing adders. those animals escaped during the second half of the s, and a population established into nearby areas of the circeo national park . at the end of the s, mongooses reached their maximum range, which covered ca. km from the whole circeo promontory to most of the protected area south of molella bay (carpaneto ; angelici ) . the collection of a specimen of h. edwardsii from capalbio (tuscany), ca. km northward of circeo, shows that at least two events of introduction occurred in italy at ca. years of interval, probably from the same captive stock. the reasons for this second introduction remain unknown. however, a letter from written by the director of the capalbio hunting estate quoted a negative advice provided by the laboratorio di zoologia applicata alla caccia (future istituto superiore per la protezione e la ricerca ambientale) about the introduction of mongooses to control populations of adders, reinforcing the idea that using these animals to control venomous snakes was rather widespread at that time. the indian grey mongoose is now considered extinct in italy (angelici ) , a unique fate among the herpestids and viverrids introduced in europe (see below). the small indian mongoose is considered as one of the world's worst invasive species. it was introduced to many islands in the pacifi c and indian oceans and the caribbean sea, mostly in the late nineteenth and early twentieth centuries, to control rats and poisonous snakes in sugar cane fi elds (lowe et al. ) . the introduction of h. auropunctatus in europe is well documented. seven males and four females purchased in india were released in on the island of mljet (current croatia), formerly known as the " island of snakes ." at that time, the austro-hungarian authorities had decided to introduce wild mongooses in order to exterminate the horned viper vipera ammodytes from the island. given the rapid decrease in the number of snakes and the growing numbers of mongooses on mljet isl., the species was soon introduced on nearby islands (korcula, peljesac, brac) between and . afterwards, several attempts of introduction-with various levels of success-were planned onto a series of adriatic islands but also in the mainland of former yugoslavia (currently bosnia-herzegovina and macedonia) until the s (tvrtkovic and krystufek ; krystufek and tvrtkovic ) . interestingly, the historical record kept track of a transportation of ca. mongooses from mljet isl. to venezuela around , thus suggesting that part of the small indian mongooses introduced in the caribbean isl. originated from europe (tresic pavicic ) . conversely, the scenario of introduction of the egyptian mongoose in europe is highly speculative. the absence of paleontological records in southwestern iberiathe european range of the species-and the existence of archaeological remains dated from the arab occupation led some authors to postulate an introduction of the egyptian mongoose associated to migrant berber farmers between the eighth and thirteenth centuries ad (riquelme-cantal et al. ; detry et al. ). however, this scenario is somewhat contradicted by the discovery of an egyptian mongoose remain in a carthaginian site from the fi fth to fourth centuries bc in sardinia (campanella and wilkens ) , evidencing the historical transportation of the species by an earlier civilization. besides, it has long been said that there is no evidence for the domestication or taming of h. ichneumon by north african people during historical times (geoffroy saint-hilaire ). as a matter of fact, traces of manipulation or taming as could be the case with tooth abrasion, presence of associated artifacts or intentional disposal practices, have never been observed on any of the archaeological remains found in europe. the scenario of introduction of the common genet in southwestern europe (the species is present from southern iberia to southwestern france and in several balearic islands) is highly speculative and calls to earlier periods than the arab conquest. the greek historian herodotus (fi fth century bc ) mentioned a " weasel from tartessos " (southwestern iberia) similar to the one found in libya, which has been identifi ed as a common genet (amigues ) . this led authors to suggest an early introduction of the species through the political network between the greek colonies and the kingdom of tartessos. according to posidonius (fi rst century bc ), this "weasel" was used in southern iberia as a bio-control agent against rabbit proliferation (amigues ) . the common genet was also mentioned in a faunistic list from the gallic site of ambrussum (southern france) as associated with domestic furniture from the third century bc (columeau ) . however, the remains of the animal have been lost. despite such possibilities for anterior introductions, the common genet has traditionally been associated to the arab conquerors of europe. a legend relates that after the defeat of moor armies near poitiers, france ( ad ), the king's majordomo charles martel found in the loot of the defeated armies such a great quantity of furs-but also living animals-belonging to the common genet that he decided to create the "ordre de la genette" (favyn ) . although this order of chivalry is a total myth, this narrative long stood as the main evidence supporting the introduction of the species through arab invasions. such hypothesis was further supported by the fact that there is no fossil record of the species in europe and the only known archaeological remain dates back to the almohads-an arab dynasty-in portugal, at the thirteenth century ad (morales ) . the material representing the extinct indian grey mongooses in italy is very scarce. only four specimens are known to be preserved in collections: three fl at skins from the early s are kept at the ispra museum (ozzano dell'emilia, italy) and one mounted specimen from the s is exhibited at the museum visitors' centre of sabaudia at circeo np (angelici ) . those represent the two distinct sites where the species was introduced, including circeo np and capalbio (tuscany), ca. km north of the former. to date, a single genetic analysis based on mitochondrial dna (mtdna) and including the four remaining specimens of the mongooses introduced in italy has been conducted. it clearly confi rmed the indian grey mongoose as the species having been introduced in italy during the twentieth century and traced the introduced pool's origin to pakistan or india, which is the core distribution of the species in its native range. the mtdna diversity of italian mongooses was null, thus suggesting a very limited number of founders (gaubert and zenatello ) . it is likely that the low number of preserved italian individuals will significantly limit the contribution of future genetic studies on the assessment of the species' introduction in europe. the introduction history of the small indian mongoose has been assessed in more details. genetics-and notably, rapidly evolving markers such as microsatelliteshas shown its utility in tracing the introductions of the small indian mongoose worldwide and allowed to discover new paths of transportations (thulin et al. ; watari et al. ). it has also provided insights into the demographic characteristics of introduced populations and potential admixture with h. edwardsii in the species' native range that may be used to better delineate the dynamics of the introduced populations (thulin et al. ) . despite this, no detailed genetic study has so far been conducted on the small indian mongooses introduced in europe. to date, only a study on the systematic status of the small indian mongoose and the javan mongoose h. javanicus confi rmed that the former was the species introduced in croatia ( veron et al. ). thus, further genetic investigations will have to be undertaken to characterize in detail the introduction patterns of the small indian mongoose in the balkans. the dispersal history of the egyptian mongoose has been assessed by a mitochondrial analysis based on ca. samples from africa, the middle east and europe (gaubert et al. ) . the results of this study radically contradicted the established idea that the egyptian mongoose was introduced in europe. instead, gaubert et al. ( ) proposed a natural crossing of the mediterranean sea by h. ichneumon via the strait of gibraltar during the middle pleistocene, long before the earliest (paleolithic) human exchanges between north africa and europe. the strong genetic differentiation between european and north african haplogroups, the signifi cant level of genetic diversity found in europe, and the important phenotypic differences between european and north african mongooses all pointed to a scenario of long-term in situ evolution of european populations. these molecular results supported the hypothesis that natural dispersal across the strait of gibraltar was possible for nonfl ying vertebrates during the pleistocene cyclical lowering of sea levels. the swimming abilities of the egyptian mongoose make plausible a sweepstake migration using a partially emerged shoal such as the archipelago of cape spartel (where the mythic city of atlantis was possibly located) that is now to m below sea level (collina-girard ) . the long-term stability of mongooses' effective population size in europe was supported by various genetic indices and the remarkable correspondence between the limits of the proposed ice age refugium in southwestern iberia (hewitt ) and the distribution of suitable ecological conditions for the species (specifi cally, low rainfall and warm temperatures; borralho et al. ) . niche modelling approaches have since supplied independent evidence for the long-term stability (climatic niche conservatism) of the egyptian mongoose in southwestern iberia (papeş et al. ) . the introduction scenario of the common genet in europe has been assessed by the genetic analysis of ca. individuals from the native and introduced species' ranges, using mtdna gaubert et al. ) and more recently, microsatellite markers . the combined evidence supported multiple introductions from north africa into europe, including the balearic isl. (with three distinct introduction events on ibiza, mallorca and later cabrera), southwestern iberia (corresponding to the tartessian kingdom's zone of infl uence), and possibly northeastern spain and southwestern france (secondary introduction from iberia for the latter). those studies suggest that the common genet was intentionally introduced in southern iberia at a time (< bc) antedating the arab invasion, possibly via phoenicians' commercial routes. subsequent introduction in france, longterm genetic drift, and admixture between the iberian and french pools likely shaped the species' genetic variation currently observed in continental europe. the mtdna-based demographic scenario of multiple, historical introductions of common genets in europe followed by sudden population expansion is characteristic of populations at disequilibrium gaubert et al. ) . such scenario was supported by niche modelling analysis through the detection of a climatic niche shift in the northern european range of the species (papeş et al. ) . altogether, these results suggest that an exceptional combination of factors including multiple introductions, local admixture, and ecological adaptation promoted the successful spread of the common genet in continental europe. the number of indian grey mongooses in italy abruptly decreased from the early s, and the species was considered extinct by . a survey conducted in summer failed to recover any evidence for the presence of the mongoose (biondi ) . although poorly documented, it is probable that the extinction process of h. edwardsii in italy might have taken place quickly after the species reached its maximum range between and (carpaneto ) , possibly due to harsh winters. mongooses were seen wandering in villages close to the circeo promontory, apparently searching for food and shelter . the species showed a tame, diurnal behavior, consuming tourists' leftovers and accepting direct feeding from humans. its sudden extinction in italy fi ts with crashes observed in populations with very restricted ranges within the years following their time of introduction (duncan and forsyth ) . because the mitochondrial diversity among italian individuals was null, it is reasonable to conclude that a combination of deleterious factors including low genetic diversity, restricted range, and non-adaptation to western palearctic winter conditions was likely responsible for the extinction of the species in italy (gaubert and zenatello ) . documentation of interspecifi c competition with native carnivores is scarce, although a dominance of the indian grey mongoose over polecats mustela putorius was suggested during the years of mongooses' maximal expansion. during the brief establishment of the indian grey mongoose in circeo np, no impact on the density of black rats rattus rattus was observed (carpaneto ). the small indian mongoose successfully established and spread in europe, with the notable exception of the island of brac where it went extinct for unknown reasons. the two introduction sites on the continent (peljesac peninsula, bosnia-herzegovina and mostar, macedonia) are supposed to be the sources of the populations having spread ca. km southwards into montenegro. at present, the european range of the species includes the thick mediterranean vegetation of the adriatic coast, from skrda isl. and the neretva river in the north to albania in the south (barun et al. ; Ćirović et al. ) . given the favorable (higher) mean annual temperatures in southern europe, the further spread of the species' range should be expected towards southern albania and greece (Ćirović et al. ). on european islands, the small indian mongoose can show drastic annual fl uctuations of population densities . because the species' range in europe is characterized by temperatures well below its previously known isothermal limit ( °c), episodic cold winters could be the cause of such large density fl uctuations (tvrtkovic and krystufek ). in comparison with h. edwardsii , the small indian mongoose shows a series of characteristics that may promote invasive success: ( ) effi cient physiological mechanisms for dealing with hot and moderately cold environments; ( ) aggressive behavior against direct competitors/predators such as domestic cats; and ( ) wide range of deleterious pathogens, including rabies (gaubert and zenatello ) . the success of the small indian mongoose as a biocontrol agent is questionable because the species is a generalist predator preying on other species than rodents and snakes (hinton and dunn ) . reductions or extinctions of populations of birds, reptiles, and amphibians caused by h. auropunctatus have been reported on islands worldwide, although there is controversy over whether the small indian mongoose has genuinely been the main culprit (lewis et al. ; hays and conant ) . a secondary aspect of the deleterious impact of the species resides in its role of main reservoir for viruses (e.g., rabies) and parasites (e.g., weil's disease) impacting wildlife and humans in several parts of the caribbean (hatcher et al. ; everard and everard ) . this latter point remains undocumented in europe. in croatia , the species is accused of having a deleterious impact on wild fowl, poultry and several cultivars, and so is subject to extermination campaigns led by hunting federations (tvrtkovic and krystufek ) . it has also been speculated that the species could have " catastrophic consequences " on the balkan continental herpetofauna (Ćirović et al. ). however, a study conducted on korcula isl. evidenced a low consumption of reptiles and amphibians by the small indian mongoose, and in comparison a high consumption of small mammals, birds, arthropods and plants (cavallini and serafi ni ) . the minor representation of the herpetofauna in the mongoose's diet is actually a general trend throughout its introduced range ( table in hays and conant ) . on the other hand, it was observed that reptiles and amphibians were generally rare or absent from the islands occupied by the species whereas they were common on the mongoose-free island of brac (barun et al. ) . unfortunately, predation of the native herpetofauna by other invasive species such as the black rat and the domestic cat has not been evaluated. the egyptian mongoose must have occurred in the papyrus swamps of the nile valley at the time of ancient egypt. the reasons for its extinction are unknown, but were probably linked to its artifi cial maintenance as a semi-domestic animal or to the progressive disappearance of such habitat (osborn and osbornova ) . in europe, suitability models predicted the expansion of the species in southern and central spain in areas with a high rabbit abundance, thus foreseeing the existence of large regions of potential confl ict with hunting interests (recio and virgos ) . climatic niche modelling outputs were less conservative and predicted most of the iberian peninsula as potentially suitable for the egyptian mongoose (papeş et al. ) . because there is no signifi cant change in the composition of the carnivore community at the northern fringe of the european range of the species (wilson & mittermeier, ) , interspecifi c competition cannot be considered a limiting factor. in addition, release from biotic/historical constraints, including h abitat disruption and climate warming , could lead to local or temporary range expansion of the egyptian mongoose, as refl ected by its recent spread into northern portugal related to rural depopulation (barros ). whether this current trend can be assimilated to a colonization front and whether the recent records of the species in northwestern spain (balmori and carbonell ) refl ect a genuine increase of northern dispersals will have to be evaluated. in northwestern portugal, mongooses prey mostly upon mammals (especially lagomorphs) but also on reptiles and arthropods, with males preferentially consuming mammals ). in case of competition with other carnivores, the egyptian mongoose may modify its realized niche by having more diurnal activities (santos et al. ) and can shift its microhabitat use (e.g., by preferentially using thicker scrubland) to prevent deadly encounters with dominant species such as the iberian lynx lynx pardinus (viota et al. ) . so far, the role of h. ichneumon in carrying zoonotic diseases seems very limited. in europe, rabies spillover infection from red foxes ( vulpes vulpes ) was not detected (müller et al. ) . in portugal, a high prevalence of parvovirus dna was detected in mongooses ( %), potentially carrying a risk to susceptible populations at the wildlife-domestic interface and to threatened species of sympatric carnivores (duarte et al. ) . the common genet was probably present in the papyrus swamps of the nile valley further north from its current range, as suggested by remains found in the south galala plateau cave, egypt, and illustrations on papyrus and in stone reliefs from the nile valley (osborn and osbornova ) . the reasons for its extinction are unknown, but were probably similar to those of the egyptian mongoose (i.e. artifi cial maintenance by humans or progressive disappearance of the habitat). in europe, the species has recently crossed its traditional range barriers of the rhône (southeastern france) and loire (northwestern france) rivers (gaubert et al. ; léger and ruette ) . climatic niche modelling predicted a large portion of europe as suitable for the species, italy being the best candidate for a near future colonization via the liguria-southern piedmont corridor (papeş et al. ) . the common genet is an opportunistic carnivore that may expand its trophic niche on the mediterranean islands (ibiza and cabrera) where it is the sole mesopredator (virgós et al. ) . conversely, marked trophic differentiation occurs on another island (mallorca) where the species coexists with the pine marten martes martes (clevenger ) . in continental europe, niche overlap among the common genet, the egyptian mongoose, and other carnivores is generally high, but subtle and dynamic (i.e., seasonal) adjustments in foraging behavior and in the use of microhabitats and main prey items seem to balance the coexistence of such small carnivores' communities (zabala et al. ; lopez-martin ; carvalho and gomes ; melero et al. ; santos-reis et al. ; monterroso et al. ; zapata et al. ). the common genet eats signifi cantly more fruits than the egyptian mongoose and shows little overlap (in terms of fruit diversity) with the other mediterranean carnivores . interestingly, the invasive american mink seems to have a deleterious impact on the abundance of the common genet in northeastern spain because of high niche overlap (melero et al. ) . similarly to the egyptian mongoose, the common genet avoids suitable habitats where densities of iberian lynxes are high, suggesting a " mesopredator release " when larger carnivores competing for food and interspecies-killing disappear (palomares and caro ) . the role of g. genetta in carrying zoonotic diseases is unproven. asian viverrids such as the masked palm civet paguma larvata were identifi ed as the source of sars cases with mild symptom in in china (shi and hu ) , but so far, no similar coronaviruses were detected in the common genet. on the other hand, in portugal and southwestern france, the species suffers from a high prevalence of a host-adapted canine parvovirus ). the species of herpestids and viverrids present in europe fall into three categories: ( ) introduced and spreading ( g. genetta , h. auropunctatus ), ( ) introduced and extinct ( h. edwardsii ), and ( ) natural disperser and spreading ( h. ichneumon ). usually, species introduced within the last century are considered deleterious ("invasive") by nature , whereas species having naturally dispersed or introduced during historical times (i.e., before ad ) have been considered as "naturalized." thus, in our case, only the introduction of the small indian mongoose in the balkans has been envisaged in an invasive framework. from the above-mentioned amount of evidence, there is weak support for a deleterious impact of herpestids and viverrids on the european fauna (except possibly on the herpetofauna of small mediterranean islands in the case of the small indian mongoose), notably in comparison with genuine invasive species such as the black rat and the domestic cat. in fact, the small indian mongoose is only th on the list of alien species affecting native species in europe, far behind the american mink, the domestic cat, the domestic goat, the european hedgehog erinaceus europaeus , and rats (genovesi et al. ) . coexistence among native european carnivores seems to occur through a dynamic adjustment of their niches, and there is no body of evidence to refute the fact that the mongooses and genet have fi tted this framework without disrupting the equilibrium of carnivores' communities. my conclusions should have some impact on the way mongooses and genets are considered and managed in european countries. indeed, the episodic, local control operations of those carnivores-notably of mongooses in portugal and croatiahave been shown to be expensive, ineffi cient, and/or potentially deleterious for the rest of the carnivores' communities, while favoring the pullulating of the species on which they prey (e.g., rabbits) (hays and conant ; barun et al. ; beja et al. ). eradication successes of mongooses seem somehow limited to small islands up to . km (barun et al. ) , whereas extirpation from larger islands or areas might require enormous means not affordable by most governments (see abe et al. ; fukasawa et al. for an example on another species of mongoose in japan). predator control is a contentious issue that is becoming under the scrutiny of the general public, with sectors of the society expressing ethical and biological arguments against the killing of predators (barun et al. ) . instead, we suggest that the attention of governments should be focused on restoration programs including ( ) large carnivores that are natural regulators of mesocarnivore populations (palomares and caro ) , ( ) small carnivores' communities, and ( ) their natural habitats, which all may be a safe buffer to the deleterious impacts potentially related to introduced small carnivores ( letnic et al. ; mcdonald et al. ) . we urge ecologists to conduct long-term surveys on the population dynamics and trophic overlap of the small indian mongoose with sympatric carnivores and invasive species in europe, in order to provide scientifi cally based guidelines on the attitude to adopt for the management of the species (notably on adriatic islands). future studies should also be directed on the benefi cial aspects of herpestids and viverrids on european ecosystems, including their role as seed dispersers and as regulators of potential pest species such as native and invasive rodents and insects. the potential colonization fronts of the mongooses and genet in europe provide a tremendous framework for studying the dynamics of mesopredators at disequilibrium with their environment. yet, there is a crucial need for comparative studies in areas such as northwestern iberia ( h. ichneumon ), northwestern and southeastern france ( g. genetta ), and the balkans ( h. auropunctatus ) to better understand the processes behind the spread of herpestids and viverrids in europe. eventually, a global perspective on the natural history of those small carnivores in their native ranges (including reproduction strategies, interspecifi c competition with other carnivores, and zoonotic prevalence) would help understanding their successful establishment-or not ( h. edwardsii )-in europe, but is still lacking. reproductive responses of the mongoose ( herpestes javanicus ), to control operations on herpestes edwardsii expansion and distribution of the egyptian mongoose ( herpestes ichneumon ) 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-cwhmm f authors: nan title: challenges to the european exception: what can s&t do? date: journal: a new deal for an effective european research policy doi: . / - - - - _ sha: doc_id: cord_uid: cwhmm f nan a quick review of the available evidence shows, however, that, while great strides have been made over the past few decades towards the achievement of these goals, europe is facing significant challenges in most if not all of these areas. economic growth is slow. europe's competitive position is feeble. there are not enough jobs, and not enough of them are high-level. europe is still characterised by significant poverty and regional inequality. an important demographic challenge is emerging. europeans' health is affected by serious lifestyle and contagious diseases. and the environment is being degraded. this is undermining what europeans are most proud of and turning europe into a negative exception at global level. the term "european exception" is most often used to refer to a european country not acting in accordance with what most other european countries are doing, whatever the field. sometimes, however, the vocabulary is also used to refer to how europe behaves differently from other advanced world economies. usually, reference to the european exception has a positive tone to it. europeans are proud of their commonly held values, their social model based on egalitarianism and solidarity, their high level of environmental awareness and protection and so on. however, europe appears to be the only advanced economy suffering from chronic low growth and high unemployment, and an unceasing lack of dynamism. its levels of poverty and of individual and regional income inequality are not that far removed from us levels. and this makes europeans feel anxious, and unsure of themselves, their future and further european integration. significant change has characterised the world economy over the past few decades. world trade has been liberalised as both formal and informal trade barriers have been reduced significantly, or disappeared altogether. capital roams the planet freely in search of the best investment opportunities as barriers to capital mobility have been eliminated. global communication and transportation networks have become denser and better integrated through a combination of technological and organisational innovation. the speed of technological change has accelerated while technologies are standardised more rapidly and use is made of modular production systems. as the combination of these factors has made it possible to locate the production of goods and services anywhere on the planet and still serve global markets, the global production system is in the process of being reconfigured. the new international division of labour not only provides both developing and developed countries with ample opportunities, it also has shady sides. on the one hand, low-, medium-and to an increasing extent high-technology manufacturing and services industries are under threat from delocalisation or so-called off-shoring and outsourcing, resulting in at least short-term disruption and unemployment. employment is also under threat from rapid process innovation leading to productivity increases. on the other hand, rapid product innovation provides developed countries with opportunities to improve competitiveness and serve global markets by fleeing forward as it were. the race to upgrade the economy is never-ending, however, and innovation-based advantages are fleeting and unsustainable as rapid standardisation and modular production techniques quickly allow the production process to move partially or completely to developing countries. as reflected in its lacklustre economic growth performance, europe has not yet adapted to the rules of this new game. in the first half of the post-war period, the european economy grew as fast as the world economy ( fig. . ) . in the second half of the post-war period, however, the decline in economic growth was more pronounced in europe than in the united states, japan and other oecd economies (figs . and . ) . in the last years or so, europe has done worse than the united states, while japan has once again started to outperform europe, and the large bric (brazil, russia, india, china) economies and smaller east asian economies continue to grow rapidly. the growth of output amounted to . per cent in the euro area in , substantially lower than the . per cent in the united states and the . per cent in japan, and the . per cent at world level. output is projected to grow by a higher . per cent in the euro area in , still economic growth in the euro area has been lagging that of the best performing oecd countries since the mid- s. it should be acknowledged, however, that some eu countries have performed rather well economically in the past decade. this group includes the member states formerly classified as cohesion countries (especially ireland), as well as finland, the netherlands and the uk. year cumulative growth gap fig. . . slow european economic growth in the second half of the post-war period compared to other industrialised countries (cumulative economic growth gap between the eu and the other industrialised countries (current prices and current ppps)) source: dg research data: oecd note: for both the eu- and the non-eu- oecd countries, gdp at current prices and current ppps (billions of dollars) was taken as . for all following years, gdp growth in percentages relative to the amount was calculated. then the series for the non-eu oecd countries (australia, canada, iceland, japan, korea, mexico, new zealand, norway, switzerland, turkey, us) was set to and the difference with the series for the eu- calculated. significantly lower than the . per cent in the united states and the . per cent in japan, and the . per cent at world level. whenever europe has been able to increase productivity in the past it has suffered in the field of employment, and vice versa, pointing to the existence of structural barriers to growth. underlying europe's lacklustre economic growth performance is its weak competitive position. the most common definition of competitiveness refers to the overall capacity to improve standards of living in a sustainable way. states during the s and s. but since the s, european standards of living have not increased relative to the united states ( fig. . ) . labour productivity is another common measure of competitiveness. though, except for a few countries, the productivity gap was never closed in the end, for most of the post-war period the eu somehow caught up on average with the united states. this catch-up has now stopped and is even being reversed. since , for the first time in three decades, growth in us labour productivity has outstripped that of the union (fig. . ) . this eu productivity downturn is of a structural nature and mainly due to an outdated and inflexible industrial structure slow to adapt to the intensifying pressures of globalisation and rapid technological change. deindustrialisation is often taken as a further sign of europe's deteriorating competitiveness. the fear is that slow labour productivity growth, high labour costs, year gdp per capita (us= ) eu euro area fig. and short and inflexible working hours drive entire industries to low-cost, hightech countries in eastern europe and asia. the evidence for deindustrialisation is not clear-cut. some analyses point out that industry still accounts for the same important share of gross domestic product in terms of volume as in the past, while the declining share in terms of value added and employment is due simply to decreasing prices because of productivity gains and exposure to competition higher than that for services. should it occur, the impact of deindustrialisation would indeed be worrying: the existence of many services depends on the presence of industry; industry pays better wages than services, even for low-skilled jobs; industry accounts for most innovations and technological revolutions; and industry has an important strategic role. europe's feeble competitive position is also clear from its weak trade performance, especially that at the high-tech end. europe's most dynamic export products are generally not those one would closely associate with the knowledge-based economy. the top three products with the fastest growing market share are floor coverings, pork and poultry fat, and hemp. on the other hand, if one looks at products for which market share is in major decline (> per cent loss in market share), the eu has many more ( product groups) than the united states ( ) or japan ( ). what is more, in europe many technological products are among them (e.g. air launchers, turbines, insulating glazing, drugs containing alkaloids or hormones, telephones, photographic film). high-tech manufacturing exports represent a much smaller proportion of total manufacturing exports in europe than in the united states or japan (in , . per cent vs. . per cent and . per cent respectively). europe's share of global high-tech manufacturing exports, though increasing, is lower than that of the united states (in , . per cent vs. . per cent respectively). and europe runs a structural deficit in high-tech manufacturing trade, whereas the united states and japan run surpluses. the european employment input is significantly lower than that in the united states. first, though apparently catching-up, the european employment rate is still substantially lower than that of the united states ( fig. . ). in , the eu- employment rate was . per cent and the eu- one . per cent, so to percentage points below the target under the lisbon agenda, compared to . per cent in the united states. this is mainly due to the limited participation of women, the young, and the elderly in the labour force. at . per cent and . per cent, the female and older people's employment rates were about and percentage points below the lisbon targets for . second, europe also scores lower than the united states in terms of the number of hours worked annually per employee ( fig. . ). for a long time, the low employment rate and number of hours worked annually per employee were explained with reference to the european emphasis on work-life balance. a growing number of authors draw attention to the existence of disincentives to work, however, the main one being the lack of employment opportunities. this lack of employment opportunities is clear from the high unemployment rates. in , about . million europeans were out of work. this equalled . per cent of the labour force, some percentage points higher than the rates in the united states and japan ( fig. . ) . the proportion of high-level jobs is also considerably lower in europe than in the united states. though europe likes to pride itself on its superior social model, poverty rates are rather high, and regional inequality is substantial. in , the at-risk-of-poverty year eu- the gini coefficienta number between and used to express the degree of income inequality, where corresponds to perfect income equality and corresponds to perfect income inequality -was . in both the eu- and the eu- ( fig. . ) . the share of children living in households with income below the poverty line ranges from per cent in slovenia and per cent in denmark to per cent in slovakia. the eu is also marked by substantial inequality in income levels. in , gross domestic product (gdp) per capita was below per cent of the eu- average in out of nuts regions examined in the eu- . the highest eurostat. at the beginning of the s, eurostat set up the 'nomenclature of statistical territorial units' (nuts) as a single, coherent system for dividing up the european union's territory in order to produce regional statistics for the community. nuts subdivides each member state into a whole number of regions at nuts level. each of these is then subdivided into regions at nuts level , and these in turn into regions at nuts level . leaving aside regional gross domestic product per capita (inner london -united kingdom) was about times the lowest one (lubelskie -poland). enlargement, for the european union, is at one and the same time a challenge and an achievement, a "raison d'être" and a "façon d'être". it is a continuation of the historical process that started over years ago with the communities' inception, developed through several steps (in , , , , ) , and reached a high point -albeit not an end-point -with the enlargement of the european union to countries of eastern and southern europe on may . preparation for that enlargement took several years and by the time they joined, the eu- had successfully transformed their economies from centrally planned to functioning free market ones. compliance with the copenhagen criteria for accession served as a powerful catalyst for change. this assessment is detailed in a recent stock-taking exercise in which the commission services have provided strong evidence and analyses indicating that the enlargement constitutes an economic success for the "old" and the "new" member states alike. it has to be noted that enlargement has been a dynamic process rather than a discrete event and that its effects will become visible over time. figure . shows that convergence and catching up in real income have been at work throughout the period since the late s. per-capita incomes are now much closer to eu- levels than they were in , the year in which enlargement prospects crystallized in the commission's agenda . after the output collapse in the early years of transition, growth rates in the eu- have been higher than in the eu- , but also more volatile. the key contributors to actual and potential economic growth in the eu- have been capital accumulation and technical progress (the so-called total factor productivity, tfp), while the contribution of labour has been mostly negative (that being a reflection of weak employment growth and, to a lesser extent, of an ongoing decline in hours worked per employee). in general, and consistent with the convergence hypothesis, member states with lower initial ( ) per capita income tended to grow faster in the intervening years. birth rates continue to be low in europe. everywhere, the fertility rate is below the threshold needed to renew the population (around . children per woman), the local level (municipalities), the internal administrative structure of the member states is generally based on two of these three main regional levels. this existing national administrative structure may be, for example, at nuts and nuts levels (respectively the länder and kreise in germany, or at nuts and nuts (régions and départements in france, comunidades autónomas and provincias in spain). of aids deaths was estimated at . million. in europe, the number of newly reported hiv infections is increasing, while that of newly diagnosed aids cases is decreasing. in the eu countries with data available for and for both hiv infections and aids cases, the number of newly reported hiv infections increased by almost per cent (from to , ) while the number of newly diagnosed aids cases fell by over per cent (from to ). europe is also affected by other communicable diseases including sars and avian influenza. one of the most worrying challenges for europe, and indeed for the whole world, concerns the deterioration of the environment. european citizens overwhelmingly agree that the state of the environment influences their quality of life ( per cent), that policy-makers should consider the environment to be just as important as economic and social policies ( per cent), and that policy-makers should take into account environmental concerns when deciding policy in other areas such as the economy and employment. "a high level of protection and improvement of the quality of the environment" is a european community objective (see above). europe has been implementing environmental action plans and pursuing sustainable development strategies at both national and european level for quite some time now. it plays a leading role in the fight against global warming. and it occupies a strong position in the field of environmental technologies. yet, because of population growth; consumption patterns; market, policy and political failures; features of existing technologies; and world views and values, europe and the world at large are still far removed from a development trajectory that is truly sustainable, that is, which satisfies the current needs of society (growth, competitiveness, employment, etc.) without compromising the needs of future generations. european citizens worry most about water pollution (of seas, rivers, lakes, underground sources, etc.) ( per cent); man-made disasters (major oil spills, industrial accidents, etc.) ( per cent); climate change ( per cent); and air pollution ( per cent). the sixth environment action programme of the european community - ( th eap) identifies four priority areas for urgent action: ( ) climate change; ( ) nature and biodiversity; ( ) environment and health and quality of life; and ( ) resources and waste. the environmental objectives of the eu sustainable development strategy include: ( ) addressing climate change; ( ) better management of natural resources; and ( ) making transport more sustainable. a review of nine recent comprehensive analyses of global environmental problems (table . ) showed near-unanimous agreement that the three problems posing the greatest threats to the global environment and continuing economic development include: ( ) water quality and access; ( ) climate change; and ( ) loss of biodiversity. climate change forecasts indicate that, if the level of emissions is not curbed, the temperature level will rise and risks such as water shortage, malaria and hunger will increase and affect millions of people by ( fig. . ). addressing such environmental problems is highly complex. one of the premises of sustainable development is that environmental problems interact with each other, as well as with economic and social issues. climate change affects agriculture, forestry, water availability, marine systems, terrestrial ecosystems, health and, last but not least, the economy. forests and oceans act as climate regulators but also harbour a wide diversity of species. decisively tackling the issue of biodiversity will require i.a. making forestry sustainable, addressing pollution, and dealing with climate change. pollution negatively affects health, from allergies and infertility to cancer and premature death. in the mid- s damage costs to the eu caused by air pollution originated in the eu (see table . ) were calculated to be around per cent of eu gdp (ranging from . to . per cent) and damages to eu and non eu countries caused by air pollution originated within the eu were estimated to be . per cent of eu gdp (with ranges between . and . per cent), with health damages accounting for the largest share. an animal and human health problem like aviary flu also constitutes a threat to biodiversity. environmental degradation contributes to the increase recorded in the number of disasters and, in relation to this, to a heightened sense of vulnerability (see fig. . in the last section of this chapter). disasters can be man-made or natural and include wildland fires, earthquakes, volcanic eruptions, landslides/debris flows, floods, extreme weather, tropical cyclones, sea and lake ice, coastal hazards including tsunamis, pollution events, and so on. during the period - , disasters killed , people and caused billion dollars of damage. throughout history, the relation between science and society has been marked by both continuity and change. the continuity is situated in the tension between the c h a p t e r philosophical and intellectual pursuit of and search for knowledge on the one hand, and the desire of researchers and their supporters to make scientific knowledge useful and apply it on the other hand. this tension was first recognised by the ancient greek philosophers, and has been reflected in recurring calls from philosophers and scientists throughout history, including today, for more "research for its own sake". within the context of this tension, the change has been located in what has constituted or better what has been considered useful knowledge in each age, in other words in "the changing social expectation of science": "what counts as useful knowledge differed from patron to patron and society to society, so that cosimo de medici and the united states department of energy looked for quite different 'products' to be created by their clients, but both traded support for the potential of utility". from century to century, societal expectations of s&t have not just changed. they have also increased. in the era of the ancient greek philosophers, societal expectations of s&t were rather low. s&t was a highly controlled activity carried out by a small elite group of people for philosophical or religious objectives. at present, however, it is considered a powerful tool for political, economic, and social change. in between, s&t helped exploit worldwide resources as trade empires and colonies expanded ( th century); helped expanding and consolidating trade empires and colonies, and turn their natural resources into wealth, or make up for the lack of trade empires and colonies ( th century); helped fight wars (first world war and second world war); and helped producing consumer goods, consumer medicines, exploring space, addressing environmental challenges, exploring the human genome, and so on (post-war period). it is no exaggeration to say that as a result today societal expectations of s&t have never been higher in industrial countries. in the united states, the carnegie commission on science, technology, and government listed in no less than major societal goals to which s&t can contribute (table . ). and a national academies report noted in that "the nation increasingly looks to the scientific and engineering communities for solutions to some of its most intractable problems, from chronic disease to missile defence, to transportation woes, to energy security, to ensuring clean air and clean water. expectations for s&t are perhaps higher than at any other time in our history and are placing unprecedented demands on leadership". needs of society as they change over time, or in other words, to become a 'science and technology for society' ". things are no different in europe. in , the european commission remarked that "expectations of science and technology are getting higher and higher, and there are few problems facing european society where science and technology are not called upon, one way or another, to provide solutions". out of the challenges europe is facing, and recommendations have been made on how to address them. time and again the same wide range of urgently to be addressed challenges is identified. the reports are also near-unanimous in the key role assigned to s&t in this respect, as will be seen in chapter . in other words, great expectations are held of s&t as regards the tackling of the multitude of challenges europe is facing. this will be developed in chapter as part of the new policy context that enabled the genesis of the lisbon strategy as well as of the th framework programme. the role that s&t can play in addressing all these challenges is expected to be substantial. this section will show that s&t indeed has the potential to contribute to a range of economic, social and environmental challenges: it can improve economic performance, promote employment, improve public health, tackle demographic, cohesion and environmental challenges, and so on. modern mainstream economic theory -whether neoclassical, endogenous or evolutionary -has recognised for quite some time now that technological progress and innovation are the main engines of economic growth. according to baumol, innovation explains much of the extraordinary economic growth record under capitalism. the reason is that in important parts of the economy, competition is based on innovation rather than price. firms are therefore forced by market pressure to support innovative activity systematically and substantially. according to romer, productivity growth is driven by innovation resulting in the creation of new though not necessarily improved product varieties. and under the schumpeterian paradigm, growth results from "quality improving innovations that render old products obsolete, and hence involves the force that schumpeter called 'creative destruction' ". even basic research generates several direct economic benefits. it is a source of useful new information; it creates new instrumentation and methodologies. those engaged in basic research develop skills which yield economic benefits when individuals move from basic research carrying codified and tacit knowledge. through participation in basic research, access is granted to networks of experts and information. those there is also empirical support for the contribution of s&t to economic performance (see tables and sources in annex). estimates of private returns to firms' own investment in r&d still produce varying figures, but there is an emerging consensus that gross returns between and per cent are common and plausible (table . ) . microeconomic studies confirm the existence of significant spillovers of knowledge from the firms that perform the r&d to other firms and industries. taking account of measured spillovers typically raises the estimated gross rate of return on business investment into the range of to per cent (tables . - . ) . macroeconomic studies, which by definition cover all sectors of the economy, also find significantly higher returns to r&d in oecd countries, with estimates ranging from per cent to over per cent. a recent austrian report found that the rise of corporate spending on r&d from . per cent to . per cent of gross domestic product in the second half of the s produced a boost of three tenths of a per cent in growth. both microeconomic and macroeconomic studies find that an important source of productivity growth in all oecd countries comes from the international diffusion of technology. a country's ability to absorb those foreign technologies is enhanced by investment in education and by investment in own r&d. the economic literature is not conclusive on the employment effects of innovation, since process innovation (the introduction of labour-saving technologies) is likely to have a negative effect on employment, assuming all other factors remain constant, while product innovation creates new markets and employment opportunities. but empirical evidence suggests that technological change promotes employment. such evidence includes a recent study of the directorate-general employment which found that the rate of growth of total factor productivity (due to improvements in the efficiency of production or to pure technological progress) has a positive impact on the employment rate, with a one-year lag, and that both in the short-and long-term, countries with higher than average total factor productivity growth tend also to have higher than average growth in employment. clear evidence exists that more computerised or r&d-intensive industries increased their demand for college-educated workers at a faster rate in the s. such high-skilled workers also command higher wages, as the consensus is that the increase in the schooling wage premium and the rise in wage inequality are driven by technological change. support also comes from the observation that all member states saw employment levels in the high technology sector rise between and , leading to an increase of almost million for the union as a whole, with employment in high-tech services accounting for . million of this total (fig. . ) . through its contribution to product, process and service innovation, productivity growth, and the creation of more and higher paid jobs, research and innovation can also help meet the challenges of ageing and cohesion. higher employment rates and levels of productivity -to which s&t can contribute -would allow for maintaining or increasing living standards, and for the absorption of increasing medical and pension costs. doubling the growth of productivity over the next few decades would allow for maintaining current levels of industrial production and average per capita income with some million elderly in the eu. the best solution to poverty is investing in education. for instance, in general the lower the illiteracy rate, the higher per capita income. higher levels of educational attainment enhance the chance of finding work and enjoying a decent standard of living. however, education is not yet accessible for everyone and often only to those who can afford it. improving access to educations takes time and effort. education is, therefore, in its own right not powerful enough to solve the poverty problem. in the meantime, contributions to a solution to poverty can also be expected from science and technology. besides investing in education and developing skills, this means dedicating research programmes to find ways to fight inner-city poverty, to relieve the effects of urbanisation, to diminish the impacts of ever increasing mobility on our environment, and to improve the quality of life of the vulnerable groups in society, such as the handicapped and the ill, the elderly and the young. in developing countries this can take the form of helping to improve the productivity of natural and physical assets, for example, by protecting farmland against erosion and desertification, preserving an area's natural resources, building easy-tomaintain water storage facilities and de-salinisation installations, and strengthening farmers' diagnostic capabilities in relation to livestock diseases, to name a few. that these advances have important impacts on farmers' income levels has been repeatedly demonstrated by the different targeted activities across the framework programmes. science and technology can also make a large contribution to the improvement of public health. it can assist in prevention (e.g. through the development of vaccinations), it can play an important role in the quicker and more reliable diagnosis of diseases (e.g. through the further development of medical imaging), and it can find treatments for diseases or, in the absence of treatments, it can help finding ways to control them (e.g. hiv/aids retroviral drugs). s&t can also help to lessen the impact of disease. furthermore, s&t can help to find new ways to deliver treatment (e.g. ambulant rather than hospital treatment) and can provide better tools for health care system management. a good illustration of the way in which science and technology can make a positive contribution to public health is the article edctp initiative referred to in chapter . it is also useful to take a step back here. globalisation in this regards also means the globalisation of infection transmission. as travel of people (and goods) intensifies, communicable diseases constitute challenges which it is increasingly difficult to confine. interconnectedness is a defining feature of our modernity. as a case in point, healthcare systems are indeed organised as systems -which can lead to catastrophic failures such as the consequences of hiv-infected blood supplies that took a particular prominence in france but did in fact strike many countries. ours is a vulnerable society. while that vulnerability is most strikingly epitomized by ebola-type viruses, with diverse profiles of outbreaks, it is also revealed through world bank, world development report / . the international s&t cooperation with third countries (inco) is one of those programmes which have been developed around the idea that poverty can be overcome by successfully developing human and institutional resources. european and developing countries clinical trials partnership. the rise of nosocomial infections (i.e. ills originating in the very places which are devised to heal). these further illustrate the flipside -or paradoxical unanticipated consequences -of healthcare as interconnected systems. yet, while avian flu and sars together with the above examples represent the globalisation of infection transmission, they also point to the globalisation of the means to tackle public health challenges. the relative containment of avian flu and sars, and even more so the eradication of smallpox (the variola virus), constitute inspirational successes in that regard. there is no doubt that the solution to the environmental challenge has to come first and foremost from elsewhere than from new technological development. available technological best practices should first of all be disseminated as widely as possible. a change of mentality is also required leading to less consumption of more carefully selected resources and increased reuse and recycling within the limits of the current technological frontier. yet it does not seem unjustified to expect a contribution from new technological development. technology is already used in a variety of ways when it comes to the environment, and everywhere there is great scope for improvement. technology in the form of satellites is used to monitor the global environmental situation and change therein. technology in the form of super computers is used to develop climate models and make predictions. technological development has made industrial production less resource intensive. it has also reduced the energy consumption of machinery (e.g. cars). s&t has been successful at developing alternatives for harmful substances (e.g. within the context of fighting ozone depletion). technological development has increased the extent to which a larger variety of goods can be recycled. the production of green energy is wholly dependent on technological development. and s&t is needed to mitigate the impacts of environmental degradation. this need for a joint undertaking -combining existing technologies, technological innovations, as well as political innovations -is illustrated in fig. . in the case of climate change (the fight to curb greenhouse gas emissions, that is). as the next chapter will further examine, s&t is not only an indispensable source for the evidence base on challenges such as environmental degradation, they are also taken to be one of the causes of such predicaments. one can undoubtedly point to the lack of societal controls on the use of s&t, to environmentally harmful production and consumption patterns, and to other types of failures in this regard. nonetheless, the outlook can change fundamentally if one can conceive of s&t as part of the solution rather than the problem. the "precautionary principle" is a useful notion to mark that double perspective. it can first be taken as stifling innovation in the name of environmental protection; but more interestingly, it can be understood as promoting innovations that take account of social and environmental difficulties, taking account of risks as well as benefits, taking account of less tractable, longer-term consequences. its emphasiseven with its origin in german environmental legislation in the s -was as much on environmental protection as on gaining a competitive advantage through innovations on the backdrop of environmental regulation. indeed, although this remains a fiercely debated question, a recent survey of the literature indicates that a transparent and non-discriminatory regulatory framework, coupled with high environmental standards, is an engine for innovation and business opportunities. this engine functions notably through the creation of lead markets. the story of the catalytic converters provides a compelling example of such r&d-based win-win. a first step in that perspective consists in acknowledging the need to sever the link between economic growth and environmental degradation. the endeavour of a duly responsible polity -with a concern for the quality of life of present and future generations -is then to optimise the effects of its economic activity, that is to minimise adverse externalities without sacrificing part of its material well-being or endangering economic growth. a second step consists not in ignoring the above "limits to growth" understanding, but in researching other links between development and sustainability. this move is at the heart of the role of s&t in relation to the environment -and is indeed at the heart of the lisbon strategy as underscored in the conclusions of the göteborg summit. the potential of technology to create synergies between environmental protection and economic growth was emphasised by the october european council. that well-established premise is taken to its most fruitful operational conclusions in the environmental technologies action plan. more recently, the benefits of s&t for the economy and environment alike were further examined in the "towards a more sustainable eu" report for the dutch presidency and indeed in the kok report of november . in fact europe occupies a strong position in the field of environmental technologies. of course this also relates to the fragile but powerful synergies, introduced above, between environmental promotion/protection, s&t, and growth and competitiveness. these potential benefits can also be of great importance for developing countries. with appropriate technology transfer they can provide these countries with affordable solutions for reconciling their desire for strong economic growth with the need to do so without increasing the pressure on the local -or the globalenvironment. this north-south dimension highlights the sustainable development predicament as differentiated yet common. the question of sustainable development can be posed along two main lines: a question of adapting -or otherwise innovating -appropriate "clean" technologies, and a question of redefining needs and lifestyles. now it is interesting to re-consider the climate change issue in the light of the above remarks. the european union has taken a leading role in the international process to tackle global warming so as to promote environmentally responsible choices by all actors. the eu has ratified the kyoto protocol early on, joined by almost all of its international counterparts on this course -most recently russia. its successes are also the planet's successes. the eu is committed to meet its kyoto emissions reduction targets and continues to show leadership on this issue. the role of s&t is set to become even more central in the post-kyoto (post- ) regime, for which negotiations are starting now. the need for new and cleaner technologies as an indispensable means to tackle energy demands and co emissions was the main message of the latest yearly report of the more widely, s&t plays an important part in the eu's capacity to shape -and implement -international agreements. by way of conclusion, it is worthy of note that the answers which science and technology can bring to environmental problems are increasingly judged with reference to the changes they bring in society. they demand choices of policies and governance, the impact of which on economic and social groups must be measured in terms of effectiveness and efficiency, the spread of costs and benefits, and social or regional equity. this is only possible if research also seeks to develop the knowledge-base and methodologies needed by such analyses. the ultimate answer? the ultimate challenge? as the previous discussion of the contribution of s&t to employment or environmental challenges has shown, it is not always clear-cut where problems start and where solutions end. or to put these tangled matters even more simply in this case: the role that s&t can play is manifold. and nowhere is this manifoldness better encapsulated than in the predicament of the "knowledge society". here the challenges, the expectations, and indeed the role of s&t in eliciting and addressing them, are brought together in ways that it is most illuminating to examine. first, this section probes the mutual shaping of science and culture. second, it foregrounds some collateral features of the knowledge society, and in particular the vulnerability that accompanies its emergence. this will lead up, in chapter , to a discussion of our modernity -or modernities -as characterised by a distribution of goods but also of ills or risks, and of knowledge or claims thereon. indeed, in this subsequent chapter, the problematic and ambivalent relations between s&t and the public at large will be considered in the perspective of the weaknesses of european s&t. but firstly we must examine the crucial place of s&t within our knowledge society in the making. the mutual shaping of culture and s&t the examples in this chapter have already shown how profoundly our culture is marked by s&t developments. at the same time as s&t shapes our society, they are themselves produced, taken up, reconfigured, shaped by society. that is one (double) way in which culture is decidedly scientific culture, and thus in which s&t is at the heart of this nearly eponymic "knowledge society". but to allow all sections of society to benefit from those advances -as well as to take part in that shaping process -individuals need to be provided with the appropriate equipment, in terms of education, skills, awareness, and appreciation for the stakes in s&t endeavours. vital for a democratic society in this day and age, such demands point towards another crucial sense for scientific culture, also exposing the acute need for it to be developed. actions to foster a thorough public grasp of what is science and how it contributes to society are thus sine qua non to a full-fledged democratic society. importantly, s&t developments accompany and affect lifestyle changes in societies. in this respect the taking up of mobile phones or gsm provides interesting illustrations. the gsm has strikingly changed the way people communicate with their loved ones, organize their work and outings, and live everyday. as regards research, innovation, and competitiveness, the rise of the gsm standard provides an inspiring example of european leadership. in effect, new information and communication technologies open up opportunities for new lifestyles and new ways of working. remote working or online trading decouples economic activity from a particular geographic location (be it the office, capital cities or structurally favoured regions). moreover, such technologies can facilitate access to employment -and other forms of social inclusion/participation -among sections of society (people with physical disabilities, the elderly) who may otherwise be excluded. key to achieving those benefits is ensuring that people are equipped with the necessary skills to get involved. much information society literature also hypothesises that "ework" (remote working) may contribute to environmental sustainability as, in addition to other dematerialisations, travelling to work is reduced. on the other hand, transport technologies themselves -from the wheel through to the airplanecontinue to have a central role in society, for example in enabling communication. the quality of human life is made up of many more components than the ones already mentioned: greater access to knowledge, better nutrition and health services, more secure livelihoods, clean air to breathe, security against crime and physical violence, satisfying leisure hours, political and cultural freedoms and sense of participation in community activities. s&t can contribute to improvements and bring lasting solutions in each of these areas. for example, investment in research and new technologies to achieve sustainable transport solutions generates desirable impacts on the quality of life worldwide: less energy consumption; fewer air pollution; less respiratory diseases; lower noise levels; increased space and security for pedestrians and cyclists resulting in more friendly cities for children and older people; less congestion; fewer road accidents; and so on. besides, it is s&t which makes possible the novel lifestyles -and indeed the novel societydiscussed above. it may be that, in solving some age-old problems, s&t has created the possibility for new problems to emerge. yet even to address these new problems we can hardly do without s&t. but we can -and rightfully do -concern ourselves with the consequences of the solutions we devise. the vulnerable society and the knowledge society s&t has brought a mix of benefits and risks. in the modern world heightened wellbeing and security are accompanied by increased vulnerability and insecurity. this vulnerability can take many forms, from loneliness or travelling accidents to industrial disasters or the twisting of human rights in a totalitarian state. fig. . provides an illustration of the rising challenge represented by disasters. here "disasters" include both technological and natural events. the dramatic increase shown on the graph may be due not only to the consequences of concentrated urbanisation, climate change, and so on, but also to a heightened sense of vulnerability and risk, together with a better ability to measure disasters. hence the emerging knowledge society will have its problems too. besides, it will not depend solely on s&t but also on governance and on the citizens who will make up our society -and shape it. yet it is characterized by an increasingly pivotal role for s&t. the knowledge society requires a revolution in our understanding of knowledge: not only with regard to s&t researchers, but also concerning a democratisation or broadening of knowledge production. this has profound implications for decision-making, for the lay-expert divide, for the handling of risks and uncertainties, and indeed for the relations between citizens and institutions of governance, as every individual should be recognized as -and given the means to be -a person of knowledge. europe finds itself in a peculiar situation in this regard, and the following chapter will unpack the paradoxical relations between s&t and its citizen. this chapter has explored in greater detail some important economic, social and environmental challenges europe is facing, the expectations held of s&t in addressing these challenges, and the role that s&t could potentially play. the th framework programme was designed against the background of europeans feeling anxious because the continent is experiencing a number of important economic, social and environmental challenges -or indeed against the background of a europe turning from a positive into a negative "exception" at global level. economic growth is slow. europe's competitive position is feeble. there are not enough jobs, and not enough of them are high-level. europe is still characterised by significant poverty and regional inequality. an important demographic challenge is emerging. europeans' health is affected by serious lifestyle and contagious diseases. and the environment is being degraded. as will be further examined at the end of chapter and in chapter , expectations of s&t have never been higher than they are now. such expectations held of s&t are partially justified. s&t can indeed play an important role in addressing societal economic, social and environmental challenges. s&t is the engine of economic growth and competitiveness. the employment effects of s&t are positive. s&t can play a major role in addressing the consequences of ageing, and the cohesion and public health challenges. s&t can play a key role in addressing environmental challenges. s&t is part and parcel of our lives, be they framed in a knowledge society or otherwise, and they are the linchpin of the latter's emergence. however, as will be seen in the next chapter, for s&t to be able to realise its potential, some serious s&t weaknesses will have to be addressed. united nations research institute for social development, information and communication technologies and social development in senegal: an overview/les technologies de l'information et de la communication groupe spécial mobile" hosted by the european conference of postal and telecommunications administrations, and its specifications where defined by the european telecommunications standards institute in the late s. commercial operation began -and the world's first gsm phone call was made european foundation for the improvement of living and working conditions & prest european commission, dg jrc -institute for prospective technological studies impact of ict on sustainable development key: cord- -flf o nw authors: nan title: cruise geography date: - - journal: cruise operations management doi: . /b - - - - . -x sha: doc_id: cord_uid: flf o nw nan cruise geography by the end of the chapter the reader should be able to: ■ consider geography from a cruise industry perspective ■ evaluate the primary and secondary cruise sectors ■ identify major cruise ports in each sector ■ consider the attractions and features that are important in defining a cruise port and destination in a practical sense, cruise companies regard the world as a series of sectors that meet various market needs. for the largest brands, this outlook allows companies to configure operations to take account of: ■ seasonality, weather patterns, and optimum conditions for cruising ■ sales and marketing ■ supply and servicing of ships this chapter considers the influence and effect of geography on the cruise industry. to start with, it is impossible to consider cruising without reflecting on the conditions that arise from the prevailing climate. passenger comfort and safety are directly affected if a cruise ship sails in a particular part of an ocean or sea at a particular time of the year. this also holds true for destinations visited and shore activities that may be offered. to avoid potential discomfort for customers, cruise ships tend to steer clear of parts of the world where difficult sea conditions occur because of geography, climate, and seasonal variations (burton, ) . many stories are told of severe weather conditions in specific locations. for example, the bay of biscay, the cape of good hope, the bay of bengal, and the north atlantic have reputations suggesting they can provide extremes of weather for seafarers or navigators. yet knowledge of weather patterns and records of tidal variations permit cruise operators to predict where ships can travel with a high degree of safety to enable virtually all the world's oceans and seas to be traversed and all coastal ports to be visited (see figure . ). weather patterns are complex. they are influenced by many factors, including the sun's rays, the world's rotational axis (which tilts . °from the perpendicular, thus creating seasonal variations), the land masses and oceans, currents, and the moon's gravitational pull (which creates tidal variations). southern and eastern caribbean islands have fared less well than western caribbean islands, because itineraries have switched from -week tours to shorter -or -day excursions (burton, ) . competition for the tourist dollar has led to a situation where port fees for many caribbean islands are relatively inexpensive, at between us$ to us$ per customer. in this way, a vessel such as the diamond princess, with , customers, would pay approximately us$ , in port fees. in addition, cruise companies own some islands: royal caribbean has ownership of coco cay, holland america owns half moon cay, disney cruises owns castaway cay, norwegian cruise lines owns great stirrup cay, and princess cruises has an island called princess cay. the benefits of such ownership include generating revenue from shore-based activities and controlling costs associated with ports of call (a cay, or key as it is known in the united states, is a low island or reef of sand or coral). some islands are less tranquil or accommodating to tourists than may be expected. cuba, the largest of the caribbean islands and located km south of florida, has a history of being opposed to the politics of the united states and this posture has inhibited us tourist trade growth. other recent examples include political instability in haiti (bbc news, ) that has had a detrimental effect on the island's economy and has negatively affected cruise visits. however, in general, the situation on the majority of these "island paradises" is calm and settled. the cruise line industry association (clia, a) describes three specific parts to the caribbeanthe eastern caribbean and the bahamas, the western caribbean and the southern caribbean. selected destinations from these areas are described in this section. the caribbean tourism organization ( ) is a trade organization that represents many of the caribbean islands: anguilla, antigua and barbuda, aruba, bahamas, barbados, belize, bermuda, bonaire, the british virgin islands, the cayman islands, cuba, curacao, dominica, grenada, guadeloupe/st. barts the islands of the bahamas are close to the caribbean but are not part of this region (mancini, ) . however, the bahamas' close proximity to both the south florida coast and the eastern caribbean makes them a natural itinerary option for cruise planners, which means the islands are a frequent stop in caribbean cruises. the combined bahamas and eastern caribbean area is relatively accessible from us ports such as miami, port everglades, and port canaveral, as well as from san juan in puerto rico. however, because of the cumulative distance involved for this type of itinerary, the duration for some cruises is likely to be in excess of days. there is a diversity of ports in the region, including the aforementioned cays and islands that are privately owned by cruise companies (caribbean tourism organization, ) . several ports are described below, followed by a table that presents information about population, language, and currency. in all cases, for this and subsequent tables relating to destinations that appear in this chapter, populations of the port or island community are approximate. nassau and freeport on new providence island are the primary ports of call in the bahamas. in , nassau was the sixth most visited port in the world and freeport was the sixteenth (wild and dearing, a) . the name bahamas is a derivation of the spanish "baha mar," or shallow sea, and there are approximately islands in this popular self-styled "paradise archipelago" of sun, sea, and sand. the beaches are held in high regard, but the islands also offer a variety of attractions beyond miles of white or pink sand. the islands claim the world's third largest barrier reef and a diversity of sea life, including whales and dolphins. the bahamas have a population of , ( % on new providence island) and relys on tourism for % of employment and gross domestic product (gdp), or the total amount of revenue generated from sales of products and services. san juan, puerto rico is both a port of call (or destination) and a base port. this dual role makes the island the seventh most visited destination in the world, according to wild and dearing ( a) . puerto rico is described as an "island of enchantment," with a broad range of multifaceted attractions including the archetypal tropical beach scene, diverse natural attractions, and a rich cultural heritage. islanders came from a mix of cultures reflecting the scope of the island's origins, which includes african, spanish, indigenous, and us influences. the population of puerto rico is just under million. the currency is us dollars, and both english and spanish are spoken (puerto rico tourist office, ) . st. thomas and the island's port, charlotte amalie, are celebrated by shoppers. over the years, the island has become a leading tax-free haven and this, combined with the natural allure of the scenery and the island attractions, creates a powerful draw (us virgin islands tourism authority, ) . as a result, the island is the eighth most frequented port in the world (wild and dearing, a) . cruise visitors to the islands have easy access to a shopping mall next to the pier and can also enjoy water sports, such as snorkeling and scuba diving expeditions, and land based activities (dervaes, ) . the term scuba is an acronym that stands for "self-contained underwater breathing apparatus." philipsburg is st. maarten's port. with one half dutch and the other half french (referred to as st. martin) the island has two national identities and two personalities. the half of the island where most cruise ships call at philipsburg is dutch. the island is the ninth most visited port in the world according to wild and dearing's ( a) survey. visitors enjoy beach activities, water based excursions, and cultural experiences when visiting this island (mancini, ) . this island is the eighteenth most visited port in the world by cruise passengers (wild and dearing, a) . antigua is a verdant tropical island that boasts the historical attraction of nelson's dockyard, the eighteenth-century base for the british naval fleet (mancini, ) . the island is popular for snorkeling and scuba diving, and is said to be one of the sunniest of the eastern caribbean islands (antigua barbuda tourist information, the western caribbean is convenient for cruises that depart from florida or ports such as houston, galveston, and new orleans (mancini, ) . in addition, the itineraries for this region can be supplemented with mexican destinations such as cozumel (the third most visited port in the world george town in grand cayman is the main port of call and is the fifth most visited port in the world (wild and dearing, a) . the islands are famous for the opportunity to swim with stingrays, although many other attractions and experiences are available. the islands have a reputation for spectacular diving around the coral reefs, which are generously endowed with marine life. grand cayman island is also home to the world's first sea turtle farm, the spectacular limestone and coral formations known as hell, and the popular seven mile beach (cayman islands department of tourism, ). jamaica is the caribbean's second largest island, and ocho rios, jamaica's port, is fifteenth in wild and dearing's survey (wild and dearing, a) . jamaica has an array of natural wonders such dunn's river falls. cruise passengers have the opportunity to climb the waterfall, take an expedition to the blue mountains, and go on an undersea tour or visits to caves (visit jamaica, ) . the options are very wide, reflecting the natural and cultural diversity of the island. music, as epitomized by the late bob marley, plays a part in jamaican culture. jamaica is the home of reggae and boasts a rich historical heritage. this part of the caribbean tends to be seen as more exotic because the islands are located close to venezuela in south america and the itinerary usually requires using a home port from within the area, such as barbados and aruba. many cruises to the southern caribbean originate from san juan in the eastern caribbean and include a mixed itinerary of ports from both the eastern and southern caribbean. this region enjoys the caribbean's sunniest climate. georgetown is the port for the island of barbados which lies at the eastern edge of the southern caribbean. the countryside has a softly rolling landscape, in contrast to some of the other volcanic islands that have been considered so far. barbados has a strong british connection (barbados tourism authority, ) and is a former colony (it gained full independence in ). attractions include rum factory tours, touring the island, water sports, and visiting the many beautiful beaches. willemstad is curaçao's capital. curaçao is the main island of the group of islands known as the dutch antilles. curaçao has an unmistakable dutch heritage, reflected in its style of architecture (curaçao tourist board, ) . the island has a host of activities for cruise passengers, who may wish to visit the island's shops, the underwater park and seaquarium, or the island's ostrich farm. there are many other islands in this area including bonaire, trinidad, and tobago. itineraries may also include venezuelan ports such as la guaira (for caracas or venezuela) and cartagena. while the caribbean has benefited from the changing pattern of cruising in the aftermath of / , europe and the mediterranean (figure . ) are poised to develop exponentially as tensions concerning travel begin to ease (wild and dearing, b) . barcelona and palma in spain and venice in italy lead the rankings list of most visited ports in southern europe, reflecting a trend for itineraries to be located more toward the west of the mediterranean or the adriatic (wild and dearing, c) . southampton in the uk has emerged as a leading port for the northern region, being appropriately located to service a diversity of itineraries and, according to wild and dearing ( c) , it is close to the types of facilities that allow effective service of passenger and cruise ship needs. this cruise region has a number of advantages. for us passengers it offers familiarity with the culture, the geography, and the attractions offered by the major cities (mancini, ) . for european passengers it provides an easy departure from home ports. the countries and ports are, for the most part, highly sophisticated (cruise europe, ) and able to cope with the complex demands that accompany the arrival of the largest of cruise ships. a number of cruise brands, such as the cunard line and p&o cruises in southampton, have traditional roots in this region. indeed, historically the uk is the home of cruising. the season for cruising in northern europe is relatively short, but the ports are popular so traffic can be concentrated for the short cruising season (wild and dearing, c) . wild and dearing ( c) note that the majority of passengers for this type of vacation are likely to be first, north american passengers; secondly, uk passengers; and thirdly, german passengers. when marketing cruises in northern europe, cruise companies can focus on the british isles, the baltic, iceland, the arctic and the north cape, the norwegian fjords, and western europe (wild and dearing, b: ) . the following describes key destinations from this area. southampton is a city with a long maritime heritage. the city has experienced both growth and decline because of the historical development associated with shipping in general and the cruise industry in particular. it is currently experiencing growth. the port is well located for london, and it cruise geography has excellent transport links and the infrastructure to service cruise ship needs. the port provides a launch pad for ships to travel with or across the atlantic, to the mediterranean, to the ports of northern europe. because of this, it is listed by wild and dearing ( c) as the first-ranked port in northern europe. helsinki is the capital of finland. from a cruise perspective, the city is located in a strategically convenient part of the baltic for itinerary planning. it is a bustling port with as many as ferry departures daily at the height of season. the port is attractive and closely located to the city center (cruise europe, ) . finland is different from other scandinavian countries for two reasons. first, it has a different language that is more similar to russian and estonian than to the languages of the neighboring scandinavian countries. secondly, it shares a border with russia, which has resulted in finland possessing a different history and culture. with two thirds of the country covered by forest and one tenth made up of inland lakes, the finnish tourist board emphasizes nature and the environment (boniface and cooper, ) . the port is a secondary base port as well as a port of call, or destination. copenhagen is the capital of denmark, the smallest scandinavian country, and, after helsinki, it is the third most visited port in northern europe (wild and dearing, c) . copenhagen has a reputation for having lively nightclubs and bars and is a major cultural destination (boniface and cooper, ) . it is the home of the carlsberg brewery, which is both a tourist attraction and working production center, and the world famous tivoli gardens, which is europe's oldest amusement center. much is made of the figure of the little mermaid, a statue in the harbor area representing a character from hans christian andersen's stories. the city was the recipient of the world travel award as europe's leading cruise ship destination in (cruise europe, ). st. petersburg in russia has seen major growth in numbers of cruise passengers over the last five years and it was slated for calls in compared to in . the city is said to be the most beautiful in russia (boniface and cooper, tallinn is a united nations educational, scientific, and cultural organization (unesco) heritage site. it is the capital of estonia and boasts what is said to be one of the few examples of an old city that has been kept intact. tallinn has a history as a port that can be traced back to the tenth century, and evidence suggests there was a settlement on the site as long as , years ago. the city offers a number of attractions including parks, heritage buildings, palaces, and museums (cruise europe, ) . tallinn is the fifth most visited port in northern europe (wild and dearing, c) . stockholm is the sixth leading northern european port (wild and dearing, c) . it is the capital of sweden, a country that has the largest unspoiled wilderness in europe (bonifac and cooper, ) . the city of stockholm is located on a number of interconnected islands at one end of lake mälaren. the city offers a broad range of attractions such as museums, royal palaces, and heritage attractions. the city itself is attractive to visitors, with its narrow pedestrian streets, good shopping and restaurants. the northern european region may have a short season because of frequent inclement weather patterns from late autumn through to early spring, but the ports are popular and tourist-friendly. whether a cruise is seeking the "land of the midnight sun" while cruising past the fjords of norway or the northern lights of aberdeen on the northeast coast of scotland, passengers have many opportunities for memorable moments. in cruising terms, this region encompasses the eastern and western mediterranean and provides access to a range of countries from a large number of ports. with long dry sunny summers, the mediterranean climate is conducive to vacations (boniface and cooper, ) . the region offers a great diversity of attractions, including historical sites, sophisticated cities, and beach playgrounds, all within relatively accessible cruising parameters (mancini, ) . the distances between ports and attractions allow cruise planners to schedule itineraries in this region to take advantage of the best timing and economical fuel consumption and, in addition, to take advantage of high-caliber supply networks. the mediterranean is popular with many cruise passengers. us passengers can take advantage of "grand-tour" approach to visiting europe and facilitate border crossings, minimize language problems, and maintain a desired level of comfort. one drawback for us passengers can be the need to fly long distances to board the ship, although passengers are served by a multiplicity of arrival airports that provide easy access to base ports. another factor that concerns some passengers is political unrest in countries and regions close to the mediterranean. passenger concerns about destinations are easily remedied by changing itineraries-a factor that has helped to generate the growth in popularity of cruising. uk and european passengers have relatively easy access to the mediterranean. p&o cruises, cunard, saga cruises, and other cruise brands operate a variety of cruises that depart from the uk. other cruises that depart from the mediterranean are usually between and hours flying time away from local airports. the season in the mediterranean is being reappraised to stretch the shoulder periods (the months between high and low seasons). barcelona, in the western mediterranean, is a spanish city that has become the most visited port in the region (wild and dearing, c) . in addition to its status as a major base port, the city offers a broad range of attractions to make it a destination in its own right. the city is peppered with characterful architecture that was designed by antonio gaudí, and many tours visit his unfinished cathedral, the sagrada familia. the ramblas provides a main walkway through the center of the city past the barrio gótico, the medieval core of old barcelona (boniface and cooper, ) . the port offers a contemporary setting for passengers to embark and disembark, with modern terminal facilities and network of services for passengers and cruise ships (medcruise, ) . palma is also a spanish city in the western mediterranean. the island of majorca is one of the balearic islands located off the southern coast of spain. the other principal balearic islands are ibiza and minorca, which are also ports of call for cruise ships. majorca is well known as a holiday destination, and, in recent years, the port has become a popular fly, cruise, and stay product (medcruise, ) . the island provides a variety of resorts and accommodation for this type of package. palma, the capital of majorca, is an attractive city that has a typical spanish atmosphere, an impressive cathedral, a variety of shopping options, and close proximity to the beaches and other attractions. venice is actually in the adriatic sea, not the mediterranean. this northern italian city has had a long and turbulent history, and seems to be continuously struggling against the ravages of nature and time. yet, in its unique setting, with its canals and car-free environment, venice is special. the vast scale of a grand class cruise ship drifting past st. mark's square beside antiquities such as the doges palace and the basilica presents an incongruous sight. as a sea-based trading center, venice has a maritime culture and has always made a living from the sea. its excellent terminal facilities provide a point of arrival and departure and easy access to this attractive destination (medcruise, ) . recently, proposals have been made to construct a tidal barrier to counter flooding problems caused by a combination of the city sinking into the lagoon ( cm in years) and rising tides (bbc news, ) . naples is located in italy, just to the south of rome. the city is overshadowed by the ominous presence of mount vesuvius. this slumbering giant of a volcano provides a most impressive backdrop to naples and is responsible for creating two of the area's attractions-the excavated roman ruins of pompeii and herculaneum. the port gives easy access to the vast city, which can appear both lively and chaotic. this is the mediterranean's fourth most visited port after barcelona, palma, and venice (wild and dearing, c) . this unfamiliar italian port provides the gateway into rome. the city of rome is a "must see" destination for travelers to europe. the city boasts a veritable cornucopia of classical ruins and architectural gems, including the forum, the colosseum, the vatican, and st. peter's square, all within a modern metropolitan setting. getting from civitavecchia to rome usually involves a taxi or coach cruise operations management journey, although the town also has a train station, which provides regular and easy connection. the port is a large sprawling area, and ships can be located quite far from the port gate. this distance can be traversed by a coach link or shuttle service, or taxi service, to the town center. savona in liguria, northern italy, is the seventh most visited port in the mediterranean area (wild and dearing, c) . costa cruises, one of carnival corporation's cruise brands, has leased the modern terminal building in the city and makes good use of the facility to support its operations. savona is in the heart of the italian riviera, a region of pretty seaside towns, spectacular coastlines, and a wide range of attractions. livorno is a large, bustling port that services the surrounding region of tuscany in italy by providing a focal point for cargo, ferry, and cruise traffic. the cruise terminal is approximately a third of a mile from the city center. however, for many passengers that may be irrelevant because a key attraction is the city of florence, which is approximately miles ( kilometers) from the port. the port also provides access to the beaches of the area, the famous wine region (tuscany is well known for wines, including its famous chianti), and many other attractive towns such as pisa, lucca, san gimignano, volterra, and siena. dubrovnik is a major croatian city and port. despite suffering heavy shelling during the serb-croat war in and , this famous old walled city has been completely restored to enable visitors to experience its atmospheric street scenery. dubrovnik offers contrasting experiences to visitors. the city holds much interest, with its ancient walled ramparts and fortresses, narrow pedestrian lanes, and historical town buildings. the surrounding countryside and coastline provide a rich mix of geography, culture, and leisure activities. piraeus is a greek port that may be seen by some as the civitavecchia of athens. yet piraeus has long been the gateway to athens, and, as a result, it has a lively and bustling character. the harbor area is large and accommodates a diversity of shipping traffic, such as cruise ships, cargo vessels, and the ferries and hydrofoils that connect athens and the mainland to the many outlying greek islands. the olympics led to considerable investment in the infrastructure of athens and surrounding areas. athens is another key destination for cruise passengers. the city has many treasures that attract visitors, including the acropolis, the parthenon, and the agora, or marketplace (boniface and cooper, ) . athens can be reached from piraeus by taxi, public bus, tour coach, and subway. santorini is a greek island in the cycladic island group in the aegean sea, some miles from piraeus. the island offers spectacular scenery from its highest point, across the sweeping curvature of the crescent-shaped landmass out to sea. the island was originally a volcano, but when part of the cruise geography volcano collapsed into the sea the unique terrain was formed. some claim that santorini was the setting for the lost city of atlantis. rhodes, named after the phrase "the island of roses," is an attractive greek island where ancient history combines with the contemporary beach and sunshine holiday. rhodes is also the name of the capital city, which today presents itself as a medieval old town with strong historical connections to the knights of st. john. (the knights of st. john was a religious and military order that was originally founded in seventh century bc to participate in war in the holy land.) mykonos is another greek island in the aegean sea. this small island, with a population of just , , transforms during the summer, when , tourists inhabit the hotels, guesthouses, and tourist accommodation. mykonos's charm is the appearance of the main town, with its winding back streets, white painted buildings, and beautiful island scenery. the mediterranean possesses many special destinations and ports that are worth a visit. the attractiveness of this region, as well as the historical and cultural values, creates a strong lure for a broad range of cruise tourists. there are those who may have ancestral links to the area, others who seek learning and cultural enrichment, some who are attracted to the beauty of the scenery and countryside, and people who enjoy the climate. invariably, there are many who seek a combination of these features. north america provides a number of embarkation points where us customers can join cruises and where overseas customers can join as fly-cruise passengers. in some cases these ports are home ports for us vessels and cruise companies. in addition, cruise itineraries can be constructed from us and canadian ports to meet passengers' needs for cultural and geographical attractions. irrespective of a cruise ship's flag or country of registration, because of the actions of us port health officials there are critical implications from the standpoint of port health for ships visiting us ports (which are examined in depth elsewhere) (figure . ). north america is the world's largest cruise market. as a result of concerns about security abroad, the number of cruise passengers joining from us ports has seen considerable growth. of the top five cruise destinations in the world (wild and dearing, a) , miami and port everglades are as number and , respectively, and port canaveral is number . all three ports are in florida. cruise companies have benefited by consolidating their operational support in the united states and creating economies of scale from supply networks for merged brands. in addition, cruise companies have become horizontally and vertically integrated in their operations. within the cruise industry, horizontal integration is attained by using different brands strategically within a variety of market segments. vertical integration is achieved by creating synergies and generating revenue from ownership of parallel operations such as shore excursions, travel agents, terminal operations, and so on. the following list provides a brief outline of the features of major north american ports. the port of miami, on dodge island, is the busiest home port in the united states. as such, it provides a home base to carnival cruise lines, norwegian cruise line, royal caribbean international, oceania cruises, and windjammer barefoot cruises. the port has state-of-the-art facilities and has eight terminals with designated berths that can be used flexibly depending on the type of shipping. in addition to hosting passengers who are embarking on cruises, the port also provides facilities for cruise passengers arriving in miami, with many options for excursions. it can also host those arriving in the city a day or so before departure (port of miami, ) . while cruises can depart for many places, the main target is the caribbean. port everglades is located close to fort lauderdale airport, making for a relatively easy transfer for fly-cruise passengers who are primarily cruising to the caribbean. port everglades, the number port in the world, hosts many cruise brands, including carnival, celebrity, costa, crystal, cunard, holland america, imperial majesty, mediterranean shipping, orient, princess, radisson seven seas, regal, royal caribbean international, royal olympic, seabourn, and silverseas. the port provides a breadth of shore excusions (see chapter ) in the area (port everglades, ). port canaveral has six cruise terminals with another two under construction. the port is home to carnival cruise lines, disney cruise line, royal caribbean international, sterling casino lines, san cruz casino, holland america, and norwegian cruise lines. the port is in what is known as florida's space coast, and visitors can take the opportunity to tour the kennedy space center or indulge in a range of other activities (port canaveral, ) . the port of juneau provides access to the seasonal (may to september) attractions of alaska. juneau was a gold-rush town that became alaska's capital. as a cruise destination, the city provides opportunities for exploring the area's mining heritage, participating in outdoor pursuits, visiting glaciers, whale watching, and even dog sledding. glacier trips are available by helicopter. the city is more than simply a departure point for environmental pleasures, boasting an air of sophistication with its many art galleries and quality restaurants. most of the major cruise brands that are marketed to us passengers sail to juneau. ketchikan is alaska's southernmost city. despite a high average rainfall, many outdoor pursuits are available, including kayaking, trekking, and visits to national parks, lakes, and forests. the city is a center for native culture, with an array of related museums and attractions. los angeles was the original home for the love boat television series that ran between and . la is famous for its many attractions, including hollywood, disneyland, and universal studios. the world cruise center in la can manage a visit by the largest cruise ships (cruise the west, ). long beach is fast approaching the scale of operation at neighboring port los angeles (wild and dearing, a) . carnival corporation has a terminal at this port, and many cruise brands use long beach as a departure and home port. itineraries from this port can include baja california, the mexican riviera, and alaska. tampa handles a quarter of the numbers of passengers that miami does (wild and dearing, a) . however, tampa in florida is expanding rapidly and attracts many of the leading cruise brands, including carnival cruise line, holland america line, royal caribbean cruise line, and celebrity cruises. the port has a well developed, tourist-friendly, downtown waterfront area, and many excursions are available to augment the passenger experience. a host of other ports lie within this large area, including vancouver, new orleans, galveston, skagway (alaska), new york, new jersey, boston, san francisco, galveston, philadelphia, and seattle. competition is fierce and growth, combined with recent trends, means many ports are experiencing "boom" conditions (mott, ) . oceania, including australasia (australia, new zealand, and asia) and the islands of the pacific, is a major expanse of sea and land. this cruise region offers great diversity from the culturally vibrant and exotic ports of asia, such as indonesia, malaysia, the philippines, singapore, thailand, india, vietnam, china, hong kong, japan, sri lanka and the maldives, to the tropical islands of the pacific, such as tahiti, fiji, papua new guinea, new caledonia, vanuatu, samoa, tonga, and the cook islands. australia offers the attractions of her cities of sydney, melbourne, and freemantle and the uniqueness of the coast, the coastal resorts, and the countryside (cruise down under, ) . new zealand is still basking in the lord of the rings effect, which has followed the success of the movie trilogy. publicity from feature films has frequently created heightened interest in travel destinations, and this has also been evident in the increased number of ships visiting the ports of auckland and wellington in new zealand. this region is located in the southern hemisphere, so the seasons are a reversal of the pattern recognized in the northern hemisphere. as a result, the summer cruising season for australia and the south pacific extends from november to april (mancini, ) . this vast geographical area is likely to experience continuous growth, with emerging economies such as china and india fuelling opportunities for new consumer markets and new, relatively accessible itineraries (figure . ). sydney is probably the best-known city in australia, although it is not the capital (which is canberra). the city has a highly picturesque setting, with its harbor, the sydney opera house, and the sydney harbor bridge, which were blatantly and successfully exposed to the world media during the millennium new year celebrations. sydney has two cruise terminals-the overseas passenger terminal at circular quay and the wharf darling harbor passenger terminal-that are in close proximity to the city's attractions (sydney ports, ) . auckland is the largest city in new zealand's northern island. it has an idyllic setting surrounded by islands and beautiful scenery. the city is both cosmopolitan and close to nature, with tours available to volcanic regions, rainforests, and beaches and the city's attractions within easy reach for passengers. the city has polynesian and maori culture, which is reflected in the people, the place names, the history, and the heritage of the area. fiji is a group of islands in the south pacific with a population of approximately , . the largest two, viti levu and vanua levu, contain % of the country's population. the islands represent many peoples' vision of what tropical islands should be like. there are white beaches, coral reefs, and clear seas with a myriad variety of fish and sea-life, alongside rainforests and native villages. contemporary fiji also has attractive shopping facilities in the capital, suva, along with modern hotels, a wide variety of restaurants, and nightlife for all types of tourists. new caledonia is a french island that lies halfway between australia and fiji. the island, with its capital noumea, is the third largest in the pacific after new zealand and papua new guinea. the french cultural influence, coupled with the influence of the melanesian region in this part of the pacific (melanesia is the name given to the island group that new caledonia is part of), creates an interesting backdrop for this island. the geography is a mix of tropical features, with attractive sandy beaches, a large lagoon that surrounds the region, mountains, and rain forests. hong kong was formerly a british protectorate, but it was returned to china in . it retains a mix of eastern and western influences and a dynamism that reflects a city on the cutting edge of a changing world. the city promotes itself as a shopper's paradise, but, in reality, there is more to this energetic, self-styled "cruise capital" of asia. to the western tourist a visit to hong kong by cruise ship is a special opportunity to savor its unique blend of sights and sounds (hong kong tourism, ) . the republic of singapore is one main island surrounded by smaller islets. it is an economically successful country, which is proud of its contemporary feel, its diverse culture, and its friendliness. visitors can experience gardens, skyscrapers, the famous raffles hotel (home of the singapore sling), a strong sense of fashion, and a technologically aware community. the capsule descriptions of the aforementioned cruise regions are, of course, flawed because they only scrape the surface of the options for creating a cruise itinerary. further research will undoubtedly reveal a plethora of destinations that are unmentioned in this chapter but, nonetheless, hold vital importance as part of a cruise itinerary. at the end of this chapter, the reader will find links that can help with such research. some additional destinations are worth highlighting and have until now been omitted because of their geography. for instance, nothing is said about most of africa and the islands off africa, such as the canaries, mauritius, and the seychelles. south america is also omitted, despite its obvious attractiveness and a wealth of interest in the continent. a few ports from these areas are mentioned here to draw attention to their potential. a number of primarily volcanic islands form part of cruise itineraries in the northern hemisphere. these are the canary islands, madeira, and the azores. the canary islands of tenerife, lanzarote, gran canaria, and fuertenventura are governed by spain, although they fall outside the jurisdiction of the european union (eu), which means that cruise ships with an eu registration can have the opportunity to sell duty-free alcohol. an eu-registered ship that has an itinerary made up of destinations or ports that are all eu member states would not be able to make such sales. madeira and the azores are portuguese islands. the canaries are relatively close to the coastline of north africa and benefit from a temperate climate all year round. madeira has a similar climate and is a popular cruise destination for passengers who enjoy the verdant scenery and charm of funchal, the island's capital. the azores offer a different type of destination. the islands have a quietness about them that reflects their remote setting. these islands were a convenient stopping point for trans-atlantic crossings, but are now less frequented because the need for such a logistically convenient stopover is much reduced (boniface and cooper, ) . this major brazilian city conjures up images of sugarloaf mountain, with its world famous statue of christ facing over rio's population. copacabana beach and ipanema beach are also well known as playgrounds for locals and tourists alike. the city is representative of brazilian exuberance, as seen in the everpresent music, the dancing, and festivals. buenos aires is the capital of argentina. it is an optimistic and proud city with a much publicized past. its architectural heritage is european, with influences from britain, france, italy, and spain. its museums, theaters, and art galleries reveal the cultural proclivities of the locals. much is made of the links between the nation and the tango, a dance that embodies passion and drama (boniface and cooper, ) . the galapagos islands are ecuadorian islands in the pacific. despite being almost barren, these small islands are popular cruise destinations because they present an ecosystem that is unique. the water is cold, yet the islands lie on the equator so the mix of land and sea creatures is diverse. there are no natural predators, so the indigenous animals, including giant tortoises, marine iguanas, penguins, and sea lions, have no built-in fear of humans. the area is extremely sensitive, and cruise ships and passengers are managed with great care (boniface and cooper, ) to minimize environmental impacts. cape town is the capital of south africa. the city is located in a place where cold and warm collide, because of sea currents from both the atlantic and the southern oceans. cape town is a natural harbor that makes an excellent destination with a wealth of options for the cruise tourist, including the friendly locals, the dramatic scenery of table mountain , the famous regional vineyards, and the beaches. the seychelles in the indian ocean are idyllic islands that are truly beautiful. the clean sandy beaches, clear seas, palm trees, and granite outcrops peppering the shores offer a relaxing port of call for cruise itineraries. the flora and fauna on these islands are unique because of their distance from the nearest landmass. cruise tourists are most likely to visit mahe, the main island. the panama canal is not really a destination in its own right, but it is vital as a link between the atlantic and the pacific oceans and a fascinating experience for cruise passengers. the first ships used the canal in . from then it was operated by the united states until , when it was returned to the panamanian government. it has three sets of locks to facilitate the different sea and water levels, and, on average, it takes about to hours for vessels to get from one side to the other. ship dimensions must not exceed . meters in beam, draft meters, and . meters long (depending on the type of ship). the suez canal started operations in to provide a link between the mediterranean and the indian ocean. using this shortcut, ships could avoid the potentially dangerous and lengthy voyage around the cape of good hope. since that time, with occasional closures at time of war, the canal has become on of the world's most important trading routes (boniface and cooper, ) . the canal can allow vessels up to , grt with a -meter draft to traverse the canal, although plans are under way to increase this limit to a -meter draft by . this chapter provides a description of the major cruising sectors and a brief taste of a number of destinations. considerably more can be said about all the destinations that are included, as well as those that are not. however, this is not possible in such a broad-based textbook, and it is recommended that readers undertake further research to examine key issues related to destinations and cruise sectors. many good resources exist, including web-based tourism sites, geography textbooks, and tourism guides. the cruise industry generates considerable business for destinations, but for some there is a cost. that cost may be in terms of the increase in people visiting particular destinations, the demands placed on the local population to "package" and thus taint the cultural experience, the possibility of pollution, or ecological impact. these issues can also be examined further with respect to the balance of the positive and negative impacts on destinations. the following two case studies are included to stimulate discussion and widen understanding about destinations. the first is the case of "destination southwest," a regional initiative that was introduced to increase cruise business to the southwest of england. the second examines the action taken by some cruise companies to purchase and operate private islands. questions are included at the end of each case study. resorts seeking to capitalize on the burgeoning cruise phenomenon could learn by examining the case of "destination southwest." this initiative, representing an alliance among eight ports throughout the southwest of england (ilfracombe, torbay, dartmouth, plymouth, fowey, falmouth, penzance and the isles of scilly) was supported by a combination of european regional development social funds and match-funding from county and local councils, tourists bodies, and attractions such as the eden project, the national maritime museum in cornwall, the national trust, britannia royal naval college, and the ports (a total of public and private partners). the funds helped support a new partnership that aimed to develop and extend the number of cruise ship visits to ports within the region. bob harrison, an experienced professional with years of industry experience, coordinated destination southwest at sea and ashore. he was appointed director of cruise operations. harrison used his knowledge and contacts to gain access to senior managers involved with itinerary planning, and his insights into the experience and requirements of cruise passengers have been invaluable. he also recognized the difficulties that cruise executives face when planning itineraries and can orient his strategy accordingly. the £ , three-year project was launched in february . destination southwest started by establishing an informative website, www.destinationsouthwest.co.uk. the website allowed visitors to click on the port name and get access to a lot of information, including a cruise calendar to identify which ships are calling and when, marine charts, town maps, suggested shore excursions, video clips of some attractions, -degree shots of the port area where passengers land, and distances and times between ports and attractions. this information, which helps the itinerary planner make decisions, was also replicated on a dvd to provide an easy-to-use reference in support of direct selling and to give away at exhibitions. websites and dvds were produced in german and english to appropriately target the us and german cruise markets. there were a few problems. events such as the terrorist attack on new york, the outbreak of foot and mouth disease in the uk in , and the emergence of sars all affected purchasing decisions by potential cruise passengers. in many cases, people were ill informed about the implications of these critical incidents. passengers to a port in cornwall were overheard asking whether purchasing a woolly pullover might create a risk of catching foot-and-mouth disease. cruise companies such as holland america, princess, cunard, and seabourne all liked the uniform packaged approach. the results of the project show an increase from vessels calling into ports in the area in , to cruise ship calls in . by all accounts, this is a dramatic increase. some ports in this region offer berths where the ship can go alongside. indeed, the busiest port, falmouth, has such facilities. harrison believes that passengers prefer as few tender operations as possible (where launches transport passengers from ship to shore). this despite the fact that many cruise brands include a tender operation as part of the total cruise experience. in his opinion, more than two tender operations in a cruise is too many, because passengers begin to object to the time delay, the potential discomfort if sea conditions are not calm, and queues that can form at either end of the operation because of security and logistical factors. the business generated by destination southwest includes turnarounds. a turnaround port is one where the cruise starts and finishes. dartmouth is reported to operate one turnaround while falmouth has . the falmouth turnarounds involve a ship called the van gogh, which has itineraries to the mediterranean, the canary islands, and the caribbean. harrison describes recent research on passenger spending, which focused on cork in southern ireland. he quotes this irish research because he believes that cruises based in cork and those in the destination southwest program have much in common. this research identified that each passenger spends £ and that crew members spend marginally less. there is, however, disagreement about spending levels, and some sources suggest that at times the crew can actually spend more than some passengers. this is explained by patterns in port manning. minimum levels of crew must remain on board when the ship is in port to ensure safety. as a result, crew members cannot go ashore in every port but when they do go ashore they are more likely to spend greater amounts of money. harrison estimates that cruise passenger spending in the southwest of england is £ . million, while crew spending is £ . million. that is a total of £ . million from a project with a £ , budget, which could equate to jobs for the local community. when a cruise ship comes to falmouth, the local department store, marks and spencer, takes on extra staff. the project has attracted high-profile vessels to the ports in the partnership and it is reasonable to highlight the benefit to the port's image. when the 'world ' was visiting falmouth as part of her itinerary, there were , people standing on the headland to see the ship as she sailed out of the harbor. how was this level of success achieved? the website was seen to be important. the quality of information and the ease of use are fundamental. destination southwest possessed a tacit understanding of the cruise industry and its requirements. the project used business-to-business (b b) marketing. personal contacts that, developed relationships and encouraged visits to the area by decision makers were also important. attendance at trade and travel conventions was of importance because it gave destination southwest a presence. douglas ward, the author of the berlitz guide to cruising, was appointed as honorary president, and this link was also thought to be useful because of opportunities to enhance networking and raise the project's profile. the initiative has helped to develop the level of support for cruise tours, quality of welcome for cruise passengers, and overall focus for customer service. in torbay, for example, shop-mobility trolleys were made available, and the mayor attended personally to welcome the passengers. in other ports, such as plymouth and falmouth, portable tourist information display units were available for passengers to consult. local problems that negatively affect business include conflicting schedules from ferry operators competing for berths and limited under-keel clearance in port areas that inhibits ship mobility and access during certain tides and times. the project has helped lengthen the tourist season and has brought many people from the us, europe, and the uk to the region. the potential for cruising is continually expanding. the passenger shipping association states that there was a percent increase in visits to the uk between and and identifies it as the fastest growing market in the world. the potential for the southwest of england is high. even the weather, often regarded by some as a turn-off, is seen by many us passengers as an attractive experience. the local government office is impressed with the project and aims to extend it for a further two years. levels of investment are low, however, and there is a constant struggle to persuade members to contribute. there are major benefits to acting in concert. ports that do not act in competition can derive benefits through cooperation. harrison says that cruising is for everyone, and the challenge is to inform those who do not recognize how it has changed. the preceding case study presented an account of how one region in a country created a plan to develop and sustain cruise tourism growth. . consider the key actions and identify the critical elements that led to the outcome of this initiative. . what are the risks for this project and how can they be addressed with respect to the following? a. internal competition between neighboring ports b. ensuring the ports remain attractive as cruise destinations c. securing finance to ensure that the project develops private beaches, such as those owned or leased by cruise brands in the caribbean or the bahamas, are seen as a useful alternative to neighboring popular ports of call. often the beaches are on cays, the local name given to small islands, which is a derivative of the word key (as in key west). cays are small, lowlying islands consisting mainly of coral and sand. cruise lines such as disney, princess cruises, norwegian cruise line, holland america line, costa cruise lines, royal caribbean international (which has two islands), and radisson seven seas cruises are all involved in this type of investment. but what are the advantages and are there any disadvantages in having a private beach port? most of the islands are constrained by their location and facilities, thus requiring that the ship anchor off the coast, with passengers then ferried to the island jetty by tender. this transfer can add an exciting dimension to a cruise, although those with small children or with a disability may be inconvenienced. the notion of a private cay or beach can be attractive to passengers because of the implied romance or because the idea may signify to some a prestigious and unique benefit. the visit to the cay is often scheduled to include a morning arrival and late afternoon departure. this optimizes usage of the cay and allows the company to build in additional services such as barbeques, water sports, and organized games and activities. this in turn creates opportunities to generate revenue for the activities and for facilities. kayaking, sailing, snorkeling, scuba diving, and a range of children's activities can be scheduled. in addition, some companies have scheduled special activities such as massages in private cabanas (disney and holland america) and "surf and turf " olympics (costa cruises). royal caribbean has built a replica of a spanish galleon and sunk a small airplane in the waters off its bahamian island, -acre coco cay, for snorkeling tours and scuba divers. services may be provided by the cruise company or subcontracted to local employees or contract providers. the services are under the quality assurance and control of cruise management with, in some cases, shipboard staff being used ashore to create a seamless service. in addition to this approach to developing their "products," cruise companies are also introducing "beach clubs" in popular destinations, which are managed and operated directly or as part of a contract by the cruise companies. some observers are critical of this approach (robertson, ) , noting that issues relating to the environment and the amount of waste generated by tourists, both on the ship and when visiting these fragile islands are important and in need of further examination. in addition, points are raised about the ethical position of cruise companies in relation to the playgrounds of the caribbean and the bahamas. cruise companies generate large amounts of revenue from their islands by selling products and services but, it is claimed, in doing so, the direct contribution to locals trading in the caribbean is being eroded (robertson, ) . where tourists are sheltered from a local environment by barriers intended to protect the tourists and manage their experience (boniface and cooper, : ). why is this so and what are the implications? glossary archipelago: a group of many islands. duty-free: the status claimed when goods are sold without the need to port fees: levies charged per passenger for a cruise ship entering a destination port. sars: severe acute respiratory syndrome what are the primary cruising sectors? . what are the important factors that define a port or destination? . what part does weather play for cruise destinations? . what are the secondary and emerging cruise sectors? additional reading and sources of further information antigua and barbuda aruba cruise passengers experience the bahamas exploratory research of tourist motivations and planning venice launches antiflood project worldwide destinations caribbean-everything you want it to be cayman islands-close to home bahamas and the caribbean selling the sea life and learning in further education: constructing the circumstantial curriculum all about hong kong cruising: a guide to the cruise line industry cruising in the mediterranean home comforts. lloyd's cruise international cruising from port canaveral go to puerto rico mitchell beazley's family encyclopedia of nature cruise ship tourism sydney ports: first port, future port. retrieved april explore jamaica caribbean stronghold. lloyd's cruise international ( ) growth culture. lloyd's cruise international high achievers. lloyd's cruise international key: cord- -drjfwcdg authors: shephard, roy j. title: building the infrastructure and regulations needed for public health and fitness date: - - journal: a history of health & fitness: implications for policy today doi: . / - - - - _ sha: doc_id: cord_uid: drjfwcdg . to recognize the importance to the maintenance of good health of adequate public health regulations and an infrastructure that provides clean water and appropriate waste management. . to see the lack of such amenities over many centuries, but the progressive development of public health bureaucracies dedicated to provision of an appropriate infrastructure for healthy cities, beginning during the victorian era. . to observe how responsibility for the provision of adequate housing for poorer city dwellers has been shared between government, benevolent entrepreneurs and charities. . to note the new challenges to public health presented by such current issues as the abuse of tobacco and mood-altering drugs, continuing toxic auto-emissions, the epidemic of hiv/aids, a decreased acceptance of mmr vaccinations, and the ready spread of infectious diseases by air travel. opportunities for the spread of communicable diseases have increased with the growth in size of cities. the success of urban living has depended in great part on governmental ability to maintain population health through the building of an adequate infrastructure to provide clean water and to dispose of waste, as well as the enactment of appropriate regulations to control the prevent the spread of infectious diseases. in this chapter, we will look at success in meeting these objectives in various communities from early history through the classical era, the arab world, mediaeval europe, the renaissance, and the enlightenment to the victorian era, concluding with some comments on current challenges to public health. in the hey-day of the persian empire, heat, cold, dirt, stench, old age and anxiety were all thought to contribute to ill-health. cyrus the great ( - bce) thus taught his soldiers not to urinate or spit into running water. dead matter was also carefully removed from water-courses, and the clothing of dead people was systematically burnt. during the mediaeval era, interest in public health was much more advanced in the islamic world than in northern and western europe. ali ibn-rabban ( - ce), a well-respected physician living on the south coast of the caspian sea, wrote in his seven-part medical work paradise of wisdom that: "no one should live in any country which does not have four things: a just government, useful medicaments, flowing water and an educated physician." in the eleventh century, the arabic biographer al-mussawir emphasized that the main duty of a monarch was the preservation of health and well-being in his subjects. thus, islamic legislation required physicians to pay regular visits to army units, prisons and people living in outlying areas. the practice of medicine was regulated through a religious office, the hisba, headed by an official called the muhtasib with some of the powers of a modern ombudsperson. one function of the muhtasib was to act as the city medical officer of health. he prevented people with elephantiasis from using the public baths, regulated the cleanliness of public places such as markets, and ensured that garbage collectors did not handle food. one interesting example of applied hygiene was the method used to determine an appropriate location for construction of the main hospital in baghdad (chap. ). the merits of various sites were compared by hanging up pieces of meat, and noting the location where decomposition proceeded the most slowly. the city of córdoba under moorish rule further illustrates the infrastructure typical of the arab world during the tenth century ce. among other facilities, the city boasted public baths. in northern and western europe, public health infra-structure such as aqueducts and sewers fell into disrepair following departure of the roman garrisons, and during the mediaeval era the sanitary conditions in most cities were appalling. positive developments were the development of quarantine procedures and the re-emergence of a few public baths. food inspectors were appointed, and some cities also introduced zoning regulations, requiring malodorous trades such as tanning to be undertaken outside the city walls. water supply and sewage disposal untreated waste was thrown directly into the rivers of london and paris, and travellers were advised: "wise men go over bridges, and fools go under them." in ce, king edward iii ordered the mayor of london to: "cause the human faeces and other filth lying in the streets and lanes in the city top be removed with all speed to places far distant, so that no greater cause of mortality may arise…" a fourteenth century ordinance prohibiting the emptying of latrines into a creek near london's city wall remained largely ignored, so that in the fifteenth century the stream was buried underground. substantial populations of hogs and cattle roamed the streets of many large cities, adding to the urban stench. uncontaminated water was a rarity, and a lack of refuse disposal encouraged rat infestations. infrequent bathing and unwashed woolen clothing led to a proliferation of fleas and other insect vectors of infection. during the mid-fourteenth century, two thirds of the european population was killed by the flea-borne bubonic plague (the "black death", - ce). many doctors deserted their patients during this epidemic, and others proposed preposterous remedies. guy de chauliac wrote: "so contagious was the disease…. that no one could see or approach the patient without taking the disease…for self-preservation, there was nothing better than to flee the region… to purge oneself with pills of aloes, to diminish the blood by phlebotomy and to purify the air by fire and to comfort the heart with senna and things of good odor and to soothe the humours with armenian bole and resist putrefaction by means of acid things." chauliac unwittingly kept the rats and fleas away from pope clement vi, by surrounding his bedside with charcoal burners. a few years following the black death, observant physicians hypothesized that ships arriving from overseas were contributing to the recurring epidemics of plague. at first, hostels for sick townsfolk and newly arrived visitors were set up outside the city, but this was not entirely effective in containing infection. thus in ce, a trentino ( days) of isolation on an uninhabited island was required at many european ports of entry. subsequently, the isolation period was extended to days, perhaps because of an ancient greek doctrine that a contagious disease became manifest within days. in britain, recently arriving travellers were quarantined on guardships, anchored in the thames estuary ( fig. . ). most of the roman baths in northern europe had been abandoned by the mediaeval era, in part because of the high cost of heating the bath water, and in part because the church considered public bathing as a common prelude to venal sins. the church also had concerns about reinforcing belief in the supposed healing powers of celtic water deities (chap. ). nevertheless, as prosperity increased in the latter part of the middle ages, public baths were built or reopened in various parts of europe. in britain, the king's bath was built over the sulis minerva temple in the city of bath, and paris had established public baths by the thirteenth century. in germany, the tradition of river bathing had persisted from celtic times, and a growing number of new public bath-houses were constructed during the th and th centuries. admission to a bath-house was expensive, and poorer germans considered the payment of "bath money" a great blessing. the full luxury package of a spa treatment included washing, scouring and slapping of the body with a sheaf of twigs, a steam bath, rubbing to induce perspiration, swatting the skin with wet rags, scratching, hair washing, cutting and combing, lavendering, and blood letting. unfortunately, some of the baths subsequently became the scene of debauchery, prostitution and infection, and by the sixteenth century, many were closed for fears of spreading syphilis, leprosy and plague ( fig. . ). personal hygiene substantial quantities of soap were traded during the mediaeval era, but this was used more for the washing of wool than for cleansing of the skin. monasteries boasted laundry rooms, and many women listed their trade as "laundry woman." however, the laundering of clothes was an infrequent luxury for poorer people, and indeed many had no spare set of clothing, so that fleas flourished in the poorer households. food inspection basic foodstuffs such as wine, beer, bread, meat, fish and salt were frequently adulterated in mediaeval times. to counter such abuses, several european governments appointed food inspectors. in britain, in , the assize of bread and ale regulated the price of these staples in relation to the price of corn. occasional renaissance scholars expressed some interest in health promotion. the english diplomat and scholar thomas elyot (c. - ) wrote a book entitle the "castell of health," summarizing the latest medical knowledge for those unfamiliar with greek, and the venetian nobleman luigi cornaro ( - ) wrote a book on the art of living a long life. santo santorio (chap. ) also sought to put hygiene on a mathematical basis. most of renaissance society showed little interest in public health or hygiene, as shown by the outbreak and management of the great plague. however, boards of public health were set up in some cities. two small advances in personal hygiene were the introduction of cotton clothing and a growing use of toothbrushes. diligent housewives adopted a few other simple changes in household management to preserve the health of their families, and cambridge university insisted on a direct control of its food supply, the great plague the london "plague" of ce was one in a series of european epidemics of bubonic plague dating back to the "black death." the great plague claimed at least , lives in central london, this being about a half of the population who had not fled from the city. indeed, the death count was probably underestimated, since publically appointed street monitors were open to bribery by those who did not wish to disclose that their house had become infected. samuel pepys commented that the prevalence of the disease was such that corpses could not removed during the hours of darkness ( fig. . ). people were confined to their homes if one family member was infected, thus virtually ensured the death of the entire household. two watchmen were posted at the doors of infected homes for days, at a cost of d per house per day, and the victims received a public stipend of d per day to pay for food, fuel and medicaments. believing that the disease was conveyed by miasmata, the college of physicians recommended using bonfires to displace the infected air. there was probably some incidental benefit from these fires, since the smoke tended to drive away the flea-ridden rats that were vectors of the disease. the epidemic was eventually checked by the great fire, which consumed both the rats and the plagueinfested slum dwellings. in europe, local boards of public health were established; they adopted various measures for the containment of epidemics and the provision of social support to the community. in some cases, they designated specific physicians to attend plague victims, and in florence, local doctors prepared a public information booklet that summarized current knowledge on plague prevention. a further responsibility of these boards was to deal with doctors who failed to report communicable diseases in wealthy patients. one roman doctor who was arrested for this offence was ordered to serve as resident physician at the local pest-house. outbreaks of the plague placed a severe financial stress upon some municipalities. in milan, extra funding was needed to hire physicians and grave-diggers, to pay for operating a quarantine "pest-house," and to reimburse the infected for two-thirds of the estimated value of their possessions, which were summarily burned. some municipalities set up immigration offices on mountain passes to control the arrival of infected travelers, and others restricted imports, exports, market trading, travel and funerals, although it was unclear how far these costly measures were successful in reducing the toll of disease and mortality. personal hygiene and household management one positive development during the renaissance was the introduction of washable cotton clothing and sheets. this greatly curtailed the spread of insect-borne diseases, particularly among those with sufficient wealth to own several changes of clothing. another innovation was popularization of the bristle toothbrush. this device had been invented by the chinese in the thirteenth century, but did not become popular in england until the late seventeenth century, beginning with the aristocracy. without necessarily knowing why, tudor housewives achieved some sterilization of their dairy equipment by scouring with salt and hot water, and then exposing utensils to bright sunlight. infestation of houses by fleas was also countered by sprinkling appropriate herbs beneath the rush mats that covered their floors. the renaissance saw further occasional attempts to control the quality of food, particularly for the wealthy. cambridge university insisted that the direct supervision of their refectories was important to preserving the health and well-being of their students. one of those promoting hygiene during the enlightenment was the physician james mackenzie, who in wrote a text on "the history of health and the art of preserving it." the enlightenment saw some improvement of health infra-structure many dwellings for the poorer citizens of europe.were now constructed of brick and boasted glass windows. and samuel johnson ( - ) was urging a pro-active response to the prevention of disease:"we must consider how many diseases proceed from our own laziness, intemperance or negligence… and beware of imputing to god, the consequences of luxury, riot and debauchery." the diderot encyclopédie, first published in , included a section on hygiene, which wss defined as: "the things which mankind uses or handles… and their influence on our constitution and organs." gottfried wilhelm leibniz ( - ) was perhaps the greatest enthusiast for public health during this era. he strove to establish a pattern of medical training that was oriented towards public health and preventive medicine rather than the treatment of disease. he reminded his colleagues that hippocrates had registered every successful cure, and he urged a similar meticulous recording of outcomes in order to provide a modern preventive medicine data-base. he proposed that standardized questionnaires should be developed to examine eating habits, and that careful mor-the enlightenment tality statistics should be collected so that findings could be correlated with the local climate, air conditions and the nature of the soil. a few other scientists such as hales (who improved the water supply for his village of teddington), and bernouilli (with authored a probability study demonstrating the merits of vaccination) were also interested in public health. but concern about the provision of clean drinking water, adequate treatment of sewage and garbage, and protection against communicable diseases remained the exception rather than the rule, with most countries making a poor showing on indices of population health. francis bacon published studies on the percolation, filtration, distillation and coagulation of water as early as . anton van leeuenhoek described the microscopic animalicules that he had seen in dutch drinking water in , and the french scientist joseph amy patented a water filter in . however, the quality of water in most large cities left much to be desired. philippe de la hire ( - ) mapped the area around paris, seeking to improve the water supply to versailles, probably as much to service the palace ornamental fountains as to provide clean drinking water in the town, and he built a massive aqueduct for this purpose (fig. . ) . he further suggested that householders should install a sand filter to purify the water collected from the roofs of their dwellings, although he noted that one alternative source of water, from underground aquifers, was rarely polluted. in , paisley, scotland became the first british city to establish a municipal water treatment plant. it used a sand filter that had been developed by robert thom. in , paris also constructed a large water treatment facility on the seine; here, river water was allowed to settle for hours, and was then passed through sponge pre-filters and main filters that contained sand and charcoal. despite these advances, the residents of broad st., in central london, faced a massive outbreak of cholera as late as , because they were drawing water from a shallow well that was located close to a cholera-contaminated cess-pit. too often, the city dwellers of the enlightenment continued to pass sewage into open gullies or cess-pits that were fig. . ruins of an aqueduct, built by philippe de la hire to improve the water supply to the city of versailles and its royal palace (source: http://en. wikipedia.org/wiki/ canal_de_l'eure) close to wells, and garbage was thrown directly onto the street. however, in , the conseil supérieur of new france ruled that in order to reduce infection, the houses in quebec city must have latrines, and that garbage must be carried to the river st. lawrence, rather than simply thrown out of the door. populatiion health during the enlightenment vital statistics provide simple objective indices of overall population health during the enlightenment. at birth, the average european could expect to live no more than years. a third to a half of the population died before reaching the age of years. those who survived to their mid-teens lived into their s or even their early s, and at the age of the aristocracy could expect to live a further - years; this was an improvement over the years of adult survival typical of the fourteenth century. survival prospects were much worse in north america than in europe during the enlightenment. many of the population succumbed to fevers, intestinal diseases, and, in the case of the african slaves, to harsh working conditions. a quarter of european immigrant children did not survive until their first birthday, and half of all marriages ended in the death of one partner before their seventh wedding anniversary. epidemics of beri-beri, smallpox, malaria and yellow fever wreaked havoc among early colonists. two of every three deaths were attributed to typhoid, dysentery or salt poisoning. in an attempt to reduce this terrible toll, newly arrived immigrants were initially isolated in "guest houses." replacement of contaminated water by wine, beer or cider, a reduced consumption of infected clams, and a scattering of the population to areas where there were copious fresh water springs reduced deaths from typhoid and dysentery, but progress in reducing overall mortality was slow. in early canada, dispersal of the population along the major rivers made major epidemics less likely than in the urban settlements of the united states, but isolation, accidents and harsh winters made canadian life expectancy worse than those in either europe or the u.s. only a small fraction of the population lived beyond years, and many of the children suffered from rickets and anaemia. typhus and smallpox were also recurrent problems. the victorian era was marked by growing government responsibility for the health of the public in large european cities. there was a gradual improvement in the quality of housing, and demographics showed a burgeoning birth rate. social reformers also succeeded in abolishing child labour and slavery from western society (chap. ). in this section, we will discuss the role of boards of health, continued deaths from poisoning, and improvements in housing conditions. major epidemics of influenza, cholera, typhus, typhoid fever and scarlet fever sparked a deep concern about population health in victorian england. in london, england, cholera killed , people in - and , in (chap. ). however, leaders of a new sanitary movement such as edwin chadwick ( - ) and thomas southwood smith ( - ) began to recognize that ill-health of the individual soon became ill-health of the population. they thus made urgent calls for the provision of clean drinking water, proper removal of refuse and sewage treatment. chadwick and smith sat as commissioners on london's general board of health that regulated the water supply and sewer connections for all new housing in the city, and provided adequate burial grounds for those who died. the quality of london's drinking water was rapidly upgraded, and money was spent on methods of preventing death during childbirth. the public health acts of and also established public baths and wash-houses, and by the s, health-conscious municipalities were building public swimming pools. in lower canada (quebec), a physician was appointed as health officer in , with the primary responsibility of monitoring the sick and starving people who were arriving on immigrant ships from europe. by , a strengthened five-member board of health was supervising quarantine arrangements on grosse isle, in the st. lawrence river near to quebec city. nevertheless, the number of immigrants was such that this holding facility was at times overwhelmed, and cholera periodically reached quebec and montreal, killing between - % of the population. in , people also died of typhus while they were quarantined at grosse isle. a central board of health for both upper and lower canada was created in . compulsory vaccination against smallpox was introduced in the early s. in the united states, organization of sanitary reform began rather later than in canada. the city of new york enacted the metropolitan health bill in , creating a -person board of health. immigrants were processed on ellis island, just outside new york city. the original wooden structure was quickly destroyed by a catastrophic fire, but a stone replacement building opened in . many immigrants spent only a few hours in the facility, but those with contagious disease were summarily denied admission to the united states. continued deaths from poisoning many victorians died from eating adulterated or diseased food. one report to the british privy council ( ) estimated that % of meat came from diseased cattle. flour was expensive, and bakers frequently adulterated it with chalk (to whiten it) and alum; often, the bakers also kneaded the mixture with their bare feet. an act prohibiting the adulteration of food was passed in , but its enforcement was an option for local authorities, so that it was not very effective. cooking was typically done in tin-lined copper pans; wealthier citizens replaced the pots when the tin had worn away, but the poor could not afford to do this, and in consequence they sometimes developed copper poisoning. other sources of poisoning in the victorian home were leaking gas pipes, lead used in white paint, and arsenic used to colour wallpapers. in the early nineteenth century, the sudden influx of country folk into the major cities of europe created hideous slums: "in big, once handsome houses, thirty or more people of all ages may inhabit a single room." housing gradually improved over the victorian era, as many workers accumulated sufficient funds to purchase modest but well-built homes. enlightened industrialists also constructed model housing estates for their employees. robert owen ( - ) organized a model community for his workers at the new lanark mills, in scotland, complete with a nursery school. he envisaged an even more ambitious employee housing project in new harmony, in, but this project failed within two years. the quaker chocolate manufacturer george cadbury ( - ) built a model village for his employees around his factory at bournville, near birmingham, and in the u.s. george pullman, the railway carriage czar, built a model town at pullman, il, in . charitable foundations such as the peabody trust began to replace the worst of london's slums with solidly-built if spartan apartments (fig. . ). the first peabody block, at spitalfields, included dwellings for the poor, shops complete with accommodation for the shopkeepers, and on the top floor baths and laundry facilities for a total cost of £ , . in the united states, building codes were improved during the victorian era, and a national housing association was founded in , under the aegis of the commission on the congestion of population in new york. there were also attempts to persuade philanthropists to build model tenements at low rents; buildings were bought, renovated, and then rented to relocated slum dwellers who were given "friendly instruction" on management of their new households. despite substantial progress in the delivery of public health, there remain a number of continuing challenges in the twenty-first century. current issues include the definitive control of the sales of tobacco and mood-altering drugs, the regulation of automotive emissions and other source of urban air pollution, management of the hiv/aids epidemic, concern over a growing reluctance to accept childhood vaccinations, and the management of infections spread by international air travel. in the edwardian era, cigarette manufacturers had promoted their wares as the cure for various respiratory conditions such as asthma and hay fever. but in , the american physician isaac adler pointed to a growing incidence of lung cancer, and he speculated that the abuse of tobacco and alcohol might be responsible. anti-smoking groups developed in germany following world war i, and a magazine (german tobacco opponents) was published from to . the nazi regime was opposed to smoking, with hitler declaring it a waste of money. in particular, women who smoked were considered as unsuitable to be german wives and mothers. during world war ii, the axis powers made much propaganda from the fact that hitler, franco and mussolini were non-smokers, whereas churchill, roosevelt and stalin were all heavy users of tobacco. evidence of the toxicity of tobacco steadily accumulated during the modern era. in , fritz linkint dresden demonstrated an increased prevalence of lung cancers in smokers. his research was confirmed in , with a case-control study by franz hermann muller of cologne. during the s, ernst wynder at the sloan-kettering institute in new york and richard peto and bradford hill at oxford university advanced even more compelling evidence that cigarettes were carcinogenic. hill concluded that consuming cigarettes per day increased the odds of dying from lung cancer as much as forty-fold. other damning evidence came from cellular pathology, animal experimentation and the demonstration of toxic chemicals in cigarette smoke. however, for a substantial part of the post-modern era, public health workers had to combat a deliberate campaign by the cigarette manufacturers to confuse and deceive the general public. the manufacturers were well aware of the damning facts by the early s, but their misleading propaganda was able to increase u.s. cigarette sales to a peak of billion units in . as late as , only a third of u.s. doctors considered smoking as "a major cause of cancer," and % of physicians were still smoking on a regular basis. beginning in the mid s, there was a dramatic decrease in the social acceptability of cigarette smoking, and growing restrictions were placed on public areas where smoking was permitted. this resulted from demonstrations that passive exposure to cigarette smoke gave rise to small but significant increases in the risks of chronic respiratory disease and asthma in childhood, and carcinoma of the lungs and cardiovascular disease in adults. public polls showed a growing acceptance of public health measures to control smoking in public spaces. cigarette manufactur-ers went to particularly great pains to obfuscate the risks of passive exposure to cigarette smoke, but adverse effects were clearly demonstrated during the s, not only by epidemiological research, but also by the exposure of volunteers to machine-generated cigarette smoke while they exercised in closed chambers. public health workers continue to face many challenges in reducing the sales of tobacco products, as manufacturers doggedly resist measures to reduce consumption through increased taxation, prohibition of sponsorships, and plain packaging. they constantly seek methods of creating new addicts, both through extensive advertising in third world countries and through such tactics as the marketing of electronic cigarettes. as recently as , cigarette smoking still accounted for . % of deaths world-wide. the toll from cigarettes is now compounded by the effects of mood-altering drugs. several countries (including canada) have abandoned attempts to prohibit the marketing of marijuana, with as yet no clear standards of dosages compatible with worker and road safety, and an ever growing segment of the north american population is becoming addicted to powerful opiates, with a high risk of deaths from overdoses. british columbia alone had deaths from opiate overdoses in , despite providing emergency workers with supplies of the antidote naloxone. the modern era saw a dramatic drop in the sulphurdioxide/large particulate smog associated with coal fires in many developed societies, but air pollution problems have continued from coal-fired power station and sautomotive emissions, particularly during thermal inversions. the exposure of cyclists and pedestrians to carbon monoxide was studied during the s. substantial concentrations of carbon monoxide were recorded on congested city streets, particularly if air movement was impeded by tall buildings, but any build-up of carboxyhaemoglobin in the blood stream was reversed quite quickly when the individual moved to a less polluted area. the only adverse clinical effect from carbon monoxide exposure was a somewhat earlier onset of angina if a person with coronary atherosclerosis exercised on a heavily polluted street. chamber experiments by steve horvath in santa barbara, ca, and larry folinsbee in toronto documented acceptable ceilings of exposures to the ozone that was formed by the action of sunlight upon the nitrogen oxides from vehicle and aircraft exhaust. the threshold concentration causing a minor disturbance of respiratory function in healthy exercisers was around . p.p.m., a level that was exceeded in some north american cities on heavily polluted days. to date, in many cities improved automotive emission controls have done little more than match the increase in vehicle registrations, and places such as paris and beijing have needed to forbid the access of drivers to the centre of cities on alternating days in order to reduce pollution levels. since ozone levels show a marked diurnal cycle, one immediate remedy for the active individual is to exercise at less heavily polluted times of the day (early morning or late at night). the ultimate solution to the problem of automotive exhaust probably lies in the replacement of gasoline-driven by electric or hydrogen-powered vehicles. the hiv/aids epidemic officially began in the u.s. in , when the centers for disease control reported a clustering of cases of pneumocystis pneumonia among homosexual men in los angeles. it was quickly realized that the condition was not limited to homosexual individuals, but was seen also in intravenous drug users, haemophiliacs and others receiving blood transfusions. thus, in august , the cdc coined the new term aids. a year later, luc montagnier and his associates at the pasteur institute in paris discovered the virus responsible for this disease. much effort has since been devoted not only to finding highly effective antiretroviral agents, but also in devising measures to reduce transmission of the disease. particular emphasis has been placed upon the wearing of condoms during sexual intercourse, in providing sterile needles for intravenous drug users through programmes of needle exchange and supervised injection sites, in closer control of blood banks and in ensuring sterility during drug injection treatments of tropical diseases. nevertheless, success in controlling the epidemic has as yet been only partial. in the u.s. the disease had already claimed , lives by ; a further million were living with the disease, and , fresh cases were diagnosed in that year. in rural africa, the situation remains even worse, with as many as a third of young adults currently infected. during the early part of the post-modern era, successful childhood vaccination campaigns brought the incidence of mumps, measles and rubella to a very low level in most developed countries, and the who set the year ce for the total elimination of measles and rubella from the european region. however, the percentage of children receiving vaccination has decreased in recent years, with parents weighing the low current risk of infections relative to the supposed dangers of developing meningo-encephalitis and autism. fears that vaccination would cause autism stemmed from a paper published by the british physician andrew wakefield, in . extensive research found no evidence to support his claims, and the british medical journal recently declared that the original article was fraudulent. further, the british general medical council found wakefield had been guilty of serious professional misconduct, and he was struck from the medical register. there have since been small outbreaks of measles consequent upon the decreased proportion of vaccinations in britain and in canada, and unfortunately many of the general public remain convinced that vaccination can cause autism. infectious diseases can now spread very rapidly, due to the ever-growing number of people who engage in global air travel. this problem is well exemplified by an epidemic of sars (severe acute respiratory syndrome). this began in mainland china in november of , and due to delayed reporting by the chinese authorities it spread rapidly around the world. the who issued a global health alert on april th . fortunately, application of rigid quarantine measures contained the epidemic, with relatively few deaths in north america, and by july th , the who was able to declare that the sars epidemic was over. many of the major epidemics of earlier eras were due largely to poor hygiene-a lack of clean water, poor sewage treatment, and an inadequate control of people who were already infected. although we often assume that these issues have now been resolved, it is important to recognize that in many third world countries supplies of clean water and adequate supplies of food are still lacking, with shortages often exacerbated by ethnic conflicts. the same issues of clean water, waste disposal and burial of the dead could still arise in wealthier countries today if there were to be an earthquake, a typhoon or a tsunami, and emergency services must be prepared to give the highest priority to an early re-establishment of the basic health infrastructure following any natural disaster. issues in the adulteration of food have now been largely overcome in developed society, but the current obesity epidemic underlines that problems still have to be resolved in terms of persuading food processors to avoid tactics designed to persuade consumers to overeat. for those who can afford housing, the modern single-family home is generally well-equiped to optimize the health of those who are living in it. massive tower blocks are less suited to a healthy and active life-style, particularly for families with young children. moreover, ever-increasing minimum specifications for housing, a growing world population and a lack of land is presenting public health agencies with the issue of a growing proportion of homeless individuals in many large cities. globalization is presenting new challenges to public health, not only with the rapid spread of infections, but also with the international enforcement of regulations on issues ranging from emission controls on cars to the quality of foods and medications. the ideal forum for developing appropriate preventive measures would seem the world health organisation, but unfortunately (as with many international bodies) its effectiveness is often limited by political considerations, including threats from some nations to slash funding unless criticism of their practices is shelved. . are the infrastructure constraints of an earlier era still compromising public health in third world countries? questions for discussion child against measles, mumps and rubella? what will be the likely new challenges to public health agencies over the next years? public health foundations: concepts and practices cigarette smoking: health effects and challenges for tobacco control plague and the poor in renaissance florence principles of water resources bathing in public in the roman world mission and method: the early nineteenth century french public health movement history of hygiene asian medical systems: a comparative study hygiene in the early medical tradition public health victorian medicine and popular culture private choices and public health. the aids epidemic in an economic perspective health, civilization and the state; a history of public health from ancient to modern times the nazi war on cancer housing in urban britain environmental policy and public health: air pollution, global climate change and wilderness a history of public health shephard rj. the risks of passive smoking on the mode of communication of cholera the new public health the establishment of a board of health for new york city in further reading some early societies had an infrastructure that provided clean water and the removal of sewage, but since this was usually available only to wealthy citizens, its impact upon the course of epidemics was limited. major cities such as london did not build a comprehensive infrastructure until the middle of the victorian era, when appropriate initiatives were taken by newly formed boards of public health. although the traditional concerns of public health have now been largely met in developed societies, new challenges are constantly arising. these include the control of tobacco products and mood-altering drugs, the reduction of automotive emissions and other forms of urban pollution, management of the hiv/aids epidemic, overcoming a growing reluctance to vaccinate infants, and countering the rapid spread of infections by air travel. key: cord- -hprwqi n authors: löscher, thomas; prüfer-krämer, luise title: emerging and re-emerging infectious diseases date: - - journal: modern infectious disease epidemiology doi: . / - - - - _ sha: doc_id: cord_uid: hprwqi n emerging infectious diseases (eids) are characterized by a new or an increased occurrence within the last few decades. they include the following categories emerging diagnosis of infectious diseases: old diseases that are newly classified as infectious diseases because of the discovery of a responsible infectious agent. europe including great britain as well as in india, china, and japan. emerging vector-borne disease events concentrated in densely populated subtropical and tropical regions mostly in india, indonesia, china, sub-saharan africa, and central america (see figs. . , . , and . ). the identification of new infectious agents in old diseases with unknown etiology is still the basis in many epidemiological studies. such newly detected bacteria and viruses in the last few decades are listed in table . . since the detection of helicobacter pylori in , this infection has been identified as the causative agent in % of b-gastritis cases. the risk of duodenal ulcer is increased by - -fold in patients with helicobacter-associated gastritis. who declared h. pylori as a carcinogen of first order because of its potential to enhance the risk of stomach carcinoma and malt lymphoma in long-term infection. in highprevalence regions for h. pylori, the frequency of stomach carcinoma is significantly higher compared to low-endemic areas (correa et al. ). the identification of h. pylori facilitates curative treatment of most associated diseases in individuals. but the most important epidemiological effect on associated diseases is attributed to increased hygienic standards in industrialized countries with a substantial reduction of h. pylori prevalences in younger age cohorts. transmission of h. pylori occurs mainly in childhood. in western developed countries the overall prevalence is around %, higher in older age groups due to a cohort effect, and this increases with low socioeconomic status (rothenbacher et al. ). in countries with low hygienic standards the prevalences are still high in younger age groups and reach % in developing countries. in developed countries, migrant subpopulations from less-developed regions show significantly higher prevalences in comparison to the nonmigrant population (mégraud ). since the early th century, a characteristic expanding skin lesion, erythema migrans (em), and an arthritis associated with previous tick bites were known. borrelia for many decades. increased outdoor activities facilitated contacts between humans and ticks in the s and the s and increased transmission of borrelia to humans at the northeastern coast of north america, leading to the discovery of borrelia burgdorferi in by willy burgdorfer. three different stages of the disease that describe the stage of infection and the involvement of different organ systems are known: stage , early localized infection; stage , early but disseminated infection; and stage , late stage with persistent infection. lyme disease is endemic at the east coast and in minnesota in the united states, in eastern and central europe, and russia. seroprevalence rates that reflect about % of nonclinical infections vary between and % in the general population in germany (hassler et al. ; weiland et al. ) . in high-risk groups like forest workers in germany the prevalences reach - % (robert koch institute a). in ticks (ixodes) the prevalences are between and % depending on the geographical area and the testing method used [immunofluorescence test, ift and polymerase chain reaction (pcr)]. in most studies the main risk factors of infection are age (children: - years, adults - years), outdoor activities, skin contacts with bushes and grass, and the presence of ticks in domestic animals (robert koch institute b) . the probability of infection (seroconversion) after a tick bite in germany is - % and the probability of a clinical disease is . - . %. the probability that the bite of an infectious tick leads to infection in the host is - %. this depends on the time duration that the tick is feeding on the human body. since the detection of the etiologic infectious agent and the subsequent development of laboratory diagnostic tests in the s, the number of reported cases of lyme disease has increased from to , per year, indicating that it is an "emerging diagnosis." the reported numbers vary depending on the reproduction of the hosting rodents for ticks as well as the contacts between humans and nature (spach et al. ) . ticks may live for several years and their survival, reproduction rate, and activity are directly affected by changes in seasonal climate through induced changes in vegetation zones and biodiversity, hence causing local alterations of the tick's habitat and in the occurrence of animals that are carriers of different pathogens (like small rodents). several studies in europe have shown that in recent decades the tick ixodes ricinus, transmitting lyme borreliosis and tick-borne encephalitis (tbe), has spread into higher latitudes (e.g., sweden) and altitudes (e.g., czech republic, austria), and has become more abundant in many places. such variations have been shown to be associated with recent variations in climate. as a result, new risk areas of both diseases have recently been reported from the czech republic. climate change in europe seems likely to facilitate the spread of lyme borreliosis and tbe into higher latitudes and altitudes, and to contribute to extended and more intense transmission seasons. currently, the most effective adaptive strategies available are tbe vaccination of risk populations and preventive information to the general public (danielova et al. ; lindgren et al. ; materna et al. ). an effective vaccine was licensed for b. burgdorferi in . in europe, where different variants of borrelia are present (mostly b. afzelii and b. garinii), this vaccine is not protective. trivalent vaccines for europe are in clinical trials. in recent years, norovirus infections are increasingly recognized as the cause of large outbreaks of diarrheal diseases in the general population, school classes, nursing homes, hospitals, and cruise ships in western countries with peaks in colder seasons (winter epidemics) (centers of disease control ; verhoef et al. ; robert koch institute a) . this is a typical example for emerging diagnosis due to increasing availability of routine pcr testing for these viruses in stool samples. noroviruses (family caliciviridae) are a group of related, single-stranded rna viruses first described in an outbreak of gastroenteritis in a school at norwalk, ohio, in . five genogroups are known. immunity seems to be strain specific and lasts only for limited periods, so individuals are likely to get the infection repeatedly throughout their life. it is estimated that noroviruses are the cause of about % of all food-borne outbreaks of gastroenteritis. for several years there has been an ongoing epidemic in several european countries due to drift variants of a new genotype (gg ii. jamboree) previously unknown to this nonimmune population (robert koch institute a). as a result of an analysis of outbreaks in the united states between and , direct contamination of food by a food handler was the most common cause ( %), person-to-person transmission was less prevalent ( %), and even less frequently waterborne transmission could be proved ( %) (centers for disease control ). vomiting is a frequent symptom of norovirus enteritis and may result in infectious droplets or aerosols causing airborne or contact transmission. this may explain the difficulty to stop outbreaks in hospitals, nursing homes, and similar settings despite precautions to prevent fecal-oral transmission. also on cruise ships, person-to-person transmission is most likely in those closed settings, and drinking tap water is a risk factor as well (verhoef et al. ). searching for an agent which causes large outbreaks of enterically transmitted non-a hepatitis in asia and other parts of the world, the hepatitis e virus (hev) was first described in and cloned and sequenced in (reyes et al. ). meanwhile, hev has been shown to be a zoonotic virus circulating in pigs and other animals. it is implicated in about % of sporadic cases of acute hepatitis in developing countries and associated with a high case fatality rate in the third trimester of pregnancy ( - %). hev is a major cause of large epidemics in asia, and to a lesser extent in africa and latin america, typically promoted through postmonsoon flooding with contamination of drinking water by human and animal feces. recent data show hev also to circulate in european countries and to be associated with severe and fatal disease not only during pregnancy but also in the elderly and in patients with chronic liver conditions. in patients with solid organ transplants, hev may even cause chronic hepatitis and liver cirrhosis (kamar et al. ) . a recombinant hev vaccine candidate has demonstrated a high protection rate of approximately % during clinical trials in nepal (shrestha et al. ). for years, specific human papillomaviruses have been linked to certain human cancers and have been identified as causative agents of malignant proliferations. in the s the detection of papillomavirus dna from cervical carcinoma biopsies were published, showing that hpv types and are the most frequent (dürst et al. ; boshart et al. ) . the relation of hpv infections and cancer is further discussed in chapter . definition: only infections that are newly discovered in humans are listed in this chapter: hiv, new variant of creutzfeldt-jakob disease (vcjd), hemorrhagic uremic syndrome (hus) caused by enterohemorrhagic escherichia coli, viral hemorrhagic fevers like hanta, lassa, ebola, and marburg fever, nipah virus encephalitis, monkeypox, human ehrlichiosis, severe acute respiratory syndrome (coronavirus infection, sars), and avian influenza (h n ) (see fig. . and table . ). these infections mostly have their origin in zoonotic wildlife (e.g., avian influenza, monkeypox, hantavirus, nipah virus, and filoviruses) or livestock (e.g., vcjd). factors promoting the spread of these infections in humans are contacts with wildlife, mass food production of animal origin, and globalization (migration, transportation of goods and vectors) (see fig. . ). in addition, new strains or variants of well-known pathogens have emerged showing increased or altered virulence such as clostridium difficile ribotype or staphylococcus aureus strains expressing the panton-valentine leukocidin (see also chapter ). the epidemiology of hiv is treated in chapter and that of avian influenza and new influenza h n in chapter . in the year , years after the peak of the bse epidemic in the united kingdom, with an annual incidence rate in cows of . per million bovines aged over months, the first mortalities in humans with a new variant of creutzfeldt-jakob disease were observed in the united kingdom. until , smaller incidence rates of bse cases had been reported by other european countries in indigenous bovines and up to more than , per million in in ireland. from , bse started to increase in switzerland and portugal, from in spain and in recent years has spread to eastern european countries (organisation mondiale de la santé animale ). the infectious agent is a self-replicating protein, a "prion." the source of infection for cows is infectious animal flour. the transmission to humans occurs through oral intake of cow products, most likely undercooked meat and nerval tissues as well as transplants of cornea, dura mater, contaminated surgical instruments, or the treatment with hypophyseal hormones extracted from animal tissues. after a statuary ban on the feeding of protein derived from ruminants to any ruminant and the export ban of all cow products from england, the epidemic of bse in cows and the occurrence of human infections decreased in the united kingdom since . by june the total number of deaths in definite/probable cases of vcjd in the united kingdom was (the national creutzfeldt-jakob disease surveillance unit ). only a few numbers of vcjd were reported from other european countries and the united states (who ). nipah virus encephalitis was first observed in / in malaysia. the disease was transmitted by pigs to laborers in slaughterhouses and showed a lethality of %. the infectious agent was detected in (chua et al. ; lam and chua ) . since then, several outbreaks of nipah virus infections have been observed in asian countries: singapore in , india , and bangladesh since (who a harit et al. ) . the virus has been isolated repeatedly from various species of fruit bats, which seem to be the natural reservoir (yob et al. ). west nile is a mosquito-borne flavivirus that was first isolated from a woman with a febrile illness in uganda in . from the s, west nile fever endemicity and epidemics started being reported from africa and the middle east. severe neurological symptoms were thought to be rare. more recent epidemics in northern africa, eastern europe, and russia suggested a higher prevalence of meningoencephalitis with case fatality rates of - %. in , west nile virus was identified as the cause of an epidemic of encephalitis at the east coast of the united states (nash et al. ) . a seroepidemiological household-based survey showed that the first outbreak consisted of about , infections of which about , developed fever and less than % experienced neurological disease ). since then, epidemics occur during summer months in north america each year, with an estimated , febrile illnesses and over , encephalitis or meningitis cases in the united states in (centers for disease control ). age above years is the main risk factor for developing severe disease. the virus is transmitted mainly by culex mosquitoes, but also by sandflies, ceratopogonids, and ticks, with birds as reservoir hosts and incidental hosts such as cats, dogs, and horses. efforts are made to reduce the transmitting mosquito population and to prevent mosquito bites through personal protection as well as to prevent transmission through blood donations by screening (centers of disease control ). the first case of sars occurred in guangdong (china) in november of , leading to an outbreak with cases in china and hong kong ( cases worldwide) until july . the case fatality rate was . %. a new coronavirus (sars-cov) was identified as the causative agent (drosten et al. ) , being transmitted first by infected semidomesticated animals such as the palm civet and subsequently from human to human. some cases were exported to other countries, causing smaller outbreaks there, canada being the most affected country outside asia with cases, before control of transmission was effective. eight thousand and ninety-six cases were reported worldwide, until july , then further transmission stopped (besides one more case of laboratory transmission in ), indicating an efficient international cooperation in disease control (who b) . recently, sars-cov has been found in horseshoe bats, which seem to be the natural reservoir of the virus. about , - , cases of hemorrhagic fever with renal syndrome (hfrs) caused by hantaviruses are reported annually worldwide, with more than half in china, many from russia and korea, and numerous cases from japan, finland, sweden, bulgaria, greece, hungary, france, and the balkan with different death rates depending on the responsible virus, ranging from . % in puumala to - % in hantaan infections (schmaljohn and hjelle ) . hantaviruses are transmitted from rodent to rodent through body fluids and excreta. only occasionally do humans get infected. different types of hantaviruses are circulating in europe and the eastern hemisphere, predominantly puumala virus, dobrava virus, and tula virus, adapted to different mouse species. depending on the virus type the case fatality rate is between and %. as an example, the annual rate of reported cases in germany was about cases per year from onward. this started to change in with reported cases and rose dramatically to cases in . that year, hantavirus infections were among the five most reported viral infections in germany. reasons for the rise in human infections were an increase in the hosting rodent population due to a very mild winter / and an early start of warm temperatures in spring which led to favorable nutritional situations for the mice influencing their population dynamics. in addition, favorable climatic conditions enhanced the outdoor behaviors of humans facilitating transmission in rural areas (robert koch institute b; hofmann et al. ) . since , a previously unknown group of hantaviruses (sin nombre, new york, black creek canal, bayou-in the united states and canada; andes, in south america) emerged in the americas as a cause of hantavirus pulmonary syndrome (hps), an acute respiratory disease with high case fatality rates (approx. %), causing a new, significant public health concern. a total of cases had been reported until march in states, most of them in the western part of the united states (centers for disease control ). lassa virus was detected for the first time in during an outbreak affecting nurses in a missionary hospital in lassa, nigeria. however, the disease had previously been described in the s. lassa virus is enzootic in a common peridomestic rodent in west africa, the multimammate rat mastomys natalensis, which is chronically infected and sheds the virus in urine and saliva. human infection through direct or indirect contact with rats or their excretions is rather common in some west african countries and estimates from seroepidemiological and clinical studies suggest that there are several hundred thousand cases annually. however, only a minority of infections seems to progress to severe hemorrhagic disease with a case fatality rate of - % in hospitalized cases. the virus can be transmitted by close person-to-person contact and nosocomial spread has been observed under poor hygienic conditions. marburg and ebola viruses, which were first detected during outbreaks in and , respectively, have so far been observed only during several limited outbreaks and a few isolated cases in certain countries of sub-saharan africa. however, very high case fatality rates ( - %), the occurrence of outbreaks that were difficult to control in resource-poor settings, and the obscure origin of these viruses have attracted considerable public interest worldwide. recently, evidence was found for both marburg and ebola viruses to occur in certain species of bats that probably constitute the natural reservoir of these filoviruses (towner et al. ). although the disease burden of these viral hemorrhagic fevers is low, they gained considerable international attention due to -their high case fatality rates, -the risk of person-to-person transmission, -several imported cases to industrialized countries, and -fears of abuse of these agents for bioterrorism. as a consequence, considerable resources have been invested, even in nonendemic countries, in the setting up of task forces and high containment facilities for both laboratory diagnostic services and treatment of patients using barrier nursing. this highly virulent strain of c. difficile expresses both cytotoxins a and b and, in addition, the binary toxin cdt, an adp-ribosyltransferase. due to a deletion in the regulatory tcdc gene, the synthesis rates of toxin a and b are increased by -and -fold, respectively. this strain was detected in for the first time in pittsburgh, usa. since then it has spread to canada, and in it reached europe causing multiple outbreaks in hospitals and nursing homes (warny et al. ) . c. difficile -associated colitis has shown high case fatality rates ( - %) and an increased relapse rate. containment of outbreaks in hospitals and other institutions necessitates isolation of patients or cohorts and strict hygienic measures. during recent decades, a large variety of well known infectious diseases has shown regional or global re-emergence with considerable public health relevance (table . ). globally, tuberculosis is probably the most important re-emerging infectious disease. in developing countries, tb infection still is extremely common and, in the wake of the hiv pandemic, the percentage of those developing overt disease has increased dramatically. worldwide, tb is the most common opportunistic infection in patients with aids. the significance of tb and hiv/tb coinfection is reviewed in chapters and . the re-emergence of some infectious diseases is closely related to the lack or the breakdown of basic infrastructures as seen in periurban slums and in refugee camps in developing countries, or as a consequence of war, breakdown of the civil society, or natural or man-made disasters. cholera is a formidable example for both re-emergence and epidemic spread under those conditions. another important group of re-emerging infectious diseases is caused by various vector-borne infections, such as malaria, dengue fever, and yellow fever. these major vector-borne diseases are treated in more detail in chapter . in addition, there are a variety of re-emerging infections transmitted by arthropod vectors such as various arboviral diseases and some protozoal diseases other than malaria (i.e., leishmaniasis, human african trypanosomiasis). the reasons for the emergence of several vector-borne diseases are rather variable and may range from climatic factors (e.g., global warming, rainfall), lack or breakdown of control, to changes in agriculture and farming and in human behavior (e.g., outdoor activities). these factors are usually quite specific for each of these diseases and largely depend on the specific ecology of the agent, its vectors, and reservoirs. cholera, an acute diarrheal infection transmitted by fecally contaminated water and food, had been endemic for centuries in the ganges and brahmaputra deltas in the th century before it started to spread to the rest of the world. since , six pandemics caused by the classical biotype of vibrio cholerae were recorded that killed millions of people across europe, africa, and the americas. it has been a major driving force for the improvement of sanitation and safe water supply. the seventh pandemic was caused by the el tor biotype, first isolated from pilgrims at the el tor quarantine station in sinai in . it started in in south asia, reached africa in , and is still ongoing. after more than hundred years, cholera spread to the americas in , and beginning in peru, a large epidemic hit numerous latin american countries with . million cases and more than , fatalities reported within years. out of the serogroups of v. cholerae, only o and o can cause epidemics. the serogroup o , first identified in bangladesh in , possesses the same virulence factors as o and creates a similar clinical picture. currently, the presence of o has been detected only in southeast and east asia, but it is still unclear whether v. cholerae o will extend to other regions. since , the re-emergence of cholera has been noted in parallel with the everincreasing size of vulnerable populations living in unsanitary conditions. cholera remains a global threat to public health and one of the key indicators of social development. while the disease is no longer an issue in countries where minimum hygiene standards are met, it remains a threat in almost every developing country. the number of cholera cases reported to the who during rose dramatically, reaching the level of the late s. a total of , cases were notified from countries, including , deaths, an overall increase of % compared with the number of cases reported in . this increased number of cases is the result of several major outbreaks that occurred in countries where cases had not been reported for several years such as sudan and angola. it is estimated that only a small proportion of cases -less than % -are reported. the true burden of disease is therefore grossly underestimated. the absence or the shortage of safe water and sufficient sanitation combined with a generally poor environmental status are the main causes of spread of the disease. typical at-risk areas include periurban slums where basic infrastructure is not available, as well as camps for internally displaced people or refugees where minimum requirements of clean water and sanitation are not met. however, it is important to stress that the belief that cholera epidemics are caused by dead bodies after disasters, whether natural or manmade, is false. on the other hand, the consequences of a disaster-such as disruption of water and sanitation systems or massive displacement of population to inadequate and overcrowded camps-will increase the risk of transmission. chikungunya virus, an arbovirus belonging to the alphavirus group, is transmitted by various mosquitoes. the virus was first isolated in tanzania in and since then has caused smaller epidemics in sub-saharan africa and parts of asia with low public health impact. in , the largest epidemic ever recorded started in east africa, spread to réunion and some other islands of the indian ocean, and then spread further to asia, with more than . million cases in india alone so far. characteristics of the disease are high fever and a debilitating polyarthritis, mainly of the small joints that can persist for months in some patients. now, for the first time, severe and fatal cases have been observed that may be due to certain mutations of the epidemic strain (parola et al. ) . the asian tiger mosquito aedes albopictus has proved to be an extremely effective vector in recent epidemics causing high transmission rates in big cities and leading to epidemics with high public health impact. this southeast asian mosquito species has been shipped by transport of used tires and plants harboring water contaminated with larvae to other continents and, since , ae. albopictus has successfully spread in italy and other parts of southern europe. in august , an outbreak of chikungunya fever occurred in northern italy with more than confirmed cases. the index case was a visitor from india who fell ill while visiting relatives in one of the villages and further transmission was facilitated by an abundant mosquito population during that time, as a consequence of seasonal synchronicity (rezza et al. ). ross river virus (rrv) is another arbovirus of the alphavirus group that causes an acute disease with or without fever and/or rash. most patients experience arthritis or arthralgia primarily affecting the wrist, knee, ankle, and small joints of the extremities (epidemic polyarthritis). about one-quarter of patients have rheumatic symptoms that persist for up to a year. the disease can cause incapacity and inability to work for months. it is the most common arboviral disease in australia with an average of almost , notified cases per year. rrv is transmitted by various mosquito species and circulates in a primary mosquito-mammal cycle involving kangaroos, wallabies, bats, and rodents. a human-mosquito cycle may be present in explosive outbreaks which occur irregularly during the summer months in australia and parts of oceania. heavy rainfalls as well as increasing travel and outdoor activities are considered as important factors contributing to the emergence of rrv epidemics. this flavivirus is transmitted by certain culex mosquitoes and is a leading cause of viral encephalitis in asia with , - , clinical cases reported annually. it occurs from the islands of the western pacific in the east to the pakistani border in the west, and from korea in the north to papua new guinea in the south. only in - infections will lead to encephalitis, which is, however, often severe with fatality rates of - % and with a high incidence of neurological sequelae. despite the availability of effective vaccines, je causes large epidemics and has spread to new areas during recent decades (e.g., india, sri lanka, pakistan, torres strait islands, and isolated cases in northern australia). je is particularly common in areas where flooded rice fields attract water fowl and other birds as the natural reservoir and provide abundant breeding sites for mosquitoes such as culex tritaeniorhynchus, which transmit the virus to humans. pigs act as important amplifying hosts, and therefore je distribution is very significantly linked to irrigated rice production combined with pig rearing. because of the critical role of pigs, je presence in muslim countries is low. crimean-congo virus is a bunyavirus causing an acute febrile disease often with extensive hepatitis resulting in jaundice in some cases. about one-quarter of patients present hemorrhages that can be severe. fatality rates of . - % have been reported in hospitalized patients. cchf is transmitted by hyalomma ticks to a wide range of domestic and wild animals including birds. human infection is acquired by tick bites or crushing infected ticks, and also by contact with blood or tissue from infected animals that usually do not become ill but do develop viremia. in addition, nosocomial transmission is possible and is usually related to extensive blood exposure or needle sticks. human cases have been reported from more than countries in africa, asia, southeastern europe, and the middle east. in recent years, an increase in the number of cases during tick seasons has been observed in several countries such as russia, south africa, kosovo, and greece. in turkey, where before no human cchf cases had been observed, a total of , confirmed cases, including deaths, were reported between and june . the emergence of cchf has been associated with factors such as climatic features (temperature, humidity, etc.), changes of vector population, geographical conditions, flora, wildlife, and the animal husbandry sector. rvf is a mosquito-borne bunyavirus infection occurring in many parts of sub-saharan africa. it infects primarily sheep, cattle, and goats, and is maintained in nature by transovarial transmission in floodwater aedes mosquitoes. it has been shown that infected eggs remain dormant in the dambos (i.e., depressions) of east africa and hatch after heavy rains and initiate mosquito-livestock-mosquito transmission giving rise to large epizootics. remote sensing via satellite can predict the likelihood of rvf transmission by detecting both the ecological changes associated with heavy rainfall and the depressions from which the floodwater mosquitoes emerge. transmission to humans is also possible from direct and aerosol exposure to blood and amniotic fluids of livestock. most human infections manifest themselves as uncomplicated febrile illness, but severe hemorrhagic disease, encephalitis, or retinal vasculitis is possible. in , rvf has been transported, probably by infected camels to egypt, where it caused major epidemics with several hundred thousand infections of humans. it has been suggested that introduction of rvf may be a risk to other potentially receptive areas such as parts of asia and the americas. floods occurring during the el niño phenomenon of in east africa subsequently gave rise to large epidemics and further spread to the arabian peninsula. most recent epidemics occurred in and following heavy rainfalls in kenya, somalia, and sudan, causing several hundred deaths. besides mosquito control, epidemics are best prevented by vaccination of livestock. leishmaniasis, a protozoal transmitted by sandflies, has shown a sharp increase in the number of recorded cases and spread to new endemic regions over the last decade. presently, countries are affected with an estimated million cases worldwide. there are about . million new cases of cutaneous and mucocutaneous leishmaniasis, a nonfatal but debilitating disease with % of cases occurring in afghanistan, brazil, bolivia, iran, peru, saudi arabia, and syria. the incidence of visceral leishmaniasis (vl), a disease with a high fatality rate when untreated, is estimated at around , per year. the situation is further aggravated by emerging drug resistance (table . ) and the deadly synergy of vl/hiv coinfection. epidemics usually affect the poorest part of the population and have occurred recently in bangladesh, brazil, india, nepal, and sudan. for many years, the public health impact of the leishmaniases has been grossly underestimated. they seriously hamper socioeconomic progress and epidemics have significantly delayed the implementation of numerous development programs. the spread of leishmaniasis is associated with factors favoring the vector such as deforestation, building of dams, new irrigation schemes, and climate changes, but also with urbanization, migration of nonimmune people to endemic areas, poverty, malnutrition, and the breakdown of public health. antimicrobial resistance of epidemiological relevance has emerged as a major problem in the treatment of many infectious diseases (table . ). resistance is no longer a problem that predominantly affects the chemotherapy of bacterial infections. it became increasingly important in parasitic and fungal diseases, and despite the short history of antiviral chemotherapy, it already plays a prominent role in the treatment of hiv infection and other viral diseases. resistance is also a problem in some of the emerging infections and will further complicate their treatment and control. resistance of bacterial pathogens has become a common feature in nosocomial infections, especially in the icu and in surgical wards. currently, the number one problem in most hospitals is s. aureus resistant to methicillin (mrsa, see chapter ). however, common problems of resistance also extend to other major bacterial pathogens such as enterococci, various gram-negative enteric bacilli, and pseudomonas species. resistance has developed not only to standard antibiotics (e.g., penicillins, cephalosporins, aminoglycosides, macrolides, or quinolones) but also to second-line antibiotics including carbapenems, glycopeptides, and newer quinolones. however, there is considerable geographic variation. in , the european antimicrobial resistance surveillance system (earss), a network of national surveillance systems, reported vancomycin-resistant rates among enterococci ranging from none in iceland, norway, romania, bulgaria, denmark, and hungary to % of enterococcus faecium strains in greece (earss ) . a surveillance study conducted in the united states hospitals from to showed that % of nosocomial bloodstream infections were caused by enterococci and that % of e. faecalis isolates and % of e. faecium isolates were vancomycin resistant (wisplinghof et al. ) . rates and spectrum of antibacterial resistance of e. coli and other gram-negative enteric bacilli may differ considerably from one hospital to the other. in some important pathogens of hospital-related infections such as klebsiella, enterobacter, and pseudomonas species, resistance to almost all available antimicrobials has been observed. this may complicate the choice of an effective initial chemotherapy considerably. therefore, each hospital has to monitor the epidemiological situation of resistance regularly, at least for the most important bacteria causing nosocomial infections, such as staphylococci, enterococci, gram-negative enteric bacilli, and pseudomonas. even in community-acquired infections, there has been a considerable increase in resistance problems. at present, approximately % of pneumococcal isolates in the united states are resistant to penicillin, and % exhibit intermediate resistance. the rate of resistance is lower in countries that, by tradition, are conservative in their antibiotic use (e.g., netherlands, germany) and higher in countries where use is more liberal (e.g., france). in hong kong and korea, resistance rates approach %. in addition, about one-quarter of all pneumococcal isolates in the united states are resistant to macrolides. this rate is even higher in strains highly resistant to penicillin, and increasingly there is multiresistance against other antibiotics such as cephalosporins. the prevalence of meningococci with reduced susceptibility to penicillin has been increasing, and high-level resistance has been reported in some countries (e.g., spain, united kingdom). although high-dose penicillin is effective in infections with strains of intermediate resistance, most national and international guidelines recommend broad-spectrum cephalosporins such as ceftriaxone as first-line drugs. however, in most developing countries, penicillin and chloramphenicol are the only affordable drugs. in recent years, certain strains of community-acquired s. aureus with resistance to methicillin (cmrsa) have been observed which produce a toxin (panton-valentine leukocidin) that is cytolytic to pmns, macrophages, and monocytes, and which are an emerging cause of community-acquired cases and outbreaks of necrotic lesions involving the skin or the mucosa, and in some patients also of necrotic hemorrhagic pneumonia with a high case fatality (vandenesch et al. ) . development of resistance is mainly determined by two factors: -the genetic potential of a certain pathogen, i.e., mobile elements such as plasmids, transposons, or bacteriophages, genes coding for resistance, and mutation rate. -the selection pressure caused by the therapeutic or the para-therapeutic application of antimicrobial drugs. in the hospital these factors are supported by -microbial strains that are highly adapted to this environment (e.g., rapid colonization of patients, resistance to disinfectants), -an increasing percentage of patients who are highly susceptible to infections due to old age, multimorbidity, immunosuppression, extended surgery, and invasive procedures, and -the frequent use of broad-spectrum antibiotics or combinations of antimicrobial drugs. another source of resistant bacteria has been identified in mass animal production and the use of antimicrobials as growth promoters (e.g., the glycopeptide avoparcin, the streptogramin virginiamycin) or as mass treatment in the therapy or the prevention of infections. the inadequate use of antimicrobial drugs is also an important factor responsible for the development of resistance in community-acquired infections. this is especially true in developing countries where only a limited spectrum of antibiotics is available, where shortage of drugs often leads to treatment that is underdosed or too short, and where uncontrolled sale and use of antibiotics is commonplace. as a consequence, resistance of gonococci is extremely frequent in southeast asia, and resistance of salmonella typhi, shigella, and campylobacter to standard antibiotics is common. some of the still effective second-line antibiotics have to be given parenterally or are not available because they are too costly. a typical example of the consequences of insufficient chemotherapy due to lack of compliance and/or unavailability of drugs is the alarming increase in multiresistance and extreme resistance in tb (see chapter ). resistance is also a problem in parasitic diseases such as malaria (see chapter ), leishmaniasis, or african trypanosomiasis. plasmodium falciparum developed resistance against all major antimalarial drugs as soon as they were used on a broad scale. resistance had contributed significantly to the increase in malaria-associated morbidity and mortality observed in many endemic areas (wongsichranalai et al. ) . a recent report on failures of the new artemisinin combination treatment for p. falciparum malaria at the thai-cambodian border supports fears of the development of resistance to this most promising class of drug at present (dondrop et al. ). resistance against antiviral drugs has developed almost from the beginning of antiviral chemotherapy (table . ). in the treatment of hiv infection, the risk of development of resistance has been drastically reduced by the combination of several drugs with different mechanisms of action (see chapter ). however, drug resistance remains the achilles' heel of the highly active antiretroviral therapy (haart) and may be at a considerable risk of expanding haart to the developing world. today, we have to realize that as we develop antimicrobial drugs, microbes will develop strategies of counterattack. antimicrobial resistance occurs at an alarming rate among all classes of pathogens. even in rich countries it causes real clinical problems in managing infections that were easily treatable just a few years ago. in life-threatening infections such as sepsis, nosocomial infections, or falciparum malaria, there is a substantial risk that the initial chemotherapy might not be effective. in addition, the delay caused by inadequate treatment might favor transmission to other people and support the spread of resistant pathogens (e.g., multiresistant tb). last but not the least, surveillance and control and the necessity to use expensive second-line drugs or combinations of antimicrobials are enormous cost factors. for developing countries this is a major limitation in the treatment and control of infections caused by resistant agents. so, in many ways, emerging resistance contributes to the emergence of infectious diseases. despite the availability of effective strategies for treatment and prevention, infectious diseases have remained a major cause of morbidity and mortality worldwide. however, the problems associated with infections are due to considerable changes. in industrialized countries the mortality caused by infectious diseases has decreased tremendously during more than years. however, during recent years, both mortality and morbidity associated with infections are increasing again. ironically, this is closely associated with the advances in medicine which have contributed to profound changes in the spectrum of both patients and their infections. advanced age, underlying conditions, and an altered immune response are common features in the seriously infected hospital patient today. immunosuppressive therapy is frequently used to treat neoplastic and inflammatory diseases or to prevent the rejection of transplants. some infections, most notably hiv/aids, cause immunosuppression by itself. in the compromised patient, infections are generally more severe or may be caused by opportunistic pathogens that will not harm the immunocompetent host. antimicrobial treatment is often less effective in these patients and tends to be further complicated by antimicrobial resistance which may manifest itself or develop at a higher frequency in the immunocompromised patient. an increasing percentage of infections are hospital acquired or otherwise health care associated. it is estimated that nosocomial infections affect . million patients and contribute to approximately , deaths in us hospitals annually (klevens et al. ). considering the rising number of elderly and immunocompromised patients, a further increase in severe infections can be predicted. in developing countries, the significance of infectious diseases has remained high for ages and despite the advances in medicine. until now, infections are by far the leading cause of both disability-adjusted life years and life years lost. the reasons are obvious and mostly related to poverty and lack of development causing poor and unhealthy living conditions, inadequate health systems, and lack of resources for prevention and treatment. this is, of course, just an integral part of the general socioeconomic problems of developing countries. however, poor health conditions per se are an important obstacle to development, and infections such as hiv/aids in sub-saharan africa can be a major cause of lack of development, increasing poverty, and political instability. generally, the situation of many developing countries has not improved during the last two decades, and the gap between the first and the third world has increased. however, most of the mortality and morbidity associated with infectious diseases is avoidable. as laid down in the millennium goals, a major task of the world community will be to counteract the imbalance between the industrialized and the developing countries and to find strategies to ensure participation in the progress of modern medicine for all. developing countries also carry the main burden of diseases caused by newly emerging and re-emerging infections (table . and . ) . however, the consequences of economical and political crises on emerging infectious diseases are obvious in industrialized countries also-such as the return of diphtheria or the increase in tb and multiresistant tb after the breakdown of the former soviet union. today, all countries worldwide are affected by emerging infections as well as by emerging antimicrobial resistance. in the age of globalization, travel and transport of people, animals, and goods of all kinds have increased tremendously. as a consequence, infectious agents may travel over long distances and at high speed. this is clearly evident with influenza pandemics or outbreaks such as the sars epidemic or with imported cases of viral hemorrhagic fever transmissible from person to person. the spread of antimicrobial resistance or the re-emergence of tb seems to be less spectacular, but the consequences may be at least as important in the long run. management and control of emerging and re-emerging infectious diseases can be very different from disease to disease and has to allow for all relevant factors of the populations at risk and of the specific disease including the ecology of the agent, its vectors, and reservoirs. however, some basic principles apply to all situations: -surveillance -information and communication -preemptive planning and preparedness -provision and implementation of • adequate treatment • adequate control and prevention -international cooperation active and passive surveillance systems with rapid reporting and analysis of data are essential for the early detection of outbreaks, changes in epidemiology, and other events of public health concern (see chapters and ). however, many resourcepoor countries do not have functional surveillance systems. in addition, reporting of infectious diseases may be neglected or delayed because of fears of stigma, international sanctions including trade and travel restrictions, or interference with tourism. classical examples are plague and cholera, but also recent examples such as the bse/vcjd crisis in the united kingdom or sars originating from china showed undue delays between first occurrence of cases and information to the public. although, in outbreaks of new and unknown diseases it may be difficult, or even impossible, to predict or assess the magnitude of the problem and the potential consequences, timely and adequate information and communication is not only obligatory, according to international regulations, but also the best strategy to avoid rumors, misbeliefs, panic, or disregard. in recent years, many countries have installed national plans of action for important epidemiological scenarios and outbreaks such as pandemic influenza, bioterrorism, import of viral hemorrhagic fevers transmissible from person to person, sars, and comparable diseases or outbreaks. all member states of the world health assembly that have so far not been able to install functional surveillance and/or pre-emptive planning are obliged to do so within a maximum of years after their ratification of the new international health regulations (who ) . preparedness not only means surveillance and planning but also has to include the provision of facilities to adequately treat and, if necessary, to isolate patients with infectious diseases of public health importance and relevant epidemic potential and/or at risk of transmission to other persons including health-care workers. task forces and high containment facilities for both laboratory diagnostic services and treatment of patients using barrier nursing have been set up in several countries. however, all health facilities of a certain level such as general hospitals should be prepared by their organization and structure to treat patients with infections of public health relevance such as multiresistant tb under appropriate isolation and barrier nursing conditions. this also applies to hospitals in resource-poor countries. adequate training of health-care workers and strict management have been effective to control outbreaks of highly contagious infections 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key: cord- -hkq wti authors: haukkala, hiski title: nonpolar europe? examining the causes and drivers behind the decline of ordering agents in europe date: - - journal: int polit doi: . /s - - - sha: doc_id: cord_uid: hkq wti is europe headed towards nonpolarity? what would that entail for the future stability and security of the continent? taking its cue from ir debates about the effects of polarity on international order, the article develops conceptual tools and an analytical narrative concerning europe during the post-cold war era. it refines the concept of a great power by suggesting the notion of ‘ordering agents’ and ponders whether europe is in danger of drifting towards a period of nonpolarity with no power being able to shoulder the responsibility of ordering and providing good stewardship over europe. for the past five centuries, europe has been the veritable centre of the world. at first the europeans developed the modern conceptions of statehood and international politics and then actively projected these innovations through the application of a 'standard of civilisation' well beyond the continent's boundaries (bull and watson ) . in the process, an increasingly global international system was formed, and it has been one where the europeans have continued to enjoy a pride of place. the europeans have also been one of the main sources as well as beneficiaries of western international order. since the end of the cold war, it has rested on us primacy, but it is a wider western phenomenon that has resulted in a liberal and rulebased world order (ikenberry ) . in europe, it has been manifest in a concentric hegemonic order where the us global primacy and regionally preponderant security role through nato have been complemented by the european union (eu) that has assumed the position of a regional normative hegemon in its own right ( ) with a view of ordering the continent along essentially unipolar lines by envisaging a europe of concentric circles revolving around 'brussels' (aalto ; diez and whitman ) . in europe, the usa and the eu have formed a 'matryoshka hegemony' (deyermond ) of sorts that has sought to, and largely succeeded in ordering the continent in a largely unified, or at least complementary manner. for many, these developments have been welcome and benign. unarguably europe has never been as stable and secure as it has been for the past three decades. yet there are growing signs that this era is coming to an end. on the global level, the usa has entered a period of retrenchment with tensions increasing with the rapidly rising china (allison ) . under president donald trump, it has also largely abdicated its global leadership role and the liberal rule-based international order is under an immense and growing strain (sørensen ) . china together with russia and other smaller regional powers is challenging the current international order on the global level while staking their claims for regional spheres of influence. this is visible also in europe where russia has for some time been making the case for a more equitable bipolar setting. this process of contestation culminated in the ukraine conflict in that has resulted in a low-simmering conflict between the west and russia. taking its cue from international relations (ir) debates about the effects of polarity (the number of great powers) on the evolution of international order (for a chronological lineage, see waltz ; kegley and raymond ; mearsheimer ; brooks and wohlforth ; monteiro ) , this article poses the question whether europe is experiencing not only a period of 'normal' geopolitical contestation, but could it in fact be in a transition towards a state of affairs where it will become void of great powers capable of effectively ordering the continent, let alone the wider world. in a word, is europe headed towards a period of nonpolarity? and if so, what would it entail for the future of cooperation, stability and even security on the continent? the article makes three main contributions. firstly, it links european studies with ir debates concerning polarity and the ongoing change in the structure of international politics. it situates itself in the so-called third wave of hegemony studies (ikenberry and nexon ) , but concentrates on examining the unravelling of western hegemony in europe. secondly, it seeks to conceptually expand our understanding of great powerhood by introducing the notion of 'ordering agents'. the article seeks to add nuance to the extant literature that has largely simply assumed that great powers are always also capable of generating order. instead, the article draws attention to a whole gamut of prerequisites for successful ordering role in contemporary international politics. moreover, it is argued that these requirements are particularly salient in europe that is undoubtedly the most highly institutionalised region in the world (diez and whitman ) . thirdly, the article presents an analytical narrative concerning the developments in europe during the post-cold war era. it does so in two stages: firstly recounting the story of western attempts at hegemonic ordering of europe and russia's growing contestation of it, and then moving on to analysing the main causes and drivers behind potential nonpolarity in europe. the argument will be developed in four stages. firstly, the concepts of (non) polarity and great powerhood are introduced and refined with a view of introducing the concept of 'ordering agents'. secondly, the roles that the usa, the european union and russia have played in ordering europe during the post-cold war era are analysed. thirdly, the causes, drivers and consequences of nonpolarity in europe are discussed. finally, the article concludes by pondering the question whether europe indeed is headed towards a period of nonpolarity and what that could entail for the future of the continent. it ends with a policy relevant point by warning about the possible unintended consequences of current contestation and institutional atrophy in europe. the article suggests that the current trajectory is not in the best interest of any party and engages in some normative argumentation by contending that in the twenty-first century a great power worthy of the name should be held to a higher standard in terms of providing building blocks for stability and order on both the regional and global levels than is currently the case. often order is the norm in everyday life. this is the case in our domestic societies where the monopoly on the legitimate use of violence enjoyed by the states ensures a hierarchical and, at least most of the time, also orderly conduct of our national politics. the anarchical international system does not lend to a clear-cut hierarchy along the domestic lines, but it is not entirely without order, either, that for the purposes of this article is defined as (sub-)systemwide structures and practices-institutions, norms, values and principles-that govern and regulate the conduct of international politics. in international politics, order stems mainly from two sources (see young : - from which the following is taken). it may emerge spontaneously generated by the 'hidden hand' of international anarchy. oran young has called these self-generated orders, the classic example of which is the principle of balance of power that has at times been rather successful in moderating interstate conflict (little ). yet for the purposes of this article, and indeed the increasingly interdependent and global international system in which we find ourselves, this is too rudimentary and in effect shallow conception of order. therefore, the other, and arguably more important, avenue for generating order is that of premeditated design. in young's terminology, these imposed or negotiated orders require intentional agency on the part of key actor(s) that take the lead, or act in concert, in generating, upholding and, at times, modifying and even undoing orders. there is nothing automatic in this latter type of order generation, as it takes effort and the use of power to achieve. in the final analysis, it requires not only great power but great power(s) to generate and uphold an international order. but being a great power is not in itself enough, as one must also be both able to conduct the ordering role and willing to carry the associated burden. therefore, it is suggested in this article that order-generating great powers are a particular subset of the category that should be called ordering agents that are defined here as a great power that has the capacity, ability and willingness to establish, uphold and project (sub-)systemwide ordering structures and practices-institutions, norms, values and principles-and, as a consequence, to have intended/desired ordering effects. the essential building blocks of a successful ordering agent are summarised in table . let us begin with capacity. this refers to power that is perhaps the most essential concept in the study of international politics (baldwin : ) . it is also one of the most contested ones. this is not the occasion to try to settle these debates; suffice it to say, that a multifaceted conception of power is called for. the key question here pertains to the quantity and quality of power as well as its varying effects when employed in ordering the international. according to waltz ( : ) , great powers require a whole spectrum of attributes: size of population and territory, resource endowment, economic capability, military strength, political stability and competence. traditionally the master variable has been military power, which in an anarchic setting is the ultimate arbiter of conflicts between states. yet it is possible to overstate its relevance, especially in our global and interdependent world (nye ) . other forms of power, ranging from economic to 'soft' and normative, play an increasingly important role (baldwin ; nye ; manners ) . it is also noteworthy that military power does not ensure reliable control over outcomes across the board of relevant issues in contemporary international politics: states can employ strategies that offset military power differentials and they can have meaningful geopolitical effects despite not being fully credible peer competitors. indeed, an actor may have the power to affect the behaviour of others through disruptive forms of power-power to avoid nonpreferred outcomes or simply acting as a spoilerwithout necessarily being fully able to coerce others into adopting a stance preferred by the actor. also, if military power is the hammer, not every issue of consequence in contemporary international politics is a nail. on the contrary, there are plenty and perhaps even increasingly issues in the world today that cannot be solved, nor necessarily even contained with the use of military power. the question of climate change as well as other systemic risks, such as pandemics, is a case in point (goldin and mariathasan ) . the same applies to the disruptive forms of power, as they do not generate collective capacity for problem-solving and governance. therefore, identifying the existence of great power capacity in the abstract is only the first step in the analysis. without the ability to channel, or translate, that capacity into actual influence they remain only resources, void of actual ordering effects (see also sørensen : ). analysing power differentials is imperative, yet it does not tell us anything about the quality of interaction and the nature of consequent contestation and ordering between the great powers. the exercise of power is always an empirical issue: it is an outcome of interaction and it cannot be deducted from power differentials alone, regardless of how significant they may be (arreguin-toft ) . to gain a more nuanced view of the processes at play, one can turn to the english school and the seminal work of hedley bull. he was one of the first theorists who argued that an order is not merely a pattern that grows out of mechanical interaction between like units, but it is an intentional and in the final analysis also inherently social process where the key actors take the lead in generating and upholding a particular conception of order that rests on a set of shared values, norms and institutions (bull ) . for bull, it was indeed the existence of shared institutions, such as balance of power and international law, that formed the basis of what he called table key characteristics of a successful ordering agent in international politics material capability competence, ability to act political willingness to act in an ordering role ideational/ideological foundation for organising principles external appeal/legitimacy of ideas, norms and values promoted 'international society'. but for him the common institutions represented something shared and universal. halliday ( : ) has pointed out how bull's international society is 'communitarian', implying a group with shared values. he also did not address the question of change, but adopted a rather conservative stance, advocating relative perpetuity in the constitution of the international society (see friedner parrat ). in bull's reading, norms, values and institutions were static and, by and large, seen at the same time as both prerequisites for and in their operation beneficial to the existence of an international society. the point is not that bull was entirely off the mark, however. international order always serves the interests of the wider international society, but does so unevenly. it is important to bear in mind anna leander's ( : ) insightful words that an order is never neutral: it always works to the advantage of some and to the (at least potential) disadvantage of others, inviting us to ask whose international order we are talking about (see also williams : ) . in this interpretation, an international order does not only serve certain useful functions for the society at large, but it also reflects the interests and ideas of certain key players of that society. therefore, an international order is never neutral, nor is it necessarily an entirely voluntary exercise on the part of all its members: a certain amount of co-optation and coercion, at times perhaps even domination is to be expected. the stance taken here is that when it comes to the question of order in international politics, norms, practices and institutions should be viewed as sites of contestation and struggle: in the final analysis, it is their content that reflects both the power and the ideas of those who are able to affect change in them (wiener ; see also ikenberry and nexon ; wivel and paul ). in this reading, a choice between power and ideas is a false dichotomy: it is not either ideas or power but both that will be required to make sense of any given international order (sørensen ) . although at times a single actor-or a group of actors acting in concert-may be powerful enough to dictate the rules of the game on others, brute strength alone is usually not enough to recalibrate international order. all these point towards the role of intentional agency. order does not change by itself, but it is changed by wilful actors who are able to affect that change. nor does an order sustain itself on its own, but it requires agents that seek to uphold it. this refers to the third variable in our definition, namely the willingness to act as an ordering agent and to carry the associated burden. here, ikenberry's ( ) treatment of international order as a process where the leading state(s) has sought to lock other states into a certain set of institutionalised practices is a useful starting point. in addition, order has always entailed a viable domestic model and the projection of its essential elements beyond borders to generate that very order. this is the case in two different respects. firstly, a viable domestic model is a prerequisite for effective agency: you can only function as an ordering agent internationally if you first function to a satisfactory degree internally. secondly, the reconstitution of an international order must also rely on legitimacy: of the actors involved and the normative foundation promoted (cf. hoffmann : - ; philpott : - ) . in the words of georg sørensen ( : ), 'a stable and legitimate order is founded on a fit among a power base…, a common collective image of order expressed in values and norms, and an appropriate set of institutions'. the last conceptual issue that needs to be discussed in this context deals with the relationship between great power politics and polarity, i.e. the number of great powers in any given international system (waltz : ) . power is obviously the key consideration in deciphering the number of great power poles: to count as one, their relative capabilities must be roughly commensurate across all domains with the most powerful state in the world. according to kegley and raymond ( : ) in a bi-/multipolar system, great powers must be near, but not necessarily absolute equals. the number of poles has varied historically, but in general multipolarity-the existence of more than two poles in the system-has been the norm (see kegley and raymond ) . indeed, the post-world war ii eras stand out in a sense that they witnessed, first, a period of intense rivalry between two superpowers locked into a bipolar setting during the cold war, followed by the period of unipolarity with the usa enjoying unrivalled primacy and hegemony during the post-cold war era (monteiro ; brooks and wohlforth ) . see table for a summary of great powers in europe during the modern era. table shows how although polarity has varied historically, the issue of nonpolarity has not arisen during the modern era. at first sight, the whole notion of nonpolarity might seem odd: surely we are not anticipating the wholesale collapse of the state-centric international system and the disappearance of great powers with it. to better understand how nonpolarity in the european context might be possible and perhaps even likely, we must examine the question of polarity in light of our definition of ordering agents. in its established usage, the relationship between great powers and polarity is almost tautological-great powers are poles and vice versa. but for the present purposes this is not analytically very useful. instead, the article contends that polarity in its traditional reading is a bird's-eye view of international politics based on resources and potential, whereas a more useful analytical lens would take into account the other aspects of agency, namely the ability and willingness to act as an ordering agent in the sense defined above. this entails that to count as a pole, the agent in question must be in possession of a host of attributes: a material power base, ideational foundation and perceived external legitimacy to begin with, but also a political variable concerning the essential competence to act as an ordering agent in international politics and willingness to carry the associated burdens. in light of this discussion, we may define nonpolarity as the lack of great powers that are capable, able and willing to act as ordering agents in a given international system or its sub-system. the term nonpolarity was introduced by richard n. haass who in his article written for foreign affairs over a decade ago defined it loosely as an 'international system… characterised by [too] numerous centres with meaningful (haass ; see also bremmer who spoke about a 'g- world'). yet the use of the term in this article differs from haass's conception in two respects. first, it is regional in scope, drawing attention to europe instead of overall global politics. second, it does not assume that power has drifted away to or been diffused by a host of nonstate actors to a degree that would account for nonpolarity. on the contrary, the article argues that the potential period of nonpolarity stems from changes that are taking place within the key actors at play: their indigenous capacity and willingness to act as ordering agents are atrophying. in addition, nonpolarity is also an outcome generated by the current interaction and growing contestation between the main contenders for an ordering role. in short, nonpolarity is a situation where great powers are either incapable or unwilling, either alone or in concert, to apply power to successfully create or uphold an international order in europe. the dissolution of the soviet union and the end of the cold war division opened (geo)political space in europe. the rigid bipolar confrontation gave way to a much more fluid setting where fresh opportunities and challenges rapidly mushroomed. this called for new policies on the part of both the usa and the emerging eu. for the usa, the four main objectives were: ( ) managing the transition to a new post-cold war order in a peaceful and orderly fashion; ( ) facilitating the emergence of russia as a successor state of the soviet union as a responsible and constructive player, including the development of cooperative threat reduction with russia to deal with the toxic assets left behind by the soviet union; ( ) ensuring the primacy of nato-and by extension also the usa-in european security, and downplaying the eu's potential to emerge as a fully independent security actor; while ( ) using that very eu as a proxy to organise political and economic integration and consequent transition in the emerging wider europe. (for a discussion concerning the key tenets of us policy, see goldgeier and mcfaul ; talbott ; stent .) the usa took the lead in ordering the post-cold war setting along liberal lines, first in europe and then increasingly also globally (mearsheimer ) . for quarter of a century, the usa was able to secure an unrivalled position at the top of international hierarchy. it was also successful in stabilising the conflicts in europe during the s while locking most of the continent into its preferred security structure through the expansion of nato (mastanduno ) . even if russia made some dissatisfied noises at the time, there was an expectation that it, too, could be successfully placated by offering moscow some privileged forms of partnership with the west and the usa in particular (asmus ) . the eu's rise to prominence dovetailed these developments. in the early s, it started to express ambitions and develop capacities for indigenous views about international affairs and to develop them into policies and actions on the world stage. the adoption of the common foreign and security policy (cfsp) in the maastricht treaty of was of particular significance, as it created fresh instruments for external action and institutionalised a cooperative culture that over time have resulted in impressive, although perhaps needlessly cumbersome, finesse and complexity in today's eu (see keukeleire and delreux ) . in the process, the eu was effectively thrust into assuming a leading role in responding to the economic effects of the dissolving soviet empire. the objectives of the nascent 'european foreign policy' and those of the usa were largely compatible and even complementary to each other. one way to characterise the role the two played in ordering europe is to think of 'matryoshka hegemony' where the us global primacy and regionally preponderant security role through nato set the broad liberal framework within which the eu took the lead in ordering the european continent through the expansion and outward projection of its policies, norms and values (haukkala ) . consequently, the usa and the eu, working in tandem, met practically all the requirements for a successful ordering agent in europe: they enjoyed unrivalled material preponderance while portraying both competence and political willingness to act as ordering agents. they also promoted a coherent set of idea(l)s and did so during a period when their leading role enjoyed a great deal of external legitimacy, reflected in the long queues of accession candidates in front of both nato's and the eu's doors. having established this, one should exercise some caution in assigning too much strategic intentionality on the part of the west. both nato's and the eu's eventual sprung nach osten were more reactions and responses to events and demands beyond the west's control or initial appetite rather than preconceived programmes to order or subjugate the whole continent to their will (see asmus ; smith ; hill ) . the hegemonic underpinnings of their ordering role were arrived at in a piecemeal, almost haphazard manner. this gives the western unipolar hegemony over europe a paradoxical quality. to a degree, this also explains why it fizzled out so quickly in the face of growing russian resistance. for quite some time, russia remained an outlier to the western attempts at ordering europe. it was not fully in nor fully out, while it was trying to figure out its own national interests and international identity. in the process, russia has developed an increasingly strained relationship with both the usa and the eu and adopted a highly belligerent approach towards the concentric order they have been propagating. for the russians, the crux of the issue was that it lacked a voice and a role that would have been commensurate with its own self-image as a great power. one way to interpret the events during the last quarter century in europe is to view it as a process of increasing frictions and tensions between the western nato/eu-centric attempts at ordering the continent and russia's growing frustration and even hostility towards its inability to secure a place for itself that would have allowed it a voice and a veto (marten ) . in the words of hill ( ) , in the eyes of moscow the european architecture has left 'no place for russia'. related to this is the wider russian complaint concerning the role the usa has played globally. the us post-cold war primacy in general and the way washington responded to the / terrorist strikes in accentuated the russian impression of a rampant usa bent on dominating the world unilaterally. in vladimir putin's resentful words, uttered already in , the usa had 'overstepped its national borders in every way' (putin ) . positioning itself as a counterforce to a reckless and domineering washington became the leitmotif of putin's rhetoric and russian foreign policy well before the dramatic events in ukraine. although not felt as keenly at the time, the eu enlargement also created its own frictions between russia and the west. in particular, the question of a 'common/ shared neighbourhood' created in the aftermath of the 'big bang' eastern enlargement of proved to be a source of tensions. ukraine's orange revolution-which took both the west and russia equally by surprise-changed moscow's tack concerning the eu's role in the region. moscow's previous benign neglect subsided, as it began to view the eu's growing role and the western orientation of the cis countries with increasing suspicion (gretskiy et al. ) . although it was not appreciated at the time, the orange revolution was the starting gun for the preparation of operations and practices witnessed first in georgia in and then in crimea and eastern ukraine since (franke ) . over time russia's grudging acquiescence to western liberal hegemony morphed into outright opposition. yet the current conflict between russia and the west was far from inevitable. on the contrary, in early s both parties were still looking for ways to make the relationship work. (for accounts that testify to this effect, see forsberg and haukkala ; stent .) these repeated attempts at 'resets' and other fresh beginnings were marred by the underlying and largely irreconcilable tension where the western unipolarity, however, well intended, ran counter to the growing russian calls for a more equitable and essentially bipolar setting in europe. by the end of s, russia started to take much more assertive steps to promote its preferred vision of order beyond its borders. in the first instance, this took the form of the eurasian economic community (eurasec) that soon became the eurasian economic union (eaeu) through which russia started to invest in a more institutionalised bipolar setting in europe, with moscow as the leading power in the other half of the continent with the expectation of attracting the majority, if not all, of the post-soviet states under russia's leadership (see dragneva and wolczuk ) . although the eaeu did gain some initial momentum, as exemplified by the expansion of its members from the original three to current five, the fact that russia felt compelled to resort to open blackmail and coercion to attract new members to the eaeu speaks volumes about the power of attraction of the new regional bloc. the conflict in ukraine was the culmination of these unhappy trends (haukkala ) . with its actions, russia made abundantly clear that it views eastern europe as its primary sphere of interests (trenin ) that both the eu and nato must respect and that it is willing to use all the means at its disposal to enforce this policy. russia also signalled its readiness to pay a high price in terms of economic hardship and international, although mainly western, opprobrium for doing so (menon and rumer ; wilson ) . the reasons for this are myriad, but the main point worth stressing is that the near-existential nature of russian interests in and over eastern europe creates an asymmetry that is unfavourable to the west: no matter how hard it pushes its version of order on the east, moscow is always willing to push back a little harder-and accept the eventual price for doing so. in other words, russia has been stable, able and ruthless enough to act as a spoiler in europe, but, apart from the eaeu that contains severe internal tensions and contradictions, as exemplified by the catastrophic outcome of trying to co-opt ukraine to join the organisation in - testified, it is not competent, capable or even willing to act as an ordering agent in europe. on the contrary, the dramatic escalation in ukraine in has been followed by a pattern where russia has proved ruthless in the application of power to challenge and to a degree overturn the current order on the regional level. admittedly, compared with the west russia is lacking in many of the key attributes of power. its population is stagnating and its economy is weak and almost entirely reliant on the sale of hydrocarbons on increasingly turbulent world markets. yet what it may suffer in the aggregate, it amply makes up in the skill and will to employ the wherewithal at its disposal (see baldwin : ) . when this is factored in, russia's record of accomplishment, and indeed short-to midterm potential, looks more promising. russia has also shown great acumen in projecting military means to achieve political ends beyond its borders both in its immediate vicinity in ukraine and even beyond as the events in syria have shown. this continued contestation is also a factor that feeds into the potential emergence of nonpolarity in europe, discussed next. to a degree, the above narrative is compatible with traditional forms of ordering in international politics. it is possible that the process we are currently witnessing is merely 'normal' turbulence associated with a period of intense contestation that will be followed by the creation of a new or at least amended order in europe (gilpin ). yet in recent years a myriad of factors and developments have warranted asking the question whether the notion of nonpolarity is in fact more applicable. by examining the factors outlined in the definition of an above ordering agent, we can see how the main contenders in europe portray varying drivers for the rapid decline in the current order and augur the possible emergence of nonpolarity on the continent. to begin with, one must note how the unified, even if concentric, western hegemony in europe is rapidly unravelling. both the usa and the european union portray much less cohesion and ability to act in tandem as successful ordering agents than previously. under trump, the transatlantic partnership has experienced growing strains, even signs of serious erosion. (the process is documented in brookings .) the trump administration views the eu and its institutions with hostility and its european allies with growing suspicion. over time, the europeans, too, have started to lose faith in their partnership with the americans. the relations between the eu and the usa have atrophied with no meaningful dialogue or interaction currently taking place between brussels and washington. consequently, the ability of the two to coordinate their activities and channel their respective energies in the same direction has been lost. as a result, it is difficult to talk about western hegemony in europe anymore. what is more, the whole idea of a unified 'west' is increasingly being questioned on both shores of the atlantic (kimmage ; tcherneva ) . this is a development that affects the european order negatively and has a major impact on the evolution of relations on the global level as well. if the two former hegemons have found it hard to work together, the same applies to their roles individually in europe. in the us case, the issue is not the wholesale atrophy in the capacity to act as an ordering agent. no one is suggesting that in terms of overall capacity or competence the usa is completely lacking or that it lacks economic or military power. but what it increasingly is lacking, is the ability, through the erosion of perceived legitimacy and the lack of essential willingness to uphold the current order globally and in europe. this is due to the political variable that stems from the current period of soul-searching revolving around the perceived need to recalibrate the us global role and posture in light of the new era of 'great power competition' that is seen as being in the offing. the trump presidency has accentuated and aggravated these trends, but he is not the root cause behind them. kagan ( ) might be right in arguing that trump has struck a stake through the heart of the liberal world order, but the problem is not just him. the us role would be changing in any case. in the short term, a lot will depend on the presidential elections in november . but even if trump is unseated, it will most probably affect mainly the mood and atmospherics in transatlantic relations. that can be significant, but will not undo nor necessarily even repair the damage that stems from deep-seated structural factors and tensions between the usa and the eu (polyakova and haddad ) . turning to the eu, we find it increasingly isolated, alone and adrift, essentially clinging to the vestiges of its preferred order globally and regionally without the necessary means to project or protect that very order. the fact that the eu does not seriously register as a military power would seem to exclude from the list of possible poles, yet it would be erroneous to discount it as an ordering agent. economically the eu is still in a very strong position, even if the problems of governing the european common currency cast a shadow on its prospects. in addition, waltz's ( : ) verdict concerning the europeans two decades ago seems to hold: the eu still lacks the organisational ability and the collective political will to translate its sizable power potential into credible international actorness. moreover, there are mounting signs that the eu is no longer acknowledged as a key player in global affairs, if indeed it ever was. on the contrary, european perspectives are increasingly sidelined in global politics. increasingly, the eu is not the actor, but the stage upon which others act. the eu's inability to project order, or at least stymie growing instability, is most visible around its own borders. the european neighbourhood policy (enp) that was meant to result in a 'ring of friends' around the eu effectively collapsed in the ukraine conflict. the aftermath of the so-called arab spring resulted in the tragic civil war in syria and completed the current outcome that the economist dubbed a 'ring of fire' around the union (haukkala ) . none of this to argue that these developments are primarily the eu's fault-but to act as a successful ordering agent, one needs to be able to project stability and not just protest instability around you. internally the eu's situation is equally precarious. during the last decade, it has repeatedly succumbed into crises that have sapped its energies and legitimacy even in the eyes of its own citizens (wivel and waever ) . at times, it seems as if the europeans are facing growing problems in keeping even their own eu house in order, as exemplified by brexit and the growing internal fissures concerning economic governance and the rule of law in europe (krastev ; zielonka ) . it should, however, be pointed out that we are not talking about the potential collapse of the eu itself. yet there exists serious doubt whether and to what extent the eu can keep up its role as an ordering agent even among its own ranks, let alone aspire to a successful ordering role externally. the final contender, russia, demonstrates very few or perhaps not at all signs of playing a constructive ordering role in europe for the moment. on the contrary, it does not even aim to generate order elsewhere than at home and seems busy wielding a geopolitical wrecking ball to hasten the demise of the current order. considering our definition for an ordering agent, russia has fallen short during post-cold war era, and even before, as exemplified by the collapse of the soviet union and its empire. currently it does not have the economic power base to act as an ordering agent nor does it offer any coherent alternative to the order it is criticising. currently moscow's actions do not add up to a positive agenda nor does it seem to aspire to one. consequently, the external appeal and legitimacy of russia's agenda in europe is very limited. taken together, none of these attributes translate into a capacity to act as an ordering agent in the european setting. this discussion is tentatively summarised in table : tentatively, because to assess these findings with full confidence would obviously require more rigorous analysis. that said, it is nevertheless hoped that the thesis has enough prima facie plausibility so that it merits to be taken seriously and is subjected to more rigorous research and analysis in the future. europe has entered a period of relative decline and its role and heft in global politics is rapidly shrinking. there are deep structural forces at play, and the diminution in europe's importance is inevitable. at the same time, these developments are compounded by the fact that the very order undergirding europe's own security and stability is deteriorating. this article argues that this not only is due to normal geopolitical contestation, but is a sign that europe is in danger of losing ordering agents, i.e. great powers capable, able and willing to create or sustain order on the continent. the main driver behind these developments is the changing us power and role in europe. under trump, washington has lost its appetite to act as the bulwark of stability in europe. this has resulted in the ongoing collapse of the 'matryoshka hegemony', the previously complementary concentric us and eu ordering roles in europe. to make matters worse, the eu is not up to the task on its own and, it seems, the final contender for the ordering role in europe, russia, is not even interested in it. in addition, the internal trajectories within both the eu and russia point towards decreasing capacity for successful ordering agency. therefore, it is time to put forward the question whether the conflict between the west and russia is contributing to the relative decline of europe in world politics at large, and whether the unintended consequence of this contestation could be hastening the arrival of a period of nonpolarity in europe, with no power being able nor necessarily even willing to shoulder the responsibility of ordering and providing good stewardship in and over europe. we have no historical track record of nonpolarity in the modern era, yet we can surmise about its possible effects based on conceptual and empirical understandings weak of international politics. it is argued that a period of nonpolarity would pose serious problems, for two reasons. firstly, europe is living in an era of high and constantly rising interaction capacity that creates both demands and challenges in terms of coordination and cooperation (buzan , ) . trade and other flows, both legal and illicit, as well as the increasingly important cyber space all require governance and joint management. secondly, we are living in an era of high complex interdependence (keohane and nye ) that also includes mounting risks and challenges, some of them potentially catastrophic, even on a global scale (ord ) . handling these issues requires order and ordering agents. order is the prerequisite for governance without which the risks inherent in our current world become very difficult, practically impossible to control or contain. the haphazard and uneven response to the covid- coronavirus pandemic is a case in point. these are global trends, but it is argued that in europe these issues are even more pertinent because for the last three decades, and more, europe has generated its own web of densely institutionalised forms of cooperation, rules and regulations that require capable ordering agents for their continued existence. russia might find some of these entanglements too close for comfort, but, it is argued, they, along with the us military overlay, have been instrumental in keeping the peace on the continent. a way to read the current situation is to envisage it as a dialectical process where the western thesis has now been fully countered by the russian antithesis. the synthesis remains still to be seen-but it is not an easy one to locate or arrive at due to the essential incommensurability of current positions. indeed, the crux of the potential for nonpolarity in europe is the fact that currently no one can impose an order anymore, while the sides are deeply divided and unable to agree on a new one. one avenue forward might be a return to some form of a balance of power in europe. yet the discrepancies between the various forms of power are probably too large to allow for that. moreover, the internal dynamics within the main potential ordering agents are such that the situation is unlikely to remain stable enough to allow for a sustainable recalibration of the european setting. on the contrary, a safer prognosis seems to be the continued and perhaps even expanding turbulence in europe. over time, the lack of good stewardship over europe will result in further erosion of norms and institutions, generating growing friction and potential for conflict. this means missed economic opportunities and increasing inability to work successfully together to tackle wider problems facing europe and the world. more worryingly, the hard-won gains of the past years are at risk of being undone. an open conflict between russia and the west cannot be excluded. this should be a cause for concern and rallying call for more responsible policies and politics. the emergence of a nonpolar europe cannot or should not be in anyone's interest. what is more, in the twenty-first century a great power worthy of the name should be held to a higher standard in terms of providing building blocks for stability and order on both the regional and global levels than is currently the case. this is not a new idea: as brown ( ) has argued, great powers, simply due to the virtue of their size and importance, have always been held to a higher standard than other powers. in the final analysis, the advent of possible nonpolarity in europe depends on political choices by the main protagonists. indeed, this article is not a prognosis that nonpolarity in europe is inevitable. three questions in particular stand out that will affect the future developments: ( ) the evolution of the us role globally and in europe; ( ) the eu's ability to overcome its current crises and to develop more robust forms of international actorness; and ( ) the future of russia's conflict with the west as well as the evolution of its appetite to seek more constructive roles and openings in europe. nonpolar europe can still be avoided by political choices and responsible policies by the main actors that foster the return of capable, credible and committed ordering agents in europe. european union and the making of a wider northern europe destined for war: can america and china escape thucydides's trap? how the weak wins wars? a theory of asymmetric conflict opening nato's door. how the alliance remade itself for a new era power analysis and world politics: new trends versus old tendencies paradoxes of power power and international relations every nation for itself: what happens when no one leads the world world out of balance: international relations and the challenge of 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susanna; spanu, angela; lobrano, renato; cossu, antonio; babudieri, sergio; madeddu, giordano title: epidemiology, clinical aspects, laboratory diagnosis and treatment of rickettsial diseases in the mediterranean area during covid- pandemic: a review of the literature date: - - journal: mediterr j hematol infect dis doi: . /mjhid. . sha: doc_id: cord_uid: bl bdrcm the purpose of the present review is to give an update regarding the classification, epidemiology, clinical manifestation, diagnoses, and treatment of the rickettsial diseases present in the mediterranean area. we performed a comprehensive search, through electronic databases (pubmed – medline) and search engines (google scholar), of peer-reviewed publications (articles, reviews, and books). the availability of new diagnostic tools, including polymerase chain reaction and nucleotide sequencing has significantly modified the classification of intracellular bacteria, including the order rickettsiales with more and more new rickettsia species recognized as human pathogens. furthermore, emerging rickettsia species have been found in several countries and are often associated with unique clinical pictures that may challenge the physician in the early detection of the diseases. rickettsial infections include a wide spectrum of clinical presentations ranging from a benign to a potentially life treating disease that requires prompt recognition and proper management. recently, due to the spread of sars-cov- infection, the differential diagnosis with covid- is of crucial importance. the correct understanding of the clinical features, diagnostic tools, and proper treatment can assist clinicians in the management of rickettsioses in the mediterranean area. considered to be absent in obligate intracellular bacteria. , the transmission of the infection depends on the group. sfg is transmitted by the bite of an infected tick; whereas, organisms of typhus group are transmitted through inoculation via infected louse or flea faeces (rickettsiae prowazekii and rickettsia typhi, respectively) through a bite, wound or mucous membranes. once inoculated into the skin, organisms are phagocytized by dendritic cells and transported via lymphatics to local lymph nodes where they replicate. subsequently, the bacteria spread in the bloodstream and disseminate to infect the endothelium of the microcirculation, where the rickettsiae can infect vascular endothelial cells of the small and mediumsized blood vessels. the damage of the endothelium and the subsequent endothelial dysfunction is followed by alteration in coagulation and the cytokine network. the endpoint of this pathogenetic results in a reduction in circulating peripheral cd t lymphocytes and perivascular infiltration by cd and cd t lymphocytes, b cells, and macrophages, causing a vasculitis. [ ] [ ] [ ] epidemiology. there are several pathological rickettsia species in europe, and in the last years, new species and subspecies have been implicated as human pathogens, and new rickettsial syndromes have been described. mediterranean spotted fever (msf) caused by rickettsia conorii subsp. conorii is the most frequent rickettsiosis in europe. it is endemic in southern europe, but sporadic cases have been reported in all the continents. , the first cases were first described in tunisia in by conor and buch. the brown dog tick, rhipicephalus sanguineus, is the vector and the potential reservoir of rickettsia conorii subsp. conorii in the mediterranean area. , most msf cases occur in summer when climatic conditions seem to be an essential factor in increasing the aggressiveness of rhipicephalus sanguineus ticks to bite humans. [ ] [ ] [ ] [ ] rickettsia conorii subsp. israelensis is the agent of israeli spotted fever (isf), which was first reported in in the haifa bay area, israel. [ ] [ ] [ ] [ ] in europe and the mediterranean region, the brown dog tick, rhipicephalus sanguineus, is recognized to be the vector of rickettsia conorii subsp. israelensis. the geographic distribution of the disease appears to be spread more widely in the mediterranean countries than previously thought. cases have been reported in italy, portugal, tunisia, and libya. [ ] [ ] [ ] [ ] other rickettsia conorii subspecies reported in the mediterranean area are rickettsia conorii subsp. caspia and rickettsia conorii subsp. indica. the first one is the agent of astrakhan fever, endemic in the astrakhan region, adjacent regions of the caspian sea, and described in rhipicephalus sanguineus ticks in kosovo and southern france. rickettsia sibirica subsp. mongolitimonae, the microorganism that cause of lymphangitis-associated rickettsiosis (lar), was isolated for the first time in china, from hyalomma asiaticum ticks collected in mongolia in . rickettsia sibirica subsp. mongolitimonae was detected in hyalomma anatolicum excavatumt ticks in greece and cyprus; in rhipicephalus pusillus ticks in france, portugal, and spain; and in rhipicephalus bursa ticks in spain. [ ] [ ] [ ] [ ] [ ] the first human infection with rickettsia sibirica subsp. mongolitimonae was reported in france in . rickettsia sibirica subsp. mongolitimonae is implicated in human pathogen in different countries, as france, spain, turkey, and egypt. [ ] [ ] [ ] [ ] rickettsia slovaca and rickettsia raoultii are associated with a syndrome characterized by scalp eschars and neck lymphadenopathy following tick bites (senlat). these microorganisms have been found in dermacentor marginatus and dermacentor reticulatus ticks in a vast majority of european countries. [ ] [ ] [ ] [ ] [ ] [ ] [ ] after msf, senlat is the most prevalent tick-borne rickettsiosis in europe. it has been reported in different countries, including hungary, spain, france, germany, italy, bulgaria, and portugal. [ ] [ ] [ ] [ ] [ ] [ ] senlat occurs most frequently from march to may and from september to november, which corresponds to the periods of most considerable activity of dermacentor adult ticks in europe. [ ] [ ] [ ] rickettsia helvetica is transmitted by ixodes ricinus, which is the primary vector and the natural reservoir. however, human infection is rare, and it has been documented only in austria, denmark, france, italy, sweden, slovakia, and switzerland. , , other rare rickettsial pathological species in europe and the mediterranean area are rickettsia massiliae, rickettsia monacensis, rickettsia aeschlimannii, and rickettsia sibirica subsp. sibirica. clinical manifestation. rickettsiosis is a rare disease: the incidence is around case per . people by year, but it has been increasing during the last years, probably due to better diagnostic techniques. in europe, the most important diseases are three: mediterranean spotted fever (msf), lymphangitisassociated rickettsioses (lar), and scalp eschar and neck lymphadenopathy (senlat). the other significant disease caused by rickettsia rickettsii is the rocky mountain spotted fever (rmsf), but no cases have been reported in europe to date. apart from these three pathologies, there are other minor forms caused by different pathogens. mediterranean spotted fever. msf, caused by rickettsia conorii, is the most common rickettsialdisease in europe, where the highest incidence is during summer. not all people who come into contact with this bacterium develop the disease. a spanish study, indeed, shows that - % of the population carry antibodies against rickettsia but without a previous clinical history of msf. the most common symptoms are fever ( - %), myalgia ( - %), headache ( - %), and asthenia ( %). the maculopapular rash is present in - % of the patients; the tache noir has been noticed in - % of the patients. the classic triad, fever, maculopapular rash, and inoculation eschar, is present in - % of the patients. [ ] [ ] [ ] in most cases, msf is a self-limiting disease but sometimes could be life-threatening. it was estimated that about - % of msf cases could be severe. [ ] [ ] [ ] and arthritis , have been reported. the most frequent hematological and biochemical modifications are thrombocytopenia, leukocyte count abnormalities, elevated hepatic enzyme levels and an increase of c-reactive protein. , mortality was around - % before the antimicrobial drug era. thus, it has been considered a benign illness. in some recent studies, msf appears to be more severe than it has been thought. mortality rates were . % in france, . % in portugal, . % in algeria, . % in spain and . % in italy. , , [ ] [ ] [ ] risk factors for severe msf include advanced age, immunodeficiency, chronic alcoholism, g pdh deficiency, diabetes, prior prescription of an inappropriate antimicrobial drug, or delay in treatment. , scalp eschar and neck lymphadenopathy after a tick bite. senlat syndrome is also known as tibola (tick-borne lymphadenopathy) or debonel (dermacentor-borne necrotic erythema and lymphadenopathy), and it is caused by rickettsia slovaca and rickettsia raoultii but also by other bacteria such as bartonella henselae. this disease is developed mostly during spring and autumn. the clinical description of senlat includes asthenia, headache, painful adenopathies (especially to the neck's lymph nodes), and a painful scalp eschar surrounded by a perilesional erythematous halo. low fever, rash, and face edema have also been reported less frequently. , , no malignant or fatal cases have been described in the literature. after the therapy, alopecia could potentially last for several months, with persistent asthenia. lymphangitis-associated rickettsioses. lar is caused www.mjhid.org mediterr j hematol infect dis ; ; e by rickettsia sibirica subsp. mongolitimonae. just a few cases have been reported in europe. in particular, until , only cases have been reported in the mediterranean area. the typical period of this disease is spring. commons symptoms include fever, headache, an eschar (frequently more than one) on the site of inoculation, and lymphangitis, which starts from the eschar and reaches an enlarged lymph node. the difference between lar and the other two diseases are the period of occurrence (spring), and the presence of lymphangitis and multiple eschars. until now, no deaths have been reported in patients that have been infected by rickettsia. however, some severe cases have been reported, in particular: a retinal vasculitis, sepsis with disseminated intravascular coagulation, myopericarditis and a septic shock. , mediterranean spotted fever-like. other rickettsiae in europe could infect humans; most of them cause a disease very similar to msf. for example, rickettsia conorii subsp. caspia causes an illness called "astrakhan fever." this disease is typical of the caspian sea area, but some cases have also been reported in france. astrakhan fever diverges from msf in the percentage of patients who present with an eschar (only %) and because it could cause thrombocytopenia and bleed. another similar disease is the israeli spotted fever (isf), caused by rickettsia conorii subsp. israelensis. in europe, this bacterium has been found only in portugal and in italy. the symptoms are quite similar to msf except for the presence of gastrointestinal symptoms in half of the patients. the main difference is the malignity; indeed, the mortality is higher (more than %). , , , , other rickettsiae who could cause a msf-like illness are rickettsia monacensis, , rickettsia massiliae, , rickettsia aeschlimannii, , and rickettsia helvetica which could be malignant. , , differential diagnosis with other infectious diseases including covid- . clinically, the patients with msf present the classic triad, fever, tache noir, and maculopapular rash in - % of cases. in the absence of this typical clinical picture, the diagnosis could be challenging. a small percentage of patients could present only the tache noir, which is generally pathognomonic of rickettsial diseases. however, clinical cases in which the tache noir was present in other zoonoses have been reported in the literature. [ ] [ ] [ ] the presence of fever without other signs is, probably, the most difficult challenge for clinicians because it is the expression of many diseases, both infective (bacterial, viral, fungal, and parasitic) and not infective. in these patients, a proper anamnesis, laboratory findings, and radiological features are mandatory to permit the correct diagnosis. blood cultures should be collected at the fever peak to exclude a bacterial or fungal infection. furthermore, in the area where sars-cov- is circulating in the population, the nasopharyngeal swab, together with acute phase serology, is recommended to rule it out. indeed, the common symptom in patients with coronavirus disease (covid- ) is the fever. , the other symptoms that these two diseases have in common are headache, asthenia, and myalgia. the associations of dysgeusia, anosmia, and gastrointestinal symptoms could suggest the diagnosis of covid- . [ ] [ ] [ ] the maculopapular rash is an expression of several diseases. in these cases, clinicians should pay attention to the distribution, the pattern, and the relationship between the localization at the start of it and other clinical signs, especially the fever. although respiratory symptoms are the most frequent in covid- , skin involvement should always be considered. galván casas c et al. described the most common cutaneous pattern, and magro et al. demonstrated how sars-cov- is associated with microvascular damage and thrombosis. moreover, different cutaneous vasculitis-like patterns correlated with covid- or sars-cov- therapy have been described. , diagnosis. nowadays, the majority of reference laboratories in developed countries can provide quick identification of rickettsial pathogens thanks to molecular and serological assays. in many cases, the diagnosis could be made by the clinical manifestation, but the laboratory tests are necessary at the support of it. the choice of the most appropriate diagnostic technique requires consideration of the suspected pathogen, the timing of symptoms onset, and the type of sample available for testing. serological tests remain essential diagnostic tools, but rickettsiae can be isolated from or detected in clinical specimens. the diagnostic tools available include serologic assays, molecular testing, cultures, immunochemistry, and matrix-assisted laser desorption ionization-time of flight mass spectrometry (maldi-tof). the diagnostic technique could be divided into two groups: ) diagnostic techniques used as routine. diagnostic techniques used as routine (table ) serologic tests: indirect immunofluorescence antibody assay (ifa) is a widely accepted serologic test for the detection of rickettsial infection. , it is considered the most indirect immunofluorescence antibody assay (ifa) serologic high sensitivity and specificity for igg [ , ] . low sensibility for igm; operatordependent [ , ] the enzyme-linked immunosorbent assay (elisa) serologic more sensitive than ifa for the detection of low antibodies level; absorbance of the enzyme reaction is measured with a spectrophotometer [ , ] . could be negative during the early phase [ , ] . nucleic acid amplification tests (naats) (molecular methods) quick response; could be used during acute disease [ ] ; provides the differentiation between different species [ ] . high costs; low sensitivity if used peripheral blood and serum [ ] ; antibiotics reduce the sensitivity [ ] . sensitive and specific method among serological assays. ifa consists of rickettsial antigens fixed on a slide and detected by specific antibodies present in the patient's serum, which can be identified by a fluorescein-labeled conjugate. serum of patients with clinical manifestation of disease must be collected on the day of the admission and - weeks after illness onset. ifa assays are highly sensitive at detecting antibodies after - weeks after illness onset, and their results are best interpreted if serum samples collected in acute and convalescent phases are tested at the same time. most laboratories test for igg antibodies because igm antibodies reactive with rickettsia rickettsii are frequently detected in patients with no other supportive evidence of a recent rickettsial infection. therefore, the detection of igm during the acute phase should not be considered diagnostic for an ongoing illness as there could be cross-reactivity with other species and persistence of igm beyond acute status. , the enzyme-linked immunosorbent assay (elisa) detects the binding of specific antibodies to antigens in a serum sample. when secondary anti-human antibodies conjugated with an enzyme are bound to antibodies from a serum sample and subjected to a substrate, an enzymatic reaction will be measurable in a positive specimen. elisa is sensitive, reproducible, and allows the differentiation of igg and igm antibodies. the results are more sensitive than ifa for the detection of low antibodies level, such as during late convalescence. elisa has the advantage, compared to ifa, of eliminating the subjective evaluation since the absorbance of the enzyme reaction is measured with a spectrophotometer. the inhibition elisa has been used only for the diagnosis of scrub typhus and seems to be more sensitive than ifa in the early phase of the disease. these assays are more appropriate than serology in the diagnosis of acute infection; a sample collected early at disease onset, before the development of antibodies, is more likely to produce a positive result in pcr assays. when antibody production has increased to detectable levels, bacteria are rarely found in the bloodstream or at the inoculation site. furthermore, if antibiotic treatment has been initiated, the sensitivity of pcr assays decreases for the same reason. , the most used method is nucleic acid amplification tests (naats), such as pcr, which has acquired increasing importance over the past few years. the quick response allows a prompt diagnosis without the need to wait for seroconversion or cell culture's growth time, which can take from to days. amplification of species-specific dna by pcr provides a useful method for the differentiation between the several rickettsia spp. and to gain knowledge about the genomic differences within the genus. the conventional pcr format, due to a large number of pcr products, is more prone to contamination. for this reason, a single-use primer pcr has been introduced. another molecular method is real-time pcr that offers the advantage of speed, reproducibility, quantitative capability, and reduced risk of contamination compared with conventional pcr assays. several clinical samples are suitable for pcr amplification: skin biopsy, eschar, swab, or csf. peripheral blood and serum could also be used, but pcr on these samples has a lower sensitivity compared to skin samples or eschar collected on the bite site. , pcr detection of rickettsia rickettsii in the blood is possible. still, its sensitivity is lower because of the small numbers of rickettsiae in the blood in the first stages of the disease. for this reason, during the acute phase, it is better to use the sfg tissue specimen. , doxycycline treatment decreases the sensitivity of pcr; therefore, obtaining blood before starting antibiotic therapy is recommended to minimize false-negative results. shell vial: this method requires a large number of bacteria and specific cell lines to proliferate, such as vero e cells, human embryogenic lung fibroblast, and the promyelocytic hl- leukemia cell line (the most widely used cell line for growing a. weil-felix test serologic easy to use; low cost. it is still used in developed countries [ ] . cross-reaction with other antigens. low sensitivity, low sensibility [ , ] western blot serologic highest sensitivity to early antibody, high specificity [ ] . expensive, technically difficult to perform, longer procedure [ ] . line blot serologic high specificity and sensitivity; a large number of antigens tested [ ] . no quantitative titers available; expensive [ ] . more sensitive than either the complement fixation or weil-felix [ ] rarely used, low sensitivity, long preparation [ ] . rarely used for the high cost[ ]. hight sensitivity and specificity; tests multiple rickettsial antigens simultaneously [ ] cross-reactivity [ ] ; high costs. serologic very specific; used for seroepidemiologic studies [ ] poor sensitivity, especially during the early stage of the disease [ ] indirect immunoperoxidase assay (ipa) serologic similar to ifa; very sensitive and specific [ ] needs specific instrument and trained personal [ ] shell vial culture highest specific; could be used during acute disease [ , ] . long times [ ] .; low success rate; needing specific cell lines [ ] ; low sensitivity [ ] circulating endothelial cells (cecs) other not influenced by previous antibiotic treatment; cecs level detected could be correlated with the severity of the disease [ ] low sensitivity; not easy to perform [ ] . high sensitivity [ , ] need bioptic sample, not easy to perform [ , ] . early diagnoses, differentiation between species [ ] high costs; not always available [ ] . only used to identify infections inside the arthropods [ , , ] phagocytophilum). specimens for cell cultures should be collected before starting antibiotic treatment and should not be frozen. to identify the cultivated small intracellular rickettsiae, the laboratories should label bacteria by fluorescent antibodies or staining with the gimenez method. the low success rate and the complexity of this method do not permit the routinely use of this methodic. serologic methods: the weil-felix test, based on the detection of immuneresponse to different proteus antigens that cross respond with rickettsia should not be considered a first-line testing method anymore, even if it remains an option developing countries. it allows the detection of igm antibodies - days after clinical manifestations. western blot assay (wba) was demonstrated to be more sensitive than ifa for the detection of early antibodies in rickettsia spp. nevertheless, it is generally more expensive and technically challenging to perform than other serological methods. furthermore, rickettsia cultures are required. for these reasons, its use is limited to only a few reference laboratories. the line, or dot, blot immunoassay, may be particularly useful for screening the many antigens that might be considered for patients with nonspecific or atypical clinical presentation. this test can be regarded as valuable only as a first-line test for the rapid diagnosis of acute cases in areas with high prevalence. the microagglutination test could be divided into two different methods, which included the indirect hemagglutination test and the latex agglutination method. the first one is specific for the detection of igg and igm for all rickettsiae. the latex agglutination permitted the directed detection of the r. conorii, r. prowazekii, r. rickettsia, r. typhi, and infections. this method has a high sensitivity, but it is not routinely used for the high cost. , micro immunofluorescence (mif) assay is similar to ifa except that wells are spotted with multiple rickettsial antigens for simultaneous detection. the negative aspect of this method is cross-reactivity, and its costs. complement fixation (cf) test permitted the identification detection of antibodies specific for rickettsiae. it is peculiar, but it has shown a reduced sensitivity, especially during the early stage of the disease. for this reason, it is only used for seroepidemiological studies. indirect immunoperoxidase assay (ipa). the procedure is the same as ifa, but it used the peroxidase instead of fluorescein. it needs a specific instrument and trained personal. for this reason, it is not commonly used. other tests: circulating endothelial cells (cecs) method allows the detection of r. conorii in circulating endothelial cells isolated from whole blood by using immunomagnetic beads coated with an endothelial cell-specific monoclonal antibody. the sensitivity is about %, and it is not influenced by previous antibiotic treatment. furthermore, the cecs level detected correlates with the severity of the infection, so it can be considered a prognostic indicator. immunohistochemistry (ihc) permits the rickettsia's detection directly from biopsy specimens, but it could only be used during the acute phase and only if there is a rash or tache noir. , the most recent diagnostic tool is the matrix-assisted laser desorption ionization-time of flight mass spectrometry (maldi-tof). this technique has been using with promise application for the tick-borne infections inside the arthropods. the future role of this new method could be applied to help the clinical decision. the identification of rickettsiae inside the vector or in the hemolymph is showing great potential but remained a niche method. biosensors emerging technology allows the fast detection of rickettsia-induced immune response. for example, the ompa antigen, an outer membrane protein present in the r. rickettsia, the agent responsible for the spotted fever, allows the detection of anti-ompa human igg. this is possible through an amperometric immune-sensor by using a synthetic peptide, obtained from the h pga r. rickettsia protein, homologous to ompa. treatment. rickettsiae spp. are obligate intracellular bacteria; therefore, the standard treatment is based on tetracyclines or chloramphenicol. the gold standard therapy is indeed represented by doxycycline mg per os twice daily x days in adults and . mg/kg of body weight per dose twice daily, orally or intravenously. , it has been demonstrated, in several studies, that doxycycline shortens the course of msf and induces a rapid remission of symptoms. the problem is that tetracycline should be avoided in childhood, during pregnancy, , in patients who are allergic to it, and in those who have a g pdh deficiency. an alternative to doxycycline is chloramphenicol. it should be administered at a dosage of mg/kg/day in four doses for seven days. since , chloramphenicol was used only for patients suffering from allergy, those having adverse effects to doxycycline or if fever persisted for more than five days or in those that relapsed after the therapy with tetracycline. however, chloramphenicol should also be avoided during pregnancy (grey baby syndrome), and because of the various adverse effects (aplastic anemia, bone marrow suppression), it is not recommended in children. furthermore, in a randomized study on children, the chloramphenicol group had a longer hospitalization. for this reason, in pregnant women and children, the first choice is a macrolide. different randomized studies have shown the macrolides' non-inferiority. in particular, meloni et al., bella et all and cascio et al., in their randomized studies, have demonstrated the non-inferiority, respectively, of azithromycin, josamycin, and clarithromycin vs. doxycycline. [ ] [ ] [ ] on the contrary, munoz-espin et al. have shown that erythromycin is less effective than doxycycline. studies in vitro have tested the efficacy of fluoroquinolones against rickettsiae spp., showing encouraging results. , [ ] [ ] [ ] furthermore, randomized studies have shown that there is no difference between tetracycline and fluoroquinolones. [ ] [ ] [ ] however, other studies found that fluoroquinolones are associated with increased msf severity and the worst outcome. ciprofloxacin has been shown to have a deleterious effect on rickettsia conorii-infected cells. rickettsiae spp. showed to be susceptible also to rifampicin, but in a small trial showed its inferiority in comparison with doxycycline. even trimethoprim-sulfamethoxazole has been considered as a possible therapeutic option, but in vitro and in vivo studies have demonstrated that it is not active against rickettsia spp. , in the presence of unspecific symptoms during the spring to summer months, starting azithromycin seems reasonable given the ongoing covid- epidemic in mediterranean countries. bergey's manual of rickettsioses as paradigms of new or emerging infectious diseases ancestral divergence of rickettsia bellii from the spotted fever and typhus groups of rickettsia and antiquity of the genus rickettsia classification of rickettsia tsutsugamushi in a new 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and management of tick-borne rickettsial diseases: rocky mountain spotted fever, ehrlichioses, and anaplasmosis--united states: a practical guide for physicians and other health-care and public health professionals complement associated microvascular injury and thrombosis in the pathogenesis of severe covid- infection: a report of five cases updated approaches against sars-cov- vascular skin symptoms in covid- : a french observational study laboratory diagnosis of rickettsioses: current approaches to diagnosis of old and new rickettsial diseases rickettsial diseases and their serological diagnosis a concise review of the epidemiology and diagnostics of rickettsioses: rickettsia and orientia spp manual of clinical microbiology ehrlichia, anaplasma, and related intracellular bacteria a comparison of the complement fixation, indirect fluorescent antibody, and microagglutination tests for the serological diagnosis of rickettsial diseases diagnosis of mediterranean spotted fever by indirect immunofluorescence of rickettsia conorii in circulating endothelial cells isolated with monoclonal antibody-coated immunomagnetic beads serodiagnosis of rocky mountain spotted fever: comparison of igm and igg enzyme-linked immunosorbent assays and indirect fluorescent antibody test inter-and intralaboratory comparison of ehrlichia equi and human granulocytic ehrlichiosis (hge) agent strains www.mjhid.org for serodiagnosis of hge by the immunofluorescent-antibody test diagnosis of granulocytic ehrlichiosis in humans by immunofluorescence assay enzyme-linked immunosorbent assay (elisa) quantitative assay of immunoglobulin g use of monoclonal antibodies against rickettsia tsutsugamushi kawasaki for serodiagnosis by enzyme-linked immunosorbent assay short report: detection of rickettsioses and q fever in sri lanka two human cases of rickettsia felis infection suicide pcr on skin biopsy specimens for diagnosis of rickettsioses state of the art of diagnosis of rickettsial diseases: the use of blood specimens for diagnosis of scrub typhus, spotted fever group rickettsiosis, and murine typhus comparison of two quantitative real time pcr assays for rickettsia detection in patients from tunisia evaluation of serological tests for the diagnosis of rickettsiosis in denmark correlation of rickettsial titers, circulating endotoxin, and clinical features in rocky mountain spotted fever diagnosis and management of tick-borne rickettsial diseases: rocky mountain spotted fever and other spotted fever group rickettsioses, ehrlichioses, and anaplasmosis -united states a practical guide for health care and public health professionals perspectivas sobre el diagnóstico de laboratorio de enfermedades rickettsiales en el siglo studies of spotted fever rickettsia -distribution, detection, diagnosis and clinical context. . - p laboratory diagnosis of rickettsial infections diagnostic strategy of rickettsioses and ehrlichioses indirect hemagglutination test for detection of antibody to rickettsia rickettsii in sera from humans and common laboratory animals demonstration of rickettsia conorii-induced endothelial injury in vivo by measuring circulating endothelial cells, thrombomodulin, and von willebrand factor in patients with mediterranean spotted fever detection of rickettsia spp in ticks by identification of tick species and disseminate pathogen using hemolymph by maldi-tof ms development of an electrochemical immunosensor for the diagnostic testing of spotted fever using synthetic peptides in vitro susceptibilities of rickettsiae to antimicrobials the tetracyclines transplacental effect of tetracyclines on teeth azithromycin vs. doxycycline for mediterranean spotted fever randomized trial of doxycycline versus josamycin for mediterranean spotted fever efficacy and safety of clarithromycin as treatment for mediterranean spotted fever in children: a randomized controlled trial erythromycin versus tetracycline for treatment of mediterranean spotted fever in vitro susceptibility of rickettsia conorii to ciprofloxacin as determined by suppressing lethality in chicken embryos and by plaque assay susceptibility of rickettsia conorii and r. rickettsii to pefloxacin, in vitro and in ovo susceptibility of rickettsia conorii, r. rickettsii, and coxiella burnetii to pd , , pd , , www.mjhid.org evaluation of ciprofloxacin and doxycycline in the treatment of mediterranean spotted fever randomized double-blind evaluation of ciprofloxacin and doxycycline for mediterranean spotted fever ciprofloxacin therapy for mediterranean spotted fever analysis of risk factors for malignant mediterranean spotted fever indicates that fluoroquinolone treatment has a deleterious effect deleterious effect of ciprofloxacin on rickettsia conorii-infected cells is linked to toxinantitoxin module up-regulation antibiotic susceptibility of rickettsia and treatment of rickettsioses randomized trial of -day rifampin versus -day doxycycline therapy for mediterranean spotted fever deleterious effect of trimethoprimsulfamethoxazole in mediterranean spotted fever the antigenic relationship between bacillus proteus x- and rickettsiae: iii. a study of the antigenic composition of the extracts of bacillus proteus x- key: cord- -uoek pba authors: peset, josé l. title: plagues and diseases in history date: - - journal: international encyclopedia of the social & behavioral sciences doi: . /b - - - - . - sha: doc_id: cord_uid: uoek pba in spite of the development of the medical science, during the twentieth century, individuals have observed the spread of new or reemerging diseases, from plague, cholera, and flu; measles, cancer, and malaria; to acquired immune deficiency syndrome, west nile fever, resistant tuberculosis, virus of ebola, creutzfeldt-jakob disease, and others. as individual illness is rooted in society and the environment, human life is tied up with the history of main endemic and epidemic diseases. human health is very sensitive and adaptable to changes, so the history of disease and hygiene is the core of the new ecological history. the 'sweating sickness' (sudor anglicus) . on yet other occasions, these changes are merely due to cultural appreciations, as it has happened with certain sexual practices such as masturbation or homosexuality, which used to be framed as stigmatized diseases. on the other hand, disease is not always considered only harmful: thus it may be considered a distinction of the gods, as was the case of epilepsy in ancient times, or among some historical aboriginal tribes. nevertheless, the hippocratic text on the sacred disease established the natural condition of this illness, similar to other medical affections. the same disease was associated with the devil by the christians, and historically, it had always been a supposed distinction of great personages from caesar to napoleon. disease can also be considered a way toward perfection or transformations, leading to the creation of art or to the salvation of the soul, as melancholy or sorrow were for centuries. disease may also have political repercussions: it is claimed that george the third's madness gave rise to problems for the british crown, while roosevelt's fragile health was considered to have placed him in a weak position in the yalta negotiations. socially, disease has sometimes unjustly been considered the stigma of groups (as acquired immune deficiency syndrome (aids) for homosexuals, and poor or marginal groups, or alcoholism for black or aboriginal peoples). medicine and politics have endeavored to preempt social changes by means of the contested eugenic theories and practices of social engineering, inspired by francis galton at the end of nineteenth century, which began with recommendations or laws to avoid marriages entailing risks (real or imaginary), and went on to such processes as sterilizations. heredity is today considered an important predisposition for disease, but mostly not in a deterministic way. hereditary conditions are thus intertwined with cultural, social, religious, and moral ones. besides, in contrast with the stark determination of former times, there is today an attempt to draw new optimism from the possibilities of genetic modifications. yet, in this latter respect, there is fear of a future where such a formidable force could rest in the hands of the rich and powerful. an important renewal in the study of infectious diseases was driven by bacteriological discoveries, and the theories about infection and immunity. in this respect, hans zinsser in rats, lice, and history combined them with human history, proposing biographical interpretations of epidemiological history. the study of the transmission of pathogens through animals and human beings (as vectors and hosts), living in a physical, biological, social, and cultural environment, was crucial in bringing about a new history of disease and also much later in fueling the most recent ecological history. in the meantime, the essential contributions of historical demography and social history licensed the consideration of the history of diseases as 'biographies,' shared by human cultures, living beings, and natural environment. but with the development of accurate technologies of diagnosis, the real identification of old plagues is more and more demanding. paleopathology enables us to discover the high incidence of diseases in the early inhabitants of the earth, especially where such diseases left their mark on bones. it is thus possible to detect remnants of tumors, infections, necrosis, osteoporosis, and malformations, as also traumatisms, dental alterations, rickets, rheumatism, and other diseases of the bones. today, laboratory analysis allows the possibility of detecting remnants of other diseases, germs, or lesions, in animal or human remains, including of course the famous mummies. from the first settlements in the fertile crescent, changes have taken place in the relationship of man and animals with their environment and it is possible to establish an extensive catalog of diseases that have largely subsisted down to this very day. particularly significant are the forms of settlement, the crops and hunting, and the contact of man with cattle, pets, and parasites, as well as the relations between peoples, through mixing and trade, wars, and migrations. malaria originated in tropical africa, accompanying the dawn of humanity, from plasmodia infecting animals and hominids. caused by different plasmodia (plasmodium vivax and plasmodium falciparum among others, with different geographical distribution), its relation with human populations is shaped by migrations and deforestation, hunting and farming, climate and soils, crops, animals and foods, and a complicated immunity resulting from ancient genetic mutations and new infections. thus, with the early human emigrations, it expanded through eurasia, and in the third millennia bc, malaria had already set in the early civilizations in marshy areas where the water, the climate, and the crops provided the conditions for the anopheles mosquitoes to infect in crowded populations. evidence for the existence of intermittent fevers is already to be found in ancient cultures, finding suitable conditions along the yellow, indus, ganges, euphrates, or nile rivers. different interpretations considered the disease to originate from climatic or environmental factors, from particles or small animals, because of spirits or gods, or from unbalanced or disharmonic alterations. the connection between fevers, splenomegaly, and marshy areas appears in the hippocratic texts, such as on airs, waters and places. deforestation, agriculture, temperature, and a greater population density, as well as military and commercial movements, favor the spread of the disease. in italy, in republican times, the disease becomes acute; and it was recommended that the marshy lands be either abandoned or sold and that people should dwell on high groundthe latter being traditional advice and here defense reasons also counted. also, the cleaning and draining of swamps was considered, this being the origin of systems of engineering sanitation. the spread of malaria got worse and worse in rome owing to negligence and flooding, climate and agricultural changes, wars, travels, and migrations, and it reached its zenith at the time of the fall of the roman empire, a cataclysm to which it may have contributed. but when the old empire declined, another frightening ghost traveled through the mediterranean sea. plagues were considered in ancient cultures as diseases originating in god's punishment, with a violent pattern, and quick and terrible diffusion, affecting and killing a large number of persons. destructive epidemic catastrophes were narrated frequently in mesopotamian, biblical, egyptian, indian, or chinese sources, and in - bc, thucydides describes the plague of athens in the war against sparta, but it is doubtful that this case refers to the bubonic plague. this epidemic death is considered the beginning of the decline of athenian hegemony, the crisis of the democracy, and culture of the pericles era. fear, war, siege of the city, and its maritime port were accompanied by the death of the great ruler pericles. later on, the first reliable description of this disease is that given by rufus of ephesus in the ad first to the second century, in the epoch of trajan; and in the sixth century, the plague of justinian initiates the first great epidemic cycles of bubonic plague. soldiers and merchants, animals and merchandises, and slaves and prisoners all contribute to linking up the extremes of the known world. a consequence of this contact was the antonine plague in the second century. this plague -and othersis attributed to smallpox, a disease that had already existed as far back as years ago, as certain mummies show. in the middle ages, leprosy spread widely, allegedly as a result of the increasing east-west relations trough trade, travels, and wars. this biblical and present day disease is accompanied by social repulse and malignant connotations since dirtiness and overcrowding provided the conditions for the spread of the otherwise not extremely contagious mycobacterium leprae. in this respect, the way to santiago de compostela where pilgrims slept in groups and under unhealthy and dirty conditions provided a fertile ground for this disease. another markedly religious character is to be found in the 'sacred fire,' 'st anthony's fire,' or ergotism; a disease that developed in people eating rye infected by ergot, it was soon prevented, but reappeared during the course of severe famines. these diseases are linked to many others that owed their spread to squalor and poverty, for example, parasites and infections, scabies, mycoses and lice, anthrax and ophthalmia. natural catastrophes, wars, poverty, and famines were escorted by mental diseases, tuberculosis and pneumonia, traumatisms and poisonings, diarrheal diseases and fevers, as well as smallpox and measles. in the mediterranean basin, malaria continued to be endemic with the population tending to resort to residing on the hills and mountains, far from marshy lands. the extension of malaria involved south and southeast of asia, central china and japan, and also north europe. the plague set in the growing cities with the burden of rats and fleas, making this disease an explicative example par excellence of epidemic history. a second epidemic cycle began with the black death in . commerce and the cities collapsed, giving rise to the origin of the modern european kingdoms. at this time, venice established control over persons and ships, in order to avoid the spread of plague, arriving from distant lands. dark ages are ending, and new worlds are opening in culture and geography. european expansion meant a sudden traffic of diseases mostly toward the new world. the discovery of america, with its scattered population devoted to agriculture, where there were no dirty cities, and where the inhabitants were devoid of immunity to the diseases of old europe, produced an enormous demographic crisis. certain diseases, such as smallpox (and measles) ravaged the indigenous population; this very contagious and harsh illness was introduced in the caribbean and mexico, and destroyed american indigenous populations. syphilis came supposedly from america (although other human treponematoses were present in other continents), brought back by the spaniards and it caused havoc since renaissance in europe and soon all around the world. troop movements spread an unknown disease called 'tabardillo,' or 'typhus exanthematicus,' bringing about serious suffering for armies and poor people. sea voyages led to the development of scurvy, due to the lack of fresh food. other diseases also voyaged overseas, such as yellow fever; although it originated from africa, due to the commerce of slaves and merchandise, special temperature conditions and mosquitoes as vectors were required for the contagion. in the seventeenth century, it took root in brazil and also spread to the caribbean and throughout america, reaching new york and boston and likewise colombia, ecuador, and peru. it affected warm america and europe, through the iberian peninsula. immunity and cutoffs in commerce stalled the disease, but it remains endemic in tropical areas of america and africa. also, malaria arrived to america with the european conquest in sixteenth century, beginning in the caribbean and central america and soon spreading to south and north america, becoming endemic in hot, wet, and low lands. malaria was combated since the seventeenth century by the use of cinchona bark (peruvian bark), found in peru, as an indigenous medical practice. later on, the quininethe alkaloid obtained from the bark in french laboratoriesgave rise to rich industry and trade. trees were cultivated in british and dutch colonies, mainly in java. after being taken in the second world war by the japanese army, synthetic products such as atebrine and chloroquine were obtained. getting worse with agriculture, mining and livestock changes, settlements, and slavery trade, malaria becametogether with yellow fevera scourge along the warm and hot reaches. throughout the american conflicts between european empires, and later during the american independence wars, both diseases played an important role, infecting and killing nonimmune soldiers. plague slowed demographic growth in europe since the wars between modern and powerful nations, the crowded and dirty cities, and the developing trades impeded protection against the disease. the great writer daniel defoe remembered the terrible contagion in london in in journal of the plague year. after the great european plague of marseille in , the relative peace of the eighteenth century allowed western europe to set up sea and land defenses, with austria becoming a solid bulwark in the face of the ottoman empire, thus sealing off all possible spread of the plague. toward the middle of the nineteenth century, the third wave of the disease broke out and, with the exception of europe, it spread to all countries including asia, africa, and paradises like america and australia, leaving remnants in many places. the eradication of plague in europe was a result of the advent of public hygiene, immunity to disease, and the disappearance of rats and of the old and dirty wooden buildings. the great london fire in 'purified' the city, since the hygienic rebuilding was carried out in stone, eliminating animals and dirt. the disappearance of plague from europe was followed by the outbreak of cholera, which had been endemic in india for centuries. this disease was described by western travelers in the sixteenth century and its spread to europe and america was a consequence of pilgrimages, trade, and a lack of cleanliness in water. a great pandemic broke out in from india and spread through eastern africa and southern asia, arriving to china and the philippines, and in a second wave, it spread through persia reaching russia and poland in . then this second wave swept across europe and reached america by . throughout years, terrible waves spread from the east. however, the timely and necessary cleansing of urban water supplies helped to progressively stall its advance. nevertheless, as late as , the free hanseatic city of hamburg suffered an outbreak of cholera epidemic, while the neighboring altona, governed by the prussian reich, was able to avoid the disease, thanks to the successful filtering of its water. local and national governments advanced in hygiene and they attempted to bring about healthier cities by means of appropriate public health measures. the nineteenth century sees the beginning of the demographic revolution in europe, followed by developing countries, in america for example, with a sharp decline in mortality, especially maternal-infant mortality. old inoculation and the new vaccination proposed in by edward jenner fought smallpox successfully. studies about human immunity since the last decades of nineteenth century began a new medical approach to the prevention and understanding of illness, being successful in the contention of many diseases, which have a long record of burdens and deaths. mother care also advanced both throughout pregnancy and at childbirth and during lactation. the rise of great and industrial cities with low-grade outskirts and the emigration of peasants to the city favored the spread of maladies associated with poverty, hard work, squalor, lack of appropriate food, and exposure of people devoid of defenses. some of the diseases were strictly occupational as in the case of miners and textile workers who were exposed to injury, and to industrial poisons that affected the proletariat. sir percivall pott described in the eighteenth century the cancer produced in professional cleaners (chimney sweep) by chemical toxics contained in soot. many other diseases, such as cancers, will be attributed to chemical and physical aggressions, including radioactivity. other diseases were closely related to the harsh and dirty conditions of life such as spread of typhoid fever and pulmonary diseases. tuberculosis spread over the turn between the eighteenth and nineteenth centuries, and while it was represented as the disease in fashion, affecting notable and distinguished people, it struck the proletariat much more severely. the same can be claimed regarding the enormous spread of syphilis, and drug abuse, beginning with alcohol and continuing with cocaine and morphine. the discovery of the microbiological origin of infectious diseases, and of effective therapies against them, and the development of public health changed the pathological landscape in developed countries. the long way between ignaz semmelweis and alexander fleming arrived to the contention of infections in health care. the twentieth century marked the descent of the high mortality rates in countries that reached high standards of sanitary development, investing in health care and public health. such advances have been due to public health services, hospitals, antibiotics, surgery, and vaccination, and they have been reinforced by the developments in immunology and microsurgery, pharmacology, and biotechnology and with the promising future of genetic engineering. the international health solidarity promoted by the world health organization (who), and other governmental and nongovernmental organizations (ngos), including church missionaries, were accompanied by better governance of nations, and internationalization of information and resources. the twentieth century established a serious change in geopathology of diseases. smallpox is the first disease to be considered totally eradicated with only some samples of the virus being kept at a few laboratories for study purposes. a cuban doctor (carlos finlay) found the method by which yellow fever is transmitted through mosquitoes (aedes aegypti). after the cuban war and during the opening of the panama channel, yellow fever and malaria were studied and faced by us army and american sanitarians (walter reed, william gorgas), and later by the rockefeller foundation. impeding mosquito reproduction and avoiding bites and spreading chemical products were useful. fortunately, an effective vaccine against yellow fever was later discovered. during nineteenth century, malaria expanded all around the world, arriving to the central extensions of america and eurasia. emigrations and settlements, wars, famines, climate change, and revolutions in travels, such as railroads and steamships, contributed. during the napoleonic wars and the american civil war, malaria was seriously extended, as it was also during wars and revolutions in twentieth century. in the interwar years, the rockefeller foundation and the league of nations sponsored international campaigns against the disease. many governmental campaigns also fought against malaria; several national programs were effective, from taiwan and china to the united states, brazil, and argentina, passing across the mediterranean basin, from italy to egypt. opinions and campaigns oscillated between quinine treatment, fighting against mosquitoes (by dichlorodiphenyltrichloroethane (ddt)), and improvements in life, education, and land sanitation, clearing up the marshy areas. malaria has been eradicated from europe thanks to drainage, improvements in crop cultivation, mechanical barriers, quinine and modern drugs such as atebrine and chloroquine, and insecticides. colonial settlements entered tropical areas backed by quinine, nets in beds, hygiene, and sanitation, but transmissible diseases were continuously a serious burden for colonial armies, in america, africa, or asia. some chemical products such as ddt were a successful support for soldiers, travelers, merchants, or settlers. nevertheless, in , the world health assembly, meeting in mexico, warned against the resistance of the mosquitoes to insecticides. mosquitoes are still today carrying both diseases, and also dengue. chagas disease produced by trypanosoma cruzi is endemic in america, and sleeping sickness caused by trypanosoma brucei (rhodesiense and gambiense) occurs in africa. today, an effort is being made to involve governments in the fight against malaria, a disease that represents a danger to nearly half of the world's population. in africa, the situation is very serious due to the changes in agriculture and irrigation as well as in work and migrations, the political and economic problems, the severe droughts, famines and wars, the bad sanitary conditions following in the wake of housing expansion and deforestation, and harsh social and economic exploitation. together with the who and the united nations international children's emergency fund (unicef), regional institutions such as the pan american health organization and the us government are financing programs of eradication. the who, through the st world health assembly of , set up the program 'roll back malaria' and, with aid from unicef and the world bank, is endeavoring to bring about economic and sanitary improvements in developing countries. in twentyfirst century, the global fund to fight aids, tuberculosis and malaria is attaining important amount of resources and success. nets treated with insecticides are very useful for protection against mosquitoes. today, hope is also placed on vaccination and in the sterilization, or genetic modification, of the mosquitoes. yet, malaria continues to be endemic in warm zones of america, asia, and with severe cruelty, in africa. the rapid increase of world population in huge metropolitan areas was accompanied by new settlements and emigrations, wars, conflicts and revolutions, and marginalization of aboriginal cultures and disinherited peoples. throughout the past two centuries, economical, social, and political expansion of the west led to studies on tropical medicine, creating hospitals and laboratories and institutions on public health and sanitary departments. cholera continues to be feared in asia, between india and the far east, and also in warm zones in america and africa. wars and catastrophes, travels and migrations, as well as famines and unhealthy conditions allowed the expansion of the cholera germ, the vibrio cholerae isolated by robert koch in , as was the case of the recent tragedy of haiti. at the end of nineteenth century, the third outbreak of bubonic plague allowed its bacteriological and epidemiological description. the germ of bubonic plague yersinia pestis, discovered by yersin and kitasato, is still to be found throughout the world. the germ is carried by rats, rattus rattus: rat fleas are the arthropod vectors transmitting 'epizootic' plague to humans from rodent hosts, and related species, but transmission among humans is also possible. almost forgotten in the developed world, with several and very effective antibiotic therapies, there is, nevertheless, always the possibility that the devil may once more send his rats to the old, rich cities. but other viruses have taken its place in the twentieth century. thus the very old and common influenza caused several cruel and heavy outbreaks; among many others, influenza pandemics began in and reappeared in , , and : these were known, respectively, as the 'spanish flu,' which perhaps originated in the united states, the 'asian flu,' the 'hong kong flu,' and the 'avian flu,' mostly coming from asia. vaccines are very useful in its prevention, as they are also in the control of many infectious childhood diseases, such as measles, rubella, mumps, chicken pox, whooping cough, diphtheria, and so on. old diseases such as poliomyelitis exploded in the united states and europe, affecting nonimmune children, and this disease has only been controlled in developed countries by means of vaccination. during the past century, individuals have observed astonished the spread of new or reemerging diseases, from plague, cholera, influenza, measles, and malaria, to aids, west nile fever, avian flu, severe acute respiratory syndrome, resistant tuberculosis, hemorrhagic fever (ebola virus disease), transmissible spongiform encephalopathy (creutzfeldt-jakob disease), and others. unfortunately today, many frequent or rare diseases do not have adequate treatment, and many germs are developing resistance to antibiotics, a serious threat for its affectivity. aids has meant a development in the study of viral infections, and this disease has associations with the exploitation of poor people, unsafe sex, and drug trading, but it also affected an elite sector, which has sprung rapid research in the field. the world commotion surrounding this disease has served both to reveal human altruism on the one hand, and, on the other, contempt toward those infected by the disease, since aids became more and more the lot of the poor, mostly in large areas of africa, or india, and of downcast or marginal groups such as the chronic patients, drug addicts, prostitutes, and homosexuals. nevertheless, heterosexual transmission through unsafe sex and transmission from mother to child are today serious dangers. safe sex and antiretroviral treatment are the best contention, while a vaccine will be obtained perhaps in the coming future. mental affections were considered till modern times, as devilish, criminal, or vicious behaviors, more an ethical or social than a medical problem. in the eighteenth century, the natural explanation of mental disease was established, according to alexander crichton, or philippe pinel, and in the nineteenth and twentieth centuries, its psychogenic process, following sigmund freud. from pinel to freud, the possibility of treatment and remedy of mental disease was established, leading the soul of the patient with convictions and health measures to the cure. the discovery in recent times of some effective pharmacological drugs acting on human mind, and conduct, has allowed better treatment. reclusion was considered a doubtful possibility, restricted to some severe problems. the old lunatic asylums, founded since middle ages, were being abolished or completely renewed. nevertheless, mental illnesses wreak serious havoc at present times all around the world, affecting all ages, genders, and conditions, without any distinction. sometimes, the misunderstanding regarding mental diseases still produces cruel treatments, harsh restrictions, or punishment. during the past decades, economic and social improvements led to quick globalization and urbanization, with longer human life and changes in disease patterns. political, sanitary, and economic development managed to stamp out infectious morbidity, and forms of suffering or living illnesses are changing. unicef and who, in collaboration with governments, foundations, and ngos, promote successful campaigns of vaccination, especially focusing on children. the burden of infectious, parasitic, and transmissible diseases changed to chronic diseases and sufferings related with aging and lifestyles, likewise, nutritional disorders, cancer, or heart and brain vascular diseases. on the other hand, the increase in life expectation favors the development of alzheimer and other chronic and degenerative diseases, neurological and muscular diseases, mental affections such as schizophrenia, mania and depression, diabetes, vascular diseases, and of course, the terrible presence of cancer. accidents and traumatisms, due to traffic and sports, factories and radiation, or even home accidents, are something that the twenty-first century is inheriting. blindness, deafness, dumbness, and other frequent physical and mental disabilities, with multiple origins in traumatisms or accidents, genetic, metabolic and degenerative diseases, infectious diseases such as poliomyelitis, or cerebral and vascular affections, make daily life difficult and, at the same time, make economical, institutional, and social support necessary. incapacitating and chronic diseases lead to severe dependency and so the need for protection of disabled individuals is leading to the founding of patients' associations looking for help and justice, creating new rights and demands. ghettos and migrations, hard work, poverty and unemployment, and some of the old drugs such as alcohol, heroine, and tobacco or new synthetic ones are causing havoc even to the rich world. but in developing countries, the old morbidity due to transmissible diseases continues to exist, maintaining a very low life expectation. certainly, the increase of migrations and of urban population are requiring more water, food, and energy, producing climate warming, deforestation and agriculture changes, and dangerous issues such as waste, toxics, and pollutants. potable water, health services (medical care or medical drugs), sanitation and hygiene are urgently requested. environmental degradation and the confrontations between national, social, and ethnic groupings are a serious danger for healthy life. china, japan, and south korea and other expanding countries have lived through these challenges in different ways from diverse british colonies such as australia or india. different traditions and cultures are extremely important to understand the relations between peoples and diseases. death is most rampant amid the least protected and poorest people, especially women, children, and the elderly, with harsh sufferings such as wars, famine, and exploitation. under such circumstances, diseases caused by deprivation and infection continue to be the most rampant, causing high death rates among the population. old and new diseases, such as malaria and aids, are ruining great stretches of africa. leprosy and cholera, tuberculosis and tetanus, and many child diseases, such as mumps, measles, tetanus, or meningitis are in poor countries and populations the salt of the earth. private and public funds, and international solidarity, are always necessary for relieving these harsh sufferings. the united nations millennium development goals are also facing them. according to the who report global health risks ( ), the better or worse conditions for mortality and for the burden of disease are seriously conditioned by several circumstances, related to lifestyles: blood pressure, blood glucose, physical activity, alcohol and tobacco, weight, safe sex, safe water, sanitation, and hygiene. obviously, these circumstances and their consequences are very different, depending on the social level of individuals and the public health governance of nations and peoples. if developing countries are freeing themselves from transmissible diseases, now they are fighting against noncommunicable diseases, related to social level, health organization, and hygienic customs. some american, asian, and african countries are still supporting a terrible burden of disease, which is also shared by low-income population in developed countries. the rio political declaration in the world conference on social determinants of health (who-rio de janeiro, brazil, october ) is a new call looking for equity, justice, and universality of health. it has recommended adopting better governance for health and development; promoting information, justice, and participation in policy making and during the implementation process; including civil society like indigenous people; and reducing health inequities in the health sector. this declaration promotes research on the relationships between social determinants and differences (economic, ethnic, and gender inequalities) and health equity. we are all convinced about the relation between poverty, social discrimination, low education and low sanitation, and diseases and death. history of western; science, history of; welfare state, history of plagues in world history the great pox: the french disease in renaissance europe les hommes et la peste en france et dans les pays européens et méditerranéens, vols la malaria tra passato e presente the columbian exchange: biological and cultural consequences of médecins, climat et épidémies à la fin du xviiie siècle the cambridge world history of human disease public health in asia and the pacific. historical and comparative perspectives plague and the end of antiquity: the pandemic of - mosquito empires: ecology and war in the greater caribbean plagues and peoples inescapable ecologies: a history of environment, disease, and knowledge humanity's burden: a global history of malaria rats, lice and history. printed and pub. for the atlantic monthly press by little, brown, and company key: cord- -fqy sm authors: huremović, damir title: brief history of pandemics (pandemics throughout history) date: - - journal: psychiatry of pandemics doi: . / - - - - _ sha: doc_id: cord_uid: fqy sm intermittent outbreaks of infectious diseases have had profound and lasting effects on societies throughout history. those events have powerfully shaped the economic, political, and social aspects of human civilization, with their effects often lasting for centuries. epidemic outbreaks have defined some of the basic tenets of modern medicine, pushing the scientific community to develop principles of epidemiology, prevention, immunization, and antimicrobial treatments. this chapter outlines some of the most notable outbreaks that took place in human history and are relevant for a better understanding of the rest of the material. starting with religious texts, which heavily reference plagues, this chapter establishes the fundamentals for our understanding of the scope, social, medical, and psychological impact that some pandemics effected on civilization, including the black death (a plague outbreak from the fourteenth century), the spanish flu of , and the more recent outbreaks in the twenty-first century, including sars, ebola, and zika. given to ways plagues affected the individual and group psychology of afflicted societies. this includes the unexamined ways pandemic outbreaks might have shaped the specialty of psychiatry; psychoanalysis was gaining recognition as an established treatment within medical community at the time the last great pandemic was making global rounds a century ago. there is a single word that can serve as a fitting point of departure for our brief journey through the history of pandemics -that word is the plague. stemming from doric greek word plaga (strike, blow), the word plague is a polyseme, used interchangeably to describe a particular, virulent contagious febrile disease caused by yersinia pestis, as a general term for any epidemic disease causing a high rate of mortality, or more widely, as a metaphor for any sudden outbreak of a disastrous evil or affliction [ ] . this term in greek can refer to any kind of sickness; in latin, the terms are plaga and pestis (fig. . ). perhaps the best-known examples of plagues ever recorded are those referred to in the religious scriptures that serve as foundations to abrahamic religions, starting with the old testament. book of exodus, chapters through , mentions a series of ten plagues to strike the egyptians before the israelites, held in captivity by the pharaoh, the ruler of egypt, are finally released. some of those loosely defined plagues are likely occurrences of elements, but at least a few of them are clearly of infectious nature. lice, diseased livestock, boils, and possible deaths of firstborn likely describe a variety of infectious diseases, zoonoses, and parasitoses [ ] . similar plagues were described and referred to in islamic tradition in chapter of the qur'an (surat al-a'raf, v. ) [ ] . throughout the biblical context, pandemic outbreaks are the bookends of human existence, considered both a part of nascent human societies, and a part of the very ending of humanity. in the apocalypse or the book of revelation, chapter , seven bowls of god's wrath will be poured on the earth by angels, again some of the bowls containing plagues likely infectious in nature: "so the first angel went and poured out his bowl on the earth, and harmful and painful sores came upon the people who bore the mark of the beast" (revelation : ). those events, regardless of factual evidence, deeply shaped human history, and continue to be commemorated in religious practices throughout the world. as we will see, the beliefs associated with those fundamental accounts have been rooted in societal responses to pandemics in western societies and continue to shape public sentiment and perception of current and future outbreaks. examined through the lens of abrahamic spiritual context, serious infectious outbreaks can often be interpreted as a "divine punishment for sins" (of the entire society or its outcast segments) or, in its eschatological iteration, as events heralding the "end of days" (i.e., the end of the world). throughout known, predominantly western history, there have been recorded processions of pandemics that each shaped our history and our society, inclusive of shaping the very basic principles of modern health sciences. what follows is an outline of major pandemic outbreaks throughout recorded history extending into the twenty-first century. the athenian plague of b.c. the athenian plague is a historically documented event that occurred in - b.c. during the peloponnesian war, fought between city-states of athens and sparta. the historic account of the athenian plague is provided by thucydides, who survived the plague himself and described it in his history of the peloponnesian war [ ] . the athenian plague originated in ethiopia, and from there, it spread throughout egypt and greece. initial symptoms of the plague included headaches, conjunctivitis, a rash covering the body, and fever. the victims would then cough up blood, and suffer from extremely painful stomach cramping, followed by vomiting and attacks of "ineffectual retching" [ ] . infected individuals would generally die by the seventh or eighth day. those who survived this stage might suffer from partial paralysis, amnesia, or blindness for the rest of their lives. doctors and other caregivers frequently caught the disease, and died with those whom they had been attempting to heal. the despair caused by the plague within the city led the people to be indifferent to the laws of men and gods, and many cast themselves into self-indulgence [ ] . because of wartime overcrowding in the city of athens, the plague spread quickly, killing tens of thousands, including pericles, athens' beloved leader. with the fall of civic duty and religion, superstition reigned, especially in the recollection of old oracles [ ] . the plague of athens affected a majority of the inhabitants of the overcrowded city-state and claimed lives of more than % of the population [ ] . the cause of the athenian plague of b.c. has not been clearly determined, but many diseases, including bubonic plague, have been ruled out as possibilities [ ] . while typhoid fever figures prominently as a probable culprit, a recent theory, postulated by olson and some other epidemiologists and classicists, considers the cause of the athenian plague to be ebola virus hemorrhagic fever [ ] . while hippocrates is thought to have been a contemporary of the plague of athens, even possibly treating the afflicted as a young physician, he had not left known accounts of the outbreak [ ] . it was another outbreak that occurred a couple of centuries later that was documented and recorded by contemporary physicians of the time. the outbreak was known as the antonine plague of - ad and the physician documenting it was galen; this outbreak is also known as the plague of galen [ ] . the antonine plague occurred in the roman empire during the reign of marcus aurelius ( - a.d.) and its cause is thought to be smallpox [ ] . it was brought into the empire by soldiers returning from seleucia, and before it abated, it had affected asia minor, egypt, greece, and italy. unlike the plague of athens, which affected a geographically limited region, the antonine plague spread across the vast territory of the entire roman empire, because the empire was an economically and politically integrated, cohesive society occupying wide swaths of the territory [ ] . the plague destroyed as much as one-third of the population in some areas, and decimated the roman army, claiming the life of marcus aurelius himself [ ] . the impact of the plague on the roman empire was severe, weakening its military and economic supremacy. the antonine plague affected ancient roman traditions, leading to a renewal of spirituality and religiousness, creating the conditions for spreading of new religions, including christianity. the antonine plague may well have created the conditions for the decline of the roman empire and, afterwards, for its fall in the west in the fifth century ad [ ] . the justinian plague was a "real plague" pandemic (i.e., caused by yersinia pestis) that originated in mid-sixth century ad either in ethiopia, moving through egypt, or in the central asian steppes, where it then traveled along the caravan trading routes. from one of these two locations, the pestilence quickly spread throughout the roman world and beyond. like most pandemics, the justinian plague generally followed trading routes providing an "exchange of infections as well as of goods," and therefore, was especially brutal to coastal cities. military movement at the time also contributed to spreading the disease from asia minor to africa and italy, and further to western europe. described in detail by procopius, john of ephesus, and evagrius, the justinian epidemic is the earliest clearly documented example of the actual (bubonic) plague outbreak [ ] . during the plague, many victims experienced hallucinations prior to the outbreak of illness. the first symptoms of the plague followed closely behind; they included fever and fatigue. soon afterwards, buboes appeared in the groin area or armpits, or occasionally beside the ears. from this point, the disease progressed rapidly; infected individuals usually died within days. infected individuals would enter a delirious, lethargic state, and would not wish to eat or drink. following this stage, the victims would be "seized by madness," causing great difficulties to those who attempted to care for them [ ] . many people died painfully when their buboes gangrened; others died vomiting blood. there were also cases, however, in which the buboes grew to great size, and then ruptured and suppurated. in such cases, the patient would usually recover, having to live with withered thighs and tongues, classic aftereffects of the plague. doctors, noticing this trend and not knowing how else to fight the disease, sometimes lanced the buboes of those infected to discover that carbuncles had formed. those individuals who did survive infection usually had to live with ''withered thighs and tongues'', the stigmata of survivors. emperor justinian contracted the plague himself, but did not succumb [ ] . within a short time, all gravesites were beyond capacity, and the living resorted to throwing the bodies of victims out into the streets or piling them along the seashore to rot. the empire addressed this problem by digging huge pits and collecting the corpses there. although those pits reportedly held , corpses each, they soon overflowed [ ] . bodies were then placed inside the towers in the walls, causing a stench pervading the entire city. streets were deserted, and all trade was abandoned. staple foods became scarce and people died of starvation as well as of the disease itself [ ] . the byzantine empire was a sophisticated society in its time and many of the advanced public policies and institutions that existed at that time were also greatly affected. as the tax base shrank and the economic output decreased, the empire forced the survivors to shoulder the tax burden [ ] . byzantine army suffered in particular, being unable to fill its ranks and carry out military campaigns, and ultimately failing to retake rome for the empire. after the initial outbreak in , repetitions of the plague established permanent cycles of infection. by , it is possible that the population of the empire had been reduced by %. in the city of constantinople itself, it is possible that this figure exceeded % [ ] . at this point in history, christian tradition enters the realm of interpreting and understanding the events of this nature [ ] . drawing on the eschatological narrative of the book of revelations, plague and other misfortunes are seen and explained as a "punishment for sins," or retribution for the induction of "god's wrath" [ ] . this interpretation of the plague will reappear during the black death and play a much more central role throughout affected societies in europe. meanwhile, as the well-established byzantine empire experienced major challenges and weakening of its physical, economic, and cultural infrastructure during this outbreak, the nomadic arab tribes, moving through sparsely populated areas and practicing a form of protective isolation, were setting a stage for the rapid expansion of islam [ , ] . the black death "the plague" was a global outbreak of bubonic plague that originated in china in , arrived in europe in , following the silk road. within years of its reign, by , [ ] it reduced the global population from million to below million, possibly below million, with the pandemic killing as many as million. some estimates claim that the black death claimed up to % of lives in europe at that time [ ] . starting in china, it spread through central asia and northern india following the established trading route known as the silk road. the plague reached europe in sicily in . within years, it had spread to the virtually entire continent, moving onto russia and the middle east. in its first wave, it claimed million lives [ ] . the course and symptoms of the bubonic plague were dramatic and terrifying. boccaccio, one of the many artistic contemporaries of the plague, described it as follows: in men and women alike it first betrayed itself by the emergence of certain tumours in the groin or armpits, some of which grew as large as a common apple, others as an egg...from the two said parts of the body this deadly gavocciolo soon began to propagate and spread itself in all directions indifferently; after which the form of the malady began to change, black spots or livid making their appearance in many cases on the arm or the thigh or elsewhere, now few and large, now minute and numerous. as the gavocciolo had been and still was an infallible token of approaching death, such also were these spots on whomsoever they showed themselves [ ] . indeed, the mortality of untreated bubonic plague is close to %, usually within days, while the mortality of untreated pneumonic plague approaches %. treated with antibiotics, mortality drops to around % [ ] . at the time, scientific authorities were at a loss regarding the cause of the affliction. the first official report blamed an alignment of three planets from for causing a "great pestilence in the air" [ ] . it was followed by a more generally accepted miasma theory, an interpretation that blamed bad air. it was not until the late xix century that the black death was understood for what it was -a massive yersinia pestis pandemic [ ] . this strain of yersinia tends to infect and overflow the guts of oriental rat fleas (xenopsylla cheopis) forcing them to regurgitate concentrated bacteria into the host while feeding. such infected hosts then transmit the disease further and can infect humans -bubonic plague [ ] . humans can transmit the disease by droplets, leading to pneumonic plague. the mortality of the black death varied between regions, sometimes skipping sparsely populated rural areas, but then exacting its toll from the densely populated urban areas, where population perished in excess of , sometimes % [ ] . in the vacuum of a reasonable explanation for a catastrophe of such proportions, people turned to religion, invoking patron saints, the virgin mary, or joining the processions of flagellants whipping themselves with nail embedded scourges and incanting hymns and prayers as they passed from town to town [ ] . the general interpretation in predominantly catholic europe, as in the case of justinian plague, centered on the divine "punishment for sins." it then sought to identify those individuals and groups who were the "gravest sinners against god," frequently singling out minorities or women. jews in europe were commonly targeted, accused of "poisoning the wells" and entire communities persecuted and killed. non-catholic christians (e.g., cathars) were also blamed as "heretics" and experienced a similar fate [ ] . in other, non-christian parts of the world affected by the plague, a similar sentiment prevailed. in cairo, the sultan put in place a law prohibiting women from making public appearances as they may tempt men into sin [ ] . for bewildered and terrified societies, the only remedies were inhalation of aromatic vapors from flowers or camphor. soon, there was a shortage of doctors which led to a proliferation of quacks selling useless cures and amulets and other adornments that claimed to offer magical protection [ ] . entire neighborhoods, sometimes entire towns, were wiped out or settlements abandoned. crops could not be harvested, traveling and trade became curtailed, and food and manufactured goods became short. the plague broke down the normal divisions between the upper and lower classes and led to the emergence of a new middle class. the shortage of labor in the long run encouraged innovation of labor-saving technologies, leading to higher productivity [ ] . the effects of such a large-scale shared experience on the population of europe influenced all forms of art throughout the period, as evidenced by works by renowned artists, such as chaucer, boccaccio, or petrarch. the deep, lingering wake of the plague is evidenced in the rise of danse macabre (dance of the death) in visual arts and religious scripts [ ] , its horrors perhaps most chillingly depicted by paintings titled the triumph of death (fig. . ) [ ] . the plague made several encore rounds through europe in the following centuries, occasionally decimating towns and entire societies, but never with the same intensity as the black death [ ] . with the breakdown of societal structure and its infrastructures, many professions, notably that of medical doctors, were severely affected. many towns throughout europe lost their providers to plague or to fear thereof. in order to address this shortage in times of austere need, many municipalities contracted young doctors from whatever ranks were available to perform the duty of the plague doctor (medico della peste) [ ] . venice was among the first citystates to establish dedicated practitioners to deal with the issue of plague in . their principal task, besides taking care of people with the plague, was to record in public records the deaths due to the plague [ ] . in certain european cities like florence and perugia, plague doctors were the only ones allowed to perform autopsies to help determine the cause of death and managed to learn a lot about human anatomy. among the most notable plague doctors of their time were nostradamus, paracelsus, and ambrois pare [ ] . the character of the plague doctor was drawing from experiences from ancient cultures that had dealt with contagious diseases, medieval societies observed the connection between the passage of time and the eruption of symptoms, noting that, after a period of observation, individuals who had not developed symptoms of the illness would likely not be affected and, more importantly, would not spread the disease upon entering the city. to that end, they started instituting mandatory isolation. the first known quarantine was enacted in ragusa (city-state of dubrovnik) in , where all arrivals had to spend days on a nearby island of lokrum before entering the city. this period of days (trentine) was later extended to days (quarenta giorni or quarantine) [ ] . the institution of quarantine was one of the rarely effective measures that took place during the black death and its use quickly spread throughout europe. quarantine remains in effect in the present time as a highly regulated, nationally and internationally governed public health measure available to combat contagions [ ] . the spanish flu pandemic in the first decades of the twentieth century was the first true global pandemic and the first one that occurred in the setting of modern medicine, with specialties such as infectious diseases and epidemiology studying the nature of the illness and the course of the pandemic as it unfolded. it is also, as of this time, the last true global pandemic with devastating consequences for societies across the globe [ ] . it was caused by the h n strain of the influenza virus, [ ] a strain that had an encore outbreak in the early years of the twenty-first century. despite advances in epidemiology and public health, both at the time and in subsequent decades, the true origin of spanish flu remains unknown, despite its name. as possible sources of origin, cited are the usa, china, spain, france, or austria. these uncertainties are perpetuated by the circumstances of the spanish flu -it took place in the middle of world war i, with significant censorships in place, and with fairly advanced modes of transportation, including intercontinental travel [ ] . within months, the deadly h n strain of influenza virus had spread to every corner of the world. in addition to europe, where massive military movements and overcrowding contributed to massive spread, this virus devastated the usa, asia, africa, and the pacific islands. the mortality rate of spanish flu ranged between % and %. with over a quarter of the global population contracting that flu at some point, the death toll was immense -well over million, possibly million dead. it killed more individuals in a year than the black death had killed in a century [ ] . this pandemic, unusually, tended to mortally affect mostly young and previously healthy individuals. this is likely due to its triggering a cytokine storm, which overwhelms and demolishes the immune system. by august of , the virus had mutated to a much more virulent and deadlier form, returning to kill many of those who avoided it during the first wave [ ] . spanish flu had an immense influence on our civilization. some authors (price) even point out that it may have tipped the outcome of world war i, as it affected armies of germany and the austrian-hungarian empire earlier and more virulently than their allied opponents (fig. . ) [ ] . many notable politicians, artists, and scientists were either affected by the flu or succumbed to it. many survived and went on to have distinguished careers in arts and politics (e.g., walt disney, greta garbo, raymond chandler, franz kafka, edward munch, franklin delano roosevelt, and woodrow wilson). many did not; this pandemic counted as its victims, among others, outstanding painters like gustav klimt and egon schiele [ ] , and acclaimed poets like guillaume apollinaire. it also claimed the life of sigmund freud's fifth child -sophie halberstadt-freud. this pandemic was also the first one where the longlingering effects could be observed and quantified. a study of us census data from to found that the children born to women exposed to the pandemic had more physical ailments and a lower lifetime income than those born a few months earlier or later. a study in the journal of political economy found that "cohorts in utero during the pandemic displayed reduced educational attainment, increased rates of physical disability, lower income, lower socioeconomic status, and higher transfer payments compared with other birth cohorts" [ ] . despite its immense effect on the global civilization, spanish flu started to fade quickly from the public and scientific attention, establishing a precedent for the future pandemics, and leading some historians (crosby) to call it the "forgotten pandemic" [ ] . one of the explanations for this treatment of the pandemic may lie in the fact that it peaked and waned rapidly, over a period of months before it even could get adequate media coverage. another reason may be in the fact that the pandemic was overshadowed by more significant historical events, such as the culmination and the ending of world war i. a third explanation may be that this is how societies deal with such rapidly spreading pandemicsat first with great interest, horror, and panic, and then, as soon as they start to subside, with dispassionate disinterest. hiv/aids is a slowly progressing global pandemic cascading through decades of time, different continents, and different populations, bringing new challenges with every new iteration and for every new group it affected. it started in the early s in the usa, causing significant public concern as hiv at the time inevitably progressed to aids and ultimately, to death. the initial expansion of hiv was marked by its spread predominantly among the gay population and by high mortality, leading to marked social isolation and stigma. hiv affects about million people globally (prevalence rate: . %) and has killed almost the same number of people since [ ] . it causes about one million deaths a year worldwide (down from nearly two million in ) [ ] . while it represents a global public health phenomenon, the hiv epidemic is particularly alarming in some sub-saharan african countries (botswana, lesotho, and swaziland), where the prevalence tops % [ ] . in the usa, about . million people live with hiv and about , die every year (down from over , per year in the late s). hiv in the usa disproportionately affects gay population, transgendered women, and african-americans [ ] . being a fairly slowly spreading pandemic, hiv has received formidable public health attention, both by national and by international administrations and pharmaceuticals. advances in treatment (protease inhibitors and anti-retrovirals) have turned hiv into a chronic condition that can be managed by medications. it is a rare infectious disease that has managed to attract the focus of mental health which, in turn, resulted in a solid volume of works on mental health and hiv [ ] . by studying the mental health of hiv, we can begin to understand some of the challenges generally associated with infectious diseases. we know, for example, that the lifetime prevalence rate for depression in hiv individuals is, at %, more than twice the prevalence rate in general population [ ] . we understand how depression in hiv individuals shows association with substance abuse and that issues of stigma, guilt, and shame affect the outlook for hiv patients, including their own adherence to life-saving treatments [ ] . we know about medical treatments of depression in hiv and we have studies in psychotherapy for patients with hiv. some of those approaches can be very useful in treating patients in the context of a pandemic. given the contrast between the chronicity of the hiv and the acuity of a potential pandemic, most of those approaches cannot be simply translated from mental health approach to hiv and used for patients in a rapidly advancing outbreak or a pandemic. smallpox was a highly contagious disease for which edward jenner developed the world's first vaccine in . caused by the variola virus, it was a highly contagious disease with prominent skin eruptions (pustules) and mortality of about %. it may have been responsible for hundreds of millions of fatalities in the twentieth century alone. due to the wellcoordinated global effort starting in under the leadership of donald henderson, smallpox was eradicated within a decade of undertaking the eradication on a global scale [ ] . the smallpox outbreak in the former yugoslavia in was a far cry from even an epidemic, let alone a pandemic, but it illustrated the challenges associated with a rapidly spreading, highly contagious illness in a modern world. it started with a pilgrim returning from the middle east, who developed fever and skin eruptions. since a case of smallpox had not been seen in the region for over years, physicians failed to correctly diagnose the illness and nine healthcare providers ended among cases infected by the index case and first fatality [ ] . socialist yugoslavia at the time declared martial law and introduced mandatory revaccination. entire villages and neighborhoods were cordoned off (cordon sanitaire is a measure of putting entire geographic regions in quarantine). about , individuals who may have come into contact with the infected were placed in an actual quarantine. borders were closed, and all non-essential travel was suspended. within weeks, the entire population of yugoslavia was revaccinated (about million people at the time). during the outbreak, cases were identified, with fatalities. due to prompt and massive response, however, the disease was eradicated and the society returned to normal within months [ ] . this event has proven to be a useful model for working out scenarios ("dark winter") [ ] for responses to an outbreak of a highly contagious disease, both as a natural occurrence [ ] and as an act of bioterrorism [ ] . severe acute respiratory syndrome (sars) was the first outbreak in the twenty-first century that managed to get public attention. caused by the sars corona virus (sars-cov), it started in china and affected fewer than , individuals, mainly in china and hong kong, but also in other countries, including cases in canada (toronto) [ ] . the severity of respiratory symptoms and mortality rate of about % caused a global public health concern. due to the vigilance of public health systems worldwide, the outbreak was contained by mid- [ ] . this outbreak was among the first acute outbreaks that had mental health aspects studied in the process and in the aftermath, in various part of the world and in different societies, yielding valuable data on effects of an acute infectious outbreak on affected individuals, families, and the entire communities, including the mental health issues facing healthcare providers [ ] . some of the valuable insights into the mental health of patients in isolation, survivors of the severe illness, or psychological sequelae of working with such patients were researched during the sars outbreak. "swine flu" or h n / pandemic the h n pandemic was a reprise of the "spanish flu" pandemic from , but with far less devastating consequences. suspected as a re-assortment of bird, swine, and human flu viruses, it was colloquially known as the "swine flu" [ ] . it started in mexico in april of and reached pandemic proportions within weeks [ ] . it began to taper off toward the end of the year and by may of , it was declared over. it infected over % of the global population (lower than expected), with a death toll estimated varying from , to over , [ ] . although its death rate was ultimately lower than the regular influenza death rates, at the time it was perceived as very threatening because it disproportionately affected previously healthy young adults, often quickly leading to severe respiratory compromise. a possible explanation for this phenomenon (in addition to the "cytokine storm" applicable to the h n outbreak) is attributed to older adults having immunity due to a similar h n outbreak in the s [ ] . this pandemic also resulted in some valuable data studying and analyzing the mental health aspects of the outbreak. it was among the first outbreaks where policy reports included mental health as an aspect of preparedness and mitigation policy efforts. this outbreak of h n was notable for dissonance between the public sentiment about the outbreak and the public health steps recommended and undertaken by who and national health institutions. general public sentiment was that of alarm caused by who releases and warnings, but it quickly turned to discontent and mistrust when the initial grim outlook of the outbreak failed to materialize [ ] . health agencies were accused of creating panic ("panicdemic") and peddling unproven vaccines to boost the pharmaceutical companies (in , some extra $ , billion worth of h n vaccines were purchased and administered in the usa) [ ] . this outbreak illustrated how difficult it may be to gauge and manage public expectations and public sentiments in the effort to mobilize a response. it also demonstrated how distilling descriptions of the impact of a complex public health threat like a pandemic into a single term like "mild," "moderate," or "severe" can potentially be misleading and, ultimately, of little use in public health approach [ ] . ebola virus, endemic to central and west africa, with fruit bats serving as a likely reservoir, appeared in an outbreak in a remote village in guinea in december . spreading mostly within families, it reached sierra leone and liberia, where it managed to generate considerable outbreaks over the following months, with over , cases and over , fatalities. a very small number of cases were registered in nigeria and mali, but those outbreaks were quickly contained [ ] . ebola outbreak, which happened to be the largest outbreak of ebola infection to date, gained global notoriety after a passenger from liberia fell ill and died in texas in september of , infecting two nurses caring for him, and leading to a significant public concern over a possible ebola outbreak in the usa [ ] . this led to a significant public health and military effort to address the outbreak and help contain it on site (operation united assistance) [ , ] . zika virus was a little known, dormant virus found in rhesus monkeys in uganda. prior to , the only known outbreak among humans was recorded in micronesia in . the virus was then identified in brazil in , after an outbreak of a mild illness causing a flat pinkish rash, bloodshot eyes, fever, joint pain and headaches, resembling dengue. it is a mosquitoborne disease (aedes aegypti), but it can be sexually transmitted. despite its mild course, which initially made it unremarkable form the public health perspective, infection with zika can cause guillain-barre syndrome in its wake in adults and, more tragically, cause severe microcephalia in unborn children of infected mothers (a risk of about %) [ ] . in brazil, in , for example, there were birth defects and infant deaths due to suspected zika infection [ ] . zika outbreak is an illustrative case of the context of global transmission; it was transferred from micronesia, across the pacific, to brazil, whence it continued to spread [ ] . it is also a case of a modern media pandemic; it featured prominently in the social media. in early , zika was being mentioned times a minute in twitter posts. social media were used to disseminate information, to educate, or to communicate concerns [ ] . its presence in social media, perhaps for the first time in history, allowed social researchers to study the public sentiment, also known as the emotional epidemiology (ofri), in real time [ ] . while both public health institutions and the general public voiced their concern with the outbreak, scientists and officials sought to provide educational aspect, while concerned public was trying to have their emotional concerns addressed. it is indicative that out of posts on zika on social media were accurate; yet, those that were "trending" and gaining popularity were posts with inaccurate content (now colloquially referred to as the "fake news") [ ] . this is a phenomenon that requires significant attention in preparing for future outbreaks because it may hold a key not only to preparedness, but also to execution of public health plans that may involve quarantine and immunization. since , zika has continued to spread throughout south america, central america, the caribbean, and several states within the usa. it remains a significant public health concern, as there is no vaccine and the only reliable way to avoid the risk for the offspring is to avoid areas where zika was identified or to postpone pregnancy should travel to or living in affected areas be unavoidable [ ] . disease x disease x is not, as of yet, an actual disease caused by a known agent, but a speculated source of the next pandemic that could have devastating effects on humanity. knowing the scope of deleterious effects a pandemic outbreak can have on humankind, in the wake of the ebola outbreak, the world health organization (who) decided to dedicate formidable resources to identifying, studying, and combating possible future outbreaks. it does so in the form of an r&d blueprint, though devising its global strategy and preparedness plan that allows the rapid activation of r&d activities during epidemics [ ] . r&d blueprint maintains and updates a list of so-called identified priority diseases. this list is updated at regular intervals and, as of , it includes diseases such as ebola and marburg virus diseases, lassa fever, middle east respiratory syndrome coronavirus (mers-cov) and severe acute respiratory syndrome (sars), nipah and henipa virus diseases, zika, and others [ ] . for each disease identified, an r&d roadmap is created, followed by target product profiles (i.e., immunizations, treatment, and regulatory framework). those efforts are important to help us combat a dangerous outbreak of any of the abovementioned diseases, but also to fend off disease x. since disease x is a hypothetical entity, brought by a yet unknown pathogen that could cause a serious international pandemic, the r&d blueprint explicitly seeks to enable cross-cutting r&d preparedness that is also relevant for both existing culprits and the unknown future "disease x" as much as possible. who utilizes this r&d blueprint vehicle to assemble and deploy a broad global coalition of experts who regularly contribute to the blueprint and who come from several medical, scientific, and regulatory backgrounds. its advisory group, at the time, does not include mental health specialists [ ] . the black death: the greatest catastrophe ever the great leveler: violence and the history of inequality from the stone age to the twenty-first century. chapter : the black death mortality risk and survival in the aftermath of the medieval black death an epidemiologic analysis of the ten plagues of egypt the noble qur'an surah thucydides' description of the great plague the plague of athens: epidemiology and paleopathology the thucydides syndrome: a new hypothesis for the cause of the plague of athens the thucydides syndrome: ebola déjà vu? 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military ebola mission in liberia coming to an end zika: the origin and spread of a mosquito-borne virus the microcephaly epidemic and zika virus: building knowledge in epidemiology propagating and debunking conspiracy theories on twitter during the - zika virus outbreak the emotional epidemiology of h n influenza vaccination spreading the (fake) news: exploring health messages on social media and the implications for health professionals using a case study who: r&d blueprint, about the r&d blueprint who: r&d blueprint, scientific advisory group members key: cord- -ea nbkh authors: mitzner, veera title: conclusion and further thoughts date: - - journal: european union research policy doi: . / - - - - _ sha: doc_id: cord_uid: ea nbkh the conclusion chapter not only summarizes the main results of the research conducted for this book but also connects the events and discussions between the s and s to later political developments. it shows striking ideational and institutional continuity and reveals a substantial character of european integration: by relying on powerful political framings and discourses, as well as on sturdy institutions, the european community/union was able to move into areas that were not sanctioned by the treaties. the chapter further argues that to stay relevant, the eu research policy must be capable of breaking with the past and dramatically expand its mission to embrace the social and environmental challenges of the twenty-first century. in fact, with the existential threat of climate change and other global challenges, and the urgent need for socio-technological transformation at scale, opportunities and imperatives for european level activity in research might be greater than ever. separation of europe from the technologically more advanced united states, the european political and economic elites appeared open to arguments for unifying european resources in science and innovation. with the postwar market liberalization, rapid technological change, and the gradual shift of production to the newly industrialized countries, the case for joint european research effort seemed plausible. maria nedeva and linda wedlin have divided the development of european union research policy in two main phases: "science in europe" and "european science." according to these two scholars, the first phase, "science in europe," which roughly covers the time period analyzed in this book, was characterized by the principle of subsidiarity-an idea that european-level action would only be appropriate if action at a national level was insufficient; focus on increasing collaboration amongst researchers from different european countries; and concerns of the technology gap, which nedeva and wedlin call the "european paradox," as europe as a world leader of science seemed to lag behind in the industrial and economic exploitation of scientific ideas. furthermore, "science in europe" witnessed three distinct waves: the establishment of large, transnational facilities, such as european organization for nuclear research (cern), euratom, european molecular biology organization (embo), and european molecular biology laboratory (embl); the creation of "diffuse" organizations, such as european cooperation in science and technology (cost) and the european science foundation (esf), including all fields of research and providing platforms for cross-national cooperation rather than supporting science at european level; and finally the creation of the ec/eu framework program for research, bringing the scattered research programs under one administrative umbrella. for nedeva and wedlin, "science in europe" was a period "during which a partial and fragmented science and research system was developed." it complemented rather than challenged national science, research, and innovation arrangement; it had a limited impact on universities, research institutes, and national funding agencies and landscapes; and it "didn't in a rule, include explicitly european-level research performing organizations." this book doesn't challenge nedeva's and wedlin's analysis. for a long time, the ec/eu research policy had a partial character-the first initiatives were not designed to directly challenge activity in national settings. the proponents of european level activities in the field, while often ambitious and visionary, were aware of the political realities. even the "european paradox" argument is solid, although the debate had its ebbs and flows and occurred in different variations depending on the context and advocates. fears of european technological retard did push initiatives forward, at different degrees of success, giving them rationale and a sense of urgency. also, european level research facilities were still few and far in between, and decisions in brussels barely influenced the daily operations of universities and research institutes in the ec member states. however, with a closer historical analysis, we also see an emerging policy that was constantly challenged, contested, and vetted by a number of groups, and in particular those who would mostly have been affected by it. and this is the vital "more to the story" that nedeva's and wedlin's and others' accounts do not fully tell. this book also unveils the bigger ambitions of policy-makers and dreamers by fletching out the protracted struggles for initiatives that either never quite made it to the fruition or were realized as truncated versions, to the disappointment of many. it sheds light to the already forgotten and fluid policy spaces where the feasible and unfeasible were defined, and where future pathways were sometimes painfully determined. crucially, these spaces were shaped by broader political, social, and economic circumstances within and beyond europe, and the prevalence and strength of specific ideational shifts and conditions, such as the fading of the naïve enthusiasm about science that had characterized the immediate postwar period; increasing uneasiness about growth policies and calls for better accountability of economic and scientific activity; new limitations imposed by economic austerity; persisting distrust in european level bureaucracy among academics and national policy-makers; and ongoing political battles in other policy areas within the ec context. yet one distinct thread runs through all these events and debates: a basic agreement on the beneficial role of research and research policy in achieving greater growth and competitiveness, and the need to create joint political mechanisms to that end. how this would eventually be achieved remained open for contestation. besides being a story of continuity and struggle, this book also is an account of the vulnerability of a political idea that survived, grew big, and eventually transformed european research. it was just as strong as its proponents, which at the beginning were not many. although the commission made sure that science policy experts would be involved in the elaboration of the various schemes from the start, these experts often represented governments and national science funding bodies rather than the broader science community. the lack of active participation of scientists and their advocates, as well as of industry and the wider public in the early discussion on the topic, is striking; until the s, most proposals were developed in technocratic milieus with little public attention. the backing of pro-european associations such as union des industries de la communauté européenne (unice), the european parliament, and some individuals from national research institutions and administrations remained too weak and fragmented to put significant pressure on key decision-makers. this is the tragedy of the early ec/eu research policy. politicians in the ec member states, whose main concern was often winning the support of the electorate, tended to focus on issues with more immediate political benefit. it was not the case that the citizens in the community member countries had opposed the idea of the europeanization of scientific and technological activities: in the community's surveys of public opinion, research has consistently been at the top of the list of policies that people think should not be managed exclusively at a national level. research was, nevertheless, not the kind of "high politics" that would be surrounded by glamour and drama and that would have reached the headlines. it remained distant to the lives of ordinary citizens who barely knew of the commissions initiatives. it is also exactly this technical, abstract, complex, and distant nature of this policy domain that at least in part explains the persisting gap between rhetoric and reality in european research policy from the mid- s to the mid- s. for national politicians, expressing catchy phrases and stirring rhetoric about science and its many promises for the future, could be politically advantageous but also relatively safe: sacrifices in this sector rarely had a direct impact on the lives of voters, and therefore, they seldom provoked significant public protests. the late s' protests at the ispra euratom joint research centre stand out as a notable exception, as multiple employees were threatened to lose their jobs as a result of decisions made in brussels. but in most cases, lip service in research policy came at a low political price. in the absence of a systematic backing of scientists or their representatives, the commission alone was too weak to induce the national governments to truly commit to developing a community research policy. moreover, commission's strategy was not always consistent: important tensions prevailed between the dgs, while each commissioner in charge of research pursued a slightly different policy. the existence of dg research, under various names since , however, became a central structure for guaranteeing institutional and ideational continuity. the dg constituted a center where bureaucrats and experts, sharing some important ideas and interests, could further elaborate schemes for new community activity. this finding supports katia seidel's research on dgs iv (agriculture) and vi (competition), which shows that the administrative cultures developed in those dgs and the subsequent socialization of officials into these cultures, "helped to bring about policies in relevant areas, and then to keep them on track." through the discussions initiated by dg research and others, the ec gradually formed an arena for "europeanization" in research where socialization of different experts and political actors could take place. intra-european connections were reinforced, and similarities increased, while "europe" was given new contents and contours. at the same time, it would be misleading to argue that all contacts within the realm of the research policy debate would automatically have led to greater cohesion. these exchanges also exposed to governments and experts the diverse character of european research systems and made them aware of the difficulty in creating a strongly integrated common policy. yet they prepared the ground for subsequent initiatives that would take off with a more favorable political momentum. in the early s, the various plans and scattered activities of the previous twenty years finally evolved into something that could be said to have an important scope and political and economic significance. the first step into this new direction was the launch of sizeable technological programs, the pioneer being european strategic program on research in information technology (esprit), an initiative that was intended to develop a european strategic scheme based on collaboration between major european companies, small-and medium-sized firms, universities, and research institutes. the project was successful: of the proposals received in response to the first call, less than percent could be funded. not surprisingly, after , esprit became the model for successive community programs, such as research in advanced communications in europe (race) and basic research in industrial technologies (brite). the expansion of these activities led to the creation of the first framework program for research ( ) ( ) ( ) ( ) in . the € . billion budget of the framework program, together with the budget for esprit of € million, signified a threefold increase in the community's research spending in . moreover, the program sparked off a steady and fast increase of the community's research budgets. peter tindemans has observed that after esprit, there were a growing number of scientists and industrialists involved in the consultations, projects, and evaluations, and thereby directly benefiting from the community's activity in the field. this created "an almost unstoppable dynamic of pressure [that] arose in national capitals and in the directorates-general responsible for the fp's [framework programs] to increase the budget." although the role of the ec as a focal point of common european research activities remained contested, as was demonstrated by the creation of eureka, an intergovernmental initiative intended to promote "near-market research," in , and by the difficult negotiations of the subsequent framework programs, the political context had changed. national governments were now more willing to see the ec take a central role in the field, and a horizontal and vertical growth of brussels-led activities ensued. all this was supported by the favorable conjuncture in european integration that ensued the single market program. the first framework programs were still focused on advancing applied, marketoriented research, but during the s, these programs became more comprehensive and versatile as they included new mechanisms and stretched into different disciplines and sectors. they also opened up for countries outside the ec/eu framework, developed collaboration with other european and international organizations, and finally became more closely integrated with the ec/eu core policies. an eu-centric european research space started to emerge. this is, indeed, where wedlin and nedeva see the shift to "european science," marked by a changing understanding of the "european added value." whereas the previous ec/eu activities had been primarily focused on fostering collaboration between researchers, now there was a widely shared desire to increase the level of integration in different aspects of european science and research. new tools were designed to strengthen the european knowledge base and to support basic research through competitive funding. a key concept here is the european research area (era). originally dreamed up by commissioner ralf dahrendorf in the s, the idea was revived by commissioner alberto ruberti in the s, and finally pushed to the center of the european political agenda by commissioner philippe busquin. endorsed as an ambitious effort to pool european scientific and technological resources, the initiative marked a clear break with the distributive approach that had characterized the eu activities in the preceding years. while the definition of what the era stands for has evolved over the years, it has brought new inclusiveness into the eu research policy and signaled a move toward a more europeanized research policy field, "where the era agenda provides justification for the adoption of new institutions and funding tools." era aimed to increase the commission's autonomy in initiating projects and programs with direct implications for national activities. in , the commission defined era as "a unified research area open to the world based on the internal market, in which researchers, scientific knowledge and technology circulate freely and through which the union and its member states strengthen their scientific and technological bases, their competitiveness and their capacity to collectively address grand challenges." era was launched in the political framework of the lisbon european council of march , where the eu set itself the new strategic goal of becoming "the most competitive and dynamic knowledge-based economy in the world capable of sustainable economic growth, with more and better jobs and greater social cohesion." in lisbon, research and development were drawn to the center of the eu's strategy for achieving its goal by . essentially, scientific research, technological development, and innovation were defined as key factors in growth, competitiveness, and employment in a knowledge-based european economy. this trend was continued in the eu's new growth strategy, europe , launched in . one of the seven flagship initiatives announced in the strategy was innovation union, aiming to "improve conditions and access to finance and innovation, to ensure that innovative ideas can be turned into products and services that create growth and jobs." era was considered a core element of the innovation union and the europe strategy. the eu's barcelona target to achieve r&d funding of percent of gdp-an objective largely motivated by the higher r&d investment levels in the united states and japan-gave era additional political support and visibility. according to wedlin and nedeva, "european science" has created "an organizational space for the support of research that is aligned, and in competition with national-level research spaces." a key invention in this space was the european research council (erc), created in as a part of the seventh framework program. by allowing european researchers to compete with all other researchers in the eu area on the basis of excellence, erc revolutionized the eu's approach to supporting scientific activity. with scientific excellence as the sole criterion for selection and sizeable pots of money to distribute (the first budget in the seventh framework program ( - ) was . billion euros, and it almost doubled for horizon , constituting percent of the overall program budget), erc soon became a powerful tool for boosting european knowledge space and shaping science in europe. the shifting agendas and the broadening scope of the ec/eu activities have been paralleled by the gradual strengthening of the community's legal status. after the still very restricted formulation of the single european act ( ), the treaty of maastricht ( ) included a new article , which required that "the community and the member states shall coordinate their research and technological development activities so as to ensure that national policies and community policy are mutually consistent." moreover, the commission was granted the explicit right to take any "useful initiative" to promote such consistency. the amsterdam treaty ( ) then abandoned the requirement for council unanimity for adoption of the co-decision on the framework program. from now on, the program could be adopted by a qualified majority vote. the union's competences in the domain were further widened by the article of lisbon treaty ( ), stating that: . the union shall have the objective of strengthening its scientific and technological bases by achieving a european research area in which researchers, scientific knowledge and technology circulate freely, and encouraging it to become more competitive, including in its industry, while promoting all the research activities deemed necessary by virtue of other chapters of the treaties. . for this purpose the union shall, throughout the union, encourage undertakings, including small and medium-sized undertakings, research centres and universities in their research and technological development activities of high quality; it shall support their efforts to cooperate with one another, aiming, notably, at permitting researchers to cooperate freely across borders and at enabling undertakings to exploit the internal market potential to the full, in particular through the opening-up of national public contracts, the definition of common standards and the removal of legal and fiscal obstacles to that cooperation. . all union activities under the treaties in the area of research and technological development, including demonstration projects, shall be decided on and implemented in accordance with the provisions of this title. within ten years, the ec/eu research policy activity had firmly become woven into the legal fabric of the union. while the ec's/eu's legal base strengthened and its activities broadened, the community/union gradually moved into territories traditionally occupied not only by european nation-states but also by various intergovernmental organizations promoting research. in this book we have seen how already in the s and s, the ec challenged more established organizations such as the oecd and the council of europe. in the subsequent years, this trend continued. indeed, as the eu is thus increasingly dominating the european research field, one can observe an incremental transformation of previously non-ec/eu projects and institutions into eu or quasi-eu projects and institutions, or alternatively, a launching of new eu operations practically identical to existing activities in other european organizations. a good example here is space research. the cooperation agreement signed between the eu and the european space agency in constituted a new framework for a comprehensive european space policy involving the coordination of the actions of the european commission and esa through a joint secretariat, a small team of eu administrators and esa executives, as well as ministerial-level meetings in the space council. in there was a further development when twenty-nine european countries expressed their support for a european space policy, prepared jointly by the european commission and the esa's director-general. moreover, the lisbon treaty gave the european union an explicit competence in space, calling for the development of a european space program. the implementation of this program has further increased cooperation between the eu and the esa. in the recent past, almost percent of the funds managed by esa have originated from the eu budget. the european science foundation, on the other hand, after almost nearing death in , has acknowledged the eu's growing role in promoting european science and wound down all its collaborative research instruments and networks. with a stated mission to serve the european research area for the sole benefit of science, it now focuses on running an expert division called science connect that provides services to the science community. this is a significant shift: since its creation in , esf has run over world-class science programs and networks, with support from eighty member organizations in thirty countries. through this work, it has made a solid contribution to the creation of the european research space. in the most recent years, its financial resources, however, have faced a dramatic downturn. between and , the esf member contributions diminished by . million euros. these budget cuts, together with the wishes of its members, led esf to radically reduce its activities and staff and to move policy-related work into newly formed science europe. cost, another intergovernmental institution supporting european research set up in the early s and analyzed in this book, has weathered the emergence of a comprehensive eu research policy somewhat better. it fills a specific niche in the european research funding landscape as an organization providing financial support for the creation of european-wide multi-stakeholder research networks, called cost actions. most of cost's funding, however, comes from the eu research framework program, which makes it highly dependent on the political developments in the union. the various impacts of the emergent eu research policy on the wider european research space still deserve more thorough scholarly attention. one interesting trend, however, is the emergence of stronger and more organized organizations and networks promoting the interests of researchers, research funders, and the higher education sector at the european level. these include euroscience, a grassroots non-profit organization of researchers in europe, created in to shape policies for science, technology, and innovation. with its individual members, euroscience aims to be "a direct and democratic way to influence the construction of the europe of science and technology, for the benefit of europe's international position in science, and to enhance science's contribution to society, opportunities and mobility for both young and experienced researchers." the european association of research and technology organizations (earto) was established two years later to promote research and technology organizations and represent their interest in europe. its current activities are geared toward influencing the eu policy. in , a merger between the association of european universities and the confederation of european union rectors' conferences led to the creation of the european university association (eua). eua represents over universities in forty-eight countries, and its activities are targeted at influencing the eu policies on higher education, research, and innovation. a year later, another belgium-based organization, the league of european research universities (leru), was formed with the objective to "advance the understanding and knowledge of decision makers, policy makers and opinion leaders about the role and activities of research-intensive universities." both institutions seek to promote the interests of higher education and research institutions in eu policymaking. in , twenty-three countries joined in the founding assembly of science europe, an organization representing research funders and other research organizations in the eu. science europe was built from two former advocacy groups, the esf and eurohorcs (an organization of the heads of the european research councils), aspiring to give its members a stronger and more united voice on european level policy. the list could be continued, in particular if one includes more informal networks and alliances. the rise of these various groups is largely a response to the gradual strengthening of the eu's research arm, which has made advocating for researchers' and research and higher education institutions' interests in brussels a worthwhile endeavor. undoubtedly, there is a new reality for research in europe. the current eu research funding program is exceptional in its size, long duration (seven years), budgetary framework stability, and scope: it encompasses research as well as innovation; grants as well as loans, equity, and procurement; it combines a broad top-down focus on grand societal challenges with bottom-up "frontier" research; it is crossborder and cross-sectoral, encouraging inter-disciplinary collaboration, mobility, and coordination. and it is attracting increasing attention and interest within research communities both within and beyond europe. the horizon mid-term evaluation accounted a percent increase in the annual number of applications compared to the program's predecessor, the seventh framework programme (fp ). with an . percent success rate, which was much lower than under fp ( . percent), the competition for horizon grants had become fierce. while . percent of funding went to participants from the eu member states, the program involved people from over countries. moreover, eu-funded projects are also producing top-notch research. between and alone, horizon , supporting approximately , researchers, produced more than peer-reviewed publications that were cited more than twice the world average. two-thirds of them were also openly accessible to the public. it is also noteworthy that within the european institutions, research has taken a prominent role. in , a total of of the commission's , officials worked for dg research, making this dg the fourth largest division. if this number were to include staff members in the eu joint research centre, research would occupy the first place. research also continues to be the third largest item in the eu budget. despite the prevailing uncertainties about the future of european integration and the different priorities of the member states, the trend of strengthening the role of the eu in supporting and shaping european research is likely to continue. in june , the commission published its proposal for the next eu funding program, horizon europe, which would cover the years of - , involve a budget of billion euros-an increase from horizon -and be "the most ambitious research and innovation funding programme ever." there was little modesty in the commission's statement that "'[b]eneficiaries' research capacities and scientific outputs would have significantly decreased had they received national funding instead. this decrease would have been especially large in terms of their ability to collaborate with industry and business, transfer of knowledge, the number of participations in scientific conferences and the knowledge in new areas." the covid- outbreak in , effectively highlighting the importance of research in tackling global crisis is likely to give a further boost to eu research and innovation activities. the eu acted relatively fast by providing emergency funding from horizon and processing proposals at a record speed. one could note emerging tensions between european and national research spaces, as the national funding bodies and the eu instruments might increasingly compete for resources, applicants, and legitimacy. the larger the eu research budget grows, and the more extensive the european level programs become, the more accentuated this competition will become. already now the eu research funding programs include almost all research themes and forms of research promotion that exist in national research and technology policies. linda wedlin and maria nedeva explain the shift from "science in europe" to "european science" by two important changes in policy rationales and framing. first, the understanding of "european added value" shifted from focusing on coordination to incorporating competition. epitomized in the creation of the european research area, which signaled a move away from collaboration toward integration, this new framing precipitated the implementation of policy instruments that stretched beyond simple support for collaboration between researchers and encouraged genuine competition between them. second, there was growing evidence and concern that europe was not doing so well in science compared with its main commercial competitors. this new version of the technology gap debate argued for a european retard that was more fundamental than failure in making the link between scientific research and commercial applications. "by ," wedlin and nedeva write, "the long-standing assumption of this 'european paradox' morphed into a full-blown 'gap' argument, that is, that europe was clearly lagging behind the usa and japan both in terms of science and its application." this concern led to a change of rationales and the target for policy intervention. it served as a justification for a powerful move to the realm of basic science and the creation of the european research council. tim flink, through an analysis on the creation of erc, supports this finding. a renewed concern of european global retard and a conviction of the need to strengthen the european knowledge base underpinned a political discussion that ushered the birth of erc. moreover, language played a critical role: with the concept "frontier research," the european commission avoided directly violating the principle of subsidiarity, which had curtailed its activity in basic research-an area traditionally belonging to the nation states. "frontier research," falling somewhere in between basic and applied research, aligned well with the eu's traditional mission of fostering european competitiveness and the geopolitical objective of the lisbon strategy to make europe the world's leading commercial power, drawing its strength from knowledge. "frontier research" projected an image of global competition, and it made a solid reference to vannevar bush's monumental report science, the endless frontier and the founding myth of the us national science foundation. "[i]n this policy process," concludes flink, "the narrative structure only seemed to be successful if it followed the chimera of a geostrategic security understanding (isolation by the european research area) and a prosperity identity (market imperative of the eu)." also, terttu luukkonen, while noting the critical role of stakeholder groups, such as the leading life sciences organizations, stresses the role of the gap debate in the formation of the erc. "there was a concern," she writes, "about funding being too low for basic research and about quality of science and its institutions in europe and, as in european research policy in general, usa provided a benchmark with which comparisons were made." furthermore, the focus on frontier research, provided "a strong argument that the erc is justified from the point of view of technological and economic competitiveness, not just of scientific competitiveness." this is confirmed by just a cursory reading of the commission's documents from that time period. the prominence of economic concerns and the gap narrative is striking, as well as the discourse that highlights the insufficiency of national initiatives. the commission's proposal for era, for example, argues that in europe, "the situation concerning research is worrying. without concerted action to rectify this the current trend could lead to a loss of growth and competitiveness in an increasingly global economy. the leeway to be made up on the other technological powers in the world will grow still further. and europe might not successfully achieve the transition to a knowledge-based economy." the discursive continuity is remarkable. throughout this book we have seen how european commission officials and other supporters of greater eu competences in the field of research used a specific language and political framing to advance their initiatives. this language presented scientific research as an engine for economic growth and material prosperity, which were widely accepted as favorable political goals by the european governing elites. combined with arguments about european technological delay vis-à-vis its main commercial competitors, it presented an increasingly convincing case for new european level activity. by the early s, these framings had become dominant truth claims in the european debates, and they started to essentially determine political agendas. at the same time, the scope and nature of the scientific enterprise changed, the pace of discovery and innovation accelerated, and as a result, not only did competition between research institutes, nations, and individual researchers accentuate, but science and technology became increasingly vital forces shaping societies and determining the geopolitical and economic success of countries. it could be argued that one reason for the continuous popularity of the instrumental-economic conception of research policy has been its malleability and extraordinary ability to adapt to different political conditions. as amenable as it seemed to the western european expansive welfare economies of the s and s, it has proved perfectly compatible with the intensifying drive for market liberalism since the early s. this is not only because of the prevailing appeal of growth. research policy has proved useful in facilitating and accelerating the shift to the world of open markets. in this study we have seen how research policy, especially at european level, was commonly pictured as a means to adapt to an exogenous and irreversible transformation that later became labeled as globalization. the eu research policy came into being with an explicit objective of enhancing european economic performance in an international framework in which competition was accelerating. this goal remains as one of the guiding principles of the current eu research policy. when research commissioner máire geoghegan-quinn in november said: "fundamentally, support through horizon for research, innovation and science is an economic policy," she reiterated the principle on which the union's activity had been based since the very beginning. the economic framing remains sturdily in place. the horizon mid-term evaluation report, for example, made a blatant calculation a gdp gain, concluding that "[e]very euro invested under horizon brings back to . euros." the explanatory memorandum included in the commission's proposal for establishing horizon europe included similar calculations. according to the memorandum, horizon europe was expected to generate positive effects on growth, with an increase of gdp on average by . percent to . percent over twenty-five years, "which means that each euro invested can potentially generate a return of up to euro of gdp over the same period"-better ratio than in horizon . the memorandum went on to calculate that discontinuing the union research and innovation program could result in a decline of competitiveness and growth up to billion euros of gdp loss over twenty-five years. to some degree, the eu is tied to this language. initially, the lack of a solid juridical basis for research policy forced the commission to frame research as a tool for achieving prosperity, which has traditionally been one of the union's core objectives. although the gradual strengthening of the juridical basis of research policy during the last three decades has granted the commission more room for maneuver, the eu's activity and ambitions are still limited by the principle of subsidiarity and the constant search for european added value. the eu is most likely to gain legitimacy by anchoring its initiatives and programs to the objectives of competitiveness and growth-a territory where eu activity is seldom questioned. but continuously liking research and growth and articulating science and innovation policy in economic terms, is more than a smart political strategy. it is a durable policy framing that was constructed in the early s and that has been broadly embraced and absorbed by national decisionmakers, european officials, and a number of other actors shaping research policy. it embodies a very specific understanding of the role of science and research in society and the objectives of public support for research and innovation communities. policy framings can and need to change if they become unsuited to responding to the society's most pressing needs and challenges. johan schot and w. edward steinmueller, for example, have argued for a new framing for innovation policy, "linked to contemporary social and environmental challenges such as the sustainable development goals and calling for transformative change." this framing should take priority over the two existing framings, which emerged in the s and s, and which, while still relevant, "offer little guidance for managing the substantial negative consequences of the socio-technical system of modern economic growth to which they have contributed and of which they are a part." the first framing, which dominated during the time period analyzed in this book and-as we have seen-still influences eu policy, emphasized the role of research and innovation for increasing economic growth, aimed at boosting the potential for science and technology for prosperity, and cultivated socio-technical systems supporting mass production and consumption. the second framing gained ground toward the late s and more explicitly aimed to address challenges related to intensifying international competition and globalization. with a focus on developing and analyzing national systems of innovation, enhancing capacities for learning, and supporting connectivity between different societal sectors within the system, it added a layer of sophistication and complexity to the first framing. however, it didn't depart from the premises of increasing growth through maintained and improved competitiveness. the third framing suggested by schot and steinmueller draws upon the recognition that a deep and rapid transformation of socio-technical systems is needed in the backbone systems of modern societies, including energy, mobility, food, water, healthcare, and communication, and that research and innovation policy has a vital role to play in supporting this transformation. that requires a dramatic change in thinking, broadening of perspectives and alliances, and setting entirely new goals and objectives. according to the two authors, this new framing "focuses on innovation as a search process on the system level, guided by social and environmental objectives, informed by experience and the learning that accompanies that experience, and a willingness to revisit existing arrangements to deroutinize them in order to address societal challenges." further, the innovation process in this framing "is likely to be effective in achieving these goals if it is inclusive, experimental and aimed at changing the direction of socio-technical systems in all its dimensions." essentially, this framing will propose building a new knowledge base, setting up mission-oriented policies with missions formulated in an open-ended way, encouraging new forms of engagement and networks between public, private, and third sector actors, and supporting intermediary actors to advocate competitive niches, as well as new visions and policies. it will mean a shift away from the old research and innovation policy proposition that social and economic goals can be achieved through economic growth if surpluses are redistributed and technocratic elites can regulate the externalities of growth. a more comprehensive and ambitious-if not radical-approach is needed to ensure the continued relevance of research and innovation policy in the contemporary world in rapid transition. schot and steinmueller are not alone with this proposition. in the last few years, there has been increasing scholarly interest in rethinking the premises of science and innovation policy and exploring ways of better aligning policy objectives with broader social and environmental challenges. a new policy paradigm is emerging, "layered upon but not fully replacing earlier paradigms of science and technology and innovation systems policy." according to gijs diercks, henrik laren, and fred steward, this "'normative turn' that is currently taking place insists that innovation policy must not only optimize the innovation system to improve economic competitiveness and growth, but also include strategic directionality and guide processes of transformative change towards desired societal objectives." further, this "emerging paradigm of transformative innovation policy is still a heavily contested discursive space" and "there is considerable uncertainty regarding the paths of this paradigm shift in the making." looking at the most recent eu language on research and innovation policy, one can discern elements of this shift. while competitiveness and growth retain a solid place in the framework programs, with the increasing focus on strengthening the european knowledge base and the objective of tackling grand societal challenges through research, the political framing of the eu research policy has widened. one of the earliest visible expressions of this ambition was the declaration, endorsed by over researchers, policy-makers, and representatives from industry and research funding institutions during the "new world -new solutions" conference in lund, sweden. the declaration stated that "european research must focus on the grand challenges of our time moving beyond current rigid thematic approaches. this calls for a new deal among european institutions and member states, in which european and national instruments are well aligned and cooperation builds on transparency and trust." the "grand challenges" listed in the declaration included global warming; tightening supplies of energy, water, and food; aging societies; public health; pandemics; and security. the lund declaration also states that the "european knowledge society must tackle the overarching challenge of turning europe into an eco-efficient economy." since then, broader social and global concerns have found a firmer footing in the eu's research policy agenda. between and , a total of percent of horizon funding went to reinforcing and extending the excellence of european science base and consolidating the era. the second biggest pot, percent, went to stimulating a critical mass of research and innovation efforts to help address grand societal challenges. promoting industrial leadership came only as third, with percent of funding. the remaining percent was dedicated to other priorities, such as widening participation, including society, euratom, and the pilot for fast-tracking innovation. the three pillars of horizon europe-excellent science, global challenges and european industrial competitiveness, and innovative europe-seem to continue this trend, although the commission notes that "[i]industrial leadership will be prominent in this [global challenges] pillar and throughout the program as a whole." indeed, the proposal for horizon europe was "framed by the premise that research and innovation (r&i) delivers on citizen's priorities, boosts the union's productivity and competitiveness, and is crucial for sustaining our socio-economic model and values, and enabling solutions that address challenges in a more systematic way." in other words, "horizon europe will strengthen the union's scientific and technological bases in order to help tackle major global challenges of our time and contribute to achieving the sustainable development goals (sdgs). at the same time, the programme will boost the union's competitiveness, including that of its industries." these quotes reveal a striking feature in the commission's blueprints for horizon europe: an effort to achieve the double objective of responding to global challenges and maintaining economic growth. overall, however, the program seems to be defined as serving the european economy. in march , carlos moedas, the research commissioner, noted that "ware now on track to launch the most ambitious ever european research and innovation programme in , shaping the future for a strong, sustainable and competitive european economy and benefiting all regions in europe." even the lund declaration underlines that "[m]eeting the grand challenges will be a prerequisite for continued economic growth." a vital task for the commission and the union more broadly in the future will be resolving the tension between its traditional policy goals of pursuing growth and competitiveness and its newer mission of tackling grand challenges and promoting sustainability transitions. can both objectives be successfully pursued in parallel, and how possible conflicts between growth and broader socio-environmental issues can be reconciliated, has not explicitly been addressed in any of the key documents or declarations-until very recently. ursula von der leyen's commission's proposal for a european green new deal contains explicit language, suggesting that the challenge of climate change can be addressed without compromising economic growth and competitiveness. it presents the european green new deal as "a new growth strategy that aims to transform the eu into a fair and prosperous society, with a modern, resource-efficient and competitive economy where there are no net emissions of greenhouse gases in and where economic growth is decoupled from resource use." moreover, "careful attention will have to be paid when there are potential trade-offs between economic, environmental and social objectives." the language stressing the eu's "collective ability to transform its economy and society to put it on a more sustainable path," outlines an ambitious and transformative vision that departs from narrow sectorial propositions. in the european new green deal, science and innovation also has a solid place. the document calls for "new technologies, sustainable solutions and disruptive innovation" and notes that "conventional approaches will not be sufficient." the eu's new research and innovation agenda will emphasize experimentation, and working across sectors and disciplines, thereby taking the "systemic approach needed to achieve the aims of the green deal." for now it seems that four of horizon europe's five research missions would be closely linked to the green deal objectives. also, how the covid- pandemic transforms the european research landscape, remains to be seen. in the last few decades, the eu has shown an important capacity of selfcriticism and learning. horizon europe is being built on lessons learned in horizon , such as the need for increasing support for breakthrough innovation; adopting mission-orientation and encouraging citizen involvement; strengthening international cooperation; reinforcing openness; rationalizing the funding landscape; and encouraging participation. new initiatives in horizon europe, such as european innovation council, address these objectives. ursula von der leyen's commission has set a new level of ambition for achieving a pressing transformative change that transcends several sectors of european society. the rapid response to covid- also shows proactivity and agility from an institution often seen as stiff and bureaucratic. these serve as demonstrations that the eu does not need to or even cannot be constrained by its past policy framings and discourses. and this is a real opportunity. in today's europe, torn by nationalism and distrust in governing elites, preserving peace and producing prosperity no longer suffice to provide the legitimacy that carried the process of european integration this far. it is time for a more powerful and compelling mission, aiming at a profound socio-technological transformation that a union-wide science and research effort is well positioned to shape and realize. despite its contested origins, research policy has become one of the eu's core instruments for advancing its policies, promoting european integration, and achieving change. it has won the support of researchers, both in europe and beyond, gained prestige, and found a solid place on the eu political agenda. with its extensive programs and significant funding, it has transformed the european research landscape for good. however, to remain relevant, the eu research policy needs to be tailored to serve the most compelling needs of the european societies. if designed right, it can be a powerful force, enabling critical and truly transformative effort for which none of the individual member states would be capable alone. from 'science in europe' to 'european science qualitative study on the image of science and the research policy of the european union european commission, qualitative study on the image of science and the research policy of the european union the process of politics in europe. the rise of european elites and supranational institutions europeanization in the twentieth century: historical approaches post-war research, education and innovation policy-making in europe history and memory of an institution towards european science. dynamics and policy of an evolving european research space (cheltenham and political dynamics of the era," in changing governance of research and technology policy − the european research area explaining changes and continuity in eu technology policy: the politics of ideas european research area: an evolving policy agenda political dynamics european commission communication: a reinforced european research area partnership for excellence and growth the 'european research area' idea in the history of community policy-making european research area european commission communication: europe flagship initiative innovation union european commission communication: a reinforced european research area partnership for excellence and growth broadening aims and building support in science, technology and innovation policy: the case of the european research area towards european science die entstehung des europäischen forschungsrates: marktimperative -geostrategie -frontier research (weiserswist: velbrück wissenschaft consolidated version of the treaty on the functioning of the european union-part three: union policies and internal actions, title xix: research and technological development and space-article (ex article tec) esa website the european science foundation; death or mid-life crisis? the science connect website the european science foundation from 'science in europe science europe lobby group hit by sudden exodus. brussels-based advocacy group aimed to provide single voice for scientists in the eu-but is losing members key findings from the horizon eu-forschungspolitik-von der industrieförderung zu einer pan-europäischen wissenschaftspolitik? proposal for a decision of the european parliament and of the council on establishing the specific programme implementing horizon europe-the framework programme for research and innovation eu funding for research and innovation key findings from the horizon from 'science in europe eu-forschungspolitik from 'science in europe vannevar bush, science, the endless frontier. a report to the president by vannevar bush, director of the office of scientific research and development - ; - . the author's translation from german european research area european commission: communication from the commission to the council, the european parliament, the economic and social committee, and the committee of the regions: towards a european research area innovation and science: remarks at press conference launching horizon press conference brussels key findings from the horizon interim evaluation european commission: proposal for a regulation of the european parliament and of the council establishing horizon europe-the framework programme for research and innovation, laying down its rules for participation and dissemination three frames for innovation policy: r&d, systems of innovation and transformative change goal conflicts and goal alignment in science, technology and innovation policy discourse combining insights from innovation systems and multi-level perspective in a comprehensive 'failures' framework next generation innovation policy and grand challenges in addition to scholars in sts and sustainability transitions studies, there have also been historians arguing for a change. for instance, andrew jamison wrote in that "as in the s, there is a need for fundamentally rethinking the relations between science, technology, and society, in europe as well as internationally. in particular, there needs to be much more coordination between policies for science and technology and all the other policies that national governments, as well as local authorities and intergovernmental bodies pursue. in order to meet the challenge of climate change and sustainable development, science and technology need to be reconfigured so that the 'solutions' they provide can be relevant for the problems that humanity faces. and in order to provide appropriate solutions, scientists and engineers will need to be better educated about the problems that need to be solved transformative innovation policy european research area," ; ulnicane swedish presidency: research must focus on grand challenges european commission: the lund declaration: europe must focus on the grand challenges of our time european research area key findings from the horizon interim evaluation european commission: proposal for a regulation of the european parliament and of the council establishing horizon europe-the framework programme for research and innovation, laying down its rules for participation and dissemination the next eu research and innovation investment programme european commission, the lund declaration european commission: communication from the commission to the european parliament, the european council, the european economic and social committee, and the committee of the regions, the european green deal the next eu research and innovation investment programme key: cord- -oreg rnj authors: spyrou, maria a.; bos, kirsten i.; herbig, alexander; krause, johannes title: ancient pathogen genomics as an emerging tool for infectious disease research date: - - journal: nat rev genet doi: . /s - - - sha: doc_id: cord_uid: oreg rnj over the past decade, a genomics revolution, made possible through the development of high-throughput sequencing, has triggered considerable progress in the study of ancient dna, enabling complete genomes of past organisms to be reconstructed. a newly established branch of this field, ancient pathogen genomics, affords an in-depth view of microbial evolution by providing a molecular fossil record for a number of human-associated pathogens. recent accomplishments include the confident identification of causative agents from past pandemics, the discovery of microbial lineages that are now extinct, the extrapolation of past emergence events on a chronological scale and the characterization of long-term evolutionary history of microorganisms that remain relevant to public health today. in this review, we discuss methodological advancements, persistent challenges and novel revelations gained through the study of ancient pathogen genomes. the long shared history between humans and infectious disease places ancient pathogen genomics within the inter est of several fields such as microbiology, evolutionary biology, history and anthropology. research on this topic aims to better understand the interactions between pathogens and their hosts on an evolutionary timescale, to uncover the origins of pathogens and to disentangle the genetic processes involved in their epidemic emer gence among human populations. over the past , years, major transitions in human subsistence strategies, such as those that accompanied the neolithic revolution , likely exposed our species to a novel range of infectious agents . closer contact with domesticated animals would have increased the frequency of zoonotic transmission events, and higher human population densities would have enhanced the potential of pathogens to propagate within and between groups. throughout human his tory, a number of epidemics and pandemics have been recorded or are hypothesized to have occurred (fig. ) . although most of their causative agents still remain speculative, robust molecular methods coupled with archaeological and historical data can confidently demonstrate the involvement of certain pathogens in these episodes. the investigation of past infectious diseases has tra ditionally been conducted through palaeopathological assessment of ancient skeletal assemblages , , although this approach is limited by the fact that most acute infec tions do not leave visible traces on bone. since the s, the field of ancient dna (adna) has brought molecular techniques to this study, providing a diachronic genetic perspective to infectious disease research. initial attempts relied on pcr technology [ ] [ ] [ ] [ ] [ ] , which restricted the study of ancient microbial dna to targeted, short genomic fragments that were amplified from ancient human remains. this method made infectious disease detection possible but gave limited information on the evolution ary history of the patho gen. in addition, complications associated with the study of adna, which is typically present at low quantities, is heavily fragmented and har bours chemical modifications [ ] [ ] [ ] , hampered efforts to reproduce and authenticate early findings [ ] [ ] [ ] . over the past decade, major advancements in geno mics, in particular, the development of high throughput sequencing, also called next generation sequencing (ngs) , radically increased the amount of data that can be retrieved from ancient remains. this techno logy has assisted the development of quantitative meth ods for adna authentication , , [ ] [ ] [ ] and has enabled the retrieval of whole ancient pathogen genomes from archaeological specimens. the first such genome, pub lished in (ref. ), was that of the notorious bacterial pathogen yersinia pestis, the causative agent of plague. since then, the field has expanded its directions to the in depth study of infectious disease evolution, providing a unique resource for understanding human history. here, we review the latest methodological innovations that have aided the whole genome retrieval and evolu tionary analysis of various ancient pathogens (table ) , most of which are still relevant to public health today. a scientific field focused on the study of whole pathogen genomes retrieved from ancient human, animal or plant remains. the cultural transition associated with the adoption of farming, animal husbandry and domestication as well as the practice of a sedentary lifestyle among human populations. the infectious disease transmission from animals to humans. in the second half of this review, we highlight the util ity of this approach by discussing evolutionary events in the history of y. pestis that have been uniquely revealed through the study of ancient genomes. methods for isolating ancient microbial dna the sweet spot for ancient pathogen dna. the retrieval of dna from ancient human, animal or plant remains carries with it a number of challenges, namely, its limited preservation and hence low abundance, its highly fragmented and damaged state and the perva sive modern dna contamination that necessitates a confident evaluation of its authenticity , . efficient adna recovery is best accomplished via sampling of the anatomical element that contains the highest quantity of dna from the target organism. for human adna analysis, bone and teeth have been the preferred study material, given their abundance in the archaeological record. recent studies suggest that the inner ear por tion of the petrous bone and the cementum layer of teeth have the greatest potential for successful human dna retrieval. however, petrous bone sampling and shotgun ngs sequencing of adna from five bronze age skeletons previously shown to be carrying y. pestis failed to detect the bacterium in this source material, suggesting that its preservation potential for pathogen dna is low . direct sampling from skeletal lesions, where present, has proved a rich source of adna for some chronic disease causing bacteria, such as mycobacterium tuberculosis, which was isolated from vertebrae ; mycobacterium leprae, which could be isolated from portions of the maxilla and various long bones , ; and treponema pallidum subsp. pallidum and t. pallidum subsp. pertenue, which have been isolated from long bones . of note, the sampling methods for recovering pathogen dna do not generally follow a standardized procedure, in part because of the great diversity in tissue tropism and resulting disease progression. in addition, acute blood borne infections do not typically produce diagnostic bone changes as opposed to those that affect their hosts chronically . therefore, if infections have caused mortal ity in the acute phase, as is the case for individuals from epidemic contexts who do not display skeletal evidence of infection, the preferred study material has been the inner cavities of teeth. pathogen adna is thought to be preserved within the remnants of the pulp chamber, likely as part of desiccated blood , . consequently, tooth sampling has proved successful in the retrieval of whole genomes or genome wide data (that is, low coverage genomes that have provided limited analytical resolution) from ancient bacteria such as y. pestis , [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] , borrelia recurrentis and salmonella enterica ; ancient eukaryotic pathogens such as plasmodium falciparum ; and ancient viruses such as hepatitis b virus (hbv) , and human parvovirus b (b v) . even m. leprae, which commonly manifests in the chronic form, has been retrieved from ancient teeth , . other types of specimen have also shown potential for adna retrieval. examples are dental calculus as a source of oral pathogens, such as tannerella forsythia pandemics refers to increased, often sudden, disease occurrence within populations across more than one region or continent, whereas epidemics refers to increased disease occurrences within a confined region or country. the evaluation of the health status of ancient individuals or populations, usually through the analysis of disease marker presence on skeletal assemblages. (adna). the dna that has been retrieved from historical, archaeological or palaeontological remains. tropism refers to the type of tissue or cell in which infection is established and supported. segregating the metagenomic soup: methods for pathogen detection. regardless of the source of genetic material, most ancient specimens yield complex metagenomic data sets. poorly preserved adna usually makes up a miniscule fraction of the total genetic mate rial extracted from a sample (< %), and the majority of dna usually stems from organisms residing in the envi ronment . hence, specialized protocols are necessary for the detection and isolation of ancient pathogen dna and its confident segregation from a rich environmental dna background (fig. ) . in this context, laboratory based techniques are sep arated into those that target a specific microorganism and those that screen for several pathogenic micro organisms simultaneously (fig. ). methods that screen for a single microorganism have used species specific assays of conventional or quantitative pcr (also known as real time pcr) , - , as well as hybridization based enrichment techniques , , (fig. ). these methods are particularly useful when the target microorganism is known, for example, in the presence of diagnostic skeletal lesions among the studied individuals , , or when a hypothesis exists for the causative agent of an epidemic . by contrast, broad laboratory based patho gen screening in adna research has used microarrays for both targeted enrichment and hbv that were sequenced using capillary sequencing (sanger method). a term used to describe a specimen or data set that includes nucleic acid sequences from all organisms within the sampled proportion. the diagram provides an overview of techniques used for pathogen dna detection in ancient remains by distinguishing between laboratory and computational methods. in both cases, processing begins with the extraction of dna from ancient specimens . as part of the laboratory pipeline, direct screening of extracts can be performed by pcr (quantitative (qpcr) or conventional) against species-specific genes, as done previously , , , . pcr techniques alone, however, can suffer from frequent false-positive results and should therefore always be coupled with further verification methods such as downstream genome enrichment and/or next-generation sequencing (ngs) in order to ensure ancient dna (adna) authentication of putatively positive samples. alternatively , construction of ngs libraries , has enabled pathogen screening via fluorescence-based detection on microarrays and via dna enrichment approaches . the latter has been achieved, through single locus in-solution capture , or through simultaneous screening for multiple pathogens using microarray-based enrichment of species-specific loci and enables post-ngs adna authentication. in addition, data produced by direct (shotgun) sequencing of ngs libraries before enrichment can also be used for pathogen screening using computational tools. after pre-processing, reads can be directly mapped against a target reference genome (in cases for which contextual information is suggestive of a causative organism) or against a multigenome reference composed of closely related species to achieve increased mapping specificity of ancient reads. alternatively , ancient pathogen dna can also be detected using metagenomic profiling methods, as presented elsewhere , , , through taxonomic assignment of shotgun ngs reads. both approaches allow for subsequent assessment of adna authenticity and can be followed by whole pathogen genome retrieval through targeted enrichment or direct sequencing of positive sample libraries. detection , whereby probes are designed to represent unique or conserved regions from a range of pathogenic bacteria, parasites or viruses. although amplification based or fluorescence based approaches can be fast and cost effective for screening large sample collections , , enrichment based techniques are usually coupled with ngs and therefore provide data that can be used to assess adna authenticity. when shotgun sequencing data are generated, com putational screening approaches can be used to detect the presence of pathogen dna as well as for meta genomic profiling of ancient specimens (fig. ). in cases for which a causative agent is suspected, ngs reads can be directly mapped (for example, using the read align ment software burrows-wheeler aligner ) against a specific reference genome or against a multigenome reference that includes several species of a certain genus with the purpose of achieving a higher mapping speci ficity to the target organism (fig. ). in addition, broad approaches involve the use of metagenomic techniques for pathogen screening. examples of tools that have shown their effectiveness with ancient metagenomic dna include the widely used basic local alignment search tool (blast) ; the megan alignment tool (malt) , which involves a taxonomic binning algorithm that can use whole genome databases (such as the national center for biotechnical information (ncbi) reference sequence (refseq) database ); metagenomic phylogenetic analysis (metaphlan) , which is also integrated into the metagenomic pipeline metabit and uses thousands (or millions) of marker genes for the distinction of specific microbial clades; or kraken , an alignment free sequence classifier that is based on k-mer matching of a query to a constructed database. taxonomic sequence assignments from the above methods, however, should be interpreted with caution, mainly because some pathogenic microorganisms have close environmental relatives that are often insuffi ciently represented in public databases. for example, a > % sequence identity was shown between environ mental taxa and human associated pathogens such as m. tuberculosis and y. pestis according to an analysis of s ribosomal rna genes . as such, given that envi ronmental dna often dominates ancient remains that stem from burial contexts , analyses should always ensure a qualitative assessment of assigned reads, that is, an evaluation of their mapping specificity and their genetic distance (also called edit distance) to the puta tively detected organism. in addition, one should con sider the known adna damage characteristics as criteria for data authenticity. although several types of chemical damage can affect post mortem dna survival, certain characteristics have been more extensively quantified. the first, termed depurination, is a hydrolytic mecha nism under which purine bases become excised from dna strands. this process results in the formation of abasic sites and is a known contributor to the fragmen tation patterns observed in adna. as such, an increased base frequency of a and g compared with c and t immediately preceding the ʹ ends of adna fragments is often considered a criterion for authenticity . a sec ond type of damage commonly identified among adna data sets is the hydrolytic deamination of c, whereby a c base is converted into u (and detected as its dna analogue, t) , . this base modification usually occurs at single stranded dna overhangs that are most acces sible to environmental insults, resulting in an increased frequency of miscoding lesions at the terminal ends of adna fragments , . consequently, the evaluation of dna damage profiles (for instance, by using map damage . (ref. )) is a prerequisite for authenticating ancient pathogen dna and is necessary for ensuring adna data integrity in general. more detailed overviews of authentication criteria in ancient pathogen research have been reviewed elsewhere , . targeted enrichment approaches to isolate whole ancient pathogen genomes. evolutionary relationships between past and present infectious agents are best determined through the use of whole genome sequences of pathogens. however, the recovery of high quality data is often challenging owing to the aforementioned char acteristics of adna and therefore requires specialized sample processing. for example, in cases in which adna authenticity has already been achieved in the detection step, u residues resulting from post mortem c deami nation can be entirely or partially excised from adna molecules using the enzyme uracil dna glycosylase (udg) to avoid their interference with downstream read mapping and variant calling. in addition, given the low proportion of patho gen dna in ancient remains, a common and cost effective approach for whole genome retrieval involves microarray based or in solutionbased hybridization capture. both methods constitute a form of genomic selec tion of continuous or discontinuous genomic regions through the design and use of single stranded dna or rna probes that are complementary to the desired tar get. microarray based capture utilizes densely packed probes that are immobilized on a glass slide . it is cost effective in that it permits the parallel enrichment of molecules from several libraries that can be subsequently recovered through deep sequencing, although competi tion over the probes can impair enrichment efficiencies in specimens with comparatively lower target dna con tents. nevertheless, this type of capture has shown its effectiveness in the recovery of both ancient pathogen and human dna , , , , , . more recently, in solutionbased capture approaches have gained popularity owing to their capacity for greater sample throughput without compromising capture effi ciency [ ] [ ] [ ] ; every sample library can be captured indi vidually, thus providing, in principle, an equal probe density per specimen. this technique has contributed to the increased number of specimens from which human genome wide single nucleotide polymorphism (snp) data could be retrieved , , even from climate zones that pose challenges to adna preservation (pre sented elsewhere [ ] [ ] [ ] ). in addition, in solutionbased capture has recently become the preferred method for microbial pathogen genome recovery for both bacteria and dna viruses (for examples, see refs , , , , , , ). nevertheless, deep shotgun sequencing alone has also been used for human [ ] [ ] [ ] and pathogen , , high quality an algorithm that assigns metagenomic dna reads to a species or a higher taxonomic rank (for example, genus or family) based on the sequence specificity. the matching, for each read, of multiple subsequences of length k without mismatches to a database. a hydrolytic reaction in which the β-n-glycosidic bond of a purine (adenine or guanine) is cleaved, causing its excision from a dna strand. the hydrolytic removal of an amine group (nh ) from a molecule. in ancient dna studies, the term deamination most often refers to the deamination of cytosine residues into uracils. the identification of polymorphisms (nucleotide differences) in sequenced data by comparison to a reference. www.nature.com/nrg | june | volume genome reconstruction, especially for specimens with fairly high endogenous dna yields, although this frequently carries with it a greater production cost. in the absence of ancient pathogen genomes, the tim ings of infectious disease emergence and early spread are inferred mainly through comparative genomics of modern pathogen diversity , , palaeopathological eval uation of ancient skeletal remains or analysis of his torical records , . such approaches are highly valuable and, when combined, can be used to build an inter disciplinary picture of infectious disease history; however, limitations also exist. for example, the analysis of con temporary pathogen genetic diversity considers only a short time depth of available data and cannot predict evolutionary scenarios that derive from lineages that are now extinct. in addition, skeletal markers of specific infections in past populations only exist for a few con ditions and, when present, can rarely be considered as definitive, as numerous differential diagnoses can exist for a given skeletal pathology . similarly, historically recorded symptoms can often be misinterpreted given that past descriptions may be unspecific and do not always conform to modern medical terminology . in the past decade, the reconstruction of ancient pathogen genomes has complemented such analyses with direct molecular evidence, often revealing aspects of past infections that were unexpected on the basis of existing data. the recent identification of hbv dna in a mummified individual showing a vesicopustular rash , which is usually considered characteristic of infection with varv, highlights the importance of molecular methods in evaluating differential diagnoses. the oldest recovered genomic evidence of hbv to date was from a , year old individual from present day germany , which shows that this pathogen has affected human populations since the neolithic period. in addition, the virus was identified recently in human remains from the bronze age, iron age and up until the th century of the current era (ce) in eurasia , , , . regarding bacterial pathogens, the identification of b. recurrentis in a th century individual from norway showed that -aside from y. pestis -other vector borne pathogens were also circulating in medieval europe. furthermore, the causative agents of syphilis and yaws, t. pallidum subsp. pallidum and t. pallidum subsp. pertenue, respectively, were recently identified in different individuals from colonial mexico who exhib ited similar skeletal lesions. this study demonstrates the power of ancient pathogen genomics in distinguishing past infectious disease agents that are genetically and phenotypically similar but that differ greatly in their public health significance. finally, the identification of g. vaginalis and s. saprophyticus in calcified nodules from a woman's remains ( th century troy) directly implicates these bacteria in pregnancy related com plications in the past. these findings, as well as other insights gained from analyses of ancient pathogen genomes (table ) , demonstrate the ability of adna to contribute aspects of infectious disease history beyond those accessible by the palaeopathological, historical and modern genetic records. the reconstruction of whole pathogen genomes has not only been a tool for demonstrating infectious disease presence in the past but also aided in the robust infer ence of microbial phylogeography, which is important for understanding the processes that influence pathogen distribution and diversity over time. the evaluation of genetic relationships between ancient and modern pathogens is often conducted by direct whole genome or genome wide snp compari sons of bacteria , , , , , viruses , , , or mito chondrial genomes and nuclear genome data from eukaryotic microorganisms , , . hence, accurate variant calling is critical for drawing reliable evolutionary inferences, although this process is often a challenge when handling data sets derived from samples with high rates of dna fragmentation (resulting in ultrashort read data), low endogenous dna content and high levels of dna dam age. in these cases, increased accuracy is best achieved through stringent ngs read mapping parameters and through visual inspection of the sequences overlap ping the studied snps . in addition, histograms of snp allele frequencies -used to estimate the frequency of heterozygous calls in haploid organisms , -can often demonstrate the effects of environmental contamination on ancient microbial data sets . once variant calls are authenticated, one of the most common types of evolutionary inference in patho gen research is through phylogenetic analysis, which is a powerful means of resolving the genetic history of clonal microorganisms (fig. ) . among the most commonly used tools in ancient microbial genomics are mega , which comprises several phylogenetic methods; phyml , raxml and iq tree , which implement maximum likelihood approaches; mrbayes , which uses a bayesian approach; and programs used for phylo genetic network inference, such as splitstree . two notable studies that examined phylogenetic relationships among ancient m. leprae genomes revealed a high strain diversity in europe between the th and th centuries ce , . considered alongside the oldest palaeopatholog ical cases of leprosy dating to as early as the copper and bronze age in eurasia , and the high frequency of protective immune variants against the disease identi fied in modern day europeans , these results may sug gest a long history of m. leprae presence in this region. moreover, the phylogenetic analysis of a th century s. enterica subsp. enterica genome from europe showed its placement within the paratyphi c lineage . further identification of the bacterium in th century colonial mexico revealed it as a previously unknown candidate pathogen that was likely introduced to the americas through european contact. given the low frequency of paratyphi c today, these results may be indicative of a higher prevalence in past populations. finally, an example from viral genomics is the recovery of hiv rna from degraded serum specimens , which high lighted the importance of archival collections in reconcil ing the expansion of recent pandemics. specifically, these data were able to dispute a long standing hypothesis regarding the initiation of hiv spread in the usa. when the evolutionary histories of pathogens are influenced equally by mutation and recombination, additional tools have been used to identify recombining loci and to determine genetic relationships within and between microbial populations (fig. ) . for example, the programs clonalframeml and recombination detection program (rdp ) have been used to infer potential recombination regions within ancient , , , respectively. in addition, principal component analysis (pca) and ancient admix ture component estimation using the bayesian modelling frameworks structure and finestructure on both multilocus sequence typing (mlst) and whole genome data were recently used for population assignment of a , year old h. pylori genome . these analyses revealed key information on changes of the bacterial population structure that occurred in europe over time. furthermore, the recent study of ancient t. pallidum subsp. pallidum and t. pallidum subsp. pertenue used the program tree puzzle , a maximum likelihoodbased phylogenetic algorithm, to gain a more robust phylogenetic resolution of ambiguous branching patterns among bacterial lineages. such whole genome analyses of both clonal and recombining pathogens have helped to elucidate not only past infectious disease phylogeography but also possible zoonotic or anthroponotic transmission events that reveal disease interaction networks through time. among others (table ) , a notable example is that of , year old pre columbian m. tuberculosis genomes isolated from human remains, which showed a phylo genetic placement among animal adapted lineages, being most closely related to a strain circulating in modern day seals and sea lions . although the extent to which these strains were capable of human to human transmission is unclear, this study supports the existence of tuberculosis in pre columbian south america and is helping to delineate the genomic and adaptive history of m. tuberculosis in the region before european contact . another example of intriguing evolutionary relationships revealed uniquely through the study of ancient pathogen genomes includes analy ses of neolithic and bronze age hbv. these genomes grouped in extinct lineages that are most closely related to modern strains identified exclusively among african non human p ri ma te s , , a result that raises further questions regarding past transmission events in hbv history. finally, the phylogenetic analysis of medieval m. leprae genomes suggested a european source for lep rosy in the americas , reinforcing the hypothesis that humans passed the disease to the nine banded arma dillo, the most common reservoir for this disease in the new world . importantly, the resolution of evolutionary analyses will depend on the quality, size and evenness of spatial sampling in the comparative data set. therefore, the incomplete and often biased sampling of ancient and modern microbial strains can introduce challenges for discerning true biological relationships and past evo lutionary events. nevertheless, in recent years, marked reductions in ngs costs have aided the increased pro duction of large whole genome microbial data sets from present day strains. current efforts for centralized data repositories that are continuously curated (such as the pathosystems resource integration center (patric) database and the recently introduced enterobase ) and the development of robust phylogenetic frameworks that can accommodate genome wide data from > , strains (for example, grapetree ) are becoming valua ble for integrating large sample sizes into microbial evo lutionary analyses. in combination with the increasing number of ancient microbial data sets, these tools will aid in the evaluation of genetic relationships by offering higher resolution. inferring divergence times through molecular dating. apart from providing a molecular fossil record and revealing diachronic evolutionary relationships, a third analytical advantage gained from the retrieval of ancient pathogen genomes is that their ages can be directly used for calibration of a molecular clock. the ages of ancient specimens can be determined through contextual information, through archaeological artefacts or directly through radiocarbon dating, predominantly of bone or tooth collagen. such temporal calibrations are required for high accuracy estimations of micro bial nucleotide substitution rates and in turn lineage divergence dates (fig. ) , particularly because both esti mations seem to be highly influenced by the time depth covered by the genomic data set . for such analyses, the most widely used program is the bayesian statistical framework beast , . a characteristic example of how ancient calibration points can considerably affect divergence date estimates is that of m. tuberculosis. according to modern genetic data and human demographic events, the m. tuberculosis complex (mtbc) evolution was suggested to have fol lowed human migrations out of africa, with its emer gence estimated at more than , years ago . recently, its emergence was re estimated to a maximum of , years ago on the basis of the , year old myco bacterial genomes from peru , a result that was further the diagram is an overview of whole-genome analysis applied to date for ancient microbial data sets and distinguishes the methods used for clonal and recombining pathogens; of note, the depicted summary is not meant to represent an exhaustive pipeline of all possible analyses that could be undertaken. ancient genome reconstruction is usually initiated through reference-based mapping or through de novo assembly of the data, although the latter has only been possible in exceptional cases of ancient dna (adna) preservation , . subsequently , the genomes are assessed for their coverage depth and gene content for evaluation of their quality , which is also relevant for the comparative identification of virulence genes over their evolutionary time frames. here, we show an example of virulence factor presence-or-absence analysis in the form of a heat map, as done previously , , , . in addition, a comparison of the ancient genome or genomes with modern genomes can be carried out for single-nucleotide polymorphism (snp) identification and for assessment of snp effects (using snpeff ), which is particularly relevant for variants that seem to be unique to the ancient genome or genomes. initial evolutionary inference can often be carried out through phylogenetic analysis and by testing for possible evidence of recombination in the analysed data set, for example, by comparing the support of different phylogenetic topologies and by identifying potential recombination regions and homoplasies , . if the data support clonal evolution, robust phylogenetic inference (for example, through a maximumlikelihood approach) is followed by assessment of the temporal signal in the data , . if the data set shows a sufficient phylogenetic signal, molecular dating analysis and demographic modelling are considered possible, although the size of the data set will determine whether such analyses will be feasible and meaningful. alternatively , if recombination is confirmed, genetic relationships between microbial clades or populations can be determined through phylogenetic network analysis or through the use of population genetic methods such as principal component analysis (pca) and identification of ancestral admixture components , . in this case, the assessment of the temporal signal and proceeding with molecular dating analysis is cautioned and likely best performed after exclusion of recombination regions from all genomes in the data set. mrca , most recent common ancestor. ngs, next-generation sequencing. a term used to describe that genome evolution occurs as a function of time and, therefore, the genetic distance between two living forms is proportional to the time of their divergence. a technique to estimate the age of a specimen on the basis of the amount of incorporated radiocarbon ( c) that after the death of an organism gradually becomes lost over time. denotes the frequency of substitution accumulation in an organism within a given time; usually represented as substitutions per site per year. the dates of separation between two phylogenetic lineages, for example, the split between two species. corroborated by the incorporation of th century european mtbc genomes in the dating analysis , , . in molecular phylogenies, the length of each individ ual branch usually reflects the number of substitutions acquired by an organism within a given period of time and, as such, varying branch lengths should represent heterochronous sequences. therefore, an important pre requisite for a robust dating analysis is that the nucleo tide substitution rate of the species whose phylogeny is to be dated behaves in a 'clock like' manner, meaning that phylogenetic branch lengths correlate with archaeological dates or sampling times. such relationships can be assessed through date randomization and root-to-tip regression tests (fig. ) . the former is used to assess the effect of arbi trary exchange of phylogenetic tip dates on the nucleo tide substitution rate and divergence date estimates , whereas the latter is used for estimation of a correlation coefficient (r) and coefficient of determination (r ) by relating the tip date of each taxon to its snp distance from the tree root (using, for example, the program temp est ). the resulting values determine whether there is a temporal signal in the data and suggest whether branches within a phylogeny evolve at a constant rate, in which case a strict molecular clock can be statistically tested, for example, using mega or marginal likelihood estimations , , and applied. if branches are affected by differences in their evolutionary rates, a relaxed clock would be more appropriate. in general, a constant mole cular clock will rarely reliably describe the history of a microbial species, even more so for infectious pathogens whose replication rates vary between active and latent or between epidemic and dormant phases , . in certain cases, neither of the two models may fit the data, such as when extensive rate variation weakens the temporal signal. this challenge was encountered in initial attempts to date the y. pestis phylogeny using too few ancient cali bration points , . similar limitations can arise when the evolutionary history of a microorganism is vastly affected by recombination, as observed for hbv , , although hbv molecular dating was recently attempted using a different genomic data set and suggested that the currently explored diversity of old and new world pri mate lineages (including all human genotypes) may have emerged within the last , years . molecular dating analysis requires the use of an appro priate demographic model for the available data, which can be determined through model testing approaches (for example, through marginal likelihood estimations , ). currently, the most widely used models for estimating dates of divergence are the coalescent constant size , which assumes a continuous population size history -and is unrealistic for epidemic pathogens -and the coalescent skyline , which can estimate effective population size (n e ) changes over time. moreover, the birth-death demographic model , , which is cur rently unexplored within adna frameworks, may prove an insightful analysis tool in the future. this model has shown its applicability on comprehensive pathogen data sets from modern day epidemic contexts . it has the ability to incorporate prior knowledge on incom plete sampling proportions and sampling biases within a data set, a frequent caveat of adna studies that is currently unaccounted for within molecular dating analy ses. finally, recently developed fast dating algorithms should also be noted, for example, the least squared dating (lsd) program, which does not use constrained demographic models but can handle uncorrelated rate variation among phylogenetic branches and has shown potential for analysing large genomic data sets . the pathogen best studied using adna analysis so far is y. pestis, the causative agent of plague. to date, ancient genomes of this bacterium have been published , - (fig. ) , and their analyses have yielded valuable infor mation on past pandemic emergence as well as in depth microbial evolution. integration of such knowledge into human population frameworks has provided key insights into the association of human migrations and infectious disease transmission in the past , . this sec tion describes the evolutionary history of y. pestis with the aim of demonstrating aspects of its emergence and spread as revealed through adna research. plague is a well defined infectious disease caused by the gram negative bacterium y. pestis, which belongs to the fam ily enterobacteriaceae. it evolved from a close relative, yersinia pseudotuberculosis, which is an environmental enteric diseasecausing bacterium . although the two species are clearly distinguishable in terms of their vir ulence potential and transmission mechanisms, their nucleotide genomic identity reaches % among chromo somal protein coding genes . in addition, they share the virulence plasmid pcd , which encodes a type iii secretion system common to three known pathogenic yersinia: y. pestis, y. pseudotuberculosis and yersinia enterocolitica. the distinct transmission mechanism and pathogenicity of y. pestis are conferred by the unique acquisition of two plasmids, ppcp , which contributes to the invasive potential of the bacterium , and pmt , which is involved in flea colonization , , as well as by chromosomal gene pseudogenization or loss throughout its evolutionary history . y. pestis is not human adapted. its primary hosts are sylvatic rodents such as marmots, mice, great gerbils, voles and prairie dogs, among others, in which it is continuously or intermittently maintained in so called reservoirs or foci [ ] [ ] [ ] . its global distribution includes numerous rodent species , and encompasses regions in eastern europe, asia, africa and the americas (fig. ) , where the bacterium persists in active foci, some of which have existed for centuries or even millennia , , , , . y. pestis transmission among hosts is facilitated by a flea vector (fig. ) . the best yet characterized is the oriental rat flea, xenopsylla cheopis, although others are also known to play important roles in y. pestis transmission , , . notably, recent modelling infer ences suggest important roles for ectoparasites such as body lice and human fleas in its propagation during human epidemics . landmark studies investigating the classical model of transmission have shown that y. pestis has the unique ability to colonize and form a biofilm within the flea, which blocks a portion of its a test that involves random shuffling of calibration points (tip dates) across a molecular phylogeny to evaluate the effect of randomizations compared to true data on the nucleotide substitution rate estimates. a test that uses a linear correlation to determine the relationship between branch lengths and sampling times within a time-dependent phylogeny. a mathematical model that aims to explain the size and density of a population over time. www.nature.com/nrg | june | volume foregut, the proventriculus (fig. ). this phenotype is determined by the unique acquisition and activity of certain genomic loci in y. pestis, namely, the yersinia murine toxin (ymt) gene, which is present on the pmt plasmid , and facilitates colonization of the arthropod midgut . in addition, it is dependent on the pseudogenization of certain genes, namely, the biofilm downregulators rcsa, pde (also known as rtn), pde (also known as y ) and the ure ase gene ured , , which are, by contrast, active in y. pseudotuberculosis. the biofilm prevents a blood meal from entering the flea's digestive tract, leaving it starving; as a result, the insect intensifies its feeding behaviour and promotes bacterial transmission to un infected hosts [ ] [ ] [ ] . this continuous transmission cycle among fleas and rodents, also called the enzootic phase of maintenance (fig. ) , is thought to drive the preser vation of plague foci around the world and is depen dent on environmental and climatic factors as well as on host population densities , [ ] [ ] [ ] . disruption of this equilibrium for reasons that are not well understood can cause disease eruption among susceptible rodent species, leading to so called plague epizootics (fig. ) . during that time, marked reductions in the rodent pop ulations force fleas to seek alternative hosts, which can lead to infections in humans and, as a result, trigger the initiation of epidemics or pandemics. plague manifestation in humans has three disease forms, namely, bubonic, pneumonic and septicaemic . bubonic plague is the most common form of the disease and can cause up to % mortality when left untreated . subsequent to the bite of an infected flea, bacteria travel to the closest lymph node, where excessive replica tion occurs, giving rise to large swellings, the so called buboes. in addition, following primary bubonic plague, bacteria can disseminate into the bloodstream to cause septicaemia (secondary septicaemic plague) and to the lungs, causing secondary pneumonic disease. both forms are highly lethal disease presentations and cause nearly % mortality when left untreated. only the pneumonic form can result in direct human tohuman transmission. early evolution: plague in prehistory. the time of divergence between y. pestis and y. pseudotuberculosis has been difficult to determine given the wide temporal interval produced by recent molecular dating attempts , , [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] , are shown as grey circles within their geographical country or region of isolation, and the size of each circle is proportional to the number of strains sequenced from each location (number indicated when more than one genome is shown). the areas highlighted in brown are regions that contain active plague foci as determined by contemporary or historical data. ybp, years before present. adapted with permission from the 'global distribution of natural plague foci as of march ' from https://www.who.int/csr/disease/plague/plague-map- .pdf. based on adna data ( , - , years before present (ybp)) , . nevertheless, y. pestis identification in human remains from neolithic and bronze age eurasia suggests that it caused human infections during these periods and originated more than , years ago , , . these data have revealed important details about the early evolution of the bacterium. genomic and phylogenetic analyses have shown that strains from the late neolithic and bronze age (lnba) occupy a basal lineage in the y. pestis phylogeny, and a recent study suggests the presence of even more basal variants in neolithic europe (fig. ). such analyses have demonstrated that, during its early evolution, the bacterium had not yet acquired impor tant virulence factors consistent with the complex trans mission cycle common to historical and extant strains. one of these genes is ymt, whose absence has been asso ciated with an inability for flea midgut colonization in y. pestis . in addition, these strains possess the active forms of the rcsa, pde , pde and ured genes, which suggests an impaired ability towards biofilm formation and blockage of the flea's proventriculus , . finally, they possess an active flagellin gene (flhd), which is pres ent as a pseudogene in all other y. pestis, as it is a potent inducer of the innate immune response of the host . as a result, during its initial evolutionary stages, y. pestis may have been unable to efficiently transmit via a flea vector. flea borne transmission of y. pestis is a known prerequisite for bubonic plague development ; hence, it has been suggested that this disease phenotype was not present during prehistoric times , . in addition, these results have raised uncertainty regarding the pos sible vector and host mammalian species of the bacte rium. the bronze age in eurasia was a period of intense human migrations, which shaped the genomic landscape of modern day europe , . remarkably, the y. pestis lnba lineage was shown to mirror human movements during that time and was found in regions that do not host wild reservoir populations today (fig. ) . the wide geographical distribution of these strains, their supposed limited bubonic disease potential and their relationship with human migration routes might together be indica tive of a different reservoir host species compared to wild rodents that have a central role in plague transmission in areas such as central and east asia, where the disease is endemic today. nevertheless, an alternative mode of flea transmis sion, termed the early phase transmission, which occurs during the initial phases of infection and was suggested to be biofilm independent , should also be considered as a possible way of y. pestis propagation during its early evolution . although this transmission mechanism is currently not well understood, its comparative mode and efficiency in different rodent species have recently started to be assessed evidence showing the full capacity for flea colonization similar to modern and historic strains was identified in two , year old skeletons from the samara region of modern day russia . although this strain was shown to occupy a phylogenetic position among modern y. pestis lineages (fig. ) , molecular dating analysis indicated that it originated ~ , years ago, suggesting that it over lapped temporally with the other bronze age strains that lacked the genetic prerequisites for arthropod transmis sion. similar characteristics were previously identified in a low coverage , year old isolate from modern day armenia , which suggests that multiple forms of the bacterium were circulating in eurasia between , and , years ago that may have had different transmission cycles and produced different disease phenotypes. as the propagation mechanisms of those strains are still uncer tain, and the exact timing of flea adaptation in y. pestis is unknown, additional metagenomic screening from human and animal remains may provide relevant infor mation on disease reservoirs and hosts across neolithic and bronze age eurasia. it is becoming increasingly apparent that, aside from plague, other infectious diseases, such as those caused by hbv , and b v (table ) , were circulating dur ing the same time periods. further pathogen screening coupled with a temporal assessment of human immune associated genomic variants may reveal key aspects of disease prevalence and susceptibility during this pivotal period of human history. after the bronze age, bubonic plague has been associated with three historically recorded pandem ics. the earliest accounts of the so called first plague pandemic, which began with the plague of justinian ( ce), suggest that it erupted in northern africa in the mid th century ce , and subsequently spread through europe and the vicinity until ~ ce. the sec ond historically recorded plague pandemic began with the infamous black death ( - ce) and con tinued with outbreaks in europe until the th century ce. the most recent third plague pandemic began in the mid th century in the yunnan province of china, and it was during that time that alexandre e. j. yersin first described the bacterium in hong kong, in (fig. ) and has persisted until today in active foci in africa, asia and the americas. although the majority of mod ern plague cases derive from strains disseminated in this global dispersal, the pandemic is considered to have largely subsided since the s . the association of y. pestis with the two earlier pan demics has, until recent years, been contentious. on the basis of their serological characterization, modern strains were traditionally grouped into three distinct biovars, namely, 'antiqua' , 'medievalis' and 'orientalis' , according to their ability to ferment glycerol and reduce nitrate , . in addition, historical accounts of the dis ease seemed to correlate with the supposed distinct geographical distributions of these biovars , and their phylogenetic relationships, as inferred from mlst data, reinforced the hypothesis that each was responsible for a single pandemic . by contrast, later studies identified additional, atypical biovars , and more robust phylo genetic analysis suggested that phylogeography does not correlate clearly with the phenotypic distinctions described between these bacterial populations , , . recent genomic analyses have revealed high genetic diversity of the bacterium in east asia, which invaria bly led to the assumption that y. pestis emerged there . however, a strong research focus on the diversity of the bacterium in these endemic regions, mainly china, has contributed to a profound sampling bias in the available modern data (fig. ) . more recent investigations have revealed previously uncharacterized genetic diversity in the caucasus region and in the central asian steppe that ought to be further explored [ ] [ ] [ ] [ ] (fig. ) . currently, the evolutionary tree of the bacterium is characterized by five main phylogenetic branches (fig. ) . the most ances tral, branch , includes strains distributed across china, mongolia and the areas encompassing the former soviet union. the more phylogenetically derived branches - were formed through a rapid population expan sion event and are today found in asia, africa and the americas . their wide distribution mainly reflects the geographical breadth of branch , which is associated with the third plague pandemic that spread worldwide during the th and th centuries and is still respon sible for more confined epidemics such as those reported in madagascar . the analysis of adna from historical epidemic contexts has generated important information regard ing the evolutionary history of plague. the recovery of y. pestis dna via pcr from remnants of human den tal pulp suggested the involvement of the bacterium in both the first and second pandemics; however, these results were difficult to authenticate , , . subsequent pcr based snp typing of ancient specimens offered some phylogenetic resolution and revealed an expected ancestral placement of medieval strains in the y. pestis phylogeny [ ] [ ] [ ] . more recently, full characterization and authentication of the bacterium were achieved using plasmid and whole genome enrichment coupled with ngs , , , . historical accounts of the first plague pandemic ( th to th centuries ce) suggest that the disease expanded mainly across the mediterranean basin; however, its exact breadth and impact have been difficult to assess given the limited availability of historical and archaeo logical data, with the latter being currently under revision . two recent studies have reconstructed th century y. pestis genomes from southern germany , (fig. ) , a region that lacked historical documentation of the pandemic. phylogenetic analysis showed that both genomes belong to a lineage that is today extinct and is closely related to strains from modern day china , , which suggests the possibility of an east asian origin of the first pandemic. this hypothesis was recently reinforced by the publication of a nd century to rd century y. pestis genome from the tian shan mountains of modern day kyrgyzstan , which shares a common ancestor with the justinianic plague lineage (figs , ) . however, given the > year age difference between these strains , , , as well as the aforementioned east asian sampling bias of modern y. pestis data , the geographical origin of the pandemic remains hypothet ical. retrieval of additional y. pestis strain diversity from that time period, particularly from areas known to have played an important role in the entry of this bacterium into europe, that is, the eastern mediterranean region, may hold clues about its putative source. the beginning of the second plague pandemic, years later, was marked by the notorious black death of europe ( - ce), estimated to have caused an up to % reduction of the continental pop ulation in only years . historical records suggest that the first outbreaks occurred in the lower volga region of russia, and the disease then spread into southern europe through the crimean peninsula . initial analy sis of y. pestis via pcr from victims of the black death revealed a distinct phylogenetic positioning of two mid tolate th century strains and led to the proposal that the disease entered the continent through independent pulses . by contrast, whole genome analysis of ancient strains from western, northern and southern europe demonstrated a lack of y. pestis diversity during the black death, which suggests its fast spread through the continent and favours a single wave entry model of the bacterium into europe , , , although the possible presence of additional strain diversity during that time has recently been explored . intriguingly, the phylo genetic positioning of the black death y. pestis genomes places them on branch , only two nucleotide substitu tions away from the 'star like' diversification of branches - (fig. ) , which gave rise to most of the strain diversity identified around the world today , . after the black death, plague epidemics continued to affect europe until the th century , . inferred climatic data from tree ring records in central asia and europe have recently suggested that such epidem ics were likely caused by multiple introductions of the bacterium into europe as a result of climate driven disruptions of pre existing asian reservoirs . by con trast, ancient genetic and genomic evidence supports the persistence of the disease in europe for years after the black death , , . analysis of y. pestis strains spanning from the late th to the th century ce has revealed the formation of at least two european lin eages that were responsible for the ensuing medieval epidemics (fig. ). both lineages derive from the black death y. pestis strain identified in th century west ern, northern and southern europe , , , suggesting that they likely arose locally. the first lineage survives today and gave rise to modern branch strains , (which are associated with the third plague pandemic), suggesting the european black death as a source for modern day epidemics . the second lineage has not been identified among present day diversity and currently encompasses strains from th century germany and th century france (great plague of marseille, - ce) (fig. ) . these phylogenetic patterns are consistent with a con tinuous persistence of the bacterium in europe dur ing the second plague pandemic. in addition, they are supported by analyses of historical records that suggest the existence of plague reservoirs in the continent until the th century ce . y. pestis is absent from most of europe today; specif ically, no active foci exist west of the black sea. plague is thought to have disappeared from most of europe at the end of the second pandemic ( th century ce). this finding is striking given the thousands of outbreaks that were recorded in the continent until that time , . the reasons for its disappearance are unknown, although numerous hypotheses have been put forward , includ ing a change in domestic rodent populations in europe, namely, the replacement of the black rat, rattus rattus, by the brown rat, rattus norvegicus ; an acquired plague immunity among humans and/or rodents (although this hypothesis requires an update to accommodate the recent identification of y. pestis in europe , years ago , , and the involvement of the bacterium in the first plague pandemic , ); the increased living standards such as the better nutrition and hygienic conditions at the beginning of the early modern era, which may have contributed to improved overall health conditions in europe and likely decreased the number of rats and ecto parasites in human environments , ; and the poten tial disruption of the european wild rodent ecological niche owing to habitat loss and industrialization start ing in ce . given the contribution that molecular data can offer in these discussions, future research on ancient sources of y. pestis dna will be instrumental in further revealing the history of one of humankind's most devastating pathogens. the analysis of ancient pathogen genomes has afforded promising views into past infectious disease history. for y. pestis, adna exploration of its evolutionary past has revealed how a predominantly environmental bac terium and opportunistic gastroenteric pathogen deve loped into an extremely virulent form by acquisition of only a few virulence factors. we eagerly await revelations on a similar scale for other important pathogens that are expected to arise from deep temporal sampling and genomic reconstruction, as made possible through the recent advancements 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comments to the manuscript and m. keller for his contributions in assembling comprehensive meta-information for the y. pestis modern genomic data set. in addition, the authors thank all members of the molecular paleopathology and computational pathogenomics groups at the max planck institute for the science of human history for insightful discussions during meetings. moreover, they are grateful to m. o'reilly, h. shell and r. barquera for extensive assistance with the graphics. this work was supported by the max planck society. m.a.s. researched the literature and wrote the article. all authors provided substantial contributions to discussions of the content and reviewed and/or edited the manuscript. the authors declare no competing interests. springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. nature reviews genetics thanks e. willerslev and other anonymous reviewer(s) for their contribution to the peer review of this work. key: cord- -j vylbhy authors: martin, r. title: the role of law in pandemic influenza preparedness in europe date: - - journal: public health doi: . /j.puhe. . . sha: doc_id: cord_uid: j vylbhy the european union (eu) is composed of states with widely varying histories, economies, cultures, legal systems, medical systems and approaches to the balance between public good and private right. the individual nation states within europe are signatories to the international health regulations , but the capacity of states to undertake measures to control communicable disease is constrained by their obligations to comply with eu law. some but not all states are signatories to the schengen agreement that provides further constraints on disease control measures. the porous nature of borders between eu states, and of their borders with other non-eu states, limits the extent to which states are able to protect their populations in a disease pandemic. this paper considers the role that public health laws can play in the control of pandemic disease in europe. the states of the european union (eu) form a political and economic community with supranational and intergovernmental responsibilities, and constitute a single market that seeks to guarantee the freedom of movement of people, goods, services and capital between member states. the emergence or re-emergence of diseases such as severe acute respiratory syndrome (sars) and tuberculosis highlighted the need for eu-level health policy, and led to the community action programme - in the field of public health. this programme is now the cornerstone of community public health strategy, focusing on health information and on the community's capacity to react to health threats. in the context of disease control, the executive arm of the eu, the european commission (ec), has responsibility for the co-ordination of epidemiological surveillance of disease between member states and for regulating matters such as case definitions, disease notification and development of disease networks across europe. the ec is assisted by the european centre for disease control (ecdc), which issues protocols on matters of disease reporting and communication of disease information between states and to the ec. the ec and ecdc can only recommend appropriate disease control measures to states. neither is responsible for the management of disease protection and control in individual states. public health powers in relation to disease lie with national governments. it is member states, not the eu, which are signatories to the revised international health regulations (ihr) , although the ihr recognize the role of 'regional economic integration organizations' such as the eu. a thus, if the world health organization (who) were to recommend under the ihr measures falling within eu legislation, such as restrictions on the movement of goods or the processing of personal data, b the eu would need to act collectively, at the initiative of the ec, as member states would be unable to take unilateral action. otherwise, ihr responsibilities lie with individual states. in , a report on pandemic influenza preparedness in the eu noted that substantial progress had been made in preparing for a possible pandemic influenza, but it remained the case that disease control operated at national level. despite encouragement from the eu towards harmonization of approaches, european national plans vary widely in the strategies they have adopted and the public health powers they propose for implementation of those strategies. harmonization of legislative responses to infectious diseases, based upon sound evidence, will be necessary if collaborative efforts in support of infectious disease control are to be effective. to assist in drawing together national responses to pandemic disease, the phlawflu project c was funded to develop public health law expertise across europe, and to examine the legal underpinning of pandemic disease preparedness across the eu and five further european states. d this paper examines obstacles to european commonality of legal responses to communicable disease. there is no doubt that law is an important tool in containment of communicable and non-communicable disease. in the context of pandemic influenza, it is considered that social measures authorized by law will be at least as important as medical interventions. evidence from the influenza pandemic suggests that compulsory home isolation and quarantine were not particularly effective disease control measures because of the difficulty in diagnosing mild cases. nor were such measures likely to be feasible beyond the initial cases. however, compulsory interventions such as school closures, closure of public places and restriction of mass gatherings, along with disease surveillance and hygiene improvement, have proved effective both in influenza outbreaks and in the sars epidemic. international and eu instruments require states to undertake such measures, many of which will require a legal underpinning. the requirement of compliance with the revised ihr and the globalization of disease information and exchange have prompted many states to revise their public health laws. other states, which had no public health legislation, have now enshrined public health laws in legislative form. these initiatives were long overdue. across europe, as elsewhere, national public health laws tended to be old, based on flawed science, and to predate contemporary understandings and protection of human rights. , the allocation of responsibility for public health practice and the role of the state in regulating private behaviours have very different histories across europe. not surprisingly, states have adopted very different positions on the issue of the extent to which constraints can be placed upon individuals for the public benefit. earlier research on european national public health laws in relation to tuberculosis enabled the identification of four different 'families' of public health legislative models in europe. these were: authoritarian (the enforcement of a high number of compulsory control measures); moderate (the enforcement of predominantly compulsory control measures without recourse to prevention powers such as compulsory vaccination or population screening); preventive (where compulsory provisions were oriented towards preventive measures, including screening, medical examination and/or vaccination, rather than compulsory treatment or detention); and the laissez faire model, where few or no compulsory measures existed. a further complication to a comparison of national legal approaches to disease control is the range of different legal systems in europe. while the majority of european states have a civil law legal system based on the french or german systems, some states operate common law systems, e the former soviet states have vestiges of soviet law, and the legal systems of the scandinavian states recognize civil law overlain with some common law. whereas the definitive public health law of some states can be found in statutory form, other states also include the binding decisions of courts. some national legal systems recognize customary law, local edicts or administrative orders as having legal authority. it cannot be assumed that because a particular power does not lie within public health legislation, that power does not exist. determination of the full range of public health legal powers across european states is a technical and difficult task. following the eu working paper on community influenza pandemic preparedness and response planning in , european states have published national preparedness plans. as with the range of approaches to law, there is a wide range of approaches to pandemic preparedness planning across europe. coker and mounier-jack examined european national plans against a who checklist and found considerable gaps and inconsistencies among preparedness plans, with implications for health in both individual states and for europe as a whole. the authors noted that 'the eu has a critical function in protecting its citizens from public health threats. the role of the eu will be essential to ensure improved sharing of knowledge on pandemic response among eu members, to support the effective provision of services, and to coordinate the response at a community level'. few plans address the extent to which proposed interventions are authorized by their national laws. indeed, few state plans acknowledge the need for legal authorization for their proposed measures, and there is often a lack of clarity about the legality of measures. f while there is some commonality across european states in the measures considered appropriate in an epidemic, the formulation of those measures differs from state to state, reflecting the culture and social priorities of individual states. across europe, states have proposed disease reporting networks, social distancing powers, restriction on travel and trade, closure of premises and facilities, and measures regulating the provision of goods and services. however, the extent and scope of these powers vary widely. while most states contemplate powers of isolation and quarantine, some states also propose quarantining flight crews, and authorize compulsory vaccination, compulsory administration of prophylaxis, and compulsory medical treatment. most states authorize the closure of schools and leisure facilities in a pandemic, but some states would also close diplomatic and consular representation, restrict trade union activity or prohibit visitors to inpatients in hospitals. there is variation in the extent to which states will be prepared to requisition persons and property. many states have passed, or are in the process of passing, new legislation to support their preparedness planning. in england and wales, for example, the health and social care act has introduced into the public health act new powers of isolation outside a hospital, powers of quarantine, powers to require the wearing of protective equipment, powers to require people to attend counselling or disease risk training, and the power to require individuals to provide health information. it also provides for the application of compulsory power orders to groups of persons as well as to individuals, provides new border control measures and imposes new obligations to monitor health risk. states that had taken a liberal approach to intrusion on individual liberties for the benefit of the public health have, in the face of the threat of a pandemic, passed laws providing considerable public health powers. french public health law had previously c the phlawflu project has received funding from the eu in the framework of the public health programme. d croatia, turkey, iceland, liechtenstein and norway. e including the countries of the uk, ireland, malta and cyprus. f the spanish preparedness plan, for example, expresses concern regarding the legality of proposals for isolation, restriction of movement and the proposal to make compulsory the administration of antivirals to staff in contact with patients, noting that 'the legal services of the ministry of health will need to study the legal aspects relative to compulsory vaccination and isolation and the restriction of movement according to the constitutional act / of april of special public health measures in public health, articles and '. focused on preventive measures and provided few compulsory powers for disease control. the new french public health code now authorizes isolation and quarantine, obliges individuals to submit to temperature checks, and provides powers to close facilities such as schools, restrict use of public transport, requisition health personnel including students and retired persons, and regulate distribution of medicines. school buildings will be used as centres for vaccination and for accommodation of vulnerable persons. the new code withdraws employment rights such as the right not to work in a situation of danger. employees and public servants in france currently have the right to withdraw from their workplace if they reasonably believe that their work situation presents a grave and imminent danger to life and health, provided that they have alerted their employer to the danger and provided that their leaving does not create a new risk for others. under the new code, which only applies in the particular case of pandemic influenza, this right of withdrawal will not apply in circumstances where the employer has taken all foreseeable measures to reduce the risk of exposure to disease. the formulation of public health measures across europe reflects cultural values and priorities. french law, for example, proposes the possible closure of schools in an epidemic, but the new french public health code, recognizing the importance of education in france, provides very specific measures to protect the right to education of its children. the code acknowledges the need for school closures because children are more susceptible to the influenza virus than adults. however, the code requires that during a school closure, every effort must be made to continue educational provision via the internet, radio and television, and sets out detailed provisions on ways in which education might be continued throughout the pandemic. the difficulty of predicting what legal powers will be needed to exercise effective disease control has led some states to include in their public health legislation a power to make emergency regulations to provide powers that were not foreseen or which would not be appropriate outside an emergency. the health and social care act for england and wales, for example, proposes that where there is sufficient urgency, a legal instrument may be made without following normal parliamentary procedures. the regulation will then cease to have effect after days, unless it has been ratified by a resolution of each of the houses of parliament. the new french code allows that in the case of a grave threat calling for urgent measures, particularly in the case of an epidemic, the minister responsible for health can, by means of an arête, dictate in the interest of public health measures that are proportionate to the risk and appropriate to the time and place, in order to prevent or to limit the consequences of possible threats to the health of the population. in addition to emergency powers specifically addressed to pandemic disease, many european g and other h states have also introduced or updated separate emergency powers legislation to address unexpected threats, to authorize measures that would not normally be acceptable, or to provide powers as a last resort in the face of emergencies where existing legislation is insufficient. other states have constitutional provisions authorizing emergency powers. i it has until now been the case that for the purpose of legislation, emergencies have been conceptualized as aberrations, normally involving an aspect of violence such as war, rebellion or a violent natural disaster. european emergency powers have generally been limited to a 'state of siege' (france), armed rebellion (hungary), or industrial and natural disasters such as earthquakes or the forest fires in greece. they have not been considered a tool for disease control. in the uk, the civil contingencies act has replaced the emergency powers act j in relation to temporary special legislation to respond to serious emergencies. the emergency powers act had provided power to make emergency regulations, following a royal proclamation of a state of emergency, in case of an interference with the supply or distribution of food, water, fuel, light or the means of locomotion that deprived the community, or part of it, of the 'essentials of life'. the civil contingencies act expands the domain of emergency powers so that an emergency is widely defined to include 'an event or situation which threatens serious damage to human welfare', which could potentially include a public health threat such as a serious disease outbreak. while no regulations have been passed to date, there is clearly scope for a heavy-handed response in the event of a public health threat. the civil contingencies bill in its original form underwent prelegislative scrutiny by a joint committee which noted that the bill: ' in the wrong hands, [the bill] could be used to undermine or even remove legislation underpinning the british constitution and infringe human rights. our democracy and civil liberties could be in danger if the government does not take account of our recommended improvements'. the bill was revised and the government agreed to remove a clause that would have prevented emergency regulations from being subject to judicial review with the consequence that the regulations could not be suspended or struck down by a court if they were challenged on human rights grounds. the committee recommended that certain acts of parliament of major constitutional significance should be exempted from a power to modify or disapply legislation, but this remains in the final legislation. the committee also proposed that those powers set out in part of the bill should be subject to a 'sunset clause' and expire every years from royal assent unless renewed by parliament. this was rejected by the government as inappropriate, because the bill contained enabling powers that were intended to deal with a problem that was 'not short-term'. this suggests that a new approach is being taken to the meaning of 'emergency'. under earlier emergency powers legislation, an emergency was determined by a royal proclamation, but under the civil contingencies act, a state of emergency is to be announced, without initial reference to parliament, by the secretary of state or a senior minister. public health emergency planning in the uk appears to acknowledge that the civil contingencies act will have a more general role in the control of disease, although how these plans relate to new powers under the public health act remains to be seen. a senior spokesperson from the english department of health told the author that the department does not intend to use emergency powers contained in the civil contingencies act for pandemic influenza. powers, contained in the health and social care act should provide all the necessary legal powers to contain and control disease. however, it is clear from government documents on pandemic planning that there is every expectation that civil contingencies act powers will be used should the need arise. , the finnish national preparedness plan for pandemic influenza recommended amending finland's emergency powers act so that a major epidemic can be classified as a state of emergency as defined in the act. previously, an emergency was defined to include an armed attack against finland, a serious violation of the territorial integrity of finland, a threat of war, a serious threat to the livelihood of the population or the economy by interrupted import of indispensable fuels and other energy, or a catastrophe. finland's communicable disease act of already contains quite intrusive powers including the power to administer compulsory mass vaccination by the defence forces, compulsory medical treatment, isolation from the workplace, and disease reporting that discloses personal information. the concern with use of emergency powers for disease control is that disease control ceases to be a matter of health protection, and becomes an issue of foreign and national security, with the risk of being hijacked by the agendas of security policy and politics. ,l this has become even more pronounced with the merging of responses to naturally occurring infectious disease and bioterrorism within emergency powers legislation. the who and european commission have both established committees with responsibility for public health as a security issue. m it is questionable whether the suspension of separation of powers and potentially of civil rights and liberties is justified in the name of public health, and arguable that recognition of human rights is essential for dealing effectively with an epidemic. draconian quarantine measures can be counterproductive, and may even encourage people to avoid seeking medical treatment. emergency powers exercised for public health reasons treat citizens as the enemy, and reinforce the philosophy of original public health legislation which classified diseased persons as a public health nuisance to be removed and excluded from society for the benefit of the well. hong kong, which has had recent experience of epidemic disease, considered but rejected expanding its emergency regulations ordinance to cover pandemic influenza, concluding that public health powers were sufficient and appropriate to disease control even during a pandemic. n hong kong has instead amended its quarantine and prevention of disease ordinance in the light of its sars experience. emergency powers and human rights all council of europe member states are party to the european convention for the protection of human rights and fundamental freedoms, and any person whose convention rights have been violated by a state party can take a case to the european court of human rights. in the uk, the human rights act brings provisions of the convention into uk domestic law and enables human rights actions to be brought in a domestic court. rights with particular relevance to public health powers include article (right to life), article (an absolute right to freedom from torture and inhumane and degrading treatment), article (a qualified right to liberty) and article (a qualified right to private and family life). in enhorn v sweden, a human immunodeficiency virus (hiv)-positive man detained by swedish public health authorities on public health grounds successfully challenged his detention on the grounds that it breached articles and of the convention. the european court of human rights held that any detention must comply with the principle of proportionality, there must be an absence of arbitrariness, detention must be a last resort measure, and any detention must have as its objective not only protection of the healthy but also care of the ill. there has been little judicial challenge in british courts of the exercise of emergency powers. in relation to the english emergency powers act and the emergency powers (defence) act, the courts have played a minimal role, striking down only a handful of emergency measures as ultra vires, usually well after the emergency. more recently, in a case where the british parliament had sanctioned the indefinite detention of any person not a british citizen and certified as a 'suspected terrorist', and where the government had derogated from both the european convention and the international covenant on civil and political rights (iccpr) on the grounds that there was a 'public emergency', the house of lords rejected the government's assertion that the derogation was consistent with the european convention. although the majority of judges declined to question whether there was a public emergency on the grounds that the existence of such an emergency was largely a matter for the government to determine, they concluded that imprisonment of non-citizens alone was neither proportional, given the equal threat from citizens, nor necessary, and questioned the irrationality of singling out a minority (non-citizens) for special burdens, when members of the majority could present an equal risk. lord hoffmann was prepared to consider the notion of an emergency and he found it to be a threat to the 'organised life of the community', which would include not merely a threat to the physical safety of the nation, but also to its fundamental values: 'the real threat to the life of the nation, in the sense of a people living in accordance with its traditional laws and political values, comes not from terrorism but from laws such as these.' the decision suggests a judicial role in overseeing government powers in emergencies. the concept of a 'public emergency' is considered under article of the european convention for the protection of human rights and fundamental freedoms as 'a situation of exceptional and imminent danger or crisis affecting the general public, as distinct from particular groups, and constituting a threat to the organised life of the community which composes the state in question.' o article allows that states might derogate from some of their obligations under the convention 'in time of war or other public emergency threatening the life of the nation', but not from article (right to life) or article (prohibition of torture and inhuman or degrading treatment). the former european commission of human rights, which in defined a public emergency to consist of a 'threat to the organised life of the community', was called upon to determine the criteria of a public emergency threatening the life of the nation in a case in which the greek government sought to justify derogation of rights on grounds of a public emergency. the commission held that the emergency must be actual or imminent; it must affect the whole nation; the continuance of the organised life of the community must be threatened; and the crisis or danger must be exceptional, in that the normal exceptions permitted by the convention for the maintenance of public safety, health and order are inadequate. derogations may only last for as long as, and only be exercised to the extent required by, the demands of the circumstances. they must not limit the subject's rights of access to court protected in article of the convention, nor the right of a remedy protected in article . in circumstances where a state wishes to exercise emergency powers which might contravene human rights, the state is required to make a formal derogation under article of the european convention indicating the rights and the territory to which the derogation applies, and to keep the secretary general of the council of europe informed of the measures taken, the justifications, and the cessation of operation of emergency powers. similar requirements can be found in the iccpr. if european states are to abide by their commitments under the convention, it seems that use of emergency powers will be subject to human rights examination. states will not then be able to exercise their powers in an arbitrary way, and will not be able to respond in a manner that is not proportional to the risk. despite these safeguards, the use of emergency powers legislation for serious ongoing disease outbreaks is questionable. an influenza epidemic could, on a worst case scenario, last for years, which would potentially allow the operation of emergency powers that derogate from human rights protections for a considerable period of time. there is a danger that laws made in the form of emergency regulations might, if in force for long enough, become embedded in the legal system and so constitute a permanent assault on liberties which had previously been achieved, as might be suggested of terrorism legislation in the uk. emergency powers in the context of disease, based as they are on responses to war and catastrophes, tend to operate in such a way that persons affected with disease are characterized as the enemy. they propose that in public health emergencies, there must be a trade-off between the protection of civil rights and effective public health interventions. however, the ideals of democracy, individual rights, legitimacy, accountability and the rule of law suggest that even in times of acute danger, government should be limited in the activities that it can pursue and the powers that it can exercise. as gostin points out in the context of the us model state emergency health powers act, this is not to say that individual rights should always trump public health, but that individual rights should never be infringed 'unnecessarily, arbitrarily or brutally'. nevertheless, there has been significant criticism of the us legislation, and concern that measures proposed in the act are sufficiently dangerous as to 'undermine.constitutional values'. while emergency powers might provide short-term solutions to serious threats, they could also do long-term harm to public trust in public health services, and encourage health behaviours which are counterproductive to the public health. in many countries, including the usa, there are signs that public health and national security are increasingly conflated. the ihr are framed around the assumption that disease is a security issue. however, the danger of subsuming disease control within foreign and national security is that the focus is on security rather than on health. wider national and international interests may not always coincide with public health. global public health may not always coincide with the security concerns of individual states, particularly more powerful states. mcinnes and lee note that policy responses to the sars epidemic elicited a 'garrison mentality' whereby strict border controls and control of movement of persons became central to disease containment, with consequences for the movement of persons, goods and services. it has been widely argued that the promotion and protection of human rights is inextricably linked to the promotion and protection of public health, and that lack of respect for the rights and dignity of persons or groups of persons can increase their vulnerability to disease contagion. , the importance of human rights to health has been acknowledged in the revised ihr article , which requires that the ihr be implemented with full respect for the dignity, human rights and fundamental freedoms of persons. as mann argues, '.the human rights framework is indispensable both for analyzing the central societal issues which must be confronted and for guiding the direction of societal transformation needed to promote and protect health.' states have a significant number of non-medical tools at their disposal in a disease pandemic, and public health law reform has been undertaken with pandemic influenza in mind. public health legislation around the world now authorizes a wide range of social distancing powers and compulsory screening, examination and treatment measures. in addition, much public health legislation provides for the possibility of some limited emergency measures. nevertheless, some european states have proposed the use of emergency powers legislation to provide exceptional powers in the case of a pandemic; powers which will inevitably constrain the rights of individuals. the evidence base for the need for such exceptional powers has yet to be established, and in the absence of such evidence, there is concern that too heavy a hand will result in long-term harm to public trust in the exercise of population-based disease prevention strategies. early responses to public health threats as reflected in th century public health legislation were premised on building fortresses to protect the healthy (and generally wealthy) from those suffering from disease, rather than on care and protection of the population. public health legal powers tend to focus on containment and exclusion, representing 'the community response to social and economic pressures and the wide spread fear of death and disease' rather than on positive public health outcomes. immigrant populations have long been targeted as carriers of disease, and in relation to diseases such as drug-resistant tuberculosis, increasing incidence in the western world is often attributed to persons entering from states with high tuberculosis rates. much contemporary public health policy has rejected the 'fortress' approach to disease control in favour of seeing the public health mandate as imposing duties upon all members of a society or population, or indeed duties of global health protection. the evidence base for border control as a public health, as distinct from a security, measure is limited, especially in a pandemic. in relation to other diseases such as hiv and tuberculosis, border screening has proved to be unreliable and has shown little benefit for the health of the population. compulsory border screening and refusal of entry to affected persons are contemplated by many states in their pandemic influenza preparedness plans, p and the revised ihr contemplate that who might recommend refusal of entry of suspect and affected persons and refusal of entry of unaffected persons to affected areas, subject to the ethical consideration of respect, to the extent possible, for the individual right to freedom of movement. article of the ihr requires all signatory states to establish points of entry with surveillance and border control capacities. a consequence of having no internal eu borders is that the eu needs a strong common external border. under the eu free p for example, bulgaria, denmark, greece and latvia. movement directive, member states may deny entry of eu citizens and their family members if they are considered to be a threat to public health, but only if this is proportionate and meets strict material and procedural safeguards. most eu member states q have signed the schengen convention, eliminating border controls between participating countries and creating an external frontier. the convention called for a common visa policy, harmonization of policies to deter illegal migration, and an automated schengen information system to coordinate actions in relation to individuals who had been denied entry. the amsterdam treaty incorporated the schengen convention into eu treaties, and set out a plan to integrate policies on visas, asylum, immigration and external border controls into community procedures and into the community legal framework. this has resulted in what is for all intents and purposes an eu external border, with much social and economic activity operating at regional rather than national level. however opt-out r and opt-in s possibilities make it difficult to define an administrative space that falls within the frontier, and there is no overarching political control. rather, decisions are made by means of a complexity of intergovernmental and supranational institutions, and there remains considerable sovereign power in relation to many issues of border and public health relevance. the schengen agreement includes consent to share information about people, via the schengen information system. this means that a person cannot 'disappear' simply by moving from one participant country to another. a country is permitted by article . of the schengen agreement to reinstate border controls for a short period if it is deemed to be in the interest of national security. any schengen country can impose temporary or permanent border controls if it believes itself to be unprotected by other members. under this provision, portugal restricted border entry during the european football championship, as did france for the ceremonies marking the th anniversary of d-day, and again shortly after the london terrorism bombings of july . with foot-and-mouth disease having been confirmed in france, the netherlands and britain, norway, in particular, put its border officers on high alert to prevent spread of the disease into the country. other nordic countries have also increased spot checks on entries into the region, irrespective of their new borderless status, in an attempt to contain foot-and-mouth disease. under the schengen borders code, third-country nationals may be refused entry if considered a threat to public health. one issue that arises from the lack of border controls within europe is the disparity in levels of disease preparedness across europe. in , new member states joined the eu, eight of which are former communist countries in central and eastern europe (slovenia, hungary, czech republic, poland, lithuania, latvia and estonia). these states are characterized by a history of underfunding of health and surveillance systems, unreliability of access to drugs, continuing increase in diseases such as drug-resistant tuberculosis and hiv/acquired immunodeficiency syndrome, and inadequate public health responses to disease. since these states have entered into the eu, citizens can cross borders into other, better-resourced states. in the context of a pandemic, this could mean an influx of persons who are possible disease carriers from poor states with a frail public health system and with insufficient medicines, to other eu states, putting citizens at risk and draining health resources in those states. this creates difficult choices for host countries in terms of the assistance they offer. should they fail to offer healthcare services to mobile populations, these populations will put state population health at risk. should they offer healthcare services to mobile populations, this will strain resources and drain services from home populations. in their comparative study of european national preparedness plans, mounier-jack and coker found that eu states intended to take at least one measure to restrict travel to and from the state during a pandemic, and of these states recommended border restrictions on entry and departure. one state proposed drafting new laws to give stronger border control powers. other states, however, conceded that by phase of a pandemic, while there might be political grounds for restrictions on travel, there would be little public health benefit. the possibility of border closure was an issue examined in exercise common ground, a pandemic influenza exercise for the european union, conducted by the uk's health protection agency over a -day period in november . this was the second of two eu exercises commissioned by the ec to evaluate the ability and capabilities of member states to respond to a health-related crisis, in this case an influenza pandemic. concern was expressed when switzerland indicated that it might consider the closure of its borders, given the location of drug manufacturers in switzerland. france's border closure proposals contained exceptions for pharmaceutical and vaccine materials and workers. the feasibility of instituting border controls within europe in a pandemic was then examined at an eu pandemic influenza workshop in august . it was concluded that while border closure might be a useful early containment strategy, at a pandemic stage, it would be impractical to enforce border controls within europe because of the porous nature of european borders and because of the need for cross-border traffic of goods. any prolonged border control would disrupt critical supply chains, and there was a risk that the consequent disruption of border controls within europe would result in greater harm than benefit. screening at borders for diseases such as tuberculosis and hiv is common practice in many states, but has been much criticized on grounds of evidence and ethics. a systematic review looking at the effectiveness of physical interventions such as screening in relation to respiratory viruses concluded that '(g)lobal and highly resource intensive measures such as screening at entry ports.lacked proper evaluation'. there is also limited evidence regarding the efficacy of screening international passengers on departure or arrival in a flu pandemic, except possibly in the early phase. while control and screening measures may have worked in the days of slow travel, it is now the case that travel times are likely to be shorter than incubation periods, such that port screening will be ineffective in disease identification. nevertheless, the mounier-jack and coker study found that eight eu states proposed entry screening in their pandemic preparedness plans. some european states indicated in exercise common ground that they intend to undertake border screening regardless of the evidence base, on the grounds that such measures provide reassurance to the public, and because the surveillance information might prove useful. the ihr authorize states to require information from travellers about their travels, and to undertake a non-invasive medical examination which is the least intrusive to achieve the public health objective. entry may be refused where the traveller refuses to co-operate. article of the ihr provides that invasive medical examination, t vaccination or other prophylaxis shall not be required as a condition of entry except in limited circumstances, such as to determine whether a public health risk exists, or in relation to persons seeking temporary or permanent residence. in these circumstances, if a traveller refuses to comply, entry may be refused or be made subject to the least invasive procedure to achieve the public health objective. article stipulates that such measures be undertaken within the confines of express informed consent and national and international safety guidelines, and article requires that in implementing measures, travellers are to be treated with dignity and respect, and with recognition of gender, sociocultural, ethnic or religious concerns. within the eu, border measures are a matter of community competence that require state co-ordination. where eu member states intend to adopt border measures for the control of communicable diseases, they must inform and, where possible, consult other member states and the commission in advance. the exercise common ground report and the eu pandemic influenza workshop concluded that there was variability in the extent to which member states, european economic area states (including all eu countries plus iceland, norway and liechtenstein) and switzerland have included an international dimension in their pandemic influenza plans. rather, they have focused on national, domestic issues. it is necessary to consider an international dimension because: 'in a community like the eu, free of internal borders and with many common activities and free movement of people and goods, any countermeasures taken in one member state will be bound to affect at least some if not all, other member states'. the reports noted that states also needed to address issues surrounding expatriates, travel restrictions, restriction of emigration, issues of contact persons and the potential for social disorder. there was a lack of clarity around community law on implementation of travel restrictions, and some confusion regarding the extent to which issues of freedom of mobility needed to be handled differently according to an individual's nationality. to be practical and costeffective, border measures would require policy coordination between countries of arrival and departure, and consensus between neighbouring states to avoid disruption. however, as mounier-jack and coker note, few countries address the issue of collaboration with neighbouring states on matters of travel restrictions in their plans: ' there is clearly a need for countries within a european region to be informed and to inform others of their respective strategies in order to ensure that policies are consistent where necessary, or pose as few challenges as possible to public health protection where differences or inconsistencies exist. there may also be a need to ensure that european response mechanisms work together in harmony if public health interventions are to be similar in different countries'. national generic plans in europe have addressed issues of border control rather inadequately. questions have been raised about mobile populations and their implications for healthcare resources, but the issues remain unresolved. there appears to be political reluctance in the context of a united europe to invoke exemptions from internal market rules of free movement of goods and persons on grounds that neighbouring states are failing to address public health threats, and while there is concern about the consequent risk to populations, most states have taken the pragmatic view that any border control should take place at europe's external borders and not within europe. the variation in public health resources and in public health legal powers across eu states, in a context of free borders, is a concern for europe-wide pandemic disease strategies. it is not impossible that states with the strongest national public health powers, which permit, for example, compulsory vaccination or detention, will find some citizens moving states to avoid imposition of these powers. ideally, states within the eu will work together to achieve some commonality of pandemic disease policy and some commonality in their public health legal frameworks. much has been done to develop common policy approaches to preparation for an influenza pandemic across europe. however, article of the european treaty, which states the eu objective of a high level of health protection and requires the european community to work with nation states to deal with health threats, does not allow for a policy of harmonization of state laws. the most that can be hoped for is some convergence of legal powers resulting from discussion and negotiation between states. the differing histories, politics, culture and legal systems of this group of highly divergent states does not bode well for agreement across europe on the appropriate legal response to disease threats. in an attempt to identify the extent to which there is variation in public health legal powers and the consequences of such variation for public health in europe, the phlawflu project is examining the role of national laws in the control of and protection against pandemic human influenza across europe. the objective of the project is to provide an evolving critical study of national laws supporting and constraining defined issues of communicable disease control across europe, and to provide a resource to support public health law reform and public health policy making in europe. the project methodology includes workshops bringing together public health policy makers from european states to examine legal responses to disease scenarios. it is to be hoped that some common legal responses emerge from these exercises, and given the absence of attention paid to public health laws in europe in recent years, that much can be learned by all states on ways in which to use law as a tool in pandemic disease control. meanwhile, europe is in a complex place in relation to its public health approach to pandemic disease. in times of economic strength and freedom from threats of war and disease, the commonality of eu states comes to the fore, and states are ready and willing to engage in joint enterprise. where states are at threat, however, they tend to turn inward on themselves, and political and cultural differences emerge. in times of threat, states which have traditionally been strong on public intervention in private rights are unwilling to accede to the approaches of more liberal states. traditionally, liberal states are reluctant to impose draconian measures, but at the same time may be unwilling to carry the public health burden of citizens from poorer states. the revised ihr have done much to focus public health law reform measures and to ensure some minimum commonality of content, but it is clear that some states, in accordance with their legal culture, are prepared to undertake more intrusive interventions than others. for all these concerns, it is clear that public health laws will be a mainstay of pandemic disease strategies, both in relation to the eu and in relation to nation states within europe. public health laws will be essential in providing powers to enable actions to be taken to control disease spread, but also to constrain states from taking actions that might reassure short-term security concerns but that have potentially harmful long-term public health consequences. of course, such issues are not unique to europe, but the nature of europe as a continent and as a legal entity creates particular complications for the ways in which law might best be used to create a coordinated european pandemic disease strategy. one unexpected benefit of the pandemic threat has been the renewed interest in exploring the role of law as a communicable disease tool, and in the examination of the range of public health legal approaches across europe. globally, a greater understanding of the role of public health law as a tool for managing and minimizing the spread of communicable disease will be a lasting and invaluable legacy of governance efforts in relation to pandemic influenza. none sought. none declared. european centre for disease prevention and control. technical report: pandemic influenza preparedness in the eu. status report as of autumn european public health law network website. available at: 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across the eu. london: department of health workshops and facilitated by dr miguel betancourt cravioto and dr daniel reynders physical interventions to interrupt or reduce the spread of respiratory diseases: a systematic review specifications attached to the invitation to tender document, sanco/c / / , quoted in health protection agency, exercise common ground, a pandemic influenza exercise for the european union, final report. london: health protection agency none declared. key: cord- -hpyywul authors: thaler, m.; khosravi, ismail; hirschmann, m. t.; kort, n. p.; zagra, l.; epinette, j. a.; liebensteiner, m. c. title: disruption of joint arthroplasty services in europe during the covid- pandemic: an online survey within the european hip society (ehs) and the european knee associates (eka) date: - - journal: knee surg sports traumatol arthrosc doi: . /s - - - sha: doc_id: cord_uid: hpyywul purpose: the aim of the present study was to evaluate the impact of the coronavirus (covid- ) pandemic on joint arthroplasty service in europe by conducting an online survey of arthroplasty surgeons. methods: the survey was conducted in the european hip society (ehs) and the european knee associates (eka). the survey consisted of questions (single, multiple choice, ranked). four topics were addressed: ( ) origin and surgical experience of the participant (four questions); ( ) potential disruption of arthroplasty surgeries ( questions); ( ) influence of the covid- pandemic on the particular arthroplasty surgeon (four questions); ( ) a matrix provided different arthroplasty surgeries and the participant was asked to state whether dedicated surgery was stopped, delayed or cancelled. results: two-hundred and seventy-two surgeons ( ehs, eka) from different countries participated. of the respondents, . % stated that all surgeries were cancelled in their departments, while . % responded that elective inpatient procedures were no longer being performed. with regard to the specific surgical procedures, nearly all primary tja were cancelled ( . %) as well as aseptic revisions ( . %). in most hospitals, periprosthetic fractures ( . %), hip arthroplasty for femoral neck fractures and septic revisions for acute infections ( . %) were still being performed. conclusion: during the current covid- pandemic, we are experiencing a near-total shutdown of tja. a massive cutback was observed for primary tja and revision tja, even in massively failed tja with collapse, dislocation, component failure or imminent dislocation. only life-threatening pathologies like periprosthetic fractures and acute septic tja are currently undergoing surgical treatment. level of evidence: v. electronic supplementary material: the online version of this article ( . /s - - - ) contains supplementary material, which is available to authorized users. the public health disruption in europe caused by the coronavirus disease (covid- ) pandemic has resulted in a significant reallocation of health care resources with the focus on the management of covid patients [ ] . has rapidly become a global public health threat, endangering the health and well-being of all people, but especially vulnerable older populations [ ] . the pandemic is also causing social disruption, exceptional healthcare utilization, and economic instability worldwide. the organisation for economic co-operation and development (oecd) recently reported that for each month of containment, there is a loss of percentage points in annual gdp (growth domestic product) growth. oecd further stated that the tourism sector alone is facing a decrease up to % [ ] . controlling the spread of covid- has become the singular focus of most countries in europe, with unprecedented international collaboration and rapid dissemination of emerging scientific evidence. until now, most publications have described demographic characteristics, clinical symptoms, biological behaviour, and radiological or pathological findings associated with covid- [ ] . pandemics like the covid- disease or the spanish flu have wrought massive changes in patient care [ ] . most healthcare resources as well as medical staff are needed to take care of covid- infections. hence, it can be presumed that joint arthroplasty service has substantially declined over recent weeks throughout europe [ ] . asian orthopaedic surgeons based on the lessons learned from sars in postponed or cancelled all elective surgeries requiring > h of hospitalization which predominantly affected joint arthroplasty [ ] . it is well known from other medical disciplines that a reduction in major organ transplantation (> %) as well as a significant reduction in colorectal surgery, and concerns about urology patients, especially in those with a malignant tumour, have already been reported during the covid- pandemic [ , , ] . over the last decades, total joint arthroplasty (tja) has grown rapidly and proved its added value for the benefit of nationwide healthcare and patients [ ] . the outbreak of covid- in europe has potentially influenced the frequency of elective surgeries, like primary and revision arthroplasty. the members of the european hip society (ehs) and the european knee associates (eka) are predominantly arthroplasty surgeons and a cohort with great expertise in arthroplasty. consequently, we surveyed the members of the ehs and the eka regarding the covid- pandemic and its influence on their work. the aim of the present study was to evaluate the impact of the covid- pandemic on joint arthroplasty service in europe by means of an online survey of arthroplasty surgeons in the ehs and the eka. a prospective online survey of the members of two european orthopaedic societies was performed: ehs and eka. the ehs, consisting of members ( of them are european full members), was founded in , and its aim is "to provide a forum for the discussion of research, advances in clinical practice and the results of predominantly surgical procedures of all types relating to the hip joint" (art. a ehs constitution) and a special focus is on hip replacement. the european knee associates (eka) is a section of the european society of sports traumatology, knee surgery and arthroscopy (esska). within esska, the eka is an association particularly dealing with the management of degenerative diseases of the knee joint. consequently, its members focus on knee arthroplasty and osteotomy around the knee. the eka currently has members. no approval was obtained from an institutional review board, because the survey was anonymous and no patient data were included. data were collected using survey-monkey (https ://www.surve ymonk ey.com): an online data collection program. the survey consisted of questions (single/multiple choice and ranked questions) and was conducted from march , , to april , (see online appendix for survey details). four main topics were addressed: ( ) origin and surgical experience of the participant (four questions); ( ) potential disruption of arthroplasty surgeries ( questions); ( ) influence of the pandemic on the particular arthroplasty surgeon (four questions); ( ) a matrix provided different arthroplasty surgeries and the participant was asked to state whether the dedicated surgery was stopped, delayed or cancelled at her or his department. a link to the above-mentioned survey was sent to the members of both societies via email and society's newsletter. all data gathered from the online database were calculated as frequencies and percentages. a total of surgeons ( ehs, eka) participated in the present survey. the participating surgeons were on average years (min: year, max: years) in practice. the majority worked at an academic centre ( . %) and a private hospital ( . %), while . % worked in a public hospital. arthroplasty surgeons from different countries responded. the majority lived in italy ( . %), germany ( . %) and france ( . %). . % had received a specific covid- training. of the respondents . % stated that all surgeries were cancelled in their departments, while . % responded that elective inpatient procedures were no longer being performed, and % reported that all outpatient procedures were cancelled. elective inpatient and outpatient surgery was also restricted, namely to . % and . %, respectively. only . % of the respondents reported no changes at their department. on a four-level scale of escalation, . % stated that they are at the last stage, treating only life-threatening diseases (fig. ). only . % of the participants stated that they were still doing primary tja (table ; fig. ). regarding routine aseptic revisions, only . % of the participants reported that they were still performing such procedures. in most hospitals, periprosthetic fractures ( . %), total hip arthroplasty/ hemiarthroplasty for femoral neck fractures and septic revisions for acute infections ( . %) were still being performed. second-stage revisions with re-implantation of the implants were being performed by . % of the respondents. . % of the participants reported that massively failed tja (collapse, the vast majority ( . %) of arthroplasty surgeons stated that their personal surgical volume was drastically reduced, a delay in surgeries was reported by . %, training or teaching of students, residents and fellows was stopped for . % of the surgeons and more conservative clinical care was being performed by . % of the respondents. of the arthroplasty surgeons, . % were performing more administrative work than usual, . % were even allocated to nonorthopaedic duties and % stated that they were effectively not working due to institutional or self-imposed deferral of elective surgery. regarding post-operative follow-up, . % stated that they were following only high-risk patients after tja. of the surgeons, . % and . % reported that they were still doing normal clinical and radiologic follow-ups, respectively (fig. ) . rehabilitation and physical therapy after tja were available for selected cases ( . %), for inpatient patients ( . %), for outpatient patients ( . %), and no physical therapy or rehabilitation after tja was reported in . % of cases. of the surgeons, . % stated that they tried to keep a distance to their families, . % reported that they avoided physical contact with their families and . % performed surface disinfection at home. likewise, . % lived in separate rooms at home, . % stated that they do not even go home anymore, and . % were on vacancy during the pandemic. the majority of respondents knew either patients and/or hospital staff with a positive covid- test. findings of the survey in more detail are provided in tables , the most important finding of the present study was the massive cutback in primary as well as revision tja service in europe during the covid- pandemic. primary tja was reported by only . % of survey participants as still being carried out. . % of the participants stated that they were still performing aseptic tja revisions and . % communicated that they were doing tja reimplantation after previous removal of septic implants ( nd stage). in addition, postoperative follow-up visits and rehabilitation were also reported to be drastically impaired (fig. ) . these type of approach both by the health and hospital authorities and the orthopaedic surgeons has several undoubtable reasons: save resources for covid- patients (medical and nurse staff, hospital beds, intensive care units, economical resources), to reduce the risks of contamination (of the staff, of the patients of the whole community) in an "open environment" such as the hospitals which are difficult to be controlled, to avoid contamination of fragile patients that are the majority of tja patients especially in the post-operative time, to guarantee a safe and effective rehabilitation time. when comparing our findings with those of other studies, it appears that the literature on that subject is scarce. liebensteiner et al. questioned surgeons from germany, switzerland and austria on a broad range of orthopaedic procedures [ ] . only % and % of their participants stated that they were still able to offer arthroscopic procedures, depending on the joint and procedure. liebensteiner et al. found that % of the participating surgeons were still able to offer anterior cruciate ligament reconstructions, and % of the participants reported that rotator cuff repair was no longer being performed. hardly any participants (< %) reported that even femoral fractures or sarcoma patients were postponed. in addition, similar to our findings, those authors reported drastic disruptions in postoperative follow-ups and rehabilitation facilities. in summary, the findings of that study are in good agreement with those of the current study. some publications reported similar scenarios in other surgical disciplines. angelico et al. showed that major organ transplantation was reduced by % in recent weeks due to the lack of intensive care beds [ ] . our results also show that intensive care units as well as intermediate care units are the bottleneck during the covid- pandemic (table ) . hence, one can assume that this consequently leads to a to months to months months to months more than months reduction in revision arthroplasty procedures, even when a patient has a massively failed tja. reduction of surgical volume was also reported for urology and colorectal surgeries [ , ] . our results show a massive reduction in outpatient activities. a similar scenario was shown for urology patients [ ] . during the study period, the coronavirus disease (covid- ) pandemic was evolving rapidly in europe, widely disrupting the personal, social, economic and professional life of healthcare workers. the overall goal of most governments in europe was to "flatten the curve" of new covid cases and to avoid a collapse of the national healthcare systems [ ] . at the close of the survey, there were , confirmed covid- cases in europe with , fatalities [ ] . affected by the catastrophic consequences of the pandemic, orthopaedic healthcare was substantially cut back on the whole continent. this drastic disruption has had a massive impact on tja, which is currently the international standard of care for surgical treatment of degenerative and rheumatologic joint diseases, as well as for certain fractures adjacent to the joint, like femoral neck fractures [ ] . postponing tja in patients with high-stage osteoarthritis leads to more opioid use and poorer overall outcome regarding revision rate and readmission rate after tja [ ] . however, at least life-threatening pathologies such as periprosthetic fractures and first-stage revisions of acute infected tja can still be treated appropriately even in the present difficult scenario. more than . million total hip arthroplasties and . million total knee arthroplasties are performed every year in europe [ , ] to increase quality of life and improve the mobility of patients to enhance their life expectancy. hence, the described cutback in arthroplasty services also has severe economic consequences for implant companies and their employees, as well as the families of the employees. tja outcome is outstanding, and total hip arthroplasty has been named by several reports as "the operation of the century" [ ] . in europe, more than national joint registries with over years of experience are monitoring the life expectancy of implants and are responsible for quality assessment and management in tja [ ] . the beneficial impact of tja regarding mobility, social life, work capability, prevention of cardiovascular diseases, general health, patient satisfaction, decreasing pain and increasing joint function, especially in elderly persons, but nowadays in young active people as well, is undisputed. hence, if access to tja is restricted, the direct and indirect costs to a nation's society are enormous, because of early retirement, inability to work, direct costs to the healthcare systems caused by the immobility of people and indirect costs to the healthcare system, like employment status, earnings, time missed from work (or absenteeism), and disability payments [ ] . there is no doubt that the covid- outbreak in europe influences our daily behaviour and prevention strategies [ ] . as mentioned in our results, also most arthroplasty surgeons have contact with infected patients or infected hospital staff. consequently, they change their attitude towards their families to prevent them from becoming infected with the disease. these lifestyle modifications range from affordable changes like washing and disinfecting the hands more often ( . %) to significant changes like avoiding close physical contact with their families ( . %), staying away from home ( . %) or staying in a separate room at home ( . %). the study has some limitations. first, the expert opinion of the members of two societies was evaluated jointly in one study. however, both societies consist of predominantly arthroplasty experts and opinion leaders. second, the respondents came from various countries that maintain different strategies toward the pandemic and that were at different levels of severity of the pandemic at the moment of the survey. the covid- pandemic has currently triggered a neartotal shutdown of arthroplasty surgeries in europe. a massive cutback was observed for primary tja and revision tja, even in massively failed tja with collapse, dislocation, component failure or imminent dislocation. out of trauma cases and malignancy, only life-threatening pathologies like periprosthetic fractures and acute septic tja are currently being treated surgically. author contributions mt was responsible for data collection and manuscript writing. ik wrote the survey, helped during writing of the manuscript by providing results, figures and table. mth performed a revision of the manuscript. mcl, npk, jae and lz were responsible for the data collection and also reviewing the manuscript. mt provided the concept of the study and developed the survey. all authors read and approved the final manuscript. funding none. conflict of interest the authors declare that they have no competing interest. informed consent not applicable. flattening the curve for incarcerated populations-covid- in jails and prisons the covid- outbreak in italy: initial implications for organ transplantation programs novel coronavirus and orthopaedic surgery: early experiences from singapore covid- pandemic-is virtual urology clinic the answer to keeping the cancer pathway moving? disruption of arthroplasty practice in an orthopaedic center in northern italy during covid- pandemic secretary general angel gurría's statement for the g videoconference summit on covid- international survey of primary and revision total knee replacement the operation of the century: total hip replacement massive cutback in orthopaedic healthcare services due to the covid- pandemic: an online survey of almost orthopaedic surgeons in austria the possible impact of covid- on colorectal surgery in italy mapping existing hip and knee replacement registries in europe what are the costs of hip osteoarthritis in the year prior to a total hip arthroplasty? implications of covid- for patients with pre-existing digestive diseases the direct and indirect costs to society of treatment for end-stage knee osteoarthritis the outbreak of covid- coronavirus and its impact on global mental health covid- : a potential public health problem for homeless populations novel coronavirus covid- : current evidence and evolving strategies who ( ) who coronavirus situation report- dynamic modelling of costs and health consequences of school closure during an influenza pandemic key: cord- -a u e o authors: nadeau, s. a.; vaughan, t. g.; scire, j.; huisman, j. s.; stadler, t. title: the origin and early spread of sars-cov- in europe date: - - journal: nan doi: . / . . . sha: doc_id: cord_uid: a u e o the investigation of migratory patterns of the sars-cov- pandemic before border closures in europe is a crucial first step towards an in-depth evaluation of border closure policies. here we analyze viral genome sequences using a phylodynamic model with geographic structure to estimate the origin and spread of sars-cov- in europe prior to border closures. based on sars-cov- genomes, we reconstruct a partial transmission tree of the early pandemic, including inferences of the geographic location of ancestral lineages and the number of migration events into and between european regions. we find that the predominant lineage spreading in europe has a most recent common ancestor in italy and was probably seeded by a transmission event in either hubei or germany. we do not find evidence for preferential migration paths from hubei into different european regions or from each european region to the others. sustained local transmission is first evident in italy and then shortly thereafter in the other european regions considered. before the first border closures in europe, we estimate that the rate of occurrence of new cases from within-country transmission was within the bounds of the estimated rate of new cases from migration. in summary, our analysis offers a view on the early state of the epidemic in europe and on migration patterns of the virus before border closures. this information will enable further study of the necessity and timeliness of border closures. in response to the pandemic potential of the sars-cov- virus, many nations closed their borders in order to curb the virus' spread ( ). these closures continue to incur high economic and social costs. to weigh the relative costs and benefits of border closures, it will be important to understand the efficacy of these policies. at the early stages of an outbreak, border closures can delay a pathogen's arrival, thereby giving countries additional time to prepare ( ). however, the success of this strategy depends on timely implementation and a good knowledge of where the pathogen is already circulating. to evaluate the efficacy of border closures in limiting the spread of sars-cov- , it is important to reconstruct the timeline of the early international spread of the virus, before such policies were implemented. in this analysis, we aim to estimate the early patterns of sars-cov- transmission into and across europe. we also address the more specific question of where the predominant sars-cov- lineage circulating in europe originated. we hope that by addressing these questions we can inform further analysis of the efficacy of border closures as a strategy to combat sars-cov- . the sars-cov- virus was identified as the cause of an epidemic in wuhan, china in late ( ) . the epidemic in wuhan was reported to the who on dec. and within one month, sars-cov- was confirmed to have spread to additional countries ( ) . by the end of february , the virus was detected in all who regions ( ) . currently, several lineages of the sars-cov- virus are circulating across the globe. the intermixing of these lineages in different countries and regions suggests that the virus has been transmitted across borders many times ( ) . here we focus on estimating the early introductions of sars-cov- into europe and the virus' migration across european borders. through national surveillance efforts, the first covid- cases in europe were detected in france on jan. and in germany on jan. ( , ) . of the cases detected in europe by feb. , were infected in china, were linked to the initial cases in germany, were linked to the initial cases in france, and were of unknown origin ( ) . in addition to the unknown sources of transmission, some early introductions may not have been detected. this is especially probable given that a significant proportion of infected individuals are likely to be asymptomatic ( ) . in summary, it is difficult to draw firm conclusions about the source, number, and timing of sars-cov- introductions into europe based on confirmed case data alone. viral genomes are an important secondary source of information on outbreak dynamics. if viruses acquire mutations on the same timescale as an outbreak, these mutations can provide information about past transmission events. phylodynamic methods couple a model of viral evolution describing the mutational process to an epidemiological model describing the transmission process. by fitting the combined model to viral genomes sampled from a cohort of infected individuals, we can infer the evolutionary and epidemiological model parameters. here we fit a phylodynamic model with geographic structure to sars-cov- genomes from hubei, china and several european countries before the first borders were closed in these regions. we co-infer the transmission tree linking these sequences, the geographic location of ancestral lineages, migration rates of infected individuals between regions, the effective reproductive number, and the proportion of no-longer infectious cases sequenced in each region. in addition to these inferences, we specifically focus on estimating the geographic origin of the predominant sars-cov- lineage in europe. this lineage is defined by a characteristic amino acid substitution at position in the orf b gene from proline to leucine and was provisionally named the "a a" lineage by the nextstrain team. in the more dynamic, tree-based nomenclature suggested by ( ) , this lineage corresponds to the "b. " lineage described as "a large lineage that roughly corresponds to the large outbreak in italy, and has since seeded many different countries" ( ) . as of apr. , , two-thirds of the sars-cov- sequences collected in europe belonged to this lineage and just % of sequences from the lineage were collected outside europe (data from ( ) , lineages assigned using ( ) ). here, we use the name a a to refer to the group of sars-cov- viruses defined by the orf b:p l mutation. where the a a lineage originated remains unclear. its characteristic orf b mutation was found in some of the earliest confirmed covid- cases in italy, switzerland, germany, finland, mexico, and brazil in late february ( , ) . intriguingly, a late-january sample from a german case linked to all rights reserved. no reuse allowed without permission. (which was not certified by peer review) 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 business travel from singapore shares a mutation in the s gene with the a a lineage, but does not have the lineage-defining orf b mutation. this german sample is part of a smaller "a " clade that is basal to the larger clade of a a sequences ( ) . as a result, it was hypothesized that a german transmission cluster may have seeded the larger european outbreak ( ) ( ) ( ) . however, it was quickly pointed out that incomplete and biased sampling must be taken into account before this hypothesis can be rigorously addressed ( , , ) . phylodynamic models with geographic structure aim to account for such biases. firstly, parameter estimates are generated by integrating over a distribution of potential phylogenies, which acknowledges that we cannot reconstruct the true transmission tree with certainty. secondly, sampling parameters are allowed to differ between regions, which acknowledges that testing and sequencing resources vary across regions. here, we fit a phylodynamic model with geographic structure to full-length sars-cov- genomes to (i) estimate the early patterns of sars-cov- spread into and across europe, (ii) weigh genomic evidence for competing hypotheses about the geographic origin of the predominant a a lineage in europe, (iii) report on the epidemiological parameters, and (iv) compare the rate of new cases arising from within-region transmission versus migration during the early epidemic. we fit a simplified version of the multi-type birth-death model described in ( ) . under this model, beginning with a single infected host in a single geographic region (deme), the virus can be transmitted from one host to another (a birth event), die out due to host recovery or death (a death event), be sequenced (a sampling event, assumed to correspond to a death event), or migrate from one deme to another (a migration event). the birth, death, sampling, and migration processes are assumed to occur at deme-specific rates that are constant through time. importantly, this model aims to capture heterogeneity in epidemiological parameters (birth and death rates) and sequencing effort (sampling proportion) among demes. we used a version of the model parameterized in terms of the effective reproductive number, which allows us to additionally infer this epidemiologically relevant quantity for each deme. we analyzed sars-cov- genome sequences from five different demes: hubei province in china, france, germany, italy, and a composite deme of other european countries ("other european"). all sequences were accessed from gisaid ( ) . to represent the pandemic origin, we randomly chose sequences from hubei collected on or before the lockdown of wuhan city on jan. . to investigate the earliest outbreaks in europe, we considered all available sequences collected in france, germany, and italy on or before the lockdown of the lombardy region of italy on mar. . these countries had the first detected (france and germany) and the largest (italy) early outbreaks in europe ( , ) . by limiting sampling to before regional lockdowns and border closures went into effect, we hope to (i) satisfy model assumptions that epidemiological and migration parameters are constant through time, and (ii) get a picture of the early, unimpeded spread of sars-cov- within europe. to represent the pool of sars-cov- circulating in other european countries during this time, we down-sampled sequences from other countries to the cumulative number of confirmed covid- deaths in each country by mar. plus one (table s ). we used this quantity as a proxy value roughly proportional to the outbreak size in each country. table characterizes the sequences analyzed from each deme for the main analysis. as a sensitivity analysis, we repeated the analysis while down-sampling based on confirmed death data from mar. , considering that deaths occur with a delay after transmission. this yielded a slightly larger sequence set for analysis (results in supplement). table . analyzed sequence information. location is the location of sample collection, as recorded in the nextstrain metadata ( ) . date is the date of sample collection, as given on gisaid ( ) (which was not certified by peer review) 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 prepared a sequence alignment from publicly available data on gisaid ( ) using the nextstrain pipeline for sars-cov- ( ). short sequences (< , bases), those without fully specified collection dates, and duplicate sequences from the same case were eliminated, as well as sequences from known transmission clusters or with suspicious amounts of nucleotide divergence (as determined by the nextstrain team). we aligned selected sequences to reference genome genbank accession mn . to eliminate suspected sequencing errors, we masked the first and final sites from the alignment, as well as sites , , , , , , and , (following the nextstrain pipeline). we assume that during the time span considered here, the outbreak in hubei and the different european outbreaks were only sources and not sinks for sars-cov- globally. in other words, we assume that (i) once a strain was in europe, the strain could have been transmitted from europe to other global regions, but subsequent re-introductions of this strain did not occur. similarly, we assume (ii) strains were not re-introduced into hubei. these assumptions allow us to ignore sequences from outside of hubei and europe. to justify assumption (ii), we argue there was not sufficient time between the pandemic origin in hubei and jan. , for a significant amount sars-cov- export, transmission outside-hubei, and subsequent re-introduction into hubei. furthermore, confirmed case data shows that hubei province was the epicenter of the sars-cov- pandemic until this time, with comparatively less transmission occurring outside of the province than within it ( ). to justify assumption (i), we tested whether there was evidence for significant migration into european demes by running a separate analysis on a a sars-cov- sampled from all global regions (results in supplement). for inferences, we used the implementation of the multi-type birth-death model in the bdmm package ( , ) in the beast software ( ) . since this is a parameter-rich model, we fixed some parameters to improve the identifiability of others. the values for fixed parameters, priors for estimated parameters, and the rationale behind these decisions are given in table . we ran four mcmc chains to approximate the posterior distribution of the model parameters. the first % of samples from each chain were discarded as burn-in before samples from the chains were pooled. we used tracer ( ) to assess the convergence and confirm that ess was > for all parameters. to weigh the significance of cases from migration versus within-region transmission during the early epidemic, we compare the rate at which new cases migrate into a region (= per-individual migration rate x case count in source region) to the rate at which new cases arise from within-region transmission (= transmission rate x case count in sink region). when signal in the sequence data is low, e.g. for some migration rates, our prior assumptions determine the magnitude of these rates. to assess the sensitivity of our main conclusions to the prior, we additionally analyzed the same sequences using a lower migration rate prior ( figure s b ). we note that the migration and transmission rates are assumed to be constant through time for this analysis. thus, the temporal trends depend only on the confirmed case data, which we take from the johns hopkins center for systems science and engineering ( ). (which was not certified by peer review) 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 , . to test our assumption that europe was primarily a source and not a sink of infections before mar. , we analyzed a a sequences collected from different global regions on or before that date. we aggregated sequences into five demes: africa, asia & oceania, europe, north america, and south & central america (table s ) , and then fit the multi-type birth-death model to these data. the most recent common ancestor of the global set of a a sequences was inferred to be in europe with % posterior support ( figure s ). the posterior distributions for the migration rates into europe closely matched the prior, thus the data contains little information on these rates ( figure s ). however, in the analyzed dataset, introduction events were inferred from other parts of the world into europe, while in total migration events were inferred from europe to other parts of the world (table s ) . for our main analysis we focused on estimating patterns of sars-cov- transmission into and across europe. based on the particular set of sequences analyzed, we infer that sars-cov- was introduced from hubei into france, germany, italy and other european countries approximately - times each before mar. (table ). the largest number of estimated introductions was from italy to other european countries. importantly, these estimates reflect only introductions occurring in the transmission history of the analyzed cases, not the full epidemic. in contrast, the inferred migration rate parameters should describe more general patterns of spread between regions. the sequence data were informative for inferring some, but not all, migration rates. we highlight here only the rates for which the data is the most informative; see figure s for a full comparison of posterior and prior distributions. the highest migration rate was inferred to be from italy into other european countries, with a median rate of . /year. the lowest migration rate was from italy to germany, with a median rate of . /year. the maximum clade credibility tree in figure summarizes the posterior sample of transmission trees linking analyzed sequences. the a a lineage sequences form a clear clade with posterior support of . the most recent common ancestor of the analyzed a a sequences is estimated to be in italy with % posterior support. in contrast, the location of the most recent common ancestor between this clade and the basal, singapore-linked german sequence is less certain. this ancestor is inferred to have been in either germany ( % posterior support), hubei ( %), or italy ( %). we find very little support for this ancestor having been in france or another european country ( %). several epidemiologically relevant parameters were co-inferred along with the transmission tree. firstly, we report on the reproductive number in the different demes, which varied from . to . in hubei to . to . in france ( figure s ). secondly, we report on the prevalence of no-longer infectious cases in each deme as of the collection date of the last analyzed sequence. this quantity can be backcalculated from the estimated sampling proportion (prevalence = # sequences analyzed / sampling proportion). we note that both the sampling proportion and prevalence estimates have large credible intervals ( figures s and s ). of the european demes analyzed, the outbreak in germany was estimated to be smaller in early march ( to cumulative cases) than the outbreaks in france ( to , cases) and other european countries ( to , cases), while the outbreak in italy was the largest ( , to , cases). figure compares the rate at which we estimate new cases to arise in each region from migration versus from within-region transmission. the estimated rates of new cases from migration and withinregion transmission are represented here as point estimates days before the date of case confirmation, which assumes a -day delay between infection and onward transmission or migration. beginning with the first day on which we have case data from hubei, we estimate a substantial risk of infected individuals migrating from hubei into european regions. throughout late january to mid-february , cases were sporadically detected in each european region, each of which is associated with a risk of subsequent within-region transmission. sustained within-region transmission is first evident in italy in mid-february. shortly thereafter, sustained within-region transmission occurred in other european countries, in france, and in germany. by mar. , the estimated rate of occurrence of new cases from within-region transmission is within the estimated bounds on the rate of new cases from migration for each region considered ( figure s a) . we obtain the same qualitative result in our sensitivity analysis using a very different prior on the migration rate ( figure s b ). we note that the rates in figure are underestimates of the rates of new cases arising due to migration or transmission due to the underreporting in the confirmed case data. however, assuming that the amount of underreporting is comparable across regions, we can indeed compare the rates. all rights reserved. no reuse allowed without permission. (which was not certified by peer review) 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 figure . maximum clade credibility tree. the clade of a a sequences analyzed is highlighted with dashed branches. the values above the branches are the posterior clade probabilities and the pale red bars show the % highest posterior density interval for node ages. the pie charts at nodes show posterior support for the ancestor being located in each deme (note that we assumed the root of the tree was in hubei with probability ). the deme for each tip is the deme in which the sequence was collected, irrespective of travel history. tips are annotated with gisaid accession identifier. all rights reserved. no reuse allowed without permission. (which was not certified by peer review) 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 table . median inferred number of introductions from each source deme to each sink deme along the transmission tree linking analyzed cases. hubei is assumed to be a source only. values in brackets are the upper and lower bound of the % highest posterior density interval for these estimates. source the median of these rates is show in the "migration" row. we also multiplied the number of newly confirmed cases in each sink region by the posterior sample of transmission rates for the region. the median of these rates is shown in the "within-region transmission" row. dates are lagged days to account for a -day delay between infection and migration or onward transmission. case data comes from ( ). we inferred the early spread of the sars-cov- virus into and across europe as well as the geographic origin of the predominant a a lineage spreading in europe. to do this, we applied a previously published phylodynamic model to analyze publicly available viral genome sequences from the epidemic origin in hubei, china and from the earliest detected and largest european outbreaks before mar. . after performing bayesian inference, we (i) report on inferred patterns of sars-cov- spread into and across europe, (ii) compare posterior support for several hypotheses on the origin of the a a lineage, (iii) report on epidemiological parameters, and (iv) compare the timeline of new cases resulting from migration versus within-region transmission in europe before borders were closed. genome sequence data indicates that prior to mar. , sars-cov- was introduced from hubei province into france, germany, italy and other european countries at least - times each (table ) . these estimates, which are based solely on genome sequence data, provide a complementary account of introduction events compared to line-list data ( ) . the introduction events we report here are inferred to have occurred along the transmission tree specific to the analyzed sequence set and are not all rights reserved. no reuse allowed without permission. (which was not certified by peer review) 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 attributable to individual cases. in comparison, line-list data ( , ) attributes introduction events to individual cases but cannot reconstruct previous, unobserved introductions. since we analyze only a fraction of all cases, we expect our estimates to be a minimum bound on the true number of introductions. ideally, we want to go beyond counting migration events amongst the analyzed sequences and investigate general dynamics. to do this, we would interpret inferred migration rates as representing more general patterns of sars-cov- spread. however, the sequence data was only informative for inferring some of these rates ( figure s ). in regions with few lineages circulating during the period considered, there is little signal for the amount of outward migration. we observe information about the per-individual migration rate from italy to other european countries ( figure s ). however, we do not find evidence for preferential migration paths from hubei into different european regions or from each european region to the others, although we cannot exclude this possibility. we estimate that the a a viruses spreading in europe by mar. had a common ancestor in italy sometime between mid-january and mid-february (figure ). in contrast, nextstrain places this ancestor in the u.k. with % confidence ( ) . however, the nextstrain result may be an artefact of disproportionately high sequencing effort in the u.k. since biased sampling violates the assumptions of the "mugration" method employed ( ) . we additionally report that the a a lineage was most likely carried from hubei to italy or from hubei to italy via germany. both transmission routes have almost equal posterior support under our model assumptions (figure ). since we only consider a few geographic regions, these migration routes are not necessarily comprehensive. rather than reconstructing a complete transmission chain, we compare model support for different a a transmission routes amongst the analyzed demes and report two equally plausible routes. although it is not the main focus of our analysis, we also report on epidemiological parameters of the early outbreaks considered. estimates for the reproductive number fall roughly within the range of previous estimates ( ) , though we mention a particular caveat with respect to the reproductive number in hubei below. unsurprisingly, prevalence estimates in early march generally exceed confirmed case counts by a factor of - ( figure s ). our inferences of epidemiological parameters do not challenge the idea that the early reproductive number in different outbreaks is difficult to estimate precisely, but not hugely variable, and that there is substantial under-reporting in line-list data ( ) . finally, we estimated the rate of new cases arising from migration compared with the rate of new cases arising from within-region transmission in the regions analyzed. the magnitudes of these rates are quite uncertain due to uncertainty in the inferred migration and transmission rates ( figure s ) and underreporting in case counts, which we implicitly assume to be constant in time and between demes. however, the temporal trends suggested by these data are still compelling and robust towards different prior assumptions. we see that under sustained risk of case migration from hubei, isolated cases were confirmed throughout europe beginning in late january but did not immediately cause large outbreaks. shortly after the first evidence of sustained within-region transmission in italy, outbreaks in the rest of europe also took hold ( figure ). our results based on the multi-type birth-death model take into account phylogenetic uncertainty and sampling biases between demes, which are two major concerns in genomic analyses of sars-cov- ( ) . indeed, wide confidence intervals around internal nodes in the maximum clade credibility tree and low clade support near the tips (figure ) indicate a high degree of phylogenetic uncertainty. therefore, it is important that the parameter estimates we report result from integrating over a distribution of potential phylogenies with different geographic locations assigned to ancestral lineages. in comparison, some initial studies that estimated international sars-cov- spread constructed a median-joining network instead of a phylogeny to account for this uncertainty ( , ) . in this approach, identical sequences are collapsed to single nodes and edges represent mutational differences. this disregards information from relative sampling times and means that ancestor-descendent relationships are highly dependent on the choice of the network root ( , ) . unaccounted-for sampling biases in these analyses may also yield spurious results for the geographic origin of lineages ( , ) . our analysis, which relies on a mechanistic model of migration and between-deme sampling differences, should be robust to such biases. despite the advantages of the multi-type birth-death model just mentioned, there are also several unique caveats to consider. the birth-death model assumes uniform-at-random sampling from the total all rights reserved. no reuse allowed without permission. (which was not certified by peer review) 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 infected population in each deme. however, particularly in the early stages of outbreaks, infected individuals were identified by health ministries via contact tracing ( ) . non-random sampling may be one possible explanation for why we infer markedly different transmission rates in china when analyzing cases from within hubei (as in this analysis) as opposed to cases exposed in hubei but sequenced elsewhere (as in our previous analysis ( ) ). furthermore, the multi-type birth-death model assumes that parameters are constant through time and homogenous within demes. as a result, our inferences based on province-, country-, and continent-level demes are only coarse approximations of the true, heterogeneous epidemic dynamics occurring at a local level. in particular, we do not account for a reduction in airline traffic between europe and china beginning in late january, before borders were closed ( ) . due to these limitations, we focus on estimating and interpreting particular events along the transmission tree of the analyzed sequences (e.g. table , figure ) and advise caution when interpreting inferred migration rates ( figure s ). we expect that our results will be useful in parameterizing more specialized models aimed to understand the efficacy of border closures as a means to fight pandemic disease. so far, such analyses have primarily used line-list data and information on travel networks to estimate sars-cov- migration patterns ( ) ( ) ( ) . here we present independent estimates of migration patterns based on genome sequence data. by combining case count data and our estimates for migration and transmission rates, we provide a timeline of early sars-cov- introduction and spread before border closures were implemented. despite migration risk from hubei being on the same order of magnitude as later migration risk from italy, we only observe sustained outbreaks in other european regions after the onset of sustained within-region transmission in italy. finally, before the first border closures in europe, we estimate the risk of new cases arising from within-region transmission to be within the estimated range for the risk of new migration cases. % of world population lives in countries with restricted travel amid covid- updated who recommendations for international traffic in relation to covid- outbreak a new coronavirus associated with human respiratory disease in china who, covid- situation reports coronavirus disease (covid- ) dashboard first cases of coronavirus disease (covid- ) in the who european region beschreibung des bisherigen ausbruchsgeschehens mit dem neuartigen coronavirus sars-cov- in deutschland estimating the asymptomatic proportion of coronavirus disease (covid- ) cases on board the diamond princess cruise ship a dynamic nomenclature proposal for sars-cov- to assist genomic epidemiology. biorxiv hcov- /lineages: resources for calling and describing the circulating lineages of sars-cov- nextstrain build for novel coronavirus (ncov) genomic characterization and phylogenetic analysis of sars-cov- in italy thanks to rapid global data sharing of #sarscov genomic data via https://t.co/tbvb magpy, we can reconstruct large and small scale patterns of #covid spread. this is a thread discussing this intersection of large and sma phylogenetic network analysis of sars-cov- genomes a follow up to yesterday's thread on the possible connection between the bavarian cluster and the italian #covid epidemic regaining perspective on sars-cov- molecular tracing and its implications improved multi-type birthdeath phylodynamic inference in beast phylodynamics with migration: a computational framework to quantify population structure from genomic data beast . : an advanced software platform for bayesian evolutionary analysis covid- ) cumulative cases by day worldwide download today's data on the geographic distribution of covid- cases worldwide early epidemiological analysis of the coronavirus disease outbreak based on crowdsourced data: a population-level observational study inference of transition between discrete characters and 'mugration' models -treetime . . documentation the reproductive number of covid- is higher compared to sars coronavirus repeated seroprevalence of anti-sars-cov- igg antibodies in a population global transmission network of sars-cov- : from outbreak to pandemic. medrxiv medianjoining network analysis of sars-cov- genomes is neither phylogenetic nor evolutionary on the use of median-joining networks in evolutionary biology evolving covid- conundrum and its impact sampling bias and incorrect rooting make phylogenetic network tracing of sars-cov- infections unreliable airlines suspend flights due to coronavirus outbreak -reuters the effect of travel restrictions on the spread of the novel coronavirus (covid- ) outbreak. science ( -. ) outbreak dynamics of covid- in europe and the effect of travel restrictions impact of international travel and border control measures on the global spread of the novel coronavirus outbreak s.n, t.v., j.s., j.h., and t.s. thank eth zürich for funding. all rights reserved. no reuse allowed without permission.(which was not certified by peer review) 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 , . key: cord- -kpvxdhcu authors: sanchez-lorenzo, arturo; vaquero-mart'inez, javier; calb'o, josep; wild, martin; santurt'un, ana; lopez-bustins, joan-a.; vaquero, jose-m.; folini, doris; ant'on, manuel title: anomalous atmospheric circulation favored the spread of covid- in europe date: - - journal: nan doi: nan sha: doc_id: cord_uid: kpvxdhcu the current pandemic caused by the coronavirus sars-cov- is having negative health, social and economic consequences worldwide. in europe, the pandemic started to develop strongly at the end of february and beginning of march . it has subsequently spread over the continent, with special virulence in northern italy and inland spain. in this study we show that an unusual persistent anticyclonic situation prevailing in southwestern europe during february (i.e. anomalously strong positive phase of the north atlantic and arctic oscillations) could have resulted in favorable conditions, in terms of air temperature and humidity, in italy and spain for a quicker spread of the virus compared with the rest of the european countries. it seems plausible that the strong atmospheric stability and associated dry conditions that dominated in these regions may have favored the virus's propagation, by short-range droplet transmission as well as likely by long-range aerosol (airborne) transmission. the world is currently undergoing a pandemic associated with the severe acute respiratory syndrome coronavirus (sars-cov- ), which is a new coronavirus first noticed in late in the hubei province, china , . the virus has a probable bat , origin, and causes the ongoing coronavirus disease . although it is crucial to find a proper vaccine and medical treatment for this pandemic, it is also relevant to know the main factors controlling the transmission of the virus and disease, including the role of meteorological conditions in the spread of the virus. the world health organization (who) states that robust studies are needed to refine forecasting models and inform public health measures . respiratory virus infections can be transmitted via direct and indirect contact, or by means of particles (droplets or aerosols) emitted after a cough or sneeze or during conversation by an infected person. the large particles (> μm diameter) are referred to as respiratory droplets and tend to settle down quickly on the ground, usually within one meter of distance. the small particles (< μm in diameter) are referred to as droplet nuclei and are related to an airborne transmission. these particles can remain suspended in the air for longer periods of time and can reach a longer distance from the origin . these small aerosol particles are inhalable and can penetrate all the way down to the alveolar space in the lungs , where cell receptors for some infectious respiratory viruses are located, including the angiotensin converting enzyme ii (ace ) used by sars-cov- to infect the individual . airborne transmission has been suggested to play a key role in some diseases like tuberculosis or measles, and even in coronaviruses [ ] [ ] [ ] . a recent study has described that the sars-cov- virus can remain viable at least up to hours in airborne conditions . respiratory droplets and aerosols loaded with pathogens can reach distances up to - meters under some specific conditions such as a turbulence gas cloud emitted after a cough of an infected person . a study performed in wuhan, the capital of the hubei province, has shown that the sars-cov- virus could be found in several health care institutions, as well as in some crowded public areas of the city. it also highlights a potential resuspension of the infectious aerosols from the floors or other hard surfaces with the walking and movement of people . another study has also shown evidence of potential airborne transmission in a health care institution . recent studies have pointed out a main role of temperature and humidity in the spread of covid- . warm conditions and wet atmospheres tend to reduce the transmission of the disease [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] . for example, it has also been pointed out that the main first outbreaks worldwide occurred during periods with temperatures around - ºc, never falling below ºc, and specific humidity of - g/kg aproximately . the first major outbreak in europe was reported in northern italy in late february . following that, several major cases have been reported in spain, switzerland and france in early march, with a subsequent spread over many parts of europe. at present ( th march ) italy and spain are still the two main contributors of cases and deaths in the continent, with major health, political and socio-economic implications. the main hypothesis of this work is that the atmospheric circulation pattern in february has helped to shape the spatial pattern of the outbreak of the disease in europe. the main atmospheric circulation pattern during february was characterized by an anomalous anticyclonic system over the western mediterranean basin, centered between spain and italy, and lower pressures over northern europe centered over the northern sea and iceland ( figure , figure s ). this spatial configuration represents the well-known north atlantic oscillation (nao) , in its positive phase, which is the teleconnection pattern linked to dry conditions in southern europe whereas the opposite occurs in northern europe . figure and figure s show maps for february for several meteorological fields that provide clear evidence of the stable atmospheric circulation in southern europe, with a tendency towards very dry (i.e., lack of precipitation) and calm conditions. as suggested in an earlier analysis , the sars-cov- virus seems to be transmitted most effectively in dry conditions with daily mean air temperatures between around ºc and ºc, which are the conditions shown in figure for the major part of italy and spain. by contrast, northern europe has experienced mainly wet and windy conditions due to an anomalous strong westerly circulation that is linked to rainy conditions. these spatial patterns fit with the well-known climate features associated over europe during positive phases of the nao . the arctic oscillation (ao), which is a teleconnection pattern very much linked to nao, showed in february the strongest positive value during - ( figure s ). the ao reflects the northern polar vortex variability at surface level , and it consists of a lowpressure centre located over the norwegian sea and the arctic ocean and a high-pressure belt between and ºn, forming an annular-like structure. positive values of the ao index mean a strong polar vortex, and the anomalous positive phase experienced during early has been linked with the recent ozone loss just registered over the arctic region . we argue that this spatial configuration of the atmospheric circulation might have played a key role in the modulation of the early spread of the covid- outbreaks over europe. it is known that some cases were reported already in mid-january in france, with subsequent cases in germany and other countries . thus, the sars-cov- virus was already in europe in early , but it may only have started to extend rapidly when suitable atmospheric conditions for its spread were reached. it is possible that these proper conditions were met in february, mainly in italy and spain, due to the anticyclonic conditions previously mentioned. the link between the covid- spread and atmospheric circulation has been tested as follows. we have extracted the monthly anomalies of sea level pressure (slp) and hpa geopotential height for february over each grid point of the capitals of the european countries ( figure s ) with the highest number of covid- cases reported so far (see data and methods). figure (top) shows that there is a statistically significant (r = . , p< . ) second order polynomial fit between the anomalies of the hpa and the total cases per population. italy, spain, and switzerland, which are the only countries with more than , cases/million inhabitants in our dataset, clustered together in regions with very large positive anomalies of hpa geopotential heights. for the total number of deaths the fit is also statistically significant for a second order polynomial regression (r = . , p< . ), and it shows clearly how italy and spain are out of scale compared to the rest of the european countries. similar results are obtained using slp fields (not shown). these results evidence that it seems plausible that the positive phase of the nao, and the atmospheric conditions associated with it, provided optimal conditions for the spread of the covid- in southern countries like spain and italy, where both the start and the most severe impacts of the outbreak in europe were located. to test this hypothesis further we have also analyzed the covid- and meteorological data within spain (see data and methods, figure s ). the results show that mean temperature and specific humidity variables have the strong relation with covid and fit with an exponential function ( figure ). they indicate that lower mean temperatures (i.e., average of around - ºc) and lower specific humidity (e.g., < g/kg) conditions are related to a higher number of cases and deaths in spain. nevertheless, it is worth mentioning that both meteorological variables are highly correlated (r = . , p< . ) and are not independent of each other. the temperatures as low as - ºc are only reached in a few regions such as madrid, navarra, la rioja, aragon, castille and leon and castilla-la mancha. these areas are mainly located in inland spain where drier conditions were reported the weeks before the outbreak. the rest of spain experienced higher temperatures and consequently were out of the areas of higher potential for the spread of the virus, as reported so far in the literature [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] . in addition, higher levels of humidity also limit the impact of the disease, and therefore the coastal areas seem to benefit from lower rates of infection. thus, in the southern regions of spain (all of them with more than ºc and higher levels of specific humidity) we found lower rates of infection and deceases. this is in line with the spatial pattern in italy, with the most (least) affected regions by covid- mainly located in the north (south). in contrast, when the whole of europe is considered on a country by country basis (see above and figure ), we find the opposite, a clear gradient with more severity from north to south as commented previously. the spatial pattern of covid- described above has some intriguing resemblances with the influenza pandemic, which is the latest deadly pandemic in modern history of europe. the excess-mortality rates across europe in the flu also showed a clear northsouth gradient, with a higher mortality in southern european countries (i.e., portugal, spain or italy) as compared to northern regions, an aspect that is not explained by socio-economic or health factors . in spain, a south-north gradient is also reported in the flu after controlling for demographic factors . the central and northern regions of spain experienced higher rates of mortality, and this has been suggested to be linked to more favorable climate conditions for influenza transmission as compared to the southern regions . interestingly, the slp anomalies of the months before the major wave of this pandemic (which occurred in october-november ) shows a clear south-north dipole with positive anomalies in southern europe centered over the mediterranean, and negative ones in northern europe ( figure s ). in other words, the nao was also in its positive phase just before the major outbreak of the influenza pandemic. this resembles the spatial patterns described above for the current covid- outbreak, both in terms of the spatial distribution of the mortality of the pandemic over europe as well as in prevailing atmospheric circulation conditions before the major outbreak. these intriguing coincidences need further research in order to better understand the spatial and temporal distribution of large respiratory-origin pandemics over europe. taking into account these results, we claim that the major initial outbreaks of covid- in europe (i.e., italy and spain) may be favored by an anomalous atmospheric circulation pattern in february, characterized by a positive phase of the nao and ao. taking into consideration current evidences in the literature, it seems that suitable conditions of air temperature and humidity were reached in northern italy and inland spain. indeed, meteorological conditions can affect the susceptibility of an infected host by altering the mucosal antiviral defense and the stability and transmission of the virus , as well as social contact patterns . we also hypothesize that the anomalous meteorological conditions experienced in italy and spain promoted the airborne contagion both indoors and outdoors, in addition to the direct and indirect contact and short-range droplets, which helped to speed up the rates of effective reproductive number (r) of the virus ( figure s ). equally, the anticyclonic conditions, amplified in some areas by temperature inversions, may have reduced the dispersion of the virus outdoors. this stability and lack of precipitation can also produce more processes of suspension and resuspension of the infected aerosols indoors and, especially, outdoors, in a similar way as resuspension of anthropogenic pollutants in cities , . equally, it is also suggested that high atmospheric pollutant concentrations can be positively related to increase fatalities related to respiratory virus infections , and even covid- . this is a relevant issue as the main hotspot of covid- in italy is located in the po valley, one of the most polluted regions of europe, as well as the madrid region (the most affected region so far in spain) . although the outbreak of a pandemic is controlled by a high number of biological, health, ncep/ncar , era and era c atmospheric data are used in this manuscript. the maps and data have been retrieved by using the tools and websites referenced in the main text, and more details about the spatial and temporal resolution, vertical levels, assimilation schemes, etc. can be consulted in their references. in brief, an atmospheric reanalysis like those used here is a climate data assimilation project which aims to assimilate historical atmospheric observational data spanning an extended period, using a single consistent assimilation scheme throughout, with the aim of providing continuous gridded data for the whole globe. figure s . location of the countries used in this study that provided cases and deaths of covid- . figure s . location of the autonomous communities of spain, as well as the two autonomous cities of ceuta and melilla. the canary islands has not been included in this study due to its geographical location in tropical latitudes. figure s . schematic representation of particles emitted by a cough, with the large droplets settled down nearby (e.g., m distance) and the smaller airborne particles spreading in suspension for longer time, and reaching longer distances, especially in dry and stable conditions as compared to wet environments. it is also possible that a resuspension of aerosol particles can eventually happen due to human activities (e.g., walking, cleaning, etc.) or air flows, which is enhanced under dry conditions due to the lack of precipitation. only statistically significant fields (p< . ) are plotted as estimated by a student's t-test. map composed with the data and tools provided by the knmi climate explorer website (https://climexp.knmi.nl/start.cgi). the maps show a consistent picture of an intensification of the positive nao phase, which implies that in the future winter conditions as experienced over europe past february could become more common. clinical features of patients infected with novel coronavirus in wuhan , china a pneumonia outbreak associated with a new coronavirus of probable bat origin identifying sars-cov- related coronaviruses in malayan pangolins the role of particle size in aerosolised pathogen transmission : a review covid- ): how covid- spreads transmission routes of respiratory viruses among humans recognition of aerosol transmission of 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the global climate influenza virus transmission is dependent on relative humidity and temperature the effects of weather and climate on the seasonality of influenza: what we know and what we need to know spread of sars-cov- coronavirus likely to be constrained by climate. medrxiv sanchez-lorenzo was supported by a fellowship ryc- - funded by the ministry of science and innovation. javier vaquero-martinez was supported by a predoctoral fellowship (pd ) from junta de extremadura and sgr , catalan government) and the clices project this research was supported by the economy and infrastructure counselling of the junta of extremadura through grant gr (co-financed by the european regional development fund) b conducted the analyses competing financial interests: the authors declare no competing financial interests corresponding author: arturo sanchez lorenzo key: cord- -rncleqqy authors: ramírez, j. martín title: long-lasting solutions to the problem of migration in europe date: - - journal: a shift in the security paradigm doi: . / - - - - _ sha: doc_id: cord_uid: rncleqqy this is the following of a previous publication on the refugee crisis in europe and its security challenges. here we suggest some long-lasting solutions to the problem of migration. these may be summarize in four points: dealing with the countries of origin and of transit, adequate control of borders, and positive measures to facilitate the integration of the newcomers in their countries of destination. in a previous publication on the refugee crisis in europe and its security challenges, i concluded that a global problem like this one could not be solved without an adequate orderly, and controlled immigration policy, creating systematic and controlled arrival and integration programs, because the mental structure of european societies is not prepared to face a disorderly increase in migration flows (ramirez (ramirez , . it is thus vital to regulate the arrival of migrants if we want to achieve their real integration in our culture (espaliú berdud ) . here i will try to go forward, pinpointing the terrible damage made by the massive escape of young people from countries that desperately need them in their struggle for development; their great problem is precisely the continuous loss of human capital. besides of that, who emigrate are not the "poor among the poor", but people with certain economic means to be able to afford the trip and contacts in the place they are going to. what is more important, according to me, is to argue that the best way would be to encourage migrants to stay home, preventing massive uncontrolled displacements, is addressing the factors that drive emigration of their own origin countries. to stop unwanted migration, the developed countries must promote a profound democratic and economic stabilization and development. we must always remember that the first right of every human being -after the right to live-is the right not to emigrate and to have the opportunity of living peacefully and prospering in our own home, as pope pius xii wrote in the apostolic constitution exsul familia: "all men have the right to a family living space in their place of origin". the right to emigrate is only subsidiary to the main right to have a family living space in the place of origin, when this cannot be assured. migration has been a sensitive and contentious topic for ages. escaping violence, war, poverty and environmental disasters, more people than ever are migrating worldwide. since it is not a cyclical, but a structural phenomenon, which means that whatever the method put forward migration cannot be stopped. currently, according to the uno estimates, million people live outside their country of birth ( . % of the world's population). in , about % of the world's . billion people lived abroad (unhcr ) . this figure grows due to inequality, climate change, conflicts, and the interconnectivity that facilitates the movement of people. migration itself affects values, identities, cultures, assimilation capacities of societies, and, far from being a problem in se, it may be a solution to many problems; e.g., benefits the demographic catastrophe present in the aging western societies. but it doesn't always engender positive changes; it may also show important disadvantages. this is why immigration must be orderly, capable of duly regulating the massive arrival of people; otherwise our social protection systems will not resist. the illegal immigration requires proper vetting to identify criminals and terrorists-the crime rates of the foreign immigrant population are significantly higher than those of the natives-, and sometimes, to put in metaphorical terms, surgical excision procedure without anesthesia will frequently induce pain. no country needs a trojan horse. but we will leave this so interesting aspect for another parliament. although mass emigration to developed countries is a global phenomenon -it happens even within each country, internally displacing for instance from rural areas to urban ones: china is a clear example-, the present chapter will be focused mainly on what would be the better long-lasting solutions to its present situation in europe, one of the leading destinations in the world in terms of migratory flows, with million migrants, russia included, according to the un's department for population. immigration is an irresolvable problem at short-term. migration policies should follow a long-term vision, addressing economic, security and sociological points of view (de la cámara ), creating systematic and controlled arrival and integration programs of security, trade, development and employment issues. but, being a global problem, migration will only be solved as a consequence of a frank and sincere joint co-responsibility between all countries of origin, transit and destination, sharing the burden of dealing with both regular and irregular migration whenever possible. this was the intention of the un global compact for safe, orderly and regular migration, signed at the end of by representatives of the countries of the united nations (uno) met in marraquesh, in a non-mandatory and rather controversial document that says, in an indirect manner, that for the entry to be safe, orderly and regular, the conditions of entry must be safe and not subject to the mercy of smugglers, seekers' and workers' entry profiles should be differentiated, and entries should be legal. its "objectives" were peppered with vague declarations, platitudes and split differences, such as the fight against the mafias that deal with human beings, the defence of the rights of immigrant workers or a change in narrative about migration towards a more positive approach. partly in the spirit of other global agreements like the paris climate deal, it encouraged states to co-operate on tricky cross-border matters without forcing them to do anything, and urged governments to treat migrants properly, but also to work together on sending them home when necessary. at least, it may help build the trust between "sending" and "receiving" countries that is the foundation of any meaningful international migration policy (economist ). let us offer some recommending ways of improving migration at four different levels: going to the roots in the countries of origin, dealing with the countries of transit, having an adequate control of borders, and suggesting some measures in the countries of destination. i have critized elsewhere (ramirez ) the saving buenist attitude of a migrationist maximalism that wants to open the doors, the ports, the windows and throw all the walls, in favor of a weberian realism (the ethics of convictions versus the ethics of reason) (leguina ): even if we would welcome forty or fifty million africans a year, africa will continue to have the same population. it would be good if they start helping africans in their own countries and avoiding as much as possible the reasons why they want to emigrate (ramirez ) . we want the potential migrants to have a better future in their countries. as ousman umar repeats like a mantra, "the solution is in the country of origin, not in the destination. you have to feed minds (well); if you feed the mind you are satisfying hunger for more than a hundred years" (umar ) . some african prelates within the catholic church are calling attention to the most forgotten aspect of this debate: the terrible damage made by a massive escape of young people from countries that desperately need them in their struggle for development. in a book released recently, cardinal robert sarah, currently prefect of the congregation for divine worship and the discipline of the sacraments, declares his personal position on immigration: "all migrants arriving in europe are crammed, without work, without dignity. is this what the church wants? the church cannot cooperate in this new form of slavery into which mass immigration has become" (sarah a, b; indelicato ). the european union (eu), thus, has to structurally turn over economic resources for the development of africa (and of middle east), tackling the problems that are the main cause of migratory movements, analysing them and offering real help in their own home. consequently, their priority has to be to invest in the countries of origin, because migration control has to be paid with money: financing, companies, information, facilitating their institutional, social, political and economic conditions in order that nobody will be obliged to leave their home, and creating sources of employment in those countries of origin. some political party has proposed in its program that the eu should prepare a sort of "plan marshall" for africa, similar to the one usa did for the post-war europe. according to the spanish royal academy (rae) dictionary, buenismo is the attitude of who reduces the seriousness of conflicts, acting with excessive benevolence and tolerance. this "goodism" is a demagogy destined to hold power through emotional blackmail, quite different to a real goodness, born of charity or philanthropy (robles, ) . cardinal robert sarah is a native of guinea guinean who grew up under a harsh marxist dictatorship and became archbishop at the age of with the task of guiding the diocese of conacry, when still in his country there was the socialist regime of sekou touré. so, i think he knows what he's talking about. in the forties of the last century, america passed the economic co-operation act, better known as the marshall plan, because its inspiration from a speech at harvard university by george marshall, america's secretary of state. the marshall aid, aimed to revive europe's war-ravaged economies, encouraged the europeans to quash inflation and to narrow their deficits while eventually dismantling price controls and import barriers. these reforms had enormous benefits. before fear of inflation and taxation prompted german farmers to feed their harvests to their cattle, rather than it is not enough with assigning cooperation funds. as de la concha stresses ( ), a proper management of migration flows requires working as much as possible in cooperation with the countries of origin taking into account, as appropriate, the various causes of migration (economic, security, political prosecution, climate, etc.). thus, a more ambitious measures are required, such as generating opportunities for the local population and offering fiscal incentives to the investments of european companies in those regions that seem to be condemned to diaspora. this move will also offer new markets for european products and services, as well as opening of eu markets to exports from these countries. and, what is more important, besides of contributing to the economic development of those countries, europe has to improve their social and political quality of life, which is precisely what they try to find in europe. our main objective, therefore, has to be to strength the production base and the creation of jobs in the countries of origin, the provision of basic services (health, education) to the local populations, and the literacy, ensuring that students in their countries have the tools to decide their future and thus avoid the temptation to migrate to europe, avoiding future victims (de la cámara ). either we offer them opportunities in their own countries, or they will come to ours looking for them zalba ( ). the best practical means for achieving it are probably inter-governmental agreements with the origin countries, giving them a generous economic aid. this is the stance taken by the visegrad group (v ) (check republic, hungary, poland, and slovakia): instead of uncontrolled massive immigration, we have to act in their origin countries; instead of importing problems, exporting help in situ. this attitude would also be "much more inexpensive", as is honestly admitted by juho eerola, a finn of the nordic freedom, or by the then slovak prime minister, peter pellegrini, during his first visit to brussels: "what we have to do is to invest in the countries where the problem is originated. each euro spent in northern africa is more efficient than spent in the migrants who arrive massively to eu" (eerola, april ). but, there is need to build up conditions to create secure environment within the transit african countries bordering the mediterranean sea. the north african governments are responsible for effective and transparent governance aimed at management of emigrants flows through their territories. eu's money poured into their accounts are wasted as they do not cooperate as they can. another effort to stem the flow of migrants to europe is "to save and protect the lives of migrants and refugees", motivating "operations of urgent evacuation" returning them to their origin countries through a repatriation programme that encourages those who have made it to northern africa to go home voluntarily, rather than risk sell it to the cities for money that might be diluted by inflation or seized by the government. its true significance laid not in the cash it provided but in the market-friendly policies it encouraged. to receive aid, european governments had to commit to restore financial stability and to remove trade barriers. we have a similar problem within our own countries, migration towards big cities is up siding the living in small rural areas; we have to stop it offering them "the needed modern technology to have the best of both worlds. it is not an easy problem, but i feel a deep analysis needs to be done so we understand more of the dynamics behind the movements"! (lindhard, ). a rickety boat across the mediterranean. this is what uno, eu and african union (au) jointly agreed in abiyan ( nov. ): people who turn back get a free flight-cutting out the need for a perilous return journey across the sahara. the programme has repatriated some , migrants to various west african countries, which barely scratches the surface because it reckons there are about m of them in the african shores, waiting for their risky jump to europe (economist ). the spanish government did this unilaterally in , after . immigrants arrived to the canary islands in open boats, known as cayucos: some direct forms of operative cooperation with those countries through which migrants come or transit, sending there some specific police units for working jointly with the local security forces with the aim of restraining subsequent invasions from other western african countries. since the devolution of immigrants to their origin countries is one of the best deterrent action to avoid the "calling effect", governments have to launch adequate information campaigns in their own origin countries to discourage potential migrants. the eu member states are africa's largest donors, supplying more than half the aid the continent receives. africa exported twice the value of goods to the eu as it did to china in . but it is not just a matter of addressing the factors that drive emigration. europe and africa share something much more fundamental: a future dependent on one another. as moroccan king mohammed vi pointed out in , solidarity between europe and africa has to be "built on shared responsibility and mutual dependence." the european continent is a global player worthy of genuine partnership of equals with africa that priorities concerning mutual interests through rapid funding in education, health and infrastructure for africa's youth would contribute to global growth. europe's investment must be bolder in terms of financing, policy and governance reforms than what is currently on the table (cole ) . economic development, government reforms, institutional strengthening, will result in common prosperity. europe, poor in natural resources and in demographic decline, desperately needs to contribute to the unblocking of the future of africa. up to now, the -economically important-european efforts have to qualify as at least disappointing. the eu needs to encourage, promote opportunities in africa, move from a policy built around aid to cement our relationships on trade and investment (palacio a) . cooperation between states that produce migrants and those that receive them can help to streamline migration flows. the european union has to structurally turn over resources for the development of africa and middle east, which are the main source of migrants nowadays, through agreements with extra communitarian countries for stopping irregular immigration towards europe. and this requires patience and diplomacy, treating the partner governments as equals. the optimism of the "refugees welcome" campaign in -wir schaffen esled towards an uncontrolled flood of refugees which destroyed the perception of order and stability. in june , there was a great turn in the attitudes of the rulers regarding immigration, with a broad consensus at the european council around much more restrictive. this practical agreement intended to hand over the decision-making capacity over who enters and who does not in the "fortress europe", strengthening the policies of controlling the external borders; fighting against traffickers; and more aid in the countries of origin instead of endless aid in europe. there is a need to strengthen collaboration with transit countries. it is necessary to prevent ships from leaving their points of origin. in cases where this is not possible, the practice should be implemented that those rescued at sea should be assisted and returned to the point of origin or departure of navigation. this is the specific task of frontex, the european border and coast guard agency: provide technical assistance and support to the countries of origin and transit to help strengthen border controls, even if it cannot replace national competence; it is converted into an authentic border police, but not in charge of rescuing. i will to come back to this point later. according to the ngo african center for strategic studies, there is a migratory flows that move . million people from one place to another from and within africa in the hands of traffickers; % of them are minors, and only % of those . million, will try to reach europe; the remaining % travel between african countries. in this context, i point out at a report by the department for human rights at the un, marking the horror of criminal smuggling networks which lead to humanitarian scandals such as: enslavement; imprisonment; rape; prostitution; the sale of organs; and camps, whose living conditions are beyond imagination. what alternative do citizens of many african countries have to come to europe? if the european states renounce their ethical convictions, delegating their responsibility, mafias and some connected "heroic" ngos will occupy the scene doing the dirty work. those still determined to reach europe may have to pay large sums to people-trafficking gangs and risk their lives in the sea (we may say the same about america, substituting the word "sea" by "desert"). the more borders, bureaucratic obstacles, closed routes and prohibitions the immigrant finds, the more profitable for the trafficker. no one moves as many people on the planet as immigration traffickers, nobody determines human flows as much as their implementation in a given territory, nobody has their flexibility to change plans and adapt to changing circumstances and nobody gets so many benefits as they do. their criminal business is more lucrative nowadays than drug or arms trafficking. some of those traffickers have changed tactics. before, they put hundreds of immigrants in old overloaded wooden boats with the aim of trying to reach europe. nowadays, after cashing from them, the immigrants are taken in safe boats from african territorial waters, until they know that the ship of some ngo is a few miles away. then, once in international waters, they put on life jackets, crammed them in zodiacs, which can barely sail a few hours and warn by radio that there are shipwrecked people in the area. the more rescue boats they have, the more immigrants will try to cross the mediterranean…, and the more deaths, drowning in the sea, those claimed heroes of the goodism will provoke. a ngo director denounced on television that although he had managed to rescue people from a zodiac, another had perished. what nobody asked was if he did not realize that by telling those who leave libya that there are boats a few miles away they are contributing to the death of hundreds of people who, for one reason or another, cannot be picked up. trafficking in human beings to the european destination is more profitable than drug trafficking: it moves around the mediterranean, according to the latest un report published last year, about billion dollars. just take the account: boats for people are used for , crammed, standing, and almost unable to move for hours. at , e per head, it gives , e per trip. it is paid in two parts: the first , e to take them from their country of origin to the ports of libya and the other , to move them to european port, in an offshore mothership, and then in small boats that launch into the sea in a point located by gps where they can be picked up by the rescue boats of the ngos, or by merchants, fishing or recreational. if they do not find this type of boats in the area, they make a distress call with a satellite telephone with the coordinates. if the trip is frustrated and they are returned to their countries, they try again when they have collected the money. and several thousand have not even had that opportunity because they have lost their lives. with that turnover, there is no problem in paying the corresponding bribes in each place (fernández arribas ). "the good trafficker tries not to lose the immigrants who have been his clients. his goal is to get them to europe and earn money. if they lose, e.g., a truck with immigrants between agadez and algeria or a boat that sinks with people, is not a problem, because they have already paid; but if they lose kg of cocaine or two boxes of kalashnikov, then they do have a serious problem. that is the difference". and how are these people's traffickers? "these gangsters are criminal entrepreneurs, but entrepreneurs. they must have many contacts, be credible, creative, charismatic, with the power of conviction, knowledge of the routes, the laws, the latest news… which make them very fast, elastic and flexible. they also participate in other businesses; f. inst., when the vehicles that bring immigrants back through the sahara return, they never make them empty: they carry weapons or drugs back to take advantage of the trip" (musumeci and di nicola ) . fernández arribas ( ) offers a very detailed description of how tens of thousands of human beings are stranded in territories dominated by mafias, in their expected way towards europe. although every corner of the world retains its specificities, the human traffic mafias analyzed by the un reflect some common patterns. all of them have recruitment agents from the main groups that are victims of extortion. a second level is that of the local mafias, who know the land and generally pay the collectors. one more step is that of small-scale service providers: trucks, boats and other means of transport. the most dangerous level is that of the big international mafias, who control the entire process and also add links to large international crime groups and use immigrants as a way to earn money quickly and easily. infrastructures built for the exploitation of the mineral resources of the desert, oil in libya and uranium in niger, facilitate trips through the desert. according to reports from the spanish police, nigeria and libya are the most active and most established bases of immigration mafias in central africa, with ramifications in other countries, where sudanese mercenaries act unscrupulously. in the waiting time, they live in abysmal conditions, suffering very serious violations of the human rights, such as abuse, harassment, violence, robbery, kidnapping, extortion, common torture and rape. in north africa they have their point of convergence in agadez, a town north of niger, or in sehba, south of libya, where control is exercised by heavily armed tribal groups. from that point of confluence, they are transferred to the coastal cities of the tripolitana region, where trips are negotiated and where part of the population collaborates with their garages as a temporary shelter at an abusive but obligatory price for those who see the end of your nightmare construction, agriculture or any job in order to get the money. the boats used are manufactured in libya and the fishermen always have on board some drum of gasoline, pure gold for the weak boats of the new slaves of the st century. in libya, each link in the chain receives its commission, especially those who seek protection and security, from militias to corrupt authorities. this action-paying poorer ones to set up vast holding-pens for humans in unhuman conditions-is a big business for a few behind the misery of many others, and involves something which would not be tolerated at home, but it seems somehow acceptable in these situations because it is out of sight. stopping these traffickers, which is the solution that many politicians in europe offer to regulate immigration, is almost impossible; they are always ahead of a european immigration policy, without the necessary coordination. a clear example has been the failure of the military operation eunavfor med sophia (from to ), which ambitious goal of dismantling the mafias that traffic with people from the libyan coasts to europe has not been fulfilled, partially because the closing of the italian ports to illegal immigrants has left it out of play. due to the fact that operation sophia no longer uses ships but only unmanned aerial vehicles, it cannot continue rescuing people at sea. federica mogherini, at that time high representative of the union for foreign affairs, explored a new mission, with more modest goals: to train the libyan coast guard to control their own waters and avoid the departure of irregular immigrants; but there were also no practical results. this shows the external and humanitarian action of the eu, as it really is: "lack of criteria, commitment and agreement on immigration issues…. public opinion will continue to show ships coming from the libyan coasts and criminal organizations will increase their profits" (de ramón-laca ; see also espaliu , espaliú berdud . as accurately pinpointed by bitzewski (personal communication), though, it is not the eu administration to blame but the heads of states not being willing to take the action. they point their fingers out towards the eu but, when the eu puts proposals on the table, they get reluctant to contribute to the common effort. it starts with the frontier countries, crying but doing very little to protect their own borders, and goes to the rest of europe raising any reason not to commit themselves to the program. the eu should be tougher on the north african governments, corrupted and ineffective. a carrot and stick should be one of the ways to start discussion with them. it's their obligation to control migrants movement within their territories but they make money on it! turkey and egypt are perfect examples of the game. when they want they can stop trafficking! but, obviously, the money is the main reason for action. the north african countries are interested in this business and it is up to us to give them a signal "do not be too smart". we deal with state controlled trafficking and we are very naïve not forcing these governments to take the responsibility. we can help them but we cannot work for them. a key move to avoid the "calling effect" is to guarantee security and economic agreements -migration control has to be paid with money-, with those countries migrants transit through in their way to europe, preventing them from leaving its coasts and returning to their country of origin those people whose asylum in the eu has been denied. in november the eu established the emergency trust fund for africa (eutf for africa) with an allocation of e . million covering algeria, tunisia, morocco and egypt, aimed "to contribute to safe, secure, legal and orderly migration from, to and within the region and support an effective management of migration flows that protects human rights" turkey is the main starting point for the arrival of potential refugees from middle east to europe. there are more than millions syrian refugees, and almost another one in lebanon. the repatriation agreement signed by brussels and ankara in march -entering , million euros annually in the turkish coffers + visa free travel for some turkish citizens-has been a quite good example of efficacy, convincing them to keep refugees from europe's shores: more than , migrants-three fifths of the detainees came from afghanistan and pakistan-have been detained in turkish territory since the document entered into force (turkish directorate general of migration management ). according to gerald knaus, leader of european stability initiative (esi), the entry of refugees into greece was reduced "by % and even higher in the number of deaths". and, in a more global view, the more than one million irregular migrants (mainly refugees) who arrived in europe in have fallen to . in . turkey thus has played a leading role as a dam to contain migration outside europe. in the future, eu will have to invest more in integration and public awareness programmes in turkey. erdogan himself has proposed resettling at least some of the refugees in a safe zone he wants set up in northern syria. all of this is legally possible. syrians in turkey do not enjoy formal refugee status, which would protect them from deportation, but "temporary protection", which does not. according to the high commissaire of united nations for refugees (acnur, in french), a turkish meltdown would send economic shockwaves or new surges of migrants onto the european mainland. erdogan has encouraged such fears (july nd, ), threatening the suspension of the migration deal over the eu's sanctions. another point for the arrival of potential refugees from africa is the maghreb. those eu southern members with close ties to it have an special interest in encouraging the reform of state structures, as well as working to reduce the socioeconomic disparities and lack of opportunities that remain the public's most pressing problems in those countries. two successful cases have been the attempts of cooperation of the eu with morocco and tunisia, as well as a. very important job in the control of migratory flows and the fight against mafias, terrorism and drug trafficking is due to the creation of a coordination authority for the gibraltar strait. by way of example, there is a positive counter-terrorism cooperation carried out by several eu countries working closely with northern africa on security, providing training and equipment for counter-terrorism and conducting some joint operations. morocco might be a capable security partner as the authorities closely monitor its population and controls its religious sphere. it has been successful in preventing attacks and obtaining information that can benefit its european partners, but its counter-terrorism efforts fit within a framework of conserving rather than transforming the state's unaccountable relationship with its subjects, which relies on a repressive political system and resists outside calls for reform. nato has also awarded us$ billion to turkey. four years later, just when this book is going to press, the crisis has returned. turkey does not seem proactive anymore. tayyip erdogan has called for more european support for ending the war in syria and for receiving millions of refugees. and as a pression measure, on february , , turkey decided to open its borders for migrants to move to the european union. this has brought together more than , migrants along the border with greece. three weeks later, though, following the strategies of the other countries to avoid a further spread of covid- , ankara has announced just the opposite: the closure of the eu's borders. the spanish authorities have observed with relief a downward trend in arrivals in mid-january , with a significant reduction of a % of the figures of irregular immigration: the entries, an average of about . a month, confirm that the flows have been considerably reduced since then and that they have fallen to levels below those registered the previous year, when spain became the main european gateway for irregular immigration. this proactivity of morocco, deploying agents to reinforce the fight against the mafias, stop the exits by sea and employed its coastguard in the rescues on the high seas, has been highlighted both by spain and by an internal report of the european commission as the most effective tool to contain migrants. this change of attitude coincided with the announcement of the visit of king philip vi to rabat, which was finally held on february , . on that trip, the spanish monarch asked mohamed vi to go "beyond" in the control of irregular immigration. later, the fisheries and agriculture agreements, signed by eu and rabat with an injection of million euros to contain migratory flows, have also been key to boost moroccan collaboration. besides of that, spain has approved to add the almost million that rabat asked last year to contain the exit of immigrants; that is to purchase surveillance equipment "to combat irregular immigration, immigrant trafficking and trafficking in human beings", as well as for fuel, maintenance of patrols, diets and salaries (palacio b) . the moroccan and sub-saharan return agreements are also praised as a "deterrent factor" to avoid the "call effect". morocco moves many sub-saharan people to the south, leaving them lying in the middle of the desert, or locked in small cells inside an illegal detention center in arekmane ( km from melilla) and then deported to their countries. tunisia has also made significant advances in its security policies, but it has yet to find balanced ways to deal with its porous borders and the disproportionately large number of radicalized people. unfortunately, the attempts to solve the problem of migration with libya have been rather frustrating. libya is a too fragile state, a territory without government since a few years ago, which is key in the irregular migratory flows towards italy and, in the late times, increasingly diverting the flow of west african migrants to spain, via new algerian routes (fernández-sebastián ). nowadays it is the largest and more serious migration corridor, due to the use of mafia "facilitators", as we had previously commented. in this context, some libyan militias behind much of the people-smuggling migrants across the mediterranean claim that eu and, more specifically, italy have given them money and equipment to improve the coastguard stopping migrant boats from setting sail. this may explain the falling of the number of migrants crossing the sea. finally, the european leaders seem delighted with the cooperation with egypt, where immigrants no longer arrive due to the decision of this country to prevent them from leaving its coasts. if all the countries of the south did like egypt, there would be no immigrants at sea. a punctual example of joint collaboration of countries of both sides of the mediterranean sea is the cross-border military exercise neptune, with the strategic objectives of unifying efforts and coordinating action plans among the mediterranean countries, especially in terms of detention and combating the movement of foreign terrorists through ports on both sides of the mediterranean. thus, passenger and freight transport vessels were included in the controls and the use of interpol databases could be activated participation. this activity has been developed between several ports such as tangier med, tangier city and bni-ansar (nador). in sum, the eu should remain committed to encouraging and supporting the most significant pressing remaining security challenges faced by those countries, such as: ( ) the reduction of the social frustrations, economic inequality, lack of opportunities, and governance problems that increase the likelihood that people will join extremist groups and recruit radicalized individuals; and ( ) the reform of state structures, especially in relation to: (a) improving security governance based in an adequate culture and professionalism of the security forces (f. ins., training of police officers, courts judges and staff, customs and coast guard officials); and (b) developing systematic approaches to prevent further radicalization and addressing conditions that facilitate it, such as: exploring better ways to handle radicalized individuals than large-scale incarceration; distinguishing between committed jihadists and those who are more open to reintegration into society; and developing programmes to promote religious education and awareness, gearing them towards pupils and their families from an early age, so relevant to the treatment of radicalized individuals and the prevention of further radicalization (dworkin and el malki ). although the priority has to be focused on the countries of origin and transit, the fact is that we have to face a massive amount of irregular migrants who are arriving to our borders, because a chaotic, uncontrolled immigration cannot be allowed. the main objective of eu policy in this topic should be to encourage legal and orderly immigration and deter illegal flows. what should be the european criteria for who is welcome to europe and who is not, to avoid an uncontrolled migration into our continent? how could be accomplished the aims to become a historic leap in the consolidation of a european area of freedom of movement without internal borders? a spanish writer, de prada ( ), has recently reminded the clairvoyant solutions offered by thomas aquinas already in the middle age on the obligations and limits of hospitality, making clear that the help demanded by those who suffer should not be confused with their unconditional reception. he refers to several possible types of peaceful immigrant: who passes through our land in transit to another place; who comes to settle in it as an outsider; and who wants to fully join the nation that receives it "embracing their religion" (their culture, we would say nowadays). he always puts the notion of common good, which requires a desire to integrate into the life of the host country; and he is inclined not to admit them until examining their degree of "affinity" with the nation that receives them. and, as a measure of legitimate defense, we should reject those immigrants considered hostile, understanding as such not only those who have the purpose of perpetrating crimes or violence, but in general those who harbor intentions contrary to the common good of the nation that receives them (see also : ramirez ) . the decision on who is welcome and who is not does not belong to the humanitarian people, even less to the people-smugglers, but to each state. security and protection of the borders is competence of each state member. without borders there are no states and no one else can supplant a state's right to manage and protect them, treating migrants humanely but also firmly, swiftly returning those who arrived illegally or whose claims to asylum have failed. even if the eu lacks competence over it, it does not preclude the convenience of an europeanization of the migration management, through a joint cooperation for specific purposes, even if it means losing part of the national authority over a very sensitive area of the territory. the political leaders of the eu must improve their coordination and develop common legislation on borders and immigration, creating systematic and controlled arrival and integration programs, focused on the new scenarios, such as the solution of the migratory crisis, with a common, effective, and decisive security policy, finding a balance between the implementation of measures that guarantee the security of the states, while respecting the rights of those migrants who no longer enjoy their protection in their respective countries of origin. the eu not only lacks competence over the management of the flow of refugees, but also lack of homogeneous response, as it is shown by of the dublin regulation (eu european parliament ), which has resulted an absolute failure, inept to establish a coordinated strategy with minimal effectiveness. the eu foreign policy remains hopelessly underpowered, limited to coaxing national capitals towards agreement and supporting their ad hoc initiatives (the economist economist a, b; niño ). it is good to remind again that it is not eu to blame but the states not taking actions. the dublin regulation ( ) determines the eu member state responsible for the examination of an application for asylum seekers of international protection under the geneva convention relating to the status of refugees of july , as supplemented by the new york protocol of january (eu ). according to this legislation, the first member state in which the asylum application is submitted will be responsible for the examination of the request for international protection and the asylum seekers have to stay there. this, the so-called "one stop one shop", burden the countries situated at the entry to europe, notably those in the south, and the individual preferences -that is, where people arriving into europe actually want to go to and where do they wish to live-are bound to not be properly taken into account. consequently, if they move later to another european country -known as secondary movements-, this second receptor may return them to the first state. this secondary migration penalizes those southern countries, because most refugees arrive to the coasts just as a transit towards other northern european countries, where many of the newcomers had linguistic and cultural or family ties. or with better job opportunities and welfare provision. as a matter of fact, most of them live already in germany. in front of this, the different eu member states have rather antagonistic approaches: (a) northern countries, preferential asylum for most of the refugees, are in favour of a quotes policy imposed by brussels' "eurocrats" for the reubication of refugees, and suggest an eu budget with more funds for those regions with higher number of asylum seekers. (b) mediterranean countries, plus portugal and france, suffering a heavy migratory pressure in their borders, have the feeling of being left alone to cope with immigrants, and reject the responsibility of attending by themselves everybody who arrives to their borders, because it would mean establishing a sort of sanitarian cordon with the rest of the communitarian block. their aim is a reform of the dublin regulation and the help of the other eu countries in the sharing of the irregular immigration arriving to the outer borders. for instance, the greek government and aid agencies argue that the eu must overhaul the dublin regulation, so that asylum-seekers are distributed more evenly. the current system, they say, is unfair. five countries-greece, italy, spain, france, and germanyreceived over three-quarters of europe's asylum applications in the first half of . greece has had to deal with times as many claims as hungary, a country of comparable size and wealth. the rules are also ineffective: eu money is not an adequate replacement for relocation. southern countries are also reluctant to expand frontex because this affects their rights to the sovereignty of control of the territory, but also concerns related to better registration of migrants…. this is the key problem! (c) the visegrad countries (v ) -poland, hungary, czech republic and slovakiaplus baltics (latvia and lithuania) and some recent addings (at least, austria, and partially italy), call for reform, and refuse to consider any binding sharing in , germany received . applications, almost double that of any other eu country, requesting the return of . refugees to other eu countries, but only managed to execute % of the returns of asylum seekers requesting from the eu. based on that, the german home minister, horst seehofer, wants to send tens of thousands of migrants to italy, and, on the contrary, italian home minister, feels legitimized to send those who arrive to the northern european countries; f.ins.,"france was to welcome , immigrants, but in reality accommodated only " (france has returned to italy , people in ). following the principle of solidarity, which is included in the lisbon treaty ( ), jean-claude juncker called on the member states of the eu to share refugee quotas according to the wealth of each country and population size, but it shattered and the european policy of immigration and asylum was marked by increased sovereignism in the states of europe. out of asylum-seekers. based on their right to security, they insist that their priorities are more about controlling europe's outer borders, in order to preserve the free movement of persons within the schengen space, than about managing the burden of refugees who cross them. what should be a reasonable attitude to avoid an uncontrolled moving of illegal migrants within the schengen area? the intended distribution of the burden of refugees imposing a quota system -i.e. every eu state had to admit a fixed amount of people-has not worked: only a % of the quota has been achieved by the different members. this system of quotes was firmly opposed by the central europe defence cooperation (cedc), arguing that the structures of their countries are not "ready" for supporting the social weight of the newcomers: it would be highly detrimental to the national security and sovereignty. they felt marginalized by angela merkel decision to keep germany's borders open to refugees at the peak of the crisis in , without any previous consultation; it seemed to them, the chancellor had turned them into transit corridors for undesirable migrants drawn by the promise of a cushy life there. they suggest as alternative to accept the free choice of country. following this rationale, the polish minister of foreign affairs in years - , witold waszczykowski, was backing the disagreement of his president, andrzej duda, to force the entrance of immigrants against the wishes of the polish people, asserts that "the security of poland is more important than the unjustified decisions of the european institutions on the issue of the refugees". viktor orban even dares to declare central europe a "migrant-free zone". the central european countries are pushing for the eu to get involved in the custody of the external borders and accuse the southern countries of letting irregular migrants pass unchecked through their territory to the rest of the eu, and ending up circulating in europe at will. for instance, sebastian kurz, at that time austrian kanzler and rotatory president of the council of the eu, told in a local newspaper "i am afraid that many are trying to avoid the high number of migrant records that they would have to do" (referred in abc, / , ) . his words suggested that national authorities sometimes turn a blind eye to not registering migrants and that, on the other hand, a community official who did not work directly for any state would not allow those distractions. the eu summit in brussels on june th , following a suggestion of angela merkel and horst seehofer, reached a transitory agreement based in two points: (a) bilateral agreements between different states, stopping secondary movements in their inner borders, i.e. sending the refugees back to the state in which their asylum application was first submitted, obviously with an economical compensation; and (b) more resources for setting up centres of transit (internment) or "landing regional platforms" with the task of reviewing asylum applications, "distinguishing between economic migrants and those needed of international protection". this move would speed up the deportations, disincentives dangerous adventures and reduce drownings at sea. this seems to partially accept sebastian kurz's proposal of a "copernican revolution" in asylum policy migratory model, as a new possible alternative similar to the one applied in australia: to implement the number of naval patrols for intercepting boats with refugees and confine them in islands like nauru o papua-new guinea": control first; then generosity. following this model means two things: first, taking tough action along borders, at sea and "upstream" (inside africa) to slash the number of asylum-seekers smuggled to europe; thwarting smuggling, the argument goes, would reduce drownings at sea, and reassure voters who might otherwise be tempted by the far right. second, striking deals with poorer countries to establish camps, run with un agencies, to receive, detain and, eventually, return migrants. it is a laudable but ill-defined goal, because it is unclear where to establish those camps. it was mentioned "in safe countries outside the eu". but where? some members want deals with north african countries to reduce departures, but it still unknown which non-european countries would be willing or able to host such centres. in front of this north african rejection, the danish prime minister at that time, lars lokke rasmussen, revealed that some communitarian countries are austria, which occupied the eu presidency that semester, hoped for a quick agreement to equip frontex with a supranational force of up to , members and to establish a landing platform for irregular migrants in north africa. algeria: just the day after the summit, algerian foreign minister abdelkader messahel said in an interview with the french broadcaster rfi: "i believe that europeans have enough capacity, means and imagination to manage these situations." "it is excluded that algeria opens any retention zone. "morocco: the next day, the moroccan foreign minister, naser burita, emphatically stressed that this country has always "rejected and rejected" in its territory the detention centers for foreign migrants. tunisia: for logistical and political reasons, it could be the ideal candidate to host this type of centers: its coasts are the closest to the maritime zone where the majority of migrants sailing from the western strip of libya are rescued; and, its democratic transition seems to be quite consolidated, being the country in the region that receives the highest volume of eu aid funds per capita. however, the tunisian ambassador to the eu, tahar cherif. abounded in categorical rejection by his political class and public opinion. "for tunisia, the creation of reception centers is a red line," says valentin bonnefoy, a researcher at the tunisian ftdes, a ngo specialized in migration. more than seven years after the revolution, this maghreb country does not have an asylum law, something that many observers attribute to a veiled strategy to avoid becoming a host country. egypt also rejected the possibility, although in a not-so-sharp way: "the eu migrant reception facilities in egypt would violate the laws and the constitution of our country," said parliament president ali abdel seeking to establish camps for failed asylum-seekers in a continental country, but out of ue, more specifically in the balkans. there is even a third possibility to consider: within the own eu border. jean-claude juncker, in his speech on the state of the eu, proposed to establish a more efficient control of the eu's external border, converting frontex, created in and reinforced in as a european guard of coasts and borders, into an authentic border police, but not in charge of rescuing. although still subject to the control of the national authorities, it is provided with broad competences in areas such as the control of irregular migratory flows from outside the eu, the return of irregular migrants to their countries of origin, the detection of illegal steps between countries of the club and the fight against the channels of transit in third countries. on november th , the eu decided to grow it from , s to a standing corps of , , with a % jump in funding next year, to m. e, for the first time, the eu will be able to dispatch gun-toting men and women clad in eu uniforms to patrol its fringes, without asking member-states to cough up guards. in this way, the surveillance capacity in european territory will be reinforced. this necessary hard-headed policy of tough border controls, swift return of illegal immigrants and encouraging would-be migrants to stay home obliges governments to work with others in the control of its migratory flows. europe cannot maintain the schengen system of internal free migration if it does not control its external borders. and, we have to admit it, it does not. the eu has so far failed in all its attempts to establish a common policy to address the problem; it has become impossible to have a level-headed conversation about managing migration in europe. the malta agreement (september rd, ) is a tentative deal, signed by a group of five eu interior ministers (germany and france, as well as finland, italy and malta), on a temporary scheme for a rapid relocation in other countries of asylum seekers, who are rescued from the mediterranean sea. it could open the way to a comprehensive overhaul of the dublin regulation by which the migrant's country of arrival is responsible for verifying the right to asylum of each person. it states that "the relocation member state will assume responsibility for the relocated person" and contemplates a quick procedure to say in advance the number of potential refugees each state is willing to host, setting a period of only four weeks to relocate rescued refugees in the mediterranean in other member states. this would allow the frontline first-arrival countries (the mediterranean), to be discharged from the responsibility of participating in their reception, quite heavy in periods of strong migratory pressure. in return, berlin and paris hope to achieve a reduction in the socalled "secondary movements" or movements of irregular migrants from the country of entry to other eu states. aal in welt am sonntag. in addition, aal said that his country already has millions of refugees from nearby countries, such as syria, yemen, iraq or sudan, so its reception capacity is at the limit. the eu ministers discussed on - - , in luxembourg this proposal to relocate asylum seekers rescued at sea, but they got a lack of solidarity of the whole european bloc, and the sole support of portugal, luxembourg and ireland. the agreement also speaks of a return protocol "immediately after landing", redoubling diplomatic pressure on migrant countries of origin, using "appropriate incentives to ensure full cooperation, including consular cooperation, from countries of origin", although at least it includes everyone passing a "medical and safety exam". it also underlines the need to "commit to improving the capabilities of the coastguards of mediterranean third countries". it is hoped that the deal will put an end to the game of pass-the-migrant spectacle of some countries squabbling over which should accept responsibility for small numbers of asylum-seekers, breaching in what until now has been a guiding principle: that irregular migrants must be dealt with by their country of first arrival. since participation in the system will be voluntary, much will now depend on how many countries will take part, how many asylum-seekers each will accept and whether penalties are to be imposed on those countries that refuse to co-operate (this last seems unlikely, given that such an idea would have to be approved by all the eu's members, including the countries liable to be affected (economist ). summarizing, there is a widespread perception that a series of instruments to control its external borders are not working well -the dublin asylum agreements, refugee quotas, frontex, return and development policies…-and that a lack of trust has grown not only between the member states, but also between the states and the european institutions, especially after the refugee reception crisis in . in few words, there is a deficient management of migration and a weak european solidarity on this issue (de la cámara ; de wenden ). the call thus is now for a joint cooperation towards a true common policy on asylum and immigration with a complete and efficient control of the eu's external border, reinforcing the role of frontex. everybody accepts this priority as the only possibility left for preventing a reinstatement of inner borders controls which would lead to the end of one of the most valued achievements of the eu, the schengen space. a positive step in this direction has just being announced, after the starting of their new mandate, by margaritis schinas, vice president of the european commission in charge of completing a new architecture that guarantees solidarity to the countries of the external border: the eu is going to make sure that there is a sufficient dimension of responsibility in terms of border control and returns. and as tangible measures in that direction, they promise an improvement of the management of external borders with , permanent staff; moving towards a federalization model of border management, this coming spring there will be the first community corps with their own boats and carry weapons, with the deploying the first european coastguards. the responsibility concerning the immigrants does not finish at the border. once accepted as our guests, we cannot forget about them. and, among our humanitarian obligations, we have to help properly integrating newcomers into our own society, avoiding their eventual fondness towards a multiculturalism, which only produces ghettos of their own culture, or wrongly thinking that the mere acceptance as migrants give them the right to have a claim to social welfare. and, on the contrary, who arrive without being invited cannot impose the host other people's rules. once they find a home in a new country, they have to accept the laws, rules, traditions and culture of the adopted society that welcomes them, learn the local language, mix with the natives, and be aware of the specific needs and priorities of their new home. in few words, they come to european territory with equal rights and obligations, but no more. whoever is not able to assimilate to their new society, should better return to their origin (ramirez (ramirez , . according to the dublin regulation, asylum-seekers are the responsibility of the first country to record their presence and, if they move later to another european country, this second receptor may return them to the first state, most of them arrive to the southern coasts heading north, trying to slip there unnoticed, as illegal paperless "invisible migrants", to avoid being picked up and returned to their first country of arrival. officials in the country of arrival can also use bureaucracy to slow the process of registration. and so, after six months, the new host state becomes responsible. this gives a strong incentive for foot-dragging. the recent malta tentative deal ( ) tries to partially solve this problem, allowing the frontline states to be discharged from the responsibility of participating in the relocation of the newcomers. once accepted as our guests, what to do with them? let us focus on the policy towards them in sweden and germany, preferential asylum of most migrants. strange enough, they are far from coincident at all. in sweden, immigrants received ample food and shelter, a generous welfare benefits, . times higher than the ones received by host taxpayers, as well as many facilities for family reunification, without any special focus on their social integration. even more, most of them are not allowed to work. this almost open bar policy, paying migrants to do nothing, has produced (a) an increment of the social expenses on the foreign population, with the consequent reduction of the benefits for the natives -the newcomers have priority to the swedish people; (b) a call effect on other tentative immigrants; and (c) increase of criminality and insecurity, which triggers the anti-immigrant feelings of host taxpayers who feel swamped. in my opinion, migrants should be encouraged to work, getting them language classes and education and offering job training, and introducing them into the labor market, meeting the main demands of the host country: f. ex, in nordic countries, anticipating a shortfall of geriatric nurses. in germany, the arrival of nearly one and a half million asylum seekers since polarized the country, with a consequent rise of a climate of political anxiety. it seems they have finally realized that the solution of the problem is to integrate into the labor market those who are already in the country, and relax the requirements to allow the entry of more workers. with this purpose, in december , the german government approved the fachkräfteeinwanderungsgesetz ("skilled workers immigration law"), an ambitious legislative package to attract qualified labor from non-eu countries and alleviate the pressing lack of workers in some sectors and regions of the country. this will extend the rules covering foreign graduates to vocationally trained workers, cautiously opening the door for rejected applicants for asylum, but who are already integrated into the labor market, and recruit more workers from outside the eu with medium and high education to find qualified work under certain conditions. germany economy enjoys enviable health, registering an unemployment rate of . %, the lowest since the reunification of the country. figures from the institute for employment research (iab), under the ministry of labor, estimate that there are about . million jobs vacancies, while posts actually registered in employment offices in november amounted to , ( , more than the same month of the previous year). however, one of the biggest concerns of the german businessmen, the so-called mittelstand, the motor of the exporting power and the backbone of the german economy, is the lack of skilled workers. unlike in other european countries, small and medium-sized german companies are distributed throughout the country, not necessarily concentrated in industrial centers. this often hinders the recruitment of workers who prefer to live in urban areas. there is a shortage mostly of workers with a level of professional training, such as plumbers, or drivers, and diploma courses, for example, of children's educators. elderly care and tourism, are also crying out for workers. this legislative text allows non-eu citizens to go to germany to seek work for six months provided they have the necessary training, know the language and have the means to survive during that time. in the case of persons with temporary permits, such as rejected asylum seekers, they must show that they have been working in germany for at least months and that they do not have a criminal record. the head of the employers' association, ingo kramer, recently indicated that , of the asylum seekers who arrived in are working or receiving some vocational training. in addition to the labour shortages, there are also demographic forecasts, which warn of a marked aging of the population. these projections will also affect eastern europe, where a good part of foreign workers in germany come from and whose arrival is expected to decrease in the coming years. according to thomas liebig, expert on migration issues at the oecd, "these countries are becoming places of immigration. we have to look for workers outside the eu". although the labor integration of immigrants advances, experts warn that it will take time. "it's a slow process; sometimes they are people who do not speak a word of german, and many of them come from afghanistan or somalia, where they have not had schooling" explains liebig ( ) . tangible achievements, indeed! milanovic and branco ( ) proposes an intermediate position between open to all or closed borders, under the name of "circular migration": to admit workers who cover specific positions, having salaries and work conditions similar to those of the locals, but with not vote rights, nor social benefits for children, retirement or free education; and at the end of their contracts, they will have to return to their countries. in few words, they will be partial citizens for a limited time, like it is already happening elsewhere: in gulf, singapore, iraq, usa, canada. perhaps one country may need extra workers and be in position of offering them stable working conditions; but this may not occur in other eu members. this is also suggested by alejandro portes, princess of asturias of social sciences award : offering a temporary, flexible and comprehensive program of visas to allow access to young people who want to come to work or study for a while, allowing a fruitful flow between countries. come in that way would also be much more economical, and would do a lot of damage to the traffickers, because those who come in that way would not have to pay them ( october ). psychological experiences of refugees and the response of the community in the lake chad region summa theologica (fathers of the english dominican province translation, prima secundae, question letter to the editor, the economist de la cámara m ( ) the eu migration challenge inmigración y cuestión religiosa, abc, ago de ramón-laca j ( ) operación sophia: paradojas de la acción exterior europea. análisis en minutos | nº a new european pact on immigration and asylum in response to the "migration challenge the southern frontline: eu counter-terrorism cooperation with tunisia and morocco the problem with eu foreign policy. too much historical baggage, the economist a migrant move in malta. the eu reaches a tentative deal to share out migrants rescued at sea. the economist taking european defence seriously: the naval operations of the european union as a model for a security and defence union, cuadernos europeos de deusto los buques de la operación sophia en el dique seco: elementos de un revés para la política común de seguridad y defensa regulation (eu) no / of the european parliament and of the council of maritime dimension in the fight against illegal migration on the western mediterranean route sbarchi? un nuovo schiavismo leguina joaquín ( ) migraciones sin respuestas alemania busca extranjeros para , millones de empleos, el país, dic how to stop migration towards big cities? research gate la inevitable migración hacia europa, el pais confessioni di un trafficante di uomini. reverse niño elena ( ) terrorismo e inmigración: cambiando el foco lazos y nudos con marruecos, el mundo europe's partnership with morocco. proyect syndicate apostolic constitution exsul familia nazarethana, castel gandolfo portes a ( ) princess of asturias of social sciences award buenismo ante el problema de los refugiados, migraciones en el siglo xxi: riesgos y oportunidades el terrorismo como desafío a la seguridad global the refugees issue in the frame of the european security: a realistic approach bondad y buenismo, abc, ago sarah r ( ) le soir approche et déjà le jour baisse turkish directorate general of migration management (turkish: göçİdaresi genel müdürlügü) ( ) migration management global compact for safe, orderly and regular migration. marraquesh global trends: forced displacement in he is member of the advisory board of the society for terrorism research and of the professors world peace academy. he has also chaired the complutense research group on sociopsychobiology of aggression and the departments of psychobiology at the seville and complutense universities, as well as being director of the rector office at the autonomous university of madrid. dr. martin ramirez was a humboldt and fullbright fellow but, let us close here our considerations, stressing that a revision of national and eu legislation is required, focused towards a cooperation with the countries of origin and transit; and that, instead of dreaming naively in a chimeric -non-existing-european eldorado, we have to promote the great possibilities that african continent has, knowing that, as the journalist lucia mbimio says, "we must not stop dreaming, but change the compass of dreams! returning from europe to africa is not a failure." ( , ). key: cord- -a yidr y authors: aleta, a.; moreno, y. title: age differential analysis of covid- second wave in europe reveals highest incidence among young adults date: - - journal: nan doi: . / . . . sha: doc_id: cord_uid: a yidr y most of the western nations have been unable to suppress the covid- and are currently experiencing second or third surges of the pandemic. here, we analyze data of incidence by age groups in european countries, revealing that the highest incidence of the current second wave is observed for the group comprising young adults (aged - years old) in all but of the countries analyzed. we discuss the public health implications of our findings. europe is experiencing a second wave of the covid- pandemic, with incidence levels rising across all european countries. authorities have already begun to enforce non-pharmaceutical interventions (npis) to avoid the collapse of the healthcare system, which will likely induce further drops in the estimated gross domestic product due to additional slowdowns of the economy in many sectors. whether we are able to tailor our response to this second wave in such a way that npis minimize social impact and economical losses is key for the future of europe and its rapid recovery after the pandemic is brought under full control. this fundamentally depends on understanding better how the current surge of covid- is unfolding and affecting the different strata of the population, which will eventually make it possible to adapt public policy responses and implement targeted measures on the fly. to understand the evolution of the ongoing wave, one should trace it back to its origin in the summer, when the incidence started to grow again after the effects of the strict restrictions that were imposed in the spring faded out, which resulted in an increased number of local outbreaks and community transmission of covid- in most of europe. for instance, it has been reported that a variant of sars-cov- emerged in early summer in spain and spread to multiple european countries since then [ ] . the source of the outbreak that spain experienced in the summer can be related to outbreaks that started among agricultural workers in the north-east of the country -particularly in aragon and catalonia. these outbreaks then moved to the local population and replicated through the rest of the country. an analysis of the incidence by age group in one of these regions -aragon, see figure -shows that in early summer the disease spread mainly within the - and - age groups. however, coinciding with the end of the summer and the start of the academic year, the disease spread mostly in the - age group. to elucidate if this pattern is characteristic of this region or if it is more general, we have collected data on the covid incidence in european countries aggregated by age groups during the period from september to october. figure shows the fraction of new cases in a given age bracket relative to the population of that age group. the horizontal line represents the situation in which the disease propagates homogeneously through the different age strata. several features of the data are worth highlighting. first, in all countries but three (czechia, romania, and slovenia), the maximum ratio of accumulated incidence in the period analyzed corresponds to the age bracket of young adults -mainly between - years old. secondly, the incidence curves are not markedly peaked for the elderly as it happened in march-april during the first wave [ , ] . third, the overall ratio of infected to population size of a given age group is below one for children in all countries. these very robust and regular patterns of the incidence of the current second wave are a remarkable observation given that countries in europe responded distinctly and at different times during the early stages of the pandemic. the fact that the age-differential incidence is common to most countries in europe points to common causes and similar transmission routes. noticeably, a similar pattern has also been observed in the united states [ ] . a . cc-by-nc . 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 november , . ; figure : total number of new cases since september to october in each age bracket, divided by the size of the group. in red, the age bracket with the largest deviation from . several hypotheses could be advanced as most likely explanations for the striking regularity in age differential patterns across european countries. the higher incidence in young adults could result from interventions such as reopening of universities and other educational centers across europe [ ] . nonetheless, it could also be rooted in behavioral factors associated with this age group [ ] , rather than from demographic or cultural causes specific to each european country or to differences in public interventions. these behavioral determinants could be the perception of low risk in this group and youngers' social mixing and lifestyle -this is arguably the age group with the largest mobility and contact heterogeneity. the latter hypothesis is also consistent with the observation that the high incidence in younger people does not propagate to other age groups. from a public health perspective, these data could prove fundamental to understand which factors impact the evolution of the current surge of covid- and to adapt our response to the present unfolding of the covid- pandemic. first, more efforts should be devoted to communicating with young adults to induce a change that reduces the incidence among them. reporting data of incidence by age group to the general public could help to raise science- switzerland . cc-by-nc . 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 november , . ; rooted awareness among the targeted age group. secondly and important for the current debate regarding the role of schools, children seem to be infected less often than what would be expected if the transmission of sars-cov- would be homogeneously distributed across age groups. this points to the success of policies aimed at protecting this group [ , ] . we note that it is also possible that the observed pattern for the children is either because they could be less susceptible to be infected or that they might be less likely to be tested as they are mostly asymptomatic. data however seems to indicate that the main reason is the former rather than the latter. admittedly, if a large fraction of children were transmitting the disease, a surge in the age groups of their parents -those in close contact with them-should be expected, which is not a feature of the data in most countries. likewise, the results suggest that schools for under - years old could remain unsheltered given that the benefits of keeping them open seem to overcome the social cost of a closure [ , ] . these results could help understand what are the main drivers of the second wave and to better design and adapt public health interventions during this stage of the pandemic. furthermore, the previous findings highlight the need for more research in relation to tracing and identification of transmission chains, which will disambiguate what are the sources of contagion by age-strata. we also urge authorities to make available as much epidemiological data by age, sex, and other traits as possible to enable analyses like the one discussed here. funding: aa and ym acknowledge partial support from intesa sanpaolo innovation center. ym acknowledges partial support from the government of aragon and feder funds, spain through grant e - r (fenol) and / / / , and by mineco and feder funds (fis - -p). the funders had no role in study design, data collection, and analysis, decision to publish, or preparation of the manuscript. . cc-by-nc . 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 november , . ; https://doi.org/ . / . . . doi: medrxiv preprint emergence and spread of a sars-cov- variant through europe in the summer of covid- cases and case fatality rate by age -knowledge for policy european commission the changing demographics of covid- recent increase in covid- cases reported among adults european commission/eacea/eurydice, . the organisation of the academic year in europe - / . eurydice facts and figures risk attitudes across the life course surveillance of covid- school outbreaks no evidence of secondary transmission of covid- from children attending school in ireland impact of school closures for covid- on the us healthcare workforce and net mortality: a modelling study covid- , school closures, and child poverty: a social crisis in the making key: cord- -qv oxjwd authors: more, alexander f.; loveluck, christopher p.; clifford, heather; handley, michael j.; korotkikh, elena v.; kurbatov, andrei v.; mccormick, michael; mayewski, paul a. title: the impact of a six‐year climate anomaly on the “spanish flu” pandemic and wwi date: - - journal: geohealth doi: . / gh sha: doc_id: cord_uid: qv oxjwd the h n “spanish influenza” pandemic of – caused the highest known number of deaths recorded for a single pandemic in human history. several theories have been offered to explain the virulence and spread of the disease, but the environmental context remains underexamined. in this study, we present a new environmental record from a european, alpine ice core, showing a significant climate anomaly that affected the continent from to . incessant torrential rain and declining temperatures increased casualties in the battlefields of world war i (wwi), setting the stage for the spread of the pandemic at the end of the conflict. multiple independent records of temperature, precipitation, and mortality corroborate these findings. a century ago, in the autumn of , the deadliest wave of the h n influenza pandemic, known as the "spanish flu", claimed tens of millions of victims (krammer et al., ; taubenberger & morens, ) . it marked the beginning of the end of several years of unprecedented mortality throughout europe, due to the horrors of world war i (wwi), and an unusually extreme, multiyear climate anomaly that brought torrential rains to battlefields as well as urban areas. the inescapable muddy landscapes of the war remain a common theme of surviving wwi eyewitness accounts and photographs. despite recent work on the impact of climate change on the spread of viral infections and overall mortality, the role of environmental changes in the wwi-spanish flu period remains underexamined (grant & giovannucci, ; mamelund, ) . here we present a new, high-resolution climate proxy record from the high alpine monte rosa ( , m a.m.s.l.) colle gnifetti (cg) glacier in the heart of europe, indicating abnormally high influxes of north atlantic marine air in the years - . we evaluate the glaciochemical data from this ice core with a detailed monthly record of overall mortality in europe for the same period and monthly precipitation and temperature measurements (ansart et al., ; bohleber et al., ; bunle, ; clifford et al., ; more et al., more et al., , schneider et al., ; sneed et al., ; willmott & matsuura, ) . the multiyear, extreme anomaly described here, in several independent but consilient records, had a significant impact in setting the stage for the onset, spread, and mutation of the h n pandemic, while also increasing all-cause deaths due to widespread harvest failures and worsening battlefield conditions. the influenza pandemic of - claimed between and million lives (krammer et al., ; taubenberger & morens, ) . in europe, the estimated death toll was . million (ansart et al., ). various theories have been proposed to document its spread from asia to europe. historical research has recently focused on the recruitment of allied troops by the british in asia in spring and their transport to europe via canada and the atlantic crossing, as the most likely route of transmission (humphries, ) . © . the authors. this is an open access article under the terms of the creative commons attribution-noncommercial-noderivs license, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made. studies have also suggested that the use of chlorine gas on the battlefields of wwi may have caused the virus to mutate into its most virulent form (erkoreka, ; oxford et al., ; taubenberger et al., ; worobey et al., ) . the environmental and especially climatic conditions in which the pandemic developed have received less attention in the scientific literature, even though historical accounts universally describe abnormally high precipitation and cold temperatures in the years preceding the onset of the pandemic, in , and during its deadliest wave in . in contrast, detailed research has shown how extreme weather conditions impacted the outcome of major battles on the western front, most notably during the battles of verdun ( ) ( ) , the somme ( ), the chemin-des- dames ( ) , and the third battle of ypres-passchendaele ( ) (barbante et al., ; hussey, ) . extreme weather anomalies in these years disrupted governmental efforts in collecting meteorological records (savouret et al., ) . in this study, we combine a high-resolution glaciochemical record reconstructed from cg marine air proxies (na, cl − ) evaluated together with detailed monthly records of overall mortality from european countries (figures and ) and instrumental measurements of precipitation and temperature for the same period ( figure ). previous research on this cg record exposed in great detail variations detected in climate proxies and in the concentration of pollutants for this area due to its geographic proximity to events and its location under the influence of the iceland low and azores high pressure systems ( figure ) (barbante et al., ; bohleber et al., ; döscher et al., ; more et al., ) . the glaciochemical records have been developed via discrete, inductively coupled plasma mass spectrometry (icp-ms, data points for the period - ) and ion chromatography (ic, data points for the period - ) analyses (more et al., (more et al., , sneed et al., ) . total european mortality peaked three times, concurrently or following cooling temperatures, increasing precipitation, and an extreme influx of cold marine air in winter , , and ). the glaciochemical and instrumental records corroborate historical accounts of torrential precipitation on the battlefields of wwi-resulting in increased casualties due to drowning, exposure, pneumonia, and other infections-and its severity may have significantly altered the migration patterns of birds such as the mallard duck, the primary reservoir for the h n avian influenza virus (tucker et al., ) . , marine air proxies in the cg glacier and total mortality for european countries - (ansart et al., ; bunle, ) . in in , in , and , overall mortality peaked during or immediately after periods of high marine air influx over europe. major battles of wwi where precipitation was a significant factor are labeled in black, along with the period of the three major waves of the spanish flu pandemic, the deadliest of which occurred in the autumn of . , - . mean values of instrumental measurements of temperature and precipitation with overall deaths for european countries (ansart et al., ; bunle, ; schneider et al., ; willmott & matsuura, ) . in the autumn and winter of , mortality peaked together with high precipitation, with a peak in both records in the month of october, a slight decrease in november, and another peak in december of that year. the deadliest wave of the spanish influenza pandemic claimed most of its victims in the same months, where the arrow points to a double peak in both deaths and precipitation. precipitation on british, french, and german military operations, where newly dug trenches and tunnels filled with rainwater, as bitter cold temperatures caused thousands to endure frostbite at night, while mud slowed down the movement of troops and artillery during the day (barthas, ; churchill et al., ; de lécluse, ) . the highest increase in marine air proxies (figures and figure s ). starting in january , precipitation in europe increased steadily throughout the year, with a peak in december ( figure s ), coinciding with the battles of the somme and verdun, where the mud and water-filled trenches and bomb craters swallowed everything, from tanks, to horses and troops, becoming what eyewitnesses described as the "liquid grave" of the armies (borden, ) . extended winter conditions delayed the start of the chemin-des-dames offensive until april (attal & rolland, ; savouret et al., ) . they also caused widespread harvest failures, resulting in the "turnip winter" of - , whereby the german population resorted to root vegetables for their diet, due to failed potato and cereal harvests and the allied blockade (chickering, ) . after a brief respite, rain and cold returned again in the summer and autumn of ( figure s ) , with widespread flooding of the trenches in the third battle of ypres (passchendaele) in july-november, often bringing military operations to a standstill and substantially increasing casualties (barton et al., ; lloyd, ; reid et al., ) . the first wave of h n influenza in europe emerged in the spring of , most likely originating in the fall and winter of , among allied troops that had arrived from asia and had established their base camp near boulogne (humphries, ) . the combination of extremely high precipitation, the concentration of millions of troops on the battlefields, unsanitary conditions, and the use of chlorine gas as a . / gh chemical weapon have been cited as contributing factors to the mutation and emergence of the most lethal wave of the spanish influenza pandemic in the fall and winter of - (erkoreka, ; oxford et al., ; figure s ). later peaks in marine air proxies in - and are connected to documented residual activity from north atlantic hurricanes, particularly severe in those years, but not approximating the extremes of - (landsea et al., . the deadliest wave of the flu in europe began in the autumn of , closely following a period of extremely high precipitation and cold temperatures (figure ). the coincidence between increased precipitation and mortality in this pandemic wave in late (figure ) highlights the role of environmental conditions in a pandemic's morbidity and mortality, as already suggested in studies of recent h n and other respiratory tract infections such as covid- in human populations (kissler et al., ; liu et al., ; viboud et al., ) especially in regions with extensive, long-term air pollution such as europe (clay et al., ; morales et al., ; more et al., ). an additional exacerbating factor may have been the influence of the weather anomalies on established patterns of avian migration, similar to those documented for other species in response to modern, anthropogenic climate change (tucker et al., ) . specifically, the migration of the mallard duck-one of the primary reservoirs of h n avian influenza virus-may have been disrupted by the anomaly described here, resulting in increased presence of this species throughout europe in the autumn of and , in close proximity to both military and civilian populations, as well as domesticated animals (oxford et al., ; saunders-hastings & krewski, ; taubenberger et al., ; worobey et al., ) . studies of disruptions in mallard migration have shown that changes in the environment-at start point and throughout the journey-can affect overall movement and direction (van toor et al., ) interrupting their normal migratory route (kleyheeg et al., ; tolf et al., ) . the transfer of h n influenza virus from animals (avian and mammals) to humans (zoonosis) occurs primarily via water sources contaminated with fecal droppings from infected birds (breban et al., ; carter & sanford, ; pawar et al., ; vandegrift et al., ; vittecoq et al., ; worobey et al., ) . in autumn, the rate of influenza a viral infection can be as high as % in mallard populations, due to the exposure of immunologically naïve juveniles to the virus (bengtsson et al., ; tolf et al., ) . juveniles are especially prone to remain in the same area if their migration route is disrupted (van toor et al., ) . exposure of mammalian hosts to the same infected bodies of water where mallard ducks may have remained may explain connections to the current seasonal recurrence of h n in human populations as shown in recent studies (belser & terrence, ; reid et al., ; smith et al., ; tang, ; weingartl et al., ) , suggesting that severe weather anomalies in - may have contributed to both the diffusion and mutation of the spanish flu virus, as previous studies have suggested. the influx of torrential rain accompanied by decreasing temperatures in the autumns of and provided ideal conditions for the survival and replication of the virus (brown et al., ; lowen & steel, ; reid et al., ; tang, ; weingartl et al., ) . prolonged exposure to decreasing temperatures may also have been a factor in increasing pneumococcal co-infections, which recent studies have found to be more common in the wwi years than previously thought (foxman et al., (foxman et al., , iwasaki et al., ; klugman & chien, ; meissner, ; morens et al., ; taubenberger et al., ; worobey et al., ) . retrospective epidemiological studies have now shown that a significant contribution to high mortality during the spanish flu pandemic came from pneumococcal co-infections, amounting to as much as one fifth of influenza victims, with a % mortality. the data presented here show that extreme weather anomalies captured in glaciochemistry and reanalysis records brought unusually strong influxes of cold marine air from the north atlantic, primarily between and , resulting in unusually strong precipitation events, and that they exacerbated total mortality across europe, due to the interplay of environmental, ecological, epidemiological, and human factors. as we experience increasingly severe weather anomalies brought about by global climate change, and with the persistent seasonal recurrence of h n , the contribution of environmental change and human action to pandemic morbidity, mortality, and diffusion cannot be underestimated. indeed, the pandemic development history of the spanish influenza from to sends a warning into our own time, a century later, of the ongoing risks of war zones (including the use of chemical weapons), wildlife trade, unsanitary conditions, and humanitarian crises as incubators of disease, assisted by climate-change triggers. our past and . / gh current crisis highlights our continuing and growing need for robust local and global public health and environmental agencies, such as the cdc, who and unep, dedicated to reducing the risk that climate change will aggravate epidemic outbreaks. the role of climate anomalies such as the one described in this study must be assessed in relation to more recent pandemics such as covid- . mortality burden of the - 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(afmore@fas.harvard.edu). key: cord- -acwkh ed authors: kallio-kokko, hannimari; uzcategui, nathalie; vapalahti, olli; vaheri, antti title: viral zoonoses in europe date: - - journal: fems microbiol rev doi: . /j.femsre. . . sha: doc_id: cord_uid: acwkh ed a number of new virus infections have emerged or re-emerged during the past years. some viruses are spreading to new areas along with climate and environmental changes. the majority of these infections are transmitted from animals to humans, and thus called zoonoses. zoonotic viruses are, as compared to human-only viruses, much more difficult to eradicate. infections by several of these viruses may lead to high mortality and also attract attention because they are potential bioweapons. this review will focus on zoonotic virus infections occurring in europe. during the past years a number of new virus infections have emerged or re-emerged. most of them, such as sin nombre and andes hantaviruses, sars coronavirus, avian influenza, nipah and hendra viruses, have appeared in subtropical or tropical regions. dengue is spreading to new areas and west nile virus has reached the new world. infections by several of these viruses may lead to high mortality and also attract attention because they are potential bioweapons. some viruses such as tick-borne encephalitis virus are spreading to new areas along with climate and environmental changes. most of these infections are zoonoses and clearly viruses shared by animals and humans are, unlike human-only viruses, much more difficult to eradicate. here, we review zoonotic virus infections occurring in europe. the infections like lassa fever and dengue that are imported to europe but are not indigenous to european nature will not be discussed in detail in the review. we have divided the virus infections into two categories, those that are transmitted to humans directly from vertebrate animals (like rodents, foxes, bats and birds) and those that are primarily transmitted by arthropods (mosquitoes, ticks, sandflies). the latter class is formed by arboviruses but notably they have vertebrate hosts in nature. hantaviruses are enveloped viruses with a tri-segmented negative-stranded genome and belong to the family bunyaviridae [ , ] . the . kb l (large) segment rna encodes the kda rna polymerase, the . kb m (medium) segment the two glycoproteins - kda gn and - kda gc, -formerly known as g and g ; and the . kb s (small) segment the - kda nucleocapsid protein (n) ( table , fig. ). in addition, the s segment of some hantaviruses has another open reading frame named ns but its product or function remains to be discovered. viral messenger rnas of the members of the bunyaviridae are not polyadenylated and are truncated relative to the genome rnas at the termini. messenger rnas have -methylated caps and - nontemplated nucleotides which are derived from host cell mrnas. the termini of all three segments are conserved and complementary to each other, a feature that has assisted in cloning and discovery of new hantaviruses. unlike most other bunyaviridae, hantaviruses are not arthropod-borne (arboviruses), but are rodent-borne, roboviruses. each hantavirus is primarily carried by a distinct rodent/insectivore species although a few host switches seem to have occurred during the tens of millions of years of their co-evolution with their carrier animals [ ] . we now know that the genetic diversity of hantaviruses is generated partly by (i) genetic drift (accumulation of point mutations and insertions/deletions) leading to quasispecies [ , ] , (ii) genetic shifts (reassortments of genome fragments within the same virus genotype/species), and (iii) according to recent findings [ , ] , by homologous recombination, a mechanism not previously observed for negative-strand rna viruses. hantaviruses, which cause hemorrhagic fevers with renal syndrome (hfrs) in eurasia and hantavirus cardiopulmonary syndrome (hcps) in the americas, are prime examples of emerging and re-emerging infectious agents. like most of these infections hantaviral diseases are zoonoses. with the exception of the south-american andes virus, which can be transmitted directly from human to human, hantavirus infections are thought to be transmitted to humans primarily from aerosols of rodent excreta. only some [ , ] . topografov hantavirus isolated from siberian lemmings (lemmus sibiricus) has not been detected in north european lemmings (lemmus lemmus) although it can grow in them [ ] . infections in rodents are mainly asymptomatic and persistent. hantavirus infections are quite common in europe [ ] (table ) , puumala virus is common in northern europe, european russia and parts of central-western europe (fig. ) . dobrava virus is found mainly in the balkans (fig. ) . saaremaa virus has been detected in eastern and central europe but its epidemiology is not well defined (fig. ) . apart from laboratory infections [ , ] seoul virus has been detected in wild rats, only in france [ ] . it is also apparent that many parts of europe, such as britain, poland and byelorussia, remain ''white'' on the european hantavirus map [ ] . this means either that hfrs is rare or nonexistent in these regions or is not widely recognized and diagnosed by the biomedical community. in northern europe hfrs as well as the carrier rodents exhibit peaks in - year cycles [ ] while in central europe the hfrs incidence follows the fluctuations of ''mast years'', i.e. the availability of beech and oak seeds for the hantavirus-carrying rodents. in central europe hfrs peaks in the summer while in northern europe most cases occur in late autumn and early winter, from november to january. risk factors to catch hantavirus infections and hfrs include professions such as forestry, farming, and military, or activities such as camping, and the use of summer cottages. males are more likely to be exposed than females [ , ] . puumala and dobrava viruses both cause hfrs but the infections differ considerably in severity [ ] : both are characterized by acute-onset fever, headache, abdominal pains, backache, temporary renal insufficiency -first oliguria, proteinuria and increase in serum creatinine and then polyuria -and thrombocytopenia but the extent of hemorrhages (hematuria, petecchiae, internal hemorrhages), requirement for dialysis treatment, hypotension and mortality are much higher in [ ] . this is important since the infection is so common in many areas of europe [ ] (table , fig. ). in addition, in some patients puumala virus infection may invade the pituitary gland and lead to mortality or at least hypophyseal insufficiency requiring hormone-replacement therapy [ ] . the pathogenesis of hfrs is poorly understood [ , ] . however, it is known that b integrins can mediate the entry of pathogenic hantaviruses [ ] and that hantaviruses can regulate apoptosis [ ] [ ] [ ] [ ] ] . also there is evidence [ , ] that increased capillary permeability is an essential component in the pathogenesis of both hfrs and hcps, although different target tissues, kidneys and lungs are affected in the two diseases. hfrs patients show locally increased levels of tnf-a in the plasma and kidneys [ , ] and high levels of urinary secretion of the proinflammatory cytokine il- [ ] . studies with a monkey model mimicking human puumala virus infection [ ] may assist in elucidating the mechanism of pathogenesis. of the four structural proteins, both in humoral and cellular immunity, the n protein appears to be the principal immunogen [ ] . cytotoxic t-lymphocyte (ctl) responses are seen [ ] and may be important both for protective immunity and pathogenesis of hantavirus infections [ ] . the diagnosis of acute hfrs is primarily based on serology, since viral rna cannot be regularly detected in the blood or urine of patients [ , ] . both immunofluorescence tests and enzyme immunoassays are widely used for detection of specific igm or low-avidity igg antibodies, characteristic of acute infection [ ] [ ] [ ] . in addition, immunochromatographic -min igm-antibody tests [ , ] have been developed. vaccines against hantavirus infections have been used for years in china and korea, but not in europe or the americas [ ] . no specific therapy is used in europe, although both ribavirin and interferon-a have been successfully used in trials in china [ , ] . a major problem is that at the time hfrs patients are hospitalized, virus replication is already disappearing. members of the genus lyssavirus within the family rhabdoviridae are bullet-shaped, enveloped viruses approximately nm in diameter and nm in length. the kb non-segmented negative-strand genome encodes five proteins (starting from the end): the - kda nucleoprotein (n), the - kda phosphoprotein (p), the - kda matrix protein (m), the trimeric - kda glycoprotein (g) and the kda polymerase protein (l) ( table , fig. ). proteins are separately transcribed in cascade by a special mechanism from a single -end promoter which results in a decreasing transcription and expression gradient for proteins encoded from the to end. the major antigen with neutralizing epitopes and pathogenetic determinants is the glycoprotein, which is responsible for receptor recognition and membrane fusion. after endocytosis the viral envelope fuses with endosomal membranes provoking the release of the internal viral nucleocapsid in the cytoplasm where transcription and replication takes place. the helically wound nucleocapsid results from the intimate association of the nucleocapsid protein and the rna genome. it serves as template for the polymerase (l protein and p cofactor) for transcription and replication. it buds to intracytoplamic membranes in infected neurons, but on plasma membranes in salivary gland epithelial cells. the lyssaviruses currently consist of established genotypes, or lineages, of rabies(-like) viruses [ ] of which the classical rabies virus, found throughout the world and associated with terrestrial mammalian hosts and american bats, forms genotype ( table , fig. ). other lineages, or genotypes, are found in bats, of which mokola and lagos bat viruses seem to be less pathogenic, and towards which the vaccines based on the classical genotype rabies virus are not protective [ a, b] . in addition to the genotypes, new bat lyssa- virus genotypes have been recently found, e.g. from russia [ c]. during the past years or more in europe, classical rabies virus has made two major host shifts, firstly from the dog to red foxes, and then to racoon dogs brought from east asia to be raised for fur; this species then became widely established in the wild (fig. ) . phylogenetic data also suggest that westand southward spread of rabies virus occurred during the last century [ a] . although in europe the most important carriers of classical rabies virus are foxes and racoon dogs, the virus can be transmitted to secondary hosts such as domestic animals (dog, cat, cattle, horse, sheep) or e.g. deer -practically any mammal species could be a potential carrier. bats are a special case; lyssaviruses are maintained in bats, even in the absence of classical rabies in carnivores; thus in countries where classical rabies has been eliminated, bat rabies has become the dominating or only source of rabies virus and retains the potential for host-switching into the carnivore reservoir which constitutes a more direct threat for public health [ b]. as many bats are protected species, the detection or ''absence'' of bat rabies is dependent also on the intensity of screening efforts [ , ] . as of the beginning of , the following countries in europe were declared ''rabies-free'' by who (meaning no indigenous cases occurred during the last two years): belgium, cyprus, finland, greece, iceland, ireland, italy, luxembourg, norway, portugal and sweden (fig. ) . in , rabies virus was detected in europe in wild animals (excluding bats), domestic animals; bat and human rabies cases were diagnosed (see table ). the countries where rabies was circulating include (in diminishing order of cases) russia, ukraine, lithuania, belarus, latvia, estonia, croatia, poland, slovakia, serbia-montenegro and turkey with hundred(s) to thousands of (animal) cases, romania, bosnia-herzegovina, germany, moldova and bulgaria with dozens of cases, and individual cases were registered (some imported and not affecting the rabies-free status) in slovenia, the netherlands, denmark, france, albania, finland, austria and switzerland ( members of out of the lyssavirus genotypes (except lagos bat virus, i.e. genotype ) have caused rabies disease in man. the infection is inevitably fatal in humans or other mammals unless immune intervention (vaccination and administration of antibodies) is used. transmission may occur though the bite of an animal delivering the virus deep in to striated muscle or connective tissue, but infection may also occur after abrasion of the skin or licking of mucous membranes. the bite of a bat with small teeth may go unnoticed; on the other hand the bat lyssaviruses may infect human skin more easily than has been recognised. the incubation period is - days, but has been shown in some cases to be months, even years. the classical picture of rabies includes prodromal illness with fever and non-specific symptoms, as well as itching and local paresthesia. this is followed by neurological signs, consisting of either encephalitic ''furious rabies'' or paralytic ''dumb rabies''. in the former, episodic hyperactivity and excitation of the cns manifest as, e.g. hydrophobia, hypersalivation and convulsions. the patient finally develops paralysis, coma and cardiorespiratory failure. in the paralytic form, no excitation is seen, but paralytic disease develops to coma and death [ , a, b] . after entry of the virus to the body, the virus must gain access to peripheral nerves and to be transported towards the cns. rabies virus components are attached either directly or by encapsulated vesicles to the dynein motor carrying the ''cargo'' along the axonal microtubular system towards the cell stroma, approximately at a speed of mm/day [ , , ] . it is transmitted after replication on neuronal membranes transsynaptically to adjacent neurons and finally invades the cns where it first disturbs the limbic system associated with the excitation, and later neocortex, with little histopathological changes in neurons. centrifugal spread of the virus from the cns to many tissues through somatic and autonomic nerves also occurs, where the salivary glands are especially important for the spread of the virus to the next victim. immunological responses do not occur before cns involvement. all the viruses in phylogroup i are also pathogenic to mice by i.m. injection, and can cross-neutralize each other. this has practical implications, as fortunately the vaccine strains (of genotype ) also appear to protect against the ebvl viruses [ ] . a pathogenic determinant common to phylogroup i viruses seems to be amino acid r in the glycoprotein [ ] ; substitution of this amino acid also abolishes the retrograde transport [ ] . when symptoms develop, no cure is available. however, after exposure to a bite or scratch of a potentially rabid animal, rabies must and can effectively be prevented by post-exposure prophylaxis, originally developed by louis pasteur. the treatment includes in a non-vaccinated person (a) washing (with water and detergent) and disinfecting the wound to minimize the amount of cell-free virus (this alone can increase survival %), (b) starting a post-exposure vaccine regimen which includes (in europe) five doses of cell-culture derived vaccine intramuscularly into the deltoid muscle on days , , , , and (c) in case of severe or deep injury additional passive anti-rabies immunoglobulin, which should be administered principally to the wound area. if the person was pre-vaccinated or the animal can be caught and studied for the presence of rabies, the protocol can be adjusted accordingly [ , a] . clinical suspicion of rabies in a case of encephalitis of unknown origin is the starting point. ante mortem diagnostics can be achieved most easily with rt-pcr from saliva. in addition, rabies antigen can be detected in brain or nuchal skin biopsies, and in some cases antibodies in serum or csf may be found. post-mortem diagnostics is most rapid with antigen detection or rt-pcr from the brain, virus isolation is also possible. in addition to post-exposure prophylaxis, vaccines in humans can be used for pre-exposure prophylaxis ( doses) in risk groups (veterinarians, wildlife workers, travellers to endemic areas; especially small children who may be unable to explain a potential exposure to a rabid animal) [ , a, ] . the primary method for control of rabies is vaccination of dogs (and cats). this practice was established at the beginning of the last century in most of europe, but has not yet been achieved in many developing countries, where annually people still die of rabies. in most of europe (excluding eastern europe) rabies has been eradicated from terrestrial wildlife species (carnivores) by aerial distribution of vaccine baits across the countryside. the vaccines used to protect wildlife species include attenuated vaccines as well as a recombinant vaccinia virus carrying the rabies virus glycoprotein (the latter has in one case caused a skin infection in man). although rabies in terrestrial animals can be controlled efficiently, eradication from the bat reservoir is not currently feasible. arenaviruses are the only members of the rna virus family arenaviridae. these viruses are enveloped, lipid solvent-sensitive, pleomorphic particles with a mean diameter of nm (ranging between and nm). host cell-derived ribosomes are present in the virions, and give the virus particles a ''sandy'' appearance under the electron microscope, hence the name arenavirus (arena: sand in latin). the virion structure of arenaviruses is quite simple, virus particles contain two rna segments (s and l) linked to nucleocapsid proteins and viral polymerase molecules, and these nucleocapsidpolymerase complexes are surrounded by a lipid envelope into which two glycoproteins (g and g ) are linked protruding on the outside of the virion. arenaviral rna segments have an ambisense coding arrangement, the s segment ( . kb) encoding a -kda nucleocapsid protein (n) in the viral complementary sequence, and in the viral-sense -end sequence a -kda glycoprotein precursor (gpc) which is posttranslationally cleaved to two glycosylated proteins - kda g and g ; and the l segment ( . kb) encoding a -kda viral polymerase (l) in the viral complementary sequence, and in the viral-sense -end of the sequence a - kda ring finger z protein, which has been shown to have a role in arenavirus budding [ a] (table , fig. ). initiation of transcription may involve cap-snatching, although the transcription mechanism is not yet fully elucidated. arenaviruses include viruses all carried by different rodent hosts (except tacaribe virus which has been isolated only from fruit bats) [ b]. arenaviruses are capable of causing chronic infections in their rodent hosts, and infectious virus is present in the blood and is also secreted into body fluids (saliva, urine, semen), which is presumably the route of transmission to humans. the appearance and incidence of arenaviral infections are closely associated with the distribution of the rodent host species and the rodent population dynamics. arenaviruses have co-evolved with their specific host species during millions of years, and have been divided into old world and new world groups first on a serological bass, and later into evolutionary lineages (new world group) using genetic analysis [ a, b, c]. both groups contain viruses that are included in the category a pathogen list (defined by cdc, usa), which means that the propagation of these agents is allowed only in biosafety level laboratories. these highly pathogenic arenaviruses include the south american junin, machupo, guanarito, and sabia viruses from the new world group, and the african lassa virus from the old world group. all these viruses can cause hemorrhagic fevers in humans, and are considered potential bioterrorism agents being thus included in biohazard preparedness programs. in europe, these viruses occur only rarely as imported cases. the only arenavirus endemic in europe is lymphocytic choriomeningitis virus (lcmv), shown to circulate in mus musculus populations (table ) , and associated with pet hamster derived epidemics [ b, a]. relatively few epidemiological data are available concerning the actual distribution of lcmv in europe, but in addition to serological evidence from mus sp. material from spain [ b], antibodies against lcmv have been detected in rodent species other than mus musculus (our unpublished data), which indicates that other yet unknown arenaviruses may circulate in europe. at least ten arenaviruses have been reported to be able to cause disease in humans. as mentioned above, five arenaviruses (lassa, junin, machupo, guanarito, and sabia viruses) are even capable of causing a lifethreatening viral hemorrhagic fever [ a, b] . none of these five viruses are endemic in europe, but a few imported lassa virus infections have been diagnosed in germany and great britain during the last few years with no secondary infections detected [ ] [ ] [ ] . increased travelling increases also the risk for transmission of exotic arenaviruses to non-endemic areas such as europe. lcmv is thus far the only known endemic arenavirus in europe [ b]. in humans lcmv infections are mostly either asymptomatic or influenza-like diseases. in some cases aseptic meningitis or meningoencephalomyelitis is seen. lcmv is also capable of causing congenital infections manifested by hydrocephalus, microcephalus, chorioretinitis, and mental or psychomotor retardation [ , a, b] . lcmv infections are rarely fatal for humans. the diagnosis of arenaviral infections is based on serology and/or direct detection of the virus [ ] . for serodiagnosis methods using immunofluorescence assay (ifa) as well as enzyme immunoassay (eia) have been described. either a four-fold rise in igg antibody titers or presence of igm antibodies is considered indicative of acute infection. the antibodies that appear first in the acute phase of infection are directed against the nucleocapsid protein; neutralizing antibodies against the glycoproteins appear later in the convalescent phase (if at all). this means that typing of the causative agent is difficult on a serological basis at the early stage of infection, and is actually possible only in the convalescent phase due to the slow rise of virus typespecific neutralizing antibodies. for direct detection of the virus, antigen detection assays are useful in the early diagnosis of lassa fever especially. also reverse transcriptase (rt)-pcr tests have been developed to detect arenaviral rna in patient samples [ a, b, a, b, c]. virus isolation attempts can also be successful. the supportive treatment of arenaviral infections includes ensuring the fluid, electrolyte and osmotic balance. in severe hemorrhagic fever-cases early diagnosis is important because the use of ribavirin has been found effective if the treatment commences within the first six days after onset of symptoms [ ] . immune plasma containing neutralizing antibodies has also been useful in some cases. for prevention of arenaviral diseases, several attempts to develop vaccines have been made [ a] . one vaccine, candid , has been successfully used in the prevention of argentine hemorrhagic fever caused by junin virus with a clear reduction in the number of infections observed in humans [ b, ]. the genus orthopoxvirus in the family poxviridae consists of large - nm brick-shaped viruses, with a double-stranded dna genome ( - kb) ( table ) , that are serologically cross-reactive and -protective. the middle part of the genome is very conserved among orthopoxviruses encoding structural proteins and replication machinery whereas the ends are more variable comprising genes involved with host-specificity and counteracting the immune response [ ] . replication of orthopoxviruses occurs in the cytoplasm and includes translation of early mrnas (such as dna polymerases and immune defense molecules), dna replication, translation of intermediate mrnas (for late transcription factors), and late mrnas encoding structural proteins and late enzymes, respectively. altogether, e.g. the cowpox virus genome encodes nearly open reading frames. intracellular non-enveloped virions are first formed, comprising the majority of the infectious viral progeny; some particles develop in er/golgi into enveloped, either cell-attached or extracellular viral particles, often motile due to attached actin tails [ ] . homologous recombination occurs readily between orthopoxvirus sequences which has raised some concerns about the use of vaccinia virus-based vaccines in wild animals [ ] . some orthopoxviruses are host-specific, whereas some are more promiscuous but have a distinct reservoir. their nomenclature may be misleading; e.g. monkeypox is not carried by monkeys, neither is cowpox carried by cows. smallpox or variola virus, now eradicated and historically the cause of one of the most feared human diseases, was specific to man. many other orthopoxviruses circulate in wildlife species and are often zoonotic. examples include the vaccinia virus, the modern smallpox vaccine, the origins of which are unclear but was originally described as cowpox by edward jenner [ ] in late th century england, and which later has also re-escaped to nature in other parts of the world [ ] ; monkeypox virus, pathogenic to primates, including humans, causing a smallpox-like disease with secondary transmission and with a likely reservoir in small rodents in central africa; cowpox virus, which is the main orthopoxvirus in europe and may be transmitted to man either directly from rodents or from a secondary carrier, typically cat. cowpox virus has been detected in western eurasia and in europe, voles of clethrionomys and microtus species and apodemus mice are the main reservoir hosts [ ] ( table ) . shedding of the virus from rodents is apparently transient. infection of cattle is rare; domestic cats relatively frequently present with clinical disease, but infection of zoo animals, e.g. elephants, has also been reported [ ] . following the cessation of smallpox vaccination, more than years ago, the number of humans susceptible to cowpox has increased. more than human cowpox cases have been reported in the literature since [ , ] . all age groups may acquire cowpox, but most cases have been in girls under years of age, who have had a cat or e.g. a field mouse as a pet. infection probably occurs through abrasions in the skin; persons with atopic eczema are more prone to the infection. [ ] [ ] [ ] [ ] . the incubation period is - days, after which papules develop into lesions - cm in diameter which proceed through pustular, ulceral and eschar stages over a period of a about two weeks. they may be painful and vary in number, size and severity. local lymphadenopathy, pyrexia and nausea may occur; secondary bacterial infections are common. typically, solitary lesions are found, located mainly in fingers, hands or face (e.g. eyelid) [ , ] . in - weeks the lesions heal gradually, some residual scars may remain. in some cases severe generalized skin infection occurs [ ] , especially in atopic and in immunocompromised individuals and may in extreme cases lead to death [ ] . cidofovir (a phosphorylated nucleoside analog of cytosine) may have potential as an antiviral against cowpox virus [ ] . man-to-man transmission of cowpox virus (unlike for monkeypox) has not been reported. it is usually possible to detect orthopoxvirus particles directly from the skin lesions by electron microscopy. the virus can also be readily isolated in e.g. vero cells or chorioallantoic membrane of chicken embryos from the lesions and subsequently characterised [ ] . several sensitive pcr approaches have been described, some related to the bioterrorism (smallpox) preparedness [ ] [ ] [ ] ; in each case further typing at the species level is needed. in addition, during acute cowpox infection, igm antibodies and low-avidity igg antibodies have been detected [ ] . following the cessation of smallpox vaccination approximately years ago, the younger age groups are the most susceptible population, both to smallpox and to cowpox, which is more closely related to vaccinia virus. recent estimates indicate as low as % protection levels among europeans. for instance in finland, in the age group over , everybody had orthopoxvirus antibodies as measured by immunofluorescence assay. the seroprevalence decreased gradually towards younger age groups reflecting the gradual cessation of smallpox vaccination, with the last vaccinations in finland occurring in [ ] . smallpox was finally declared to be eradicated from the world in [ ] after which few people in europe have received the vaccine. in addition to wild rodents carrying cowpox, import of exotic pets may also pose a risk for orthropoxvirus transmission, as was seen in a recent outbreak of monkeypox virus in the usa [ ] . orthomyxoviruses are enveloped, negative-strand rna viruses with - genome segments, of which avian influenza, (i.e. influenza a) viruses may cause severe disease in domestic poultry and cause zoonotic infections. the influenza viruses in wild aquatic birds are the source of these epidemics in chickens as well as providing a gene pool for reassortants with human influenza a viruses which then may become established in humanto-human transmission resulting in influenza pandemics. in addition, influenza a viruses are known pathogens of pigs, horses, mink, seals and whales [ , ] . influenza a virus is - nm in diameter and has genome segments varying in size from . to . kb. the three largest segments - encode the polymerase subunits pa ( kda), pb ( kda) and pb ( kda), respectively; whereas the segments - each encode one viral protein, namely the kda hemagglutinin (ha), the kda nucleoprotein (np), and the kda neuraminidase (na), respectively (table , fig. ). the two smallest segments, and , encode each two proteins, the kda matrix protein (m ) and the kda membrane protein (m ), and the kda ns and the kda ns proteins, respectively (table , fig. ). in common with the bunyaviridae, the genomic rna is packed in the nucleoprotein which carries polymerase subunits, and the and -ends are conserved and complementary to each other and thus able to form panhandle structures in which the promoter regions reside. ''cap-snatching'' from cellular mrnas and an oligo-u motif are used to create viral mrnas starting with a cap structure and ending in a poly-a region. the virus enters the cells after binding to the sialic acid receptors by endocytosis, which is followed by acidification of the endocytic vesicle and, mediated by the ion channel forming m protein, of the interior of the virus, which leads then to fusion of the viral and endosomal membrane and release of the viral nucleocapsids to the cytoplasm, respectively. however, untypically for an rna virus, the replication, transcription and nucleprotein assembly occur in the nucleus. the envelope proteins are processed to the plasma membrane, where budding of the virions finally occurs. the envelope proteins are also the most important antigenic determinants. the homotrimeric hemagglutinin (ha), defines the ''h type'' which is responsible for the binding to the sialic-acid containing host cell receptors and membrane fusion properties. the neuraminidase (na) defines the ''n type'', and cleaves terminal sialic acid residues from glycoconjugates enabling the virus to reach target cells in the mucin-rich epithelium and facilitating release of the virus from the cells [ , ] . the catalytic site of the neuraminidase is a target for antivirals oseltamivir and zanamivir, and the m protein is a target for amantadine and rimantadine. to become active, the hemagglutinin protein needs to be cleaved by trypsin-like proteases found in respiratory and gastrointestinal epithelia. human-adapted influenza viruses replicate in the respiratory tract, whereas in avians the virus replicates primarily in the gut. when transmitted to and within poultry, the normal hemagglutinin of influenza a virus h or h of wild aquatic birds of the ''low pathogenic type (lpai) may be mutated. accumulation of basic residues at the cleavage site makes the ha cleavable by most proteases of cells, such as furin, and results in ''highly-pathogenic avian influenza'' (hpai) virus able to replicate in most tissues killing rapidly up to % of chickens [ ] [ ] [ ] . hpai, also known as ''fowl plague'' was first described in and the virus was first isolated in suggesting that humans have been directly exposed to avian influenza a viruses for centuries [ ] . influenza a virus gene pools reside in wild aquatic birds where at least ha types and na types are found, as compared to ha (h -h ) and na (n , n ) types circulating in man. also, the genes in aquatic birds are in evolutionary stasis without undergoing changes due to selective pressures. influenza a viruses in man are under constant selective pressure imposed by population immunity causing the hemagglutinin of influenza a virus to change its antigenic properties by accumulation of mutations (genetic drift). however, through double infection and reassortment (genetic shift), novel (e.g. hemagglutinin) genes from aquatic birds may become established in human influenza viruses giving rise to pandemics due to lack of adaptation to and immunity in, humans. previously, it was thought that the different receptor specificity -favoring different side chains of sialic acid -of human and avian influenza viruses would make direct transmission of avian viruses to humans unlikely, but both could be expected to infect swine, which carry receptors for both. thus pigs are considered to be potential reservoirs for generating new influenza virus variants. it has only recently been discovered that viruses considered unique to avian species may also infect man, although this may involve change in receptor specificities [ ] . in conjunctivitis in uk caused by avian influenza viruses (and previously, by seal influenza a viruses) was reported [ , ] (table ) . direct zoonotic transmission of avian influenza viruses to man resulting in human respiratory illness, was not known to occur or had not been diagnosed before the outbreak of h n avian influenza virus in hong kong in where / patients died of lower respiratory tract infection [ ] . after this, in europe, an outbreak of h n hpai avian influenza was encountered in italy ( ) ( ) without reported transmission to humans [ ] . in , a major h n hpai avian influenza outbreak occurred in the netherlands [ , ] . during this epidemic, veterinarians and people who culled infected poultry were at greatest risk of infection. it was noted by active surveillance that human h infections (and simultaneous h infections) were occurring, and consequently prophylactic treatment with oseltamivir was started. the h virus was confirmed to be transmitted to humans of which the majority had conjunctivitis, seven had an influenza-like illness; one veterinarian (who did not receive prophylactic oseltamivir) died. his symptoms started with high fever and headache two days after visiting a farm with infected chickens. one week later, he was admitted to hospital with pneumonia, where his status deteriorated to multi-organ failure, with death due to respiratory insufficiency weeks after onset of symptoms. in addition, in three cases household primary contacts were shown to have the disease by human-to-human transmission [ ] . both na inhibitors, zanamivir and oseltamivir inhibited virus obtained from humans during this outbreak and a significant difference was found in avian influenza virus detection between oseltamivir users ( / ) and those who had not taken prophylactic medication ( / ) [ ] . outbreaks of avian influenza have continued to occur in other parts of the world, especially the devastating ongoing h n epidemic in south-east asia since late with as of june a total of deaths/ cases in viet nam, thailand and cambodia. the epidemic has had a dramatic impact on poultry farming and industry with million birds dying or being destroyed to reduce virus dispersal. this ongoing epidemic clearly has ''pandemic potential''. avian influenza viruses may be detected by virus isolation (in cell culture or embryonated eggs) or rt-pcr which may be targeted at the specific ha subtype or may be generic to influenza a viruses (e.g. targeting the matrix protein gene) [ ] . also, serological tests such as. hemagglutination inhibition may be used. typing may be based on serological methods (such as hemagglutination inhibition), specific primers/probes or sequencing. many commercial influenza a antigen tests detect the nucleoprotein or na activity and should be applicable to the avian viruses, although this is poorly studied and documented. furthermore, it should be noted that rt-pcr from throat swabs of the lethal case in the netherlands were negative [ ] . avian influenza, or ''fowl plague'' outbreaks usually arise following contact with wild aquatic birds, such as mallards and ducks, in which the virus replicates as a rule without causing symptoms. the virus that is excreted in the gut can typically be isolated (or detected by rt-pcr) from cloacal swabs. hinshaw et al. [ ] studied over nine thousand birds and detected % prevalence in young and % prevalence in adult birds. influenza virus is readily transmitted in cold environments and is stable for - days at + °c, or in wet faeces (as shown for h n virus) for at least days at °c and more than days at + °c [ , ] . the main preventive and control measures include proofing the chicken breeding facilities against wild birds. raising chickens and turkeys in the open is a risk, minimizing secondary spread of outbreaks by stamping out the infected poultry, followed by cleaning, disinfection and controlling movements of humans and animals, trade embargoes and reporting the outbreaks (''fowl plague'' is in the top priority ''list a'' of the international animal health code of the office international des epizooties). selling poultry live, a common practice in south-east asia, is a definite risk factor. vaccination of poultry has been used as an additional control measure but may lead to undetected shedding and transmission of mutant virus selected under the pressure imposed by the vaccine [ ] . to prevent further transmission to humans, rapid measures are needed due to the short incubation period. the dutch experience suggests that results can be achieved by personal protection (e.g. protective eye glasses, masks) for all workers who screen and cull poultry, vaccination with regular inactivated influenza virus vaccine and prophylactic oseltamivir for those handling potentially infected poultry, to be continued for days after last exposure [ ] . for humans, specific vaccines containing h and h antigens would be welcome. the only known zoonotic agent of the togaviridae family to cause human disease in europe is the mosquito-borne sindbis virus (sinv), in the genus alphavirus. sinv is distributed throughout the old world and australia and causes rashes and polyarthritis outbreaks in northern europe, similar to chikungunya, oÕnyong-nyong virus and ross river virus in far east asia, africa and australia, respectively, whereas other alphaviruses causing encephalitic infections in man (venezuelan, western and eastern equine encephalitis virus) are found in the new world. alphaviruses are enveloped, positive-strand rna viruses with an kb genome. the non-structural proteins (nsp - ) are encoded from the -terminus of the genome, and a separate subgenomic s rna from the -end is used as a messenger for the structural proteins: the - kda capsid protein (c), and the - kda envelope glycoproteins (e and e ) [ ] (table , fig. ). sinv was first isolated in the nile delta in the s from a pool of mosquitoes without knowledge of any disease association. it is now known to be the causative agent of mosquito-borne epidemic polyarthritis with accompanying rashes and when described in northern europe it was given the names ockelbo disease, pogosta disease, or karelian fever when found in sweden, finland and russia, respectively. most infections occur during august-september, and larger outbreaks tend to appear with a seven-year interval (e.g. in finland, serologically verified cases occurred in , cases in ; and in sweden - cases are reported during peak years) [ , ] , with a peak incidence ( %) in -year old females. the association of sinv with pogosta disease was first discovered in the early s and it is believed that the virus may have been distributed throughout northern europe around this time. this conclusion is based on the evidence that thousands of human and bird sera collected during the early s in finland, were negative for sinv antibodies, whereas in the s - % of the population were sinvantibody positive [ ] . antibodies to sinv without polyarthritis outbreaks have been recorded in italy, romania, greece and the former yugoslavia [ ] . however, human disease due to sinv has been recorded in south africa, from where it may have originated. sinv was isolated from mosquitoes in sweden, norway and russia in the early s [ ] [ ] [ ] and sinv antibodies are found in wild tetraonic and migratory birds, most commonly (in sweden) from passeriformes such as redwing (turdus iliacus), fieldfare (turdus pilaris), blue tit (parus caeluleus), chaffinch (frinigilla coelebs), songthrush (turdus philomelos); thrushes have been suggested to be a major candidate as an amplifying host [ , ] . in addition, antibodies are commonly found in galliformes [ , ] . phylogenetically, sinv strains are similar in northern europe and south africa (in the north to south dimension), but differ considerably from strains circulating in asia and australia, where sinv-associated rash-arthritis is not recorded. this is consistent with the notion of a north-south dispersal of sinv strains by migratory birds [ ] . several bird species can be infected experimentally [ ] . it is evident that sinv cycles between birds and ornithophilic (culex and culiseta) mosquitoes (table ) . however, it may spill over to other hosts (evidence from many vertebrates from a frog to a bear) and vectors (including ticks and aedes mosquitoes) [ ] . recently, during an outbreak in finland in , the causative agent of pogosta disease was isolated for the first time in europe from skin biopsies and a blood sample of patients [ ] ; the virus strains were most closely related to sinv strains isolated from mosquitoes in sweden and russia years previously. the incubation period for the disease is about one week and the onset is accompanied by arthritis/arthralgia and itchy rash as the dominant symptoms, and also fatigue, mild fever, headache and muscle pain. hematological laboratory parameters are within the normal range and levels of c-reactive protein (crp) are not elevated. the rash is usually located on the trunk and thighs and lasts for a couple of days. one third to a half of patients, suffer from joint pains for more than months [ , ] . usually several joints are affected, the most common being the ankle, wrists, knee, and finger joints ( % or more of patients), as well as hip, shoulder and elbow joints [ , a, b ]. diagnosis is based on serology using enzyme immunoassay, immunofluorescence assay or hemagglutinationinhibition, and detection of seroconversion or a -fold rise in titre between two samples, or positive igm in a single sample. the first sample is usually taken during the first week after onset of illness, another sample is required to diagnose or exclude sinv infection; igm antibodies are detectable until approximately days post-onset, and igg antibodies can be detected approximately days after onset of illness [ b, ] . in some cases persisting igm antibody can be detected years after infection [ ] . for research purposes, the virus can be detected by ] or isolated from skin biopsies [ ] . no specific preventive measures are available, apart from avoiding mosquito bites. flaviviruses comprise a diverse group of pathogens that have been traditionally classified as arthropodborne viruses. they are linear positive single-stranded rna viruses with a monopartite genome ( - kb) that encodes structural proteins: the kda capsid protein (c), the - kda major envelope protein (e) and the . kda glycoprotein m (in mature virions); and non-structural proteins (ns , ns a, ns b, ns , ns a, ns b and ns ) (table , fig. ). noncoding or untranslated regions flank the infectious rna genome. when seen in the electron microscope flaviviruses appear as uniform spherical particles, - nm in diameter. the virus particles consist of a lipid envelope that has a surface covered by protrusions that contain envelope (e) and membrane (m) structural proteins, organized as dimers. this envelope surrounds an isometric capsid protein of approximately nm in diameter [ ] [ ] [ ] . there are currently about members in the family flaviviridae [ ] which have been found infecting a wide variety of organisms including mammals, arthropods, avian and amphibians. many of these viruses are major pathogens of humans, domestic and farmed animals as well as wildlife species. with the possible exception of the dengue viruses, the flaviviruses are zoonotic, depending almost entirely for their existence on wildlife vertebrate and in many cases, invertebrate species. the type species of the genus is yellow fever virus (yfv), hence the term ''flavi'' from the latin word flavus, which in turn describes the yellowish color of the skin in yellow fever infections [ ] . the classification, and serological and phylogenetic studies of flaviviruses reflect the importance of the vector on the biology and evolution of this genus. there are essentially three groups of flaviviruses: tick-borne, mosquito-borne and non-vectored flaviviruses, although this grouping is, to some extent, arbitrary since some mosquito-borne viruses are also transmitted by ticks and vice versa [ ] (table ). phylogenetic analysis also shows very strong correlations between genetic relationships, epidemiology and ecology of these viruses [ , ] . some flaviviruses are responsible for a significant proportion of the morbidity and mortality that is registered annually worldwide. they cause epidemic outbreaks that involve encephalitis and/or haemorrhagic fever, often fatal and involving millions of humans or in some case birds or mammals. important flaviviruses affecting humans are the dengue viruses, yellow fever virus, west nile virus (wnv), tick-borne encephalitis virus (tbev), japanese encephalitis virus, saint louis encephalitis virus, and murray valley encephalitis virus among others. dengue virus alone causes more than - million cases worldwide each year and some million people are now at risk from dengue infections [ ] . the most important flavivirus in europe is tbev, which is endemic in many european countries, and also in russia, ( table , fig. ) northern china and northern japan [ , a] . it affects thousands of people annually and has a significant impact on public health. the virus is transmitted to humans mainly through a tick bite, however, the infection has also been reported to occur by drinking unpasteurised goat milk from viraemic animals [ b, c]. the virus is maintained in nature in a cycle involving ticks and wild vertebrate hosts and also by transovarial and transstadial transmission in its vector [ , ] . serological evidence and viral isolations, as well as sequence similarities have suggested that migratory birds could also play a role in the transmission of tbev from central europe to scandinavian countries; moreover, endemic areas of tbev are regions of high migratory bird activity [ ] . tbev is classified taxonomically into three subtypes: european subtype, far eastern subtype, and siberian subtype. the first subtype is transmitted mainly by ixodes ricinus, and the last two by ixodes persulcatus [ , ] . the distribution of tbev is well coordinated with the distribution of its vector, furthermore, different genotypes are located in distinct geographical areas and associated with specific vector hosts. recent data have shown the co-circulation of all three subtypes of tbev in the same geographical region, specifically in latvia, where the two vector ixodes species habitats meet [ ] . however, the endemic region in europe is patchy and covers only part of the geographical range of e.g. ixodes ricinus. there has been an increase of the incidence of tbev in many of its endemic areas but not in austria where a countrywide successful vaccination campaign was established reducing the disease incidence to lower levels [ c, d, a]. tbev affects principally the nervous system and can cause several clinical features of different severity table tick-borne enchephalitis viral infections in europe per country through time year year year year austria belarus -a croatia czech r. denmark -- estonia finland france germany - including meningitis, meningoencephalitis, meningoencephalomyelitis and meningoradiculoneuritis. hospitalization varies from days to months and in some cases years of treatment and rehabilitation are necessary as sequelae occur in approximately / of the patients. the incubation period of tbe is between and days. the disease is characteristically biphasic. the first phase (day - of onset of symptoms) is viraemic and can be either asymptomatic or fever, malaise, headache, anorexia, nausea, and muscle pains may be present. the second phase occurs in up to % of the patients after about days lag period (approximately days after the tick-bite) as a neurological disease of which about . % has a fatal outcome [ b, c, d]. the neurological symptoms and severity vary: the clinical picture includes meningitis (in about half of the patients), meningoencephalitis, meningoencephalomyelitis and meningoradiculoneuritis. hospitalization varies between days and months and in some cases years of treatment and rehabilitation are necessary in case of e.g. paresis. altogether, neuropsychiatric sequelae occur in approximately / of the patients. louping ill virus (liv) is endemic in ireland, in the northern region of great britain and in norway (fig. ) affecting principally sheep with a disease that is known as ovine encephalomyelitis, infectious encephalomyelitis of sheep, or trembling-ill. liv is transmitted to sheep by the tick vector ixodes ricinus. the natural life cycle of liv resembles that of tbev, it can be sustained in the natural environment through non-systemic transmission of virus between ticks cofeeding on rodents and other wild animals, which in turn infect grazing animals such as sheep and goat as a zoonotic disease. louping ill virus has also been observed in a bird-tick-bird cycle involving the red grouse (lagopus lagopus scoticus), ptarmigan bird species and the ixodes tick [ ] . infection with liv in sheep is characterised by a biphasic fever, depression, ataxia, muscular in-coordination, tremors, posterior paralysis, coma, and death. there is evidence for infection by liv in other domestic species and wildlife, i.e. cattle, horses, pigs, dogs, deer, shrews, wood-mice, voles, and hares [ , a] . it is generally believed that the majority of avian infections occur through a tick bite, however laboratory experiments and field observations have demonstrated that the red grouse can also become infected by feeding on infected ticks indicating that the vector bite is not the only route of infection [ b] . humans are also susceptible to infection with liv. however, the majority of the cases reported are accidentally acquired infections in laboratory workers. the second most frequent infection results from handling infected animal carcasses. infection with liv in humans can cause a neurological disease resembling the clinical picture observed for tbev infections, i.e. biphasic encephalitis, influenza-type illness, fever, articular pain, meningitis, myagia and poliomyelitis-like illness [ ] . other possible transmission routes for liv infection to humans include drinking contaminated milk from goat or sheep in an acute phase of infection [ ] , tick-bite, exposure to infective material, or through skin abrasions or wounds. antigenic and phylogenetic studies have shown that liv is most closely related to strains of the western european subtype of tbev and it is estimated to have emerged from this lineage approximately years ago [ ] . west nile virus (wnv) was first discovered in in uganda [ ] . it occurs throughout africa, the middle east, europe, russia, india and indonesia and was recently introduced into north america (new york) [ , ] . in the old world wnv is primarily considered to be an african virus which annually disperses northwards out of africa when birds migrate to europe, the middle east and asia [ ] . in humans, the majority of wnv infections cause a nonsymptomatic or mild febrile illness; however some infections can cause encephalitis and in most severe cases can lead to death, particularly in elderly patients. the incubation period is between and days after a mosquito bite (http://www.cdc.gov/ncidod/ dvbid/westnile/wnv_factsheet.htm). west nile virus is an illustrative example of the human impact on the dispersal and evolution of flaviviruses. the virus appeared for the first time in the usa, in new york in causing sixty-two confirmed human infections and seven deaths [ ] . the virus successfully over-wintered and during the next years dispersed widely throughout north america and now more recently also to central america and the caribbean. in north america the virus infects a very wide range of mosquito and animal species. the exact mechanism of introduction into north america is not known [ - a] . to date, more than human cases and deaths from wnv have been reported in the united sates of america (http:// www.cdc.gov/ncidod/dvbid/westnile). in europe, outbreaks caused by wnv have been recorded since the early s, especially in mediterranean countries, romania and southern russia (fig. ) . larger outbreaks (over cases) have been reported since the mid s in urban settings, especially a large outbreak in bucharest, romania in [ a, b, c] . in southern russia, specifically in volgograd, astrakhan and krasnodar regions, wnv has caused large epidemics of approximately human cases, with % mortality rate of reported cases. molecular epidemiological studies have shown that the latest large outbreaks in volgograd were caused by strains genetically similar to that of romania- , kenya- and newyork- reflecting the widespread distribution capacity of these epidemic viral strains [ b, b]. the incidence of wnv in europe is largely unknown. phylogenetic studies have showed that wnv has diverged into two main lineages, which form internal clusters or clades [ c, a, b, c]. more recently, a novel virus (rabensburg virus), antigenically and genetically closely related to wnv was isolated from a culex pipens mosquito pool in czech republic. this new virus could represent a third lineage of wnv, however more studies are needed to confirm this hypothesis or to determine whether or not this could represent a new member of the flaviviridae family [ a] . usutu virus (usuv) was first isolated from a mosquito in africa in [ c]. it was characterised serologically and classified within the japanese encephalitis virus serocomplex. usutu virus had rarely been isolated since then, with only one reported human case and being present only in two regions of africa. however, in the late summer of , usuv was found in vienna in austria during a study of an avian epidemic characterized by fatal encephalitis that was thought to be caused by wnv. the virus caused die-off among the bird population, especially blackbirds, in vienna (fig. ) and when isolated from birds and mosquitoes it showed % genetic identity to the african usuv [ b]. this is the first time usuv has been observed outside africa and also the first time it has been associated with fatal disease in animals. the virus re-appeared in the late summer of in the same region of vienna [ a] . most recently, in the virus has been isolated from humans (associated with rash in one patient) and from birds in austria and evidence exists as to the virus being able to overwinter establishing itself in this geographical area (nowotny, n. second european congress of virology, eurovirology ). as mentioned above the distribution of flaviviruses is worldwide, and we have described the zoonotic flaviviruses endemic to europe. however, it is important to note the increasing incidence of imported flaviviruses totaling over cases mainly due to changes in human behavior, such as increased travel to non-european destinations (http://www.eurosurveillance.org). the dengue viruses (denv) are a world-wide public health problem. they are transmitted to man by mosquitoes, particularly aedes aegypti and cause a wide range of different clinical outcomes [ c, a] . it is estimated that million cases of dengue fever (df) and of dengue hemorrhagic fever (dhf) cases occur annually [ ] . in a study based on the epidemiology and clinical course of travellers with symptoms of dengue infection it was found that the incidence of df among european travellers is underestimated, since diagnostic procedures, in general, for febrile patients often do not include tests for tropical arthropod-borne diseases, such as dengue virus [ b] . there have also been some imported cases of yfv to europe mainly by tourists travelling from endemic areas. however, the incidence of yfv as an imported disease is much lower than that of dengue infections (http://www.eurosurveillance.org) presumably because of the different nature of these diseases, denv having spread worldwide throughout the tropics and yfv occurring only in its endemic regions in africa and south america [ c]. traditionally, diagnosis of flaviviruses in europe has been restricted to detecting tbev infections through serological assays; igm-capture enzyme immunoassay, hemagglutination inhibition-, and immunofluorescence assay. igm antibodies in serum, and in some cases in cerebrospinal fluid during the neurological disease usually provide the diagnosis. rt-pcr is rarely positive at the second phase of the disease [ a]. because of the close antigenic relatedness of flaviviruses, laboratory findings can easily lead to misdiagnosis [ b]. in a study conducted in hungary, tbev-positive serum panels were tested retrospectively against wnv and some sera were found to show higher titres to wnv than to tbev when compared in serological assays (e. ferenczi, personal communication). as mentioned above, a study including travellers returning to europe from tropical destinations proved that many cases remain undetected. there is a need to improve the diagnosis for flaviviruses in order to determine the true incidence and prevalence of these infectious diseases in europe, and to study the ecology of imported viruses to determine which viruses have been able to establish themselves in the continent and which are still continuously being imported from africa or asia. meanwhile anti-vector campaigns and vaccination for travellers to endemic areas are the only measures to prevent and control these infectious diseases [ ] . there are effective vaccines for tbev and yfv but a protective immunogen does not exist for denv or wnv. tbev vaccines from two commercial manufacturers (baxter and chiron) are available and widely used, especially in austria and germany, both are based on formalin-inactivated virions, three injections are needed for full protection. booster immunizations are recommended every - years for people living or spending holidays in endemic areas. . . nairoviruses: crimean-congo hemorrhagic fever virus the genus nairovirus (family bunyaviridae) is composed of predominantly tick-borne viruses that have been divided into seven serogroups [ ] including several associated with severe human and livestock diseases (especially crimean-congo hemorrhagic fever virus (cchfv) and nairobi sheep disease virus). of the pathogenic viruses only cchfv causes significant human morbidity and mortality and is found in europe. like other members of the bunyaviridae family nairoviruses possess a tripartite single-stranded rna genome of negative polarity consisting of large (l), medium (m) and small (s) segments. the kb l segment encodes an rna-dependent rna polymerase (deduced size kda in cchfv), the . kb m segment encodes the precursor for the two envelope glycoproteins gn ( kda in cchfv) and gc ( kda in cchfv), and the . kb s segment the viral nucleocapsid n ( kda) ( table , fig. ). like with other members of the bunyaviridae viral messenger rnas (mrna) are not polyadenylated and are truncated relative to the genome rnas at the termini. messenger rnas have -methylated caps and - nontemplated nucleotides which are derived from host cell mrnas. the nairovirus l segment encoding the rna polymerase is conspicuously large, almost twice the size of many other members within the family bunyaviridae, and may thus provide other functions such as viral helicase and a papain-like cysteine protease activity predicted from the nucleotide sequence [ , ] . viral protein analysis has suggested that gn and gc may be derived from and kda precursors, of which the latter contains an n-terminal region with a highly o-glycosylated mucin-like domain [ ] . the cchfv nucleocapsid protein colocalizes and interacts with human mxa protein; this interaction may explain the antiviral effect of interferons on cchfv [ ] . similar to the hantavirus-rodent association, the high genetic variation of viruses of the genus nairovirus reflects the diversity of their predominant tick hosts [ ] . within cchfv isolates, comparison between m and s segment phylogenetic groupings suggests that reassortment events have occurred in some virus lineages [ ] . reverse genetics, recently established for cchfv [ ] , provides a unique opportunity to study the biology of nairoviruses and tailor optimal therapeutic and prophylactic measures against cchfv infections. cchfv is transmitted most efficiently by hyalomma ticks, followed by rhipicephalus, dermatocentor spp and many other species of ixodid (hard) and some argasid (soft) ticks (table ) . among ticks cchfv is capable of transmitting infection both transovarially and transstadially. the life cycle of cchfv also includes a tick-vertebrate host cycle involving both wild and domestic animals. the virus or antibodies against it have been detected in rodents, hares, hedgehogs and some birds but human infections seem to be principally from contacts with livestock (mainly cattle, sheep, goats) including in africa farmed ostriches and less often ticks [ , ] . thus cchfv is more commonly seen in persons exposed to blood and tissues of infected animals during occupational activities, such as farming, herding, veterinary examination and abattoir work. nosocomial infection is common and often results in small outbreaks. yet, outdoor and recreational activities also represent a risk factor. in addition, horizontal transmission of cchfv from mother to child may occur [ ] . the global distribution of cchf follows closely that of hyalomma spp. in the middle east, asia, africa and southeast europe [ , ] . sequence analysis of cchfv s rna segments gives patterns following links between different geographic locations, in some cases suggesting links originating from trade in livestock and long-distance carriage of virus or infected ticks during bird migration [ ] . in europe, cchf occurs in the balkan peninsula (albania, bulgaria, greece, turkey, yugoslavia) but also in southern russia, hungary, france and portugal [ , , ] . the symptoms and signs of crimean-congo hemorrhagic fever are similar to those of other viral hemorrhagic fevers [ , ] . the incubation period is generally short ranging usually from to days. there is typically a very sudden onset of illness with fever, rigors, chills, intense headache and backache or leg pains, myalgia, nausea, and vomiting. patients may also present with photophobia, somnolence and menigism with confusion or aggression. hemorrhages in the form of petecchiae, ecchymoses, epistaxis, melena and bleeding from various organs usually begin a few days later. tachycardia is common and lymphadenopathy is seen occasionally. the case-fatality rate is - %. the pathology consists of hemorrhagic and necrotic lesions in various organs as well as fibrin deposits. the methods used for detection of cchfv infection in humans or livestock include indirect immunofluorescence on virus-infected or n-expressing transfected cells. both igm and igg antibodies reactive for cchf appear within a week in patients [ , ] . alternatively a recombinant nucleocapsid protein-based enzyme immunoassay [ ] [ ] [ ] may be used. rapid detection and quantification of cchfv rna is possible by real-time reverse transcription pcr [ ] . ribavirin is clearly effective in treatment of crimean-congo hemorrhagic fever [ , ] but supportive treatment (blood, thrombocytes, coagulation factors) is equally important. immune plasma from recovered patients has also been used to treat patients but not in controlled studies with a follow-up of virus-neutralizing activities [ ] . the most effective method of preventing infections is to take measure to avoid exposure to ticks (protective clothing, tick repellent, frequent body searches to remove ticks). inactivated virus prepared in mouse brains has been used on a limited scale as a vaccine in southeastern europe and the former ussr but the sporadic and unpredictable occurrence of the disease renders it difficult to identify target populations and has slowed development of a safe and modern vaccine [ ] . orthobunyaviruses belong to the family bunyaviridae. these enveloped viruses have a three-segmented negative-strand rna genome. the . kb s segment encodes the - kda nucleocapsid protein (n) and a - kda nonstructural protein (ns); the . kb m segment encodes the polyprotein precursor of two glycoproteins, g and g ( - kda and - kda, respectively), and a nonstructural protein nsm ( ) ( ) ( ) ( ) ; and the . kb l segment encodes the rna polymerase ( kda) ( table , fig. ). viral messenger rnas are not polyadenylated and are truncated relative to the genome rnas at the termini. messenger rnas have -methylated caps and some nontemplated nucleotides which are derived from host cell mrnas. orthobunyaviruses are transmitted to humans by a variety of mosquito species, and in europe two known human pathogenic representatives of the genus circulate, tahyna virus and inkoo virus (mostly transmitted by aedes spp.) [ , , ] (table ). these viruses belong to the california serogroup, and their incidence is associated with the distribution of the carrier mosquitoes. the natural cycle of these viruses involve also mammal hosts. tahyna virus circulates throughout most of europe, whereas inkoo virus is mainly reported from northern europe [ , a] . tahyna virus causes an influenza-like disease which may also present as a meningitis. the infection caused by inkoo virus is mostly sub-clinical or a mild disease, although encephalitis has been reported. the most typical symptoms associated with encephalitis or meningitis caused by californian serogroup viruses include fever, headache, nausea, vomiting, convulsions and confusion. in europe the seroprevalence for californian serogroup viruses varies from % to %, depending on the geographic area [ ] . in finland the seroprevalence against inkoo virus varies from % to % (Å land islands) to - % (finnish lapland) [ , putkuri et al, unpublished results] . in disease-endemic areas the seropositivity of the population increases with age [ b]. the diagnosis of orthobunyaviruses is based on serology, either as a rise in igg-antibody titers, or the presence of igm antibodies. also rt-pcr methods are under development to detect viral rna in cerebrospinal fluid samples of patients with encephalitis. phleboviruses are one of the five groups within the family bunyaviridae. they have a negative singlestranded rna tripartite genome, namely: l ( . kb), m ( . - . kb) and s ( . - . kb). the l segment encodes a single protein of kda (rna polymerase) in the complementary sense. the m segment encodes a protein precursor of kda in the complementary sense which is cleaved into two glycoproteins g ( kda) and g ( kda). the s segment has an ambisense coding arrangement, and it encodes the nucleocapsid protein (n) of kda in the complementary sense and a non-structural protein (nss) of kda in the virion sense [ , ] (table , fig. ). viral messenger rnas (mrna) are not polyadenylated and are truncated relative to the genome rnas at the termini. mrnas have -methylated caps and some nontemplated nucleotides which are derived from host cell mrnas. when seen under the electron microscope the virions are spherical and enveloped and approximately - nm in diameter. glycoprotein projections of - nm are also seen embedded in the membrane. there are between and spikes per virion [ , ] . phleboviruses are arthropod-borne viruses and are transmitted mainly by phlebotomine sandflies, hence the derivation of its name ''phlebo'' (table ) . however, mosquitoes and ticks can also transmit phleboviruses. phleboviruses are distributed throughout most of the world but have not been reported in australia [ ] . the first documented record of a disease resembling those caused by phleboviruses dates back to the s in the mediterranean countries of europe [ ] . however, the first virus isolation occurred for rift valley fever virus in in kenya [ ] . retrospective serological studies have indicated that outbreaks caused by phleboviruses have occurred since in the sub-saharan africa region [ ] . phleboviruses are major causal agents of encephalitis in humans, especially among children, in mediterranean countries. they also have an important impact in livestock especially in african endemic areas. infection of livestock is characterised by a high rate of abortions and pathologies associated with hemorrhagic illness (leukopenia, thrombocytopenia, fibrin thrombi, intravascular coagulopathy, etc.) [ ] [ ] [ ] . the distribution of the disease follows that of its vector. however the natural history of phleboviruses is largely unknown and for many species the amplifying host has not been identified [ ] [ ] [ ] . in general, phlebovirus infections cause a - days illness characterised by an incubation period of - days followed by fever, general malaise, headache, photophobia, and back and joint pain [ ] . the illness occurs during the summer months when the activity of phlebotomine flies is high [ ] . there are three recognised members of the genus phlebovirus, associated with disease in humans. rift valley fever virus (rvfv), which is the type species of the genus and is transmitted by mosquitoes, causing an influenza-like disease that affects domestic animals and humans. the majority of human infections are asymptomatic; however, in . % of cases it can cause severe haemorrhagic fever, encephalitis and death. the geographical distribution of rvfv includes africa, egypt, saudi arabia and yemen and occurs as epizootics involving aedes spp. mosquitoes and domestic animals [ ] . toscana virus (tsv) causes a mild influenza-like disease that can occasionally develop into an acute neurological disease, such as meningitis or meningoencephalitis in italy and possibly other mediterranean countries. a similar virus (granada virus) was recently isolated in spain [ ] . tsv is the number one cause of encephalitis among children in italy. the distribution of the virus follows that of its vector, phlebotomus perniciosus, found in italy, spain, portugal, and cyprus. human cases have also been reported from southern france and greece. the virus replicates in the sandfly vector population; however, experimental evidence suggests that an amplifying vertebrate host is needed to sustain the virus in the arthropod population [ ] [ ] [ ] [ ] [ ] [ ] . sandfly fever virus (sfv) sicilian and naples viruses can cause a mild-influenza like disease. the distribution of sfv also follows that of its vector, phlebotomus papatasii, found in the mediterranean basin extending to the middle east and arabian peninsula, the caucasus mountains, pakistan and india [ ] [ ] [ ] . diagnostics of phlebovirus is performed mainly by igm-capture eia and ifa. the virus can be isolated using intracranial inoculation in suckling mice or using a susceptible tissue culture cell line (vero, llc-mk , bhk- ) [ , a] . toscana virus and naples sandfly fever virus group together and are distinct antigenically and phylogenetically from sicilian sandfly fever virus [ b] . prevention of infections by phleboviruses varies depending on the type species. immunising livestock with the formalin-inactivated or live-attenuated vaccines can prevent rvfv by avoiding epizootics and hence human infections [ , ] . in the case of tsv and sfv, prevention is limited to controlling the vector population through insecticides and repellents [ , ] . what are the reasons for the appearance of all these emerging and re-emerging viruses? have changes taken place in the viruses themselves? apparently not. the principal reasons are changes in the environment and human activity that have created new attacks with nature. factors such as climate change, increasing intensity of agriculture, the building of dams and introduction of other irrigation measures which generate new breeding sites for mosquitoes, crises and wars which bring rodents and arthropods closer to humans, population growth and especially in suburban slums, and global air traffic are important factors generating such new contacts, or may affect the ecological cycles of these viruses. many epidemics may be unexpected outcomes of such changes. moreover, the new molecular biology techniques facilitate detection of new viral agents. many prevention and control measures, such as the anti-aedes 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fever virus from sandflies and humans during the same season in aurangabad district, maharashtra state phlebotomus fever in egypt: isolation of phlebotomus fever viruses from phlebotomus papatasi the genus phlebovirus and its vectors clinical and serologic responses of volunteers infected with phlebotomus fever virus (sicilian type) phlebotomustransmitted toscana virus infections of the central nervous system: a seven-year experience in tuscany. scand toscana virus infections of the central nervous system in children: a report of cases evidence of toscana virus infections without central nervous system involvement: a serological study high prevalence rates of antibody to three sandfly fever viruses (sicilian, naples, and toscana) among cypriots infections due to sandfly fever virus serotype toscana in spain central nervous system involvement during infection by phlebovirus toscana of residents in natural foci in central italy ( - ) distinction between bunyaviridae genera by surface structure and comparison with hantaan virus using negative stain electron microscopy phylogenetic relationships among members of the genus phlebovirus (bunyaviridae) based on partial m segment sequence analyses climate and satellite indicators to forecast rift valley fever epidemics in kenya evaluation of a new rift valley fever vaccine: safety and immunogenicity trials immunization against rift valley fever virus. studies of the immunogenicity of lyophilized formalin-inactivated vaccine zoonotic transmission of hepatitis e virus from deer to human beings key: cord- -x ni m authors: stienen, martin n. title: covid- in europe: le roi est mort, vive le roi! date: - - journal: neurospine doi: . /ns. . sha: doc_id: cord_uid: x ni m nan covid- in europe: le roi est mort, vive le roi! there's no doubt about it. we europeans were astonished to see how such a small ( nm) corona virus could spread so quickly around the world, has since brought the global economy to its knees and dominates all areas of life. when the first reports from distant wuhan, china appeared on the evening news, many of us thought that the epidemic would likely remain local or at least regional, controlled by the chinese government's large-scale containment measures. despite a long history of bacterial & viral pandemics in europe (e.g., plague "black death" - , influenza "flu pandemic" - & "spanish flu" - , hiv/aids pandemic -today), - the impact of the viral epidemics in the last decades on us has been moderate -avian flu h n , swine flu h n , ebola epidemic, to name but a few... in contrary, the "coronavirus disease " (covid- ) was increasingly diagnosed -at a staggering rate -in europe, especially in spain, italy, germany, united kingdom, france among other countries. on january the world health organization declared the outbreak to be a public health emergency of international concern, and recognized it as a pandemic on march . , in the past couple of weeks, the covid- crisis with its near . million confirmed cases ( , casualties) has fundamentally impacted our practice as spine surgeons worldwide, as it has exerted a significant effect on us as human beings. i work as neurosurgeon at the university hospital zurich, switzerland. fortunately, switzerland was not among the first european countries to be affected, which allowed protective measures to be implemented before the pandemic could strike the country too badly. as of now ( april, ) the country has , confirmed cases of covid- , of which , succumbed ( . %). the situation in zurich is even more manageable: there are , confirmed cases of covid- , of which died ( . %). intensive care and ventilation units have been expanded, but their capacities are still not fully utilized. with the exception of the canton of ticino and some regions of the romandy (e.g., geneva), swiss hospitals and public health care were not pushed to the limits. the situation in switzerland might be generalized to whole of europe, where most regions were able to control the situation fairly well and the regions that decompensated under a wave of high caseloads were -fortunately -but few. in my role as a spine surgeon, i reduced my professional activities in accordance with national and institutional guidelines -the reasons and necessity for this are described well in the editorial by jain and wang. despite the recommendations of professional societies, i have experienced difficulties to decide from case to case which patient should be postponed or declared an emergency and be operated on in times of limited resources -mostly with the intention to avoid unbearable suffering or permanent neurological damage (fig. ). many patients are eagerly awaiting a surgical procedure, but in many countries, it is unclear yet when we will be allowed to resume elective surgery. fortunately, i have experienced a high level of understanding and acceptance of these regulations by patients and their relatives. most spine surgeons in the public sector in europe are employed by hospitals -on more or less fixed salary -without major economic pressure to operate and with the comfortable protection of high social security standards for a system-relevant profession. this makes it easier for us to accept novel "home office" concepts, shifting away from the manual act of surgery and instead focusing on academic activities and working off the long overdue "to do" list. moreover, we are privileged to be well-protected by the safety strategies of our institutions. at zurich university hospital, whenever i perform emergency procedures, i do this under special protective measures. until proven otherwise, all patients are initially treated like a "covid- case, " which has a certain impact. the conditions to operate are more difficult, as the mandatory class-ii facepiece mask (ffp- ) render breathing difficult and the sealed goggles regularly fog up during the procedure, complicating the visualization of critical structures. all of the problems that i personally faced in the covid- crisis so far appear negligible, however, when put into wider context. we are not only spine surgeons but compassionate human beings and the fact that individual fates are forgotten behind the sheer number of casualties -many of them dying alonehas touched me to the heart. moreover, i was shocked by the selfish and nationalist tendencies of some individuals and governments, competing for restricted health care goods on the global market. it is sad but very likely that the heavy blow of this crisis is yet to come: as the european economy continues to bleed out, unemployment and poverty are on the rise, which has a well-known and long-lasting (spanning over several generations) negative effect on bodily and mental health. , the european union just like other international institutions seem paralyzed, while nationalist governments, extremists and criminal societies such as the mafia cleverly exploit the situation for their own purposes and benefit. the damage that those midand long-term effects will cause are less in focus right now but are going to exceed the direct damage resulting from covid- by far. in addition, there are only few reports of covid- and fig. . case vignette of a -year-old patient with idiopathic parkinson disease (treated by deep brain stimulation), hypothyroidism, hypercholesterolemia and a history of prior spinal fusion procedures presenting with nonunion at l / and severe proximal junctional kyphosis at l / to the extent that the screw heads and rods at the l level risk to violate the skin (with subsequent risk of infection) and neurological compromise at the junctional level could occur. (a) lateral standing whole spine xray. (b) anteroposterior standing whole spine x-ray. the patient reports extreme, barely manageable back pain from the l screw stabbing the l / disc space and scratching the l vertebral endplate with every movement. the patient fulfills certain risk factors for unfavorable course in case of covid- infection and according to the nass (north american spine society) guidelines he would qualify for "elective" or potentially for "urgent" care. how long can and should appropriate surgical treatment be postponed, weighting risk of treatment vs. risk of delaying treatment? its damage produced in less developed countries, which is still in the air as serious threat to humankind. on the contrary, i have also experienced and observed many positive aspects as a result of this crisis -ceasefire in some battle regions of yemen and syria, reduction of environmental pollution and return of nature to a surprising extent, spare time to be spent with family and with reflection on the essentials. moreover, there is solidarity with friends and surgeon colleagues from particularly affected regions, ultra-fast implementation of long overdue digital solutions for remote work, covid- information and webinars organized by the eans (european association of neurosurgical societies), ao spine, and other organizations on short notice to lend a voice to and sympathize with severely affected spine surgeons. it is believed that pandemics such as the current one will become more frequent, and their severity may vary depending on infectivity and virulence, amongst other factors. viruses and other pathogens might even be used as weapons by bioterrorists or corrupt governments in the future. the patchwork carpet of european countries and federal states -many of which followed different strategies to contain the virus -offer great opportunities to compare strategies with regards to effectiveness in a highly mobile st century society. as we continue to fight back the further spread of the disease, the lessons learned by the current covid- pandemic should be used to prepare for what lies in front of us. this is true for all aspects of life, but it is our responsibility to define standards in such situations for the field of spine surgery including patient care, education of students/residents/fellows and research. initiatives such as the current neurospine emergency bulletin pave the way. recent insights into the hiv/aids pandemic world health organization. statement on the second meeting of the international health regulations world health organization world health organization. who director-general's opening remarks at the media briefing on covid- - world health organization universitätsspital zürich: years of neurosurgical patient care in switzerland covid- and the role of spine surgeons. neurospine forthcoming burr ridge (il): nass the impact of poverty on the current and future health status of children poverty and health coronavirus isn't an outlier, it's part of our interconnected viral age world economic forum; c epidemiology of the black death and successive waves of plague mortality burden of the - influenza pandemic in europe key: cord- - dn at k authors: portillo, aránzazu; ruiz-arrondo, ignacio; oteo, josé a. title: arthropods as vectors of transmissible diseases in spain() date: - - journal: med clin (engl ed) doi: . /j.medcle. . . sha: doc_id: cord_uid: dn at k different aspects related to globalization together with the great capacity of the arthropod vectors to adapt to a changing world favour the emergence and reemergence of numerous infectious diseases transmitted by them. diptera (mosquitoes and sandflies), ticks, fleas and lice, among others, cause a wide spectrum of diseases with relevance in public health. herein, arthropod-borne disease are reviewed, with special emphasis on the existing risk to contract them in spain according to different parameters, such as the presence of arthropod and the circulation or the possible circulation of the causative agents. infectious agents. most avs belong to insecta and arachnida classes (table ) . to review the broad subject of arthropod vector-borne diseases (avbd) in spain is a complex task. just listing the arthropods that transmit diseases in our environment, such as dipterans (culicids and phlebotominae sand flies), fleas, lice, bed bugs and ticks, among others, and the diseases they transmit, or that they can transmit at any given time, would be a reason for one or several treatises. in any case, before discussing the subject, it should be remembered that the infections that they transmit are usually included in the socalled zoonoses. in this regard, the world organization for animal health estimates that at least % of infections that affect humans have a zoonotic origin and, according to the pandemic emerging threats program of the american agency for international development, almost % of current threats also have this origin. one of the many known routes for the acquisition of zoonoses, apart from direct contact with animals or their products, faecal-oral or respiratory routes, bites or scratches, the consumption of undercooked - /© elsevier españa, s.l.u. all rights reserved. products or the intake of milk, is av transmission. it is difficult to limit this issue to our country, since the setting is global and very dynamic, and diseases do not understand political borders. only a few months ago new threats appeared, such as the re-emergence of yellow fever in brazil or the epidemic of plague in madagascar. however, in this review we will put the focus on avbd with greater risk to humans in our environment, without losing the "one health" perspective. avbd are subject to complex interactions (demographic, social and cultural changes, climate change, wars and famine or evolution of microorganisms) among which, undoubtedly, global transport systems and the consequent invasion of exotic species stand out. generally speaking, travel, migration and globalization contribute to the emergence of infectious diseases. its importance has been debated for many years and, possibly, dates back to ancient times. humans carry their usual microbiota, pathogens, ectoparasites and other possible vectors, the immunological history of past infections and vaccines, the genetic load (greater or lesser susceptibility), cultural preferences, behaviours, habits and customs, as well as luggage (pets, goods and others). in the case of avbd, the equation for the appearance of a certain disease would be the following: the presence of competent vector arthropods plus susceptible population, together with the presence of reservoirs and/or intermediate hosts (sick people), could give result an epidemic. the introduction of the tiger mosquito (aedes albopictus) and the threat of its expansion could be a good example. it is thought that a. albopictus was introduced in europe in through albania, by the trade of used tyres, although the first publication on its introduction in the european continent dates back to in italy. since then, a. albopictus has expanded throughout the mediterranean area. in spain, this aggressive mosquito is well established in catalonia, levante, in the coastal area of murcia and andalusia. it has also been detected in guipúzcoa, and little by little it is introduced in other non-coastal areas such as aragon, extending through travel routes (for example, motorways). the last detection was carried out in the community of madrid (fig. ) . a few months ago, the first specimens of this species were also identified in the north of portugal. this mosquito has been incriminated as a vector of numerous arboviruses in different parts of the world, including europe. a. albopictus, is the chikungunya virus vector. in this regard, most of the cases in europe are imported, although in the last two decades there have been different epidemic outbreaks in italy and, recently, in france. in spain, only imported cases have been reported. this mosquito (next to aedes aegypti which, as will be detailed later, has been detected in a timely manner in europe) can act as a vector of the dengue virus and with less effectiveness of the zika virus. in france, a. albopictus was responsible for the first autochthonous cases of dengue and of those reported in the same country during the following years, one of them with a history of travel to madeira, where a large outbreak had been reported (more than a thousand cases) between and . in , the occurrence of autochthonous cases of dengue in croatia were also attributed to a. albopictus, establishing the transmission by this mosquito in europe. in spain we are only suffering from their annoying bites, for now. table shows arbovirus infection and table shows other infections transmitted by dipterans worldwide, with the risk of transmission in spain. we have evaluated the risk of emergence and/or re-emergence of these diseases in spain according to the existing studies for each pathogen, the experience according to other diseases, previous immunity and other criteria, some of them subjective, that do not appear in the text. a. aegypti is the main zika vector and also a transmitter of yellow fever, dengue and chikungunya. in principle, this species is not a problem because it is not settled in europe, although it has been detected in some areas, such as in an airport in the netherlands and, more recently, in fuerteventura (canary islands) (fig. ) . in view of the zika epidemic in the americas, the ministry of health, social services and equality, in collaboration with the carlos iii health institute and the autonomous regions, has established a zika virus disease surveillance in spain. to date (last update in july ), confirmed cases have been reported, all imported, except congenital cases whose mothers were infected in the risk zone and autochthonous cases of sexual transmission. it should be noted that it is not necessary to resort to invasive or exotic species to refer to avbd. thus, anopheles atroparvus is present in spain, a good malaria vector. the official map of the distribution of this mosquito is not updated; however, although the risk of a malarial outbreak is low in our country, recent events have involved this species in the two cases of autochthonous malaria registered in the north of the peninsula. spain was an endemic country of malaria until , when who declared it a the risk of emergence/re-emergence is calculated based on three factors: (a) presence of cases of the disease in humans in the last years in europe, mediterranean, central and south american countries with a significant relationship with spain; (b) presence of the vector in spain; (c) pathogenicity of the virus for humans. each factor is scored with one point (presence in the first two factors and low pathogenicity in the third factor) or with zero points (absence in the first two factors and high pathogenicity in the third factor). the first two factors are added and the third is subtracted. the total score can range between and , with being: low risk; : moderate risk; : high risk. free zone. in europe, after the eradication of malaria, most cases are imported, although sporadic cases have recently been reported in many mediterranean countries such as france, italy, greece. the emergence of autochthonous cases in greece between and has raised doubts about the real situation in europe as a malaria-free zone. other diptera present in spain which we cannot ignore are phlebotominae sand flies. the species phlebotomus perniciosus and phlebotomus ariasi, are the competent vectors of the leishmaniasis agent (leishmania infantum). there are also other potential vectors of l. infantum in spain, as they are phlebotomus papatasi and phlebotomus sergenti. leishmaniasis is endemic throughout the mediterranean basin in europe and its geographic scope is spreading. usually, the epidemiology of leishmaniasis was linked to the rural habitat with the presence of dogs. the great epidemic outbreak of fuenlabrada with a high number of cases in an urban area, in which leishmaniasis was not common, showed the dangers of changing the urban model in spain. many houses were built in rural agricultural areas with gardens and peri-urban green spaces where wildlife was present. in these places the concentration of phlebotominae sand flies was high, and, in their environment, there were not only dogs but also other l. infantum reservoirs, such as hares and rabbits. this fact together with mild temperatures in recent years, decreasing the mortality of the vector, seems to be what caused the great outbreak. [ ] [ ] [ ] undoubtedly, the presence of phlebotominae sand flies throughout the iberian peninsula is a great threat, since not only do they transmit leishmania, but they are also toscana virus vectors, which is causing numerous cases of meningoencephalitis in some areas of spain and other phleboviruses such as the granada virus (without proven pathogenic power), the naples virus or the sicily virus. another species of mosquito to which special attention is to be paid is culex pipiens. this species, which is distributed and well represented throughout the iberian peninsula, is capable of transmitting the west nile virus (wnv). west nile fever is becoming a serious problem in some areas of europe, as in greece, where there has been an outbreak with numerous neuroinvasive forms, and in cases have been reported in france, italy, romania, hungary, croatia, serbia and austria. in spain, according to the data from the situation report and wnv risk assessment, published in , there are several species of mosquitoes capable of virus transmission. for example, culex modestus, culex perexiguus and culex theileri show a high vector competence, while c. pipiens and a. albopictus have a moderate vector competence. the first human case of neuroinvasive disease due to wnv in our country was identified, retrospectively, in a patient diagnosed with meningitis in september who, in the days before the onset of symptoms, visited a village in badajoz, extremadura (spain). in , the ministry of the environment reported the detection of wnv in equine farms in the provinces of cádiz, sevilla and málaga. through this active surveillance, suspected cases were investigated and two human cases of wnv meningoencephalitis were confirmed. between and , virus activity was detected in equines, suggesting that the virus is endemic in our country. in addition, there was previous evidence about its circulation in birds that were considered for the development of a predictive virus circulation model in our country. another factor that clearly influences infections transmitted by arthropod vectors is climate change. in the international conference on climate change and health was held in atlanta, which revolved around the idea that: "health is the human face of climate change". following this meeting, a special article was published in the new england journal of medicine which stated that the distribution of infectious diseases such as lyme borreliosis, rickettsiosis or west nile fever are expanding at the same rate as their avs. we know that climate variations and extreme weather events have a profound impact on avbd. mosquitoes and ticks are devoid of temperature regulation mechanisms and, for this reason, fluctuations in temperature greatly affect their reproduction and survival. in our country, it is more than possible that the great increase in the number of ticks in recent years is due to the fact that winters, in general, are much milder than years ago. just to mention an example, ixodes ricinus, the tick that most frequently bites people in the north of spain, is very sensitive to climate warming. this, among other factors, is increasing its survival. this species of tick transmits very prevalent diseases in europe, such as lyme disease or tickborne encephalitis, or others such as rickettsia monacensis infection, human anaplasmosis, and babesiosis. , in spain, human cases of all of them have been described, except for tick-borne encephalitis. although there is a high suspicion of the circulation of the virus in spain, the molecular screening of hundreds of ticks has been carried out in our laboratory, with negative results. in addition, other pathogens have been detected in i. ricinus specimens collected in spain, such as rickettsia helvetica, candidatus neoehrlichia mikurensis or borrelia miyamotoi, which leads us to be alert to the possible occurrence of human cases. [ ] [ ] [ ] as a consequence of climate change, the hypothesis about the probable changes in the distribution of another species of tick, hyalomma marginatum, which is the crimean-congo hemorrhagic fever (cchf) vector in europe, has also been established. under warmer climate conditions, according to prediction models, it is expected that the distribution of this tick species will extend to new areas which were previously free of the vector. in relation to this issue, the epidemiology of mediterranean spotted fever seems clearly associated with climate change, especially with low rainfall values and it has been shown that warming causes greater aggressiveness in its avs. table shows the tick-borne diseases throughout the world, with the prediction of risk for spain (subjective assessments). to be able to show a perspective on the avbd, it is essential to monitor and identify microorganisms in vertebrates and arthropods, designing strategies before their transmission to humans. early detection and implementation of control strategies allow minimizing the impact on the population. between and , % of emerging infections spread from a wild-type focal point. occasionally, the infection is spread directly from reservoirs such as bats, rats or chimpanzees to domestic animals, which amplify the infection, or to people; other times, infection dissemination (spill-over) occurs through av such as ticks, fleas or mosquitoes. in any case, it is essential to carry out a surveillance and to know the microorganisms carried by av. a recent example in spain is the detection of cchfv in ticks of the species hyalomma lusitanicum collected in deer a few years ago in the province of caceres and the explanation of one of the possible ways of the arrival of the virus to our country. detection of the disease that appeared in as, to some extent, it was predictable. on september , , the ministry of health issued a press release reporting the death of a man by cchf and the contagion of the nurse who had taken care of him in the icu of the vallecas hospital where he had been treated. the first two autochthonous cases of cchf in spain were confirmed (fig. ) . in the last cchfv situation report and transmission risk assessment in spain, the diagnosis of tick-borne diseases is not always easy. we must bear in mind that a tick bite history is usually absent in at least half of the cases and that incubation periods can be very long. depending on the size of the tick, they can be very difficult to see (they can simulate a small mole), and their bite is painless. unless there is awareness or a high index of suspicion when faced with certain signs and/or clinical symptoms, who is going to think of a tickborne disease? it is clear, "what is not sought, is not found". in , who revised the list of emerging pathogens that could cause serious epidemics in the future and those that need to be investigated, including cchfv, ebola/marburg virus, zika virus, middle east respiratory syndrome coronavirus (mers-cov), severe acute respiratory syndrome coronavirus (sars-cov), lassa virus, nipah virus and rift valley fever virus. in addition, this year the list is completed with disease x, referring to an international epidemic that could be caused by a pathogen whose pathogenic potential and route of transmission is unknown at the moment. this list takes into account the transmissibility between humans, the severity of cases and the percentage of mortality, the difficulty of control and diagnosis and the context of public health and global expansion. in addition, there are other diseases that need more attention as soon as possible: hemorrhagic fevers by other arenaviruses, chikungunya virus, diseases by other highly pathogenic coronaviruses or by emerging enteroviruses and febrile syndrome with severe thrombocytopenia. many of these diseases are avborne. high high debonel/tibola: dermacentor-borne necrosis, erythema and lymphadenopathy/tick-borne lymphadenopathy; lar: rickettsiosis associated with lymphangitis. a in spain, borrelia hispanica relapsing fever. the risk of emergence/re-emergence is calculated based on two factors: (a) presence of cases of the disease in humans in the last years in europe, mediterranean countries and central and south american countries with a significant relationship with spain; (b) presence of the vector in spain. each factor is scored with one point (presence in the two factors) or zero points (absence in the two factors) and both are added. the total score can range between and , with being: low risk, : moderate risk and : high risk. another av that is said to have killed more people than all wars together is the body louse (human pediculus), transmitting exanthematic or epidemic typhus (rickettsia prowazekii), endemic recurrent fever (borrelia recurrentis) and the trench fever (bartonella quintana). body lice have been a serious public health problem until recently. they live in the seams of clothes and multiply in cold weather, lack of hygiene and war conditions. a person can be infested with thousands of lice, and each specimen is capable of biting an average of five times a day. it is said that body lice were one of the main problems during the russian revolution, where three million people affected by exanthematic typhus died. thus, vladimir ilyich lenin ( - ) stated: either socialism defeats the louse, or the louse will defeat socialism". here in spain, it was also a problem during the post-war period and was used as propaganda by franco's regime. we can ask ourselves: is there a risk of an epidemic or an epidemic outbreak of exanthematic typhus? it could happen, as it occurred in burundi in , when a large epidemic affected more than one hundred thousand patients. all the alarms went off when a red cross nurse was diagnosed after returning from work in the affected country. body lice are not seen on the body surface but live in the seams of clothing, in ± • c temperatures. parasitism by body lice should be suspected in persons with signs of scratching and lack of hygiene, more frequently in cold times of the year. at present, body lice have reappeared in refugee camps in europe, as in the second world war. in november , the european center for disease prevention and control reported the emergence of cases of recurrent fever due to body lice at different points along the route followed by refugees arriving in italy from the syrian war. in western europe, although we have not experienced any epidemic since the post-war period, and the fact that the condition had been eradicated, occasionally, there are r. prowazekii and b. quintana infection reports in homeless people parasitized by lice and cases of brill-zinsser disease have been described in people who have suffered from exanthematic typhus which could lead to an epidemic outbreak in certain conditions. fleas are other bloodsucking insects of worldwide distribution with an impact in public health. rickettsia can be transmitted to humans by at least two species: the rat flea (xenopsilla cheopis), which is the endemic or murine typhus vector (caused by rickettsia typhi), and the cat flea (ctenocephalides felis), which is the key vector of rickettsia felis and, occasionally, of r. typhi. as far as we know, rickettsias are not transmitted by the human flea (pulex irritans). in europe, murine typhus is a common avbd in mediterranean countries such as greece, cyprus, croatia and spain, including the canary islands. it develops as a non-specific febrile disease, with or without rash, which is often underdiagnosed. in clinical practice, murine typhus should be included in the differential diagnosis of any patient with fever of intermediate duration, that is, in a patient with fever (more than • c) of more than and less than days of progression, without focality to guide the diagnosis, which remains without a diagnosis after an initial evaluation that includes a complete clinical history, physical examination, complete blood count, chest x-ray and biochemical blood and urine tests. r. felis infection is another rickettsiosis with characteristics similar to murine typhus, of which cases have also been published in spain and that should be considered in patients with fever and/or rash, with a history of contact with cats or flea bites. despite the fact that there have been no reports of autochthonous yersinia pestis infection transmitted by the rat flea (x. cheopis) in spain, there is an alert for travellers at the time of writing this manuscript due to an epidemic outbreak in madagascar that has affected several thousand people. finally, we should remember the phrase written by hans zinsser in in his book entitled: rats, lice and history: "nothing in the world of living creatures remains constant. infectious diseases are constantly changing, new ones are in the process of development and the oldest ones are changing or disappearing". currently, ticks are considered the most dangerous avs in the world, because of their ease in moving from animals to people, because of their ubiquitous nature (they are present on all continents, including antarctica) and because of their capacity to agglutinate inside them a host of pathogenic microorganisms potentially transmissible through their hematophagous habits. the human tampering of ecosystems (deforestation, erosion of geographical limits to facilitate travel, etc.) or climate change are some of the factors that are favouring a greater contact between wild animals (with their ticks and the diseases they transmit) and people, facilitating the expansion of ticks to new previously unoccupied areas. diptera, ticks or other av may play the leading role in the next pandemic. therefore, anticipating the next public health crisis is in our hands. the authors declare no conflict of interest. biology of disease vectors ecology of zoonoses: natural and unnatural histories agency for international 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should this pathogen be considered for the diagnosis of tickborne infectious diseases in spain? boutonneuse fever and climate variability crimean-congo hemorrhagic fever virus in ticks, southwestern europe crimean-congo hemorrhagic fever virus in ticks from migratory birds autochthonous crimean-congo hemorrhagic fever in spain informe de situación y evaluación del riesgo de transmisión de fiebre hemorrágica de crimea-congo (fhcc) en españa. ministerio de sanidad fiebre hemorrágica de crimea-congo: «lo que no se busca no se encuentra list of blueprint priority diseases outbreak of epidemic typhus associated with trench fever in burundi rapid risk assessment: communicable disease risks associated with the movement of refugees in europe during the winter season ectoparasitism and vector-borne diseases in homeless people from marseilles zinsser disease in moroccan man fever of intermediate duration: new times, new tools and change of spectrum cluster of cases of human rickettsia felis infection from southern europe (spain) diagnosed by pcr we wish to thank jorge garcía labeaga, of urbe ingeniería, for his collaboration in the preparation of fig. . key: cord- -yrc qnmr authors: akbulut, nurcan; limaro, naomi; wandschneider, lisa; dhonkal, rhanjeet; davidovitch, nadav; middleton, john; razum, oliver title: aspher statement on racism and health: racism and discrimination obstruct public health’s pursuit of health equity date: - - journal: int j public health doi: . /s - - -y sha: doc_id: cord_uid: yrc qnmr nan the covid- pandemic has unmasked structural racial inequalities. association of schools of public health in the european region (aspher) member schools need to act against racism now. the covid- public health crisis has elicited strong public health system responses. but the pandemic has also uncovered profound and neglected structural inequalities and injustices in our societies. these structural inequalities developed through enduring discrimination against ethnic, cultural and other minority groups. they became apparent in several ways over the last months. • people of asian descent experienced discrimination in public spaces in reaction to the pandemic presumably having originated in china (devakumar et al. a ). • ethnic/racial minority groups in europe are more adversely affected by the covid- pandemic compared to most white people. in the uk, black people are four times more likely to die from covid- than white people, even after controlling for socio-economic disadvantage (platt and warwick ) . • ethnic/racial minority groups in europe often live in crowded conditions, especially so when they are refugees. under such circumstances, physical distancing is a privilege that they cannot afford (bozorgmehr et al. ). • ethnic/racial minority groups in europe often live in poor social conditions with precarious forms of employment, so they suffer most from the adverse socio-economic consequences of the pandemic. at the same time, they lack equal access to health care as well as social protection, putting them at greater risk of adverse health outcomes. • ethnic/racial minority groups in europe are also often in occupations which have key functions in the pandemic. examples are health and social care, transport, delivery services, food supply and security roles. workers in these fields have been particularly vulnerable to infection (devakumar et al. a ). in summary, the pandemic has not only caused a global public health crisis; it has also increased and accentuated longstanding structural social inequalities and ethnic/racial discrimination (devakumar et al. b) . the amalgamation of different forms of inequalities resulting from racism and socio-economic disadvantages signals an urgent need to protect the health of vulnerable groups. on the one hand, social inequalities which the pandemic reinforces need to be tackled; on the other hand, inappropriate government policy responses to it must be addressed. a striking current instance of this fact is provided in the failure of the european union and its member states to evacuate migrants and refugees from the camps on greek islands to enable living circumstances that allow physical distancing and provide safe spaces (veizis ) . apart from the uk rapid review, there is as yet little work addressing the differential ethnic/racial impact of the pandemic or of social countermeasures taken, of diminished health and social care and of economic disruption. aspher, as europe's representative organization for schools of public health, accordingly has issued its first statement on covid- impact on health inequalities and vulnerable populations on june (aspher ). in addition, aspher will pursue health equity by fighting systemic racism and discrimination. . we will continue to call upon all public health organizations and governments in all countries to strengthen the protection of the health of vulnerable groups. we also call for urgent and decisive action to minimize the social impact of the covid- pandemic on socially and economically marginalized minorities. . racism has a considerable impact on health inequalities. we therefore call on public health scientists to routinely include racism as a fundamental social determinant of health in all research and to strengthen cross-disciplinary collaboration on issues related to racism and health. . we need to rigorously name and scrutinize such systemic disadvantages for what they are, i.e. structural racism (hardeman et al. ). it is a task for society to put an end to systemic racism and structural inequalities through civic engagement, critical awareness, education, equal opportunities in life, political integrity and scientific evidence. in addition, we must hold politicians accountable for their actions, including their handling of information and media. . we advocate for communities and governments to embrace comprehensive public health strategies for addressing all causes of violence in our cities and places. preventive models addressing communities as a whole have to be implemented to address violence and inequalities. these must include significant partnership working and retraining of all statutory workers including those with regulatory powers and workforces, including police, prisons and places of detention. . aspher member schools of public health should be role models for eliminating all forms of racism, discrimination, inequality and disadvantage. . we reassert our commitment to health as a fundamental human right, to equality and fairness, to respect for all people worldwide, to solidarity with oppressed people and to protecting and improving the health of all the people we serve. member schools should review systematically their curricula and teaching with respect to racism, discrimination and inequalities in health and in public health interventions to reduce inequalities and improve health more fairly. . we also call on schools of public health to critically address their own policies with regard to racism and discrimination-as employers, and in their recruitment of staff and students; as landowners and procurers of goods and services, and in their policies towards acceptance of grants and donations. . we call on all our schools of public health to work within their academic institutions to audit, review and develop policies and programmes to address and eliminate racism. racism and discrimination are public health issues, globally and in europe. they are contributing factors to the covid- crisis. as public health researchers and practitioners, we must be aware of this. we need to take the necessary actions to address racism and discrimination in order to attain health equity. acknowledgements open access funding provided by projekt deal. conflict of interest the authors declare that they have no conflict of interest. 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://creativecommons. org/licenses/by/ . /. covid- -how and why is the pandemic exacerbating and amplifying health inequalities and vulnerabilities in europe? aspher sars-cov- in aufnahmeeinrichtungen und gemeinschaftsunterkünften für geflüchtete: epidemiologische und normativ-rechtliche aspekte abubakar i ( a) racism and discrimination in covid- responses racism, the public health crisis we can no longer ignore naming institutionalized racism in the public health literature: a systematic literature review are some ethnic groups more vulnerable to covid- than others? the institute for fiscal studies leave no one behind'' and access to protection in the greek islands in the covid- era key: cord- -mbg e j authors: hardstaff, jo l; häsler, barbara; rushton, jonathan r title: livestock trade networks for guiding animal health surveillance date: - - journal: bmc vet res doi: . /s - - - sha: doc_id: cord_uid: mbg e j background: trade in live animals can contribute to the introduction of exotic diseases, the maintenance and spread endemic diseases. annually millions of animals are moved across europe for the purposes of breeding, fattening and slaughter. data on the number of animals moved were obtained from the directorate general sanco (dg sanco) for . these were converted to livestock units to enable direct comparison across species and their movements were mapped, used to calculate the indegrees and outdegrees of european countries and the density and transitivity of movements within europe. this provided the opportunity to discuss surveillance of european livestock movement taking into account stopping points en-route. results: high density and transitivity of movement for registered equines, breeding and fattening cattle, breeding poultry and pigs for breeding, fattening and slaughter indicates that hazards have the potential to spread quickly within these populations. this is of concern to highly connected countries particularly those where imported animals constitute a large proportion of their national livestock populations, and have a high indegree. the transport of poultry (older than hours) and unweaned animals would require more rest breaks than the movement of weaned animals, which may provide more opportunities for disease transmission. transitivity is greatest for animals transported for breeding purposes with cattle, pigs and poultry having values of over %. conclusions: this paper demonstrated that some species (pigs and poultry) are traded much more frequently and at a larger scale than species such as goats. some countries are more vulnerable than others due to importing animals from many countries, having imported animals requiring rest-breaks and importing large proportions of their national herd or flock. such knowledge about the vulnerability of different livestock systems related to trade movements can be used to inform the design of animal health surveillance systems to facilitate the trade in animals between european member states. electronic supplementary material: the online version of this article (doi: . /s - - - ) contains supplementary material, which is available to authorized users. animal trade is an effective way of introducing, maintaining and spreading animal diseases, as observed with the spread of different strains of foot and mouth disease (fmd) in africa, the middle-east and asia [ ] and the spread of bovine spongiform encephalopathy (bse), for example into oman and canada through the importation of infected cattle [ , ] . within a year, millions of live animals of many different species are transported between countries within europe for breeding, fattening, sports, companionship, conservation and slaughter. this creates opportunities for communicable diseases to be spread across the european union (eu), which is the focus of this study, even though animals must be in a fit state to be transported i.e. healthy animals without clinical signs of illness [ ] . however, animals with sub-clinical infections may go unnoticed, providing an opportunity to transport disease to different regions. live animal trade complicates tracing the origin of any disease outbreak that may occur due to an infected animal being displaced. for this reason, the eu has established a trade control and expert system (traces) to monitor imports, exports and trade in animals and animal products across the eu and to ensure traceability within the food chain [ ] , in addition to livestock movements recorded by the food and agricultural organisation of the united nations (fao). traces records the number of animals and consignments entering and leaving eu countries. despite the availability of this comprehensive database, animal health surveillance systems are rarely based on international live animal movements. to understand better livestock trade within europe with a view to inform disease surveillance we analysed trade networks across the eu for all major livestock species and purposes of movements. animal health surveillance includes the systematic, continuous or repeated, measurement, collection, collation, analysis, interpretation and timely dissemination of animal health and welfare related data from defined populations, essential for describing health hazard occurrence and to contribute to the planning, implementation and evaluation of risk mitigation measures [ ] . recent outbreaks and spread of exotic or emerging diseases such as avian influenza (ai), schmallenberg virus (sbv) and bluetongue virus (btv) in previously unaffected territories of the eu have emphasised the need for well-developed and adequately resourced health systems, including surveillance, to ensure early detection and rapid containment, the complexities of which are highlighted by braks et al. ( ) [ ] . at the same time investment is being constrained due to significant financial budget reductions in many european countries. livestock disease is important economically with regards to a loss of productivity, its potential impact on human and animal health, and the mitigation activities implemented when disease occurs (for example trade or movement bans, testing and culling). for example, the economic cost of bse in the uk accrued from the value loss in infected carcasses, disposal costs, and, most importantly, the sharp drop in domestic beef demand due to consumer scares (sales of beef products declined by % once the possible link between bse and new variant creutzfeldt-jakob disease (cjd) was announced, but the costs were partly offset by an increase in consumption of substitute meat), and a complete loss in export markets [ ] . further costs accrued from operating various public schemes, establishment and enforcement of new legislation and the adjustment of the industry to the new structure and markets [ ] . livestock disease can be spread directly for example the introduction of fmd from irish calves imported to the netherlands that were also held responsible for the infection of a farm near to the port of introduction to mainland europe [ ] . it can be spread by infected equipment, crates or transporter vehicles which can be contaminated by microbes. for example escherichia coli (e. coli) bacteria were detected on the sides and floors of lorries [ ] and contaminated transporters were found to be responsible for spreading classical swine fever to different farms in lithuania [ ] . by moving animals with latent or asymptomatic infections this enables disease to spread to wherever the animal travels or where the necessary vectors may be present. particularly in the case of epidemic diseases where the reduction of time from introduction of a hazard to its detection can enable early response and thereby lead to a reduction in intervention costs to contain an outbreak [ ] , effective surveillance is critical. few surveillance systems however, are designed based on international livestock movement data, even though such data can provide information on the quantity and seasonality of livestock movements, the types of movement (for example flows from production of point of lay birds to laying units), the route the animals take and associated stopover or resting points. surveillance for many livestock species occurs at the farm where it is the responsibility of the farmer (and veterinarian) to report notifiable diseases or at the abattoir where it is the role of the official veterinarian to inspect livestock according to council regulation (ec) / [ ] and report notifiable diseases to the national authorities, which in the uk is the department of the environment, food and rural affairs (defra), which in turn must inform the european food safety authority (efsa) as stated in council regulation (ec) / [ ] . network analyses are useful ways of visualising the countries that are importing animals from a great number of other countries (high level of indegree) and countries that are exporting to a high number of countries (outdegree), these are values that can change temporally. they have been used to find out movement between farms of different species, for example, fish movement between farms in scotland [ ] and a study of pig and cattle movement between farms in sweden [ ] . countries with a high indegree, which for the purposes of this study has a maximum number of (the number of countries, i.e. (nodes, within this study and the eu as of ) that could be used to rank countries, can be more vulnerable to introducing disease due to importing animals from a greater number of countries than those with a low indegree whilst countries with a high outdegree may have a great ability to be able to transmit a disease to many countries; this highlights the importance of understanding levels of disease within trading countries. information about the indegree and outdegree of farms was used by frössling et al. ( ) [ ] to investigate whether it could be used to target the surveillance of two cattle diseases in sweden, based on a threshold of in-and out-degrees. they found a positive association between a positive test result and the purchase of animals and proposed approaches to design risk-based surveillance based on cattle movement data. networks can also be used to quantify the proportion of international partners trading with each other (dyadic contacts) compared with the maximum number of national trading partners available for trade within an area allowing a comparison to be made between species and production systems [ ] . the higher the density the more connected countries are with respect to the animal being traded and the more countries that may be at risk from contracting a disease from buying in infected livestock. a measure of mixing within a network is to look at its transitivity which indicates whether countries that a country is trading animals to are also trading animals with each other (a triad) [ ] . the greater the level of transitivity the faster a disease can spread between countries and potentially infect many countries within the european area [ ] . transitivity and density for different communities of wild and domestic ungulates were investigated for the propensity to transmit e. coli by vanderwaal et al. ( ) [ ] . however, the network may only consider the point of origin and destination and not necessarily consider the route itself that may involve briefly stopping in other countries where a disease transmission event may occur, for example fmd in france [ ] . we hypothesise that the description of trade networks can inform the design of more efficient animal health surveillance systems that may enable a more rapid investigation or response to be implemented. different species being transported for different purposes will have networks of different densities and different countries with the greatest indegree or outdegree. the aim of this project was to map live animal trade networks in eu countries and assess potential differences between species and purposes of transport. this was done by illustrating the number of live animal imports and exports between eu countries including the number of country contacts and numbers of livestock units (lsu, a unit that takes into account the age, sex, purpose of animals with dairy cows having a reference number of ) moved determining the density of networks and similarities of networks between species. table illustrates the median livestock intra-community movements (expressed in livestock units) and the densities of the transport networks. by far the most heavily moved animal species within europe in were poultry for slaughter and breeding, followed by poultry for 'other' purposes, pigs for fattening, pigs for slaughter and cattle for fattening; goats were the least traded species. generally more lsus were transported for fattening than for slaughter. the density of movement (table ) shows that there was greater connectivity for cattle than for the heavily traded poultry. breeding networks were found to be denser than those for other purposes. this may be due to the number of consignments needed to move the relative units of animals. the geographical trade flows are shown in figures , , , , and . the transitivity indicates that disease would spread more slowly for 'other' purposes of animal movement than for breeding, fattening or slaughter with the exception of poultry and equines. figures , , , , and show the in-and outdegrees of livestock unit movements in the eu on the left and the geographical trade flows in the right, which are separated by species and by purpose of trade. the axes of the graphs of the in-and outdegrees reflect the numbers of trading partners. the countries in the top right received and exported animals with the greatest number of countries, whilst the bottom left indicates those that have little or no export or import trade with other countries. some countries are found in the top right corner with regards to many different animal movements e.g. germany, whilst others rarely buy or sell to the other countries considered in this study e.g. cyprus, finland and sweden, whilst other countries import from many countries and export to few e.g. italy. very few shipments of weaned cattle, sheep and goats require a rest period of hours (additional file ), whereas many unweaned animals would require a hour break in their journey from their point of origin to their figure the outdegree is shown against the indegree for the trade of cattle for different purposes on the left column of the table and the geographical movement across europe is shown on the right column of the table. the arrows between the countries indicate trade between the countries. the numbers in the figures refer to the corresponding countries: [ ] austria, [ ] belgium, [ ] bulgaria, [ ] cyprus, [ ] czech republic, [ ] denmark, [ ] estonia, [ ] finland, [ ] france, [ ] germany, [ ] greece, [ ] hungary, [ ] ireland, [ ] italy, [ ] lithuania, [ ] latvia, [ ] luxembourg, [ ] malta, [ ] netherlands, [ ] poland, [ ] portugal, [ ] romania, [ ] slovakia, [ ] slovenia, [ ] spain, [ ] sweden and [ ] uk. and exporting high proportions of their national population, the officially recorded number of animals of that species in the particular country. the poultry and pig sectors had the greatest number of lsu movements, which are being used to indicate breeding fattening slaughter other figure the outdegree is shown against the indegree for the trade of pigs for different purposes on the left column of the table and the geographical movement across europe is shown on the right column of the table. the arrows between the countries indicate trade between the countries. the numbers in the figures refer to the corresponding countries: [ ] austria, [ ] belgium, [ ] bulgaria, [ ] cyprus, [ ] czech republic, [ ] denmark, [ ] estonia, [ ] finland, [ ] france, [ ] germany, [ ] greece, [ ] hungary, [ ] ireland, [ ] italy, [ ] lithuania, [ ] latvia, [ ] luxembourg, [ ] malta, [ ] netherlands, [ ] poland, [ ] portugal, [ ] romania, [ ] slovakia, [ ] slovenia, [ ] spain, [ ] sweden and [ ] uk. the potential opportunities of pathogen introduction and spread, implying that they require more attention in terms of disease prevention and management, while the equine and goat sectors had the greatest and lowest densities of movements respectively. in addition to lsu movements larger proportions of national pig populations are imported breeding fattening slaughter other figure the outdegree is shown against the indegree for the trade of sheep for different purposes on the left column of the table and the geographical movement across europe is shown on the right column of the table. the arrows between the countries indicate trade between the countries. the numbers in the figures refer to the corresponding countries: [ ] austria, [ ] belgium, [ ] bulgaria, [ ] cyprus, [ ] czech republic, [ ] denmark, [ ] estonia, [ ] finland, [ ] france, [ ] germany, [ ] greece, [ ] hungary, [ ] ireland, [ ] italy, [ ] lithuania, [ ] latvia, [ ] luxembourg, [ ] malta, [ ] netherlands, [ ] poland, [ ] portugal, [ ] romania, [ ] slovakia, [ ] slovenia, [ ] spain, [ ] sweden and [ ] uk. compared with species such as goats increasing the possibility for the introduction of infected animals to an existing population. for poultry, the highest numbers of lsus moved were for slaughter, which may present less of a risk of introducing disease to an existing population, as the animals are likely to be transported from the production site directly to the slaughter point. however, many poultry journeys would require a break in transit emphasising the breeding fattening slaughter other figure the outdegree is shown against the indegree for the trade of goats for different purposes on the left column of the table and the geographical movement across europe is shown on the right column of the table. the arrows between the countries indicate trade between the countries. the numbers in the figures refer to the corresponding countries: [ ] austria, [ ] belgium, [ ] bulgaria, [ ] cyprus, [ ] czech republic, [ ] denmark, [ ] estonia, [ ] finland, [ ] france, [ ] germany, [ ] greece, [ ] hungary, [ ] ireland, [ ] italy, [ ] lithuania, [ ] latvia, [ ] luxembourg, [ ] malta, [ ] netherlands, [ ] poland, [ ] portugal, [ ] romania, [ ] slovakia, [ ] slovenia, [ ] spain, [ ] sweden and [ ] uk. vulnerability of the chain and need for adequate surveillance. poultry for breeding had the second highest lsu movements overall, which likely reflects the current structure of commercial poultry production. pure line grandparent and parent stock for breeding are produced by only a limited number of breeding organisations worldwide. for example, the two companies aviagen and cobb, have a market share of more than % of the commercial broilers produced in the eu and use their global network of distributors to serve almost all european countries [ ] . the breeder farms supplied with young breeding stock have links to hatcheries that produce day old chicks, broiler or layer farms, and slaughterhouses. this system leads to transport of young breeders, hatching eggs and day old chicks. in pigs, heavy movements were recorded for fattening, which reflects ongoing changes in production centres in the eu. in fact, more than two thirds of breeding pigs are produced in denmark, germany, spain, france, the netherlands and poland with half of the breeding pigs at regional level being concentrated in eleven regions in these six countries [ ] . germany is the main importer of fattening pigs, with an indegree of and denmark is the main exporter with an outdegree of . moreover, pigs for breeding and fattening as well as poultry for breeding were shown to have among the highest transitivities, indicating that disease spread in these networks would be fast if uncontained. hence, solely taking into breeding slaughter other figure the outdegree is shown against the indegree for the trade of poultry for different purposes on the left column of the table and the geographical movement across europe is shown on the right column of the table. the arrows between the countries indicate trade between the countries. the numbers in the figures refer to the corresponding countries: [ ] austria, [ ] belgium, [ ] bulgaria, [ ] cyprus, [ ] czech republic, [ ] denmark, [ ] estonia, [ ] finland, [ ] france, [ ] germany, [ ] greece, [ ] hungary, [ ] ireland, [ ] italy, [ ] lithuania, [ ] latvia, [ ] luxembourg, [ ] malta, [ ] netherlands, [ ] poland, [ ] portugal, [ ] romania, [ ] slovakia, [ ] slovenia, [ ] spain, [ ] sweden and [ ] uk. account trade data, surveillance efforts would need to focus on poultry for breeding and pigs for breeding and fattening. however, a mapping of surveillance in seven european countries showed that the highest proportion of surveillance components in place were for cattle [ ] . similarly, a recent literature review on animal health issues (including zoonoses) researched in the eu showed that cattle and buffalo were the species most breeding slaughter other registered figure the outdegree is shown against the indegree for the trade of equines for different purposes on the left column of the table and the geographical movement across europe is shown on the right column of the table. the arrows between the countries indicate trade between the countries. the numbers in the figures refer to the corresponding countries: [ ] austria, [ ] belgium, [ ] bulgaria, [ ] cyprus, [ ] czech republic, [ ] denmark, [ ] estonia, [ ] finland, [ ] france, [ ] germany, [ ] greece, [ ] hungary, [ ] ireland, [ ] italy, [ ] lithuania, [ ] latvia, [ ] luxembourg, [ ] malta, [ ] netherlands, [ ] poland, [ ] portugal, [ ] romania, [ ] slovakia, [ ] slovenia, [ ] spain, [ ] sweden and [ ] uk. frequently studied in the eu [ ] ; this may reflect differences in resource allocation for surveillance and disease mitigation. the reasons for this may be that cattle harbour or are perceived to harbour more pathogens than other species, that outbreaks in cattle systems have higher impact, that cattle receives more attention than other species for cultural or historical reasons, or that disease prevention and management in cattle systems are of lower quality. currently, there are no multipathogen, multi-species systematic risk assessments available at eu level that would allow a comparison of these factors. breeding networks were found to be more highly connected with more trade between countries indicating disease may spread more easily through them. this is of concern as these animals are not intended to be slaughtered on arrival and will produce new animals, therefore stringent precautions are needed to protect these populations, particularly if they are diseases not covered by eu legislation, for example the diseases listed in council regulation (ec) / [ ] . the density of international agri-trade calculated by ercsey-ravasz et al. ( ) [ ] was . which was comparable with density of many networks in this study. however, in national networks the densities and transitivities are smaller, which are due to the greater number of farms involved in national animal production compared with the number of countries involved in this study. the cattle trade network in france had a very low annual level of transitivity indicating that disease spread would be slower than that between european countries [ ] . the pig and cattle networks in sweden had lower transitivities than international networks of these species [ ] as did the transitivity of pig movements in denmark [ ] and the uk [ ] . the location of countries in figures , , , , and gave an indication of where surveillance could be targeted with countries in the upper right quadrant both importing and exporting high numbers of lsu, which means that they need to monitor both production to export healthy animals and import processes to avoid introduction of disease. countries in the lower right quadrant may need to consider strengthening surveillance related to import processes. many national studies have found that the majority of animal movements are between premises with lower indegrees and outdegrees as shown in a study by smith et al. [ ] , this reduces the likelihood of disease transmission to many different areas, reducing the level of surveillance needed. many countries trading cattle were found to have an in or out degree equal or greater than five. this was the threshold that was calculated to require enhanced surveillance for bovine coronavirus in a study on trade and cattle in sweden by frössling et al. [ ] . consequently, there seems to be ample opportunity to take advantage of trade network data to enhance surveillance. the evolution of trade networks over time at the eu level could be monitored using indegrees, outdegrees, and transitivity. such monitoring would provide information at the systems level and allow observations of changes in networks over time and where consequent surveillance efforts should be focused. higher-level surveillance capturing trends or changes in trade patterns could complement existing surveillance systems that are commonly disease centered. the differences across countries in terms of indegrees and outdegrees also bring up the question of who has the responsibility for disease control, including surveillance the buyer, the seller or relevant food business operator depending on the stage of livestock production [ ] . while the draft new eu animal health law [ ] refers to listed diseases and pre-dominantly supports disease centered surveillance, it also creates a framework for the better use of the synergies between surveillance undertaken by the different actors in the field to ensure the most effective and cost efficient use of surveillance resources as well as promotion of data availability and facilitation of data exchange. transportation itself is stressful for animals as indicated in many studies in many species for example cortisol in pigs [ ] ; heart rate and cortisol in cattle [ ] ; cortisol in lambs [ ] ; cortisol in horses [ ] ; increasing susceptibility to disease and may enhance the likelihood of shedding pathogenic agents in transit or in the receiving country, which may lead to infection in other animals. it is common to refer to malaise post-transportation as shipping illness [ ] . however, pathogens may be introduced or spread from transporters and not just from the animals that they transport. studies have demonstrated that transporters need to be thoroughly cleaned to prevent them from acting as a source of pathogens to subsequently carried animals, for example to prevent transmission of porcine reproductive and respiratory syndrome virus, that can survive in transporters, being transferred to pigs [ ] . rest stops are infrequent for some species, however, if animals from more than one origin are rested in the same place it may allow for disease spread. this is most likely to impact animals traded for breeding and fattening purposes that have more lsus and are more highly connected than animals already at slaughter weight. these are animals that will live in the receiving country for a period of time that may enable pathogen transfer. many of the highly connected countries (with high in and out degrees in the top right of figures , , , , and ) for example germany are geographically located in an area (central europe) that minimises the distances and therefore time that animals have to travel reducing the need for rest breaks and the consequent potential for pathogen transfer. many of the long distances are from countries that rarely trade with mainland europe for example cyprus. many animals undergo long journeys between countries. the time in transit is a concern with regards of the potential for disease to spread along trade routes [ ] . this has implications for policy around the planning of livestock production and slaughter. ideally, large production facilities would not be placed adjacent to well-known and used trade routes and or resting points. however, such information is only of use to policy makers if it is captured in a systematic and continuous way allowing to monitor trends, change and modify policies accordingly if deemed necessary. the analyses have only considered the spatial aspect of trade and not taken into account temporal variations that may occur altering the relationships between the countries (nodes) and the respective network, and affect the likelihood of an animal being infectious with a disease. animal populations fluctuate within a year and the population recorded in december was used to calculate the proportion of animals being imported or exported into a country, therefore it may have under or overestimated the actual population at the time of movement. for example the majority of lambs are born between january and april increasing the sheep population until they reach slaughter weight and are culled, which occurs before december. networks are highly dynamic and these changes in movements between countries will need to be considered by surveillance programs using this approach. one method that may address this is to use exponential random graph models that can incorporate a range of different distributions of connectivity between the nodes to create many different networks, which can be compared with the data to find a model that best fits the current trade pattern [ ] . the distances that animals are transported between countries may be shorter or longer than the distances between centroids. in addition, there are many different routes across europe that may be used and this may be worth investigating in future analyses with regards to distance, time and mixing between countries. this means that our calculations for whether particular species need a rest break for movement between particular countries are generalised so that there may be fewer or greater numbers of animals being rested en-route to their destination country altering the potential for pathogen exposure. the analyses did not take into account the numbers of convoys or animals and the mixing of animals: from different farms per convoy, at resting places, at borders, when received by individuals and at markets in the country of destination. these factors will have an impact on contact between potentially naïve and infectious animals, pathogen exposure and susceptibility. the analyses could not take into animals being bought and sold on to more than one country i.e. the chain of infection [ ] and assumed that an animal moved once between countries in its lifetime. creating networks has enabled us to visualise the countries that have a higher level of involvement in animal trade. using network analysis we were able to determine the extent to which a disease may spread, the production systems where disease spread may be more rapid, for example registered horses and breeding cattle, pigs and poultry, and facilitates comparisons with networks in other areas. similarities between countries, species and production purposes has the potential to inform international surveillance policies that take into account trade patterns. the study has highlighted the vulnerability of the pig network to disease, which is of increasing concern due to the proximity of african swine fever to the eu and the potential for wildlife to introduce the disease [ ] . this information could complement the national movement recording systems that are mandatory for cattle throughout the eu [ ] that will soon be implemented in sheep and goats now that their form of identification tags have been decided upon [ ] , and being planned for porcines [ ] to produce a more robust surveillance plan. data on numbers of live cattle, goats, horses, pigs, poultry and sheep movements in eu countries were obtained from directorate general sanco animal health dg sanco unit g activity report for the year obtained from http://ec.europa.eu/food/animal/resources/publications_en. htm. the data obtained related to the production purpose of the animals, which fell into five categories: breeding, fattening, slaughter, registered and other (e.g. pets, show animals). these categories were analysed separately and combined for each species. the numbers of animals were converted into livestock units to enable comparison between species using the following conversion factors derived from the eurostat glossary on statistics ( ) [ ] : pigs . (breeding), pigs . (other), goats . , sheep . , horses . and poultry . . all data were obtained at a national level from publically accessible databases and no animal experimentation occurred nor consultation with animal owners therefore ethical approval was not needed. all the analyses and associated network figures were created and carried out using r . . . [ ] . networks were created from adjacency matrices and their densities were calculated using network function found in r package network [ ] . the in and out degrees were calculated and respective graphs were produced using the degree and network.layout.degree functions in r package network [ ] . the transitivity of each network was calculated using the gtrans function in the sna package [ ] . trade maps in the figures , , , , and were produced by merging shapefiles of all the countries of europe downloaded from maplibrary.org (www.gadm.org/, , gadm version ) into one polygon (europe) using arcgis . [ ] . the map of europe was then read into r using the function readshapepoly found in the maptools package [ ] . centroids (the co-ordinates for the centre of a country) were calculated for each country and linked with respective importing and exporting countries were calculated using the calccentroid function in r package pbsmapping [ ] . curved lines and arrows were drawn between the centroids for each movement using the gcintermediate function found in the geosphere package [ ] . to be able to relate the numbers of animals being traded with the animal populations of the countries, the numbers of animals of each species were obtained for from the eurostat database. the data used was for december as this was the only calendar month available for all species. a movement:standing population ratio was calculated for both animal imports and exports through adding the total number of breeding, fattening, slaughter, registered and other animals being moved and dividing by the total population of animals of that species in the exporting or importing country. to illustrate the number of animal journeys that require hour rest periods during transit, distances that animals would have to travel were approximated by estimating arc distances from one capital city to the other using www.timeanddate.com. the time in transit before animals are required to have a hour rest period were obtained from council regulation ec / [ ] . the regulation states that unweaned cattle, goats, sheep, pigs and horses require a hour rest period after hours of travel. weaned cattle, goats and sheep can be in transit for hours without a rest, whereas weaned pigs and domestic horses need to be rested after hours of transportation. any animal being transported by boat should be rested for hours at the port after being unloaded. the law for poultry and rabbits states that they can travel for up to hours without food or water and whereas chicks within hours of hatching can travel for up to hours without food or water. to gauge whether a journey between two rest points would need a break the following equation was used given the assumption that a vehicle would be travelling at an average kilometres an hour. hour rest period ¼ distance between cities duration of travel before hours rest period à km=h combining livestock trade patterns with phylogenetics to help understand the spread of foot and mouth disease in sub-saharan africa, the middle east and southeast asia bovine spongiform encephalopathy identified in a cow imported to canada from the united kingdom-a case report european union council regulation (ec) / . the protection of animals during transport and related operations and amending directives / / eec and / /ec and regulation (ec) no / l european union council regulation (ec) / . commision decision of august concerning the development of an integrated computerised veterinary system known as traces proposed terms and concepts for describing and evaluating animal-health surveillance systems towards an integrated approach in surveillance of vector-borne diseases in europe the economic impact of bse on the uk beef industry the foot-and-mouth disease epidemic in the netherlands in the effects of transport and lairage on counts of escherichia coli o in the feces and on the hides of individual cattle international disease monitoring economic principles for resource allocation decisions at national level to mitigate the effects of disease in farm animal populations european union council regulation (ec) / . the laying down specific rules for the organisation of official controls on products of animal origin intended for human consumption council regulation (ec) / . laying down the general principles and requirements of food law, establishing the european food safety authority and laying down procedures in matters of food safety small-and large-scale network structure of live fish movements in scotland network analysis of cattle and pig movements in sweden: measures relevant for disease control and risk based surveillance application of network analysis parameters in risk-based surveillance -examples based on cattle trade data and bovine infections in sweden collective dynamics of "small-world" networks disease evolution on networks: the role of contact structure quantifying microbe transmission networks for wild and domestic ungulates in kenya chapter production and consumption of poultry meat and eggs in the european union pig farming in the eu, a changing sector mapping of surveillance and livestock systems, infrastructure, trade flows and decision-making processes to explore the potential of surveillance at a systems level review of the emerging animal health and food security issues council regulation (ec) / approving annumal and multiannual programmes and the financial contribution from the union for the eradication, control and monitoring of certain animal diseases and zoonoses presented by the member states for and the following years complexity of the international agro-food trade network and its impact on food safety vulnerability of animal trade networks to the spread of infectious diseases: a methodological approach applied to evaluation and emergency control strategies in cattle relationship of trade patterns of the danish swine industry animal movements network to potential disease spread descriptive and social network analysis of pig transport data recorded by quality assured pig farms in the uk european union council regulation (ec) / . laying down of specific hygiene rules on the hygiene of foodstuffs council regulation (ec) / . approving annual and multiannual programmes and the financial contribution from the union for the eradication, control and monitoring of certain animal diseases and zoonoses presented by the member states for and the following years shipping stress and social status effects on pig performance, plasma cortisol, natural killer cell activity, and leukocyte numbers a comparison of the welfare and meat quality of veal calves slaughtered on the farm with those subjected to transportation and lairage effects of weaning and h transport by road and ferry on some blood indicators of welfare in lambs effects of transport, lairage and stunning on the concentrations of some blood constituents in horses destined for slaughter isolation of respiratory bovine coronavirus, other cytocidal viruses, and pasteurella spp of shipping fever an evaluation of disinfectants for the sanitation of porcine reproductive and respiratory syndrome virus-contaminated transport vehicles at cold temperatures an introduction to exponential random graph (p*) models for social networks council regulation (ec) / : implementing regulation (ec) no / of the european parliament and of the council as regards eartags, passports and holding registers report from the commission to the council on the implementation of electronic identification in sheep and goats council regulation (ec) / : the identification and registration of pigs eurostat glossary: livestock unit (lsu) -statistics explained r core team: r. a language environment for statistical programming package network package sna desktop: release . environmental systems research institute maptools: tools for reading and handling spatial objects pbsmapping: mapping fisheries data and spatial analysis tools 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 acknowledgements bh acknowledges financial support from the leverhulme centre for integrative research on agriculture and health (lcirah). additional file : journeys that would require rest breaks due to being over hours long or over hours long. these data are displayed in tables.additional file : journeys that would require rest breaks for unweaned animals. the data are displayed in a table.additional file : journeys that would require rest breaks for poultry other than chicks < hours old. the data are displayed in a table.additional file : the proportions of national animal imports and exports compared with the national population. these data are displayed in separate tables for each species. the authors declare that they have no competing interests.authors' contributions jh obtained the data and undertook the analyses. jh, bh and jr interpreted the results and had an equal contribution to the manuscript. all authors have read and approved the final manuscript. key: cord- - qhumjas authors: brown, lisa; murray, virginia title: examining the relationship between infectious diseases and flooding in europe: a systematic literature review and summary of possible public health interventions date: - - journal: disaster health doi: . /dish. sha: doc_id: cord_uid: qhumjas introduction many infectious diseases are sensitive to climatic changes; specifically, flooding. this systematic literature review aimed to strengthen the quality and completeness of evidence on infectious diseases following flooding, relevant to europe. methods a systematic literature review from – was performed. focused searches of the following databases were conducted: medline, scopus, pubmed, cochrane library, and evidence aid. personal communications with key informants were also reviewed. results thirty-eight studies met the inclusion criteria. evidence suggested that water-borne, rodent-borne, and vector-borne diseases have been associated with flooding in europe, although at a lower incidence than developing countries. conclusion disease surveillance and early warning systems, coupled with effective prevention and response capabilities, can reduce current and future vulnerability to infectious diseases following flooding. defining what constitutes a flood can be quite complex as floods can take many forms; therefore, no universal definition exists. generally and in the context of this review, a flood is defined as the overflow of areas that are not normally submerged with water or a stream that has broken its normal confines or has accumulated due to lack of drainage. overall, different flood characteristics affect the severity of the flood event; specifically, regularity, speed of onset, velocity of flow, and depth of water. quantifying the level of flooding has proven to be difficult; however, the emergency events database (em-dat) provides information about flood events and the impact of floods. for a flood to be classified as a disaster or flood event by em-dat one of the criteria must be fulfilled: either ten or more people killed; or more people affected; declaration of a state emergency; and/or call for international assistance. em-dat defines a flood as a significant rise in water level in a stream, lake, reservoir, or coastal region and includes general river floods, flash floods, and storm surges or coastal flooding. flood disasters hit some european regions very frequently, and in some circumstances every year. in europe from - , flash floods and general floods were reported by em-dat. in terms of the number of people affected, out of the most important floods ever recorded in europe occurred during the - decade. a study concluded a rising number in flood disasters from - in the european union (eu). according to frei et al. there has been a significant trend toward increased intense winter rainfall events in europe. other studies do not find a rising incidence of flooding. for example mudelsee et al. examined river flood patterns in central europe, and despite the occurrence of two flood events exceeding the -year flood level in and , found no increased trend in extreme flood frequency over recent decades. analyzing the more frequent, small-magnitude flood events as well as high-magnitude floods can make it easier to detect shifting trends in flood frequency. flood trend analysis is essential to understand future flood risk and vulnerability. • what evidence-based public health interventions are used to minimize infectious disease incidence following flooding. • knowledge gaps and issues for further research. the initial search generated , relevant articles. after reviewing the abstracts, full-text articles were examined in more detail for eligibility. of these articles, peer-reviewed articles were found to fit the inclusion criteria. increased infectious disease transmission and outbreaks following global flood events have been documented ( table ). the study design and main results of all papers found meeting the inclusion criteria are listed in detail in appendices a-d. some articles and gray literature not meeting the specific inclusion criteria were incorporated into the conceptual framework to give a better contextual outline. water-borne outbreaks are an acute aftermath of flood disasters, mainly as a result of contaminated drinking water supply. intense precipitation can mobilize pathogens in the environment and transport them into the aquatic environment, increasing the microbiological agents on surface water. [ ] [ ] [ ] [ ] chen et al. found extreme torrential rain (> mm) was a significant risk factor for enteroviruses (rr = . ; % ci . - . ) and bacillary dysentery (rr = . ; % ci . - . ). globally, water-borne epidemics have shown an increasing trend from - which coincides with the increasing number of flood events. according to a global systematic literature review performed by cann et al. the most common water-borne pathogens to be identified following flooding were vibrio spp. the most common water-borne pathogens associated with heavy rainfall were campylobacter, followed by vibrio spp. appendices a, b list published studies which have reported post-flood increases in cholera, cryptosporidiosis, non-specific diarrhea, rotavirus, and typhoid and paratyphoid. [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] several studies have implicated excess rainfall in water-borne disease outbreaks because of the transportation of bacteria, parasites, and viruses into water systems. marcheggiani et al. showed a potential association between flood events and a range of water-borne infectious diseases in italy; including, legionellosis, salmonellosis, hepatitis a, and infectious diarrhea. reacher et al. performed a historical cohort study following a severe flood in in lewes, both climatic and non-climatic impacts, such as land-use dynamics, are expected to influence future flooding in europe. although considerable limitations remain in the ability to make robust projections of changes in flood size and frequency due to climate change, common projections appear to be emerging. according to the latest intergovernmental panel on climate change's (ipcc) srex report there is a - % probability that the intensity of heavy precipitation and the proportion of total rainfall will increase particularly in northern mid-latitudes and high latitudes of europe. the highest total precipitation increases are projected to occur during the winter months. although the ipcc states a general decrease in mean precipitation in the southern european region, rainfall may become more irregular and intense. however there remains low confidence in projections of changes in riverine floods. climate change is likely to increase the frequency of storm surges and coastal flooding due to rise in sea levels, and threaten an additional . million people per year in europe by the s. overall, changes in the climate that may affect the transmission of infectious diseases include temperature, humidity, altered rainfall, and sea-level rise. flooding can have a range of health impacts but this review focused solely on infectious diseases. the diseases most likely to be affected by flooding are those that require a vehicle for transfer from host to host (water-borne) or a host/vector as part of its life cycle (vector-borne). flood-affected areas serve as ideal breeding grounds for pathogens and may alter vector breeding grounds and zoonotic reservoirs. , where infectious disease transmission is endemic, it can present a major public health concern following flooding. the risk of infectious diseases following flooding is exacerbated by the fact many factors work together to increase incidence. the significance of the association between precipitation and disease is potentially amplified when considering the effects of global climate change and land use changes. flooding can alter the equilibrium of the environment and may affect the incidence and geographic range of climate-sensitive infectious diseases. a better understanding of the associations and underlying mechanisms of infectious disease outbreaks following flooding will help support evidence-based flood policies and mitigation strategies. this systematic literature review aimed to identify and examine the relationship between infectious disease incidence and flooding in order to gain a better understanding of: outcome (combined with or) amoebiasis, bacillary dysentery, burul*, campylo*, chikungunya, cholera, communicable disease*, contamination, crypto*, dengue, dengue virus, dermatitis, diarrhea*, diarrhea*, disease*, disease vector*, disease outbreak*, epidemic*, enteric fever, escherichia coli, gastrointestinal, giardia*, hanta virus infections, health, health effect*, health impact*, hemorrhagic fever, hepatitis a, hepatitis e, illness, infectio*, infectious disease*, japanese encephalitis, legionellosis, leptospirosis, lyme disease, lymphatic filariasis, malaria, morbidity, mosquito*, norovirus, naeg*, outbreak*, onchocerciasis, physical health, plague, pollut*, public health, q fever, risk factor*, rodent*, rodentborne, rodent-borne, rodent related, rodent-related, salmonellosis, sars virus, severe acute respiratory syndrome, shigellosis, schistosomiasis, tick*, tick-borne encephalitis, tularaemia, tularemia, typhoid, water, waterborne, water-borne, water related, water-related, west nile fever, vector*, vectorborne, vector-borne, vector related, vector-related, yellow fever, yersini* risk, rising temperatures, overcrowding, poor sanitation, poor health care, poverty, and an abundance of rats and other animal reservoirs. rodent-borne pathogens can be indirectly affected by ecological determinants of food sources which have an effect on the size of rodent populations. for example, lack of garbage management and collection following flooding where rubbish is left on the streets contributes to an increased rodent population. appendices a, c summarize the key studies assessing the relationship between flooding and rodent-borne diseases. outbreaks of leptospirosis were observed in the czech republic following floods in and . , the rate of serologically confirmed cases of leptospirosis was three times higher than usual at . cases/ , inhabitants (average incidence rate was . cases/ , inhabitants). the first leptospirosis outbreak in austria in july , involved four athletes who swam in recreational waters during a triathlon. heavy rains had preceded the triathlon ( mm). this outbreak demonstrates a risk of contracting leptospirosis in recreational waters, especially after heavy rainfall. in marseilles, france the incidence of leptospirosis identified in the laboratory increased significantly between january and july (p < . ). between and , the rate of leptospirosis incidence in southern france was very low, . cases/ , inhabitants. in , this incidence increased to england. the risk of gastroenteritis was significantly associated with depth of flooding in people whose households were flooded (rr = . ; % ci . - . ; p for trend by flood depth = . ). additionally, an outbreak of norovirus in american tourists was linked to direct exposure to floodwater contaminated with raw sewage in germany. earlier research has shown an association between waterborne diseases and flooding in high-income countries. from - , more than half of the water-borne disease outbreaks in the united states were preceded by heavy rainfall (p = . ). research from finland found that water-borne disease outbreaks from - were associated with un-disinfected groundwater contaminated by floodwaters and surface runoff. surveys in high-income countries where individuals reported their own symptoms have indicated an increase in water-borne diseases following flooding. , [ ] [ ] [ ] rodent-borne rodent-borne diseases are climate sensitive and may increase during heavy rainfall and flooding because of altered patterns of human-pathogen-rodent contact. flooding and heavy rainfall have been associated with numerous outbreaks of leptospirosis from a wide-range of countries around the world. , , [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] areas at the highest risk for leptospirosis outbreaks are those where multiple risk factors are likely to coexist; such as, increased flooding ahern et al. reviewed earlier studies addressing flood-associated outbreaks of leptospirosis from a wide-range of countries: argentina, brazil, cuba, india, korea, mexico, nicaragua, portugal, and puerto rico. in in the krasnodar territory in russia, a severe outbreak of leptospirosis took place in connection with a high flood. sanders et al. stated that flooding after heavy rain favors leptospires. it prevents animal urine from being absorbed into the soil or evaporating; therefore leptospires may pass directly into the surface water or persist in mud. the evidence of this review, supported by several other reviews, suggests the association between leptospirosis and flooding is fairly robust even in high-income countries. vector-borne precipitation changes are known to effect the reproduction, development, behavior, and population dynamics of arthropod vectors, their pathogens, and non-human vertebrate reservoirs. mosquito-borne infections tend to increase with warming and certain changes in rainfall patterns. vector-borne diseases are unlikely to be a problem during the onset phase of the flood, as many vector breeding habitats are expected to . cases/ , inhabitants. the first three autochthonous cases identified in marseilles (october ) were preceded by heavy rainfall. the study showed the first autochthonous case was identified after a period of flooding preceded by heavy rainfall over several days ( . mm/day; . mm/day; mm/ day with an episode of mm/ hr). similarly, the other two autochthonous cases occurred during a period of high rainfall ( . - . mm). pellizzer et al. performed a sero-epidemiological study to evaluate the risk of leptospirosis in a population in northeast italy exposed to a severe flood event. this area is endemic for leptospirosis and exhibits and average of cases/ , inhabitants. seven out of subjects exposed to floodwaters exhibited anti-leptospira specific igm antibodies and five were confirmed positive by micro-agglutination test. re-testing a few months later found significant antibody titers greater than against serovar copenhangeni in three cases ( . % seroconversion rate). overall, the rate for seroconversion for leptospirosis appeared to be low, and while flooding appeared to be the sole risk factor, confirmation was not possible due to a lack of a control group. ahmed et al. pakistan, cross-sectional study- , flood affected individuals interviewed to determine frequency of infectious diseases. gastrointestinal ( %), skin and soft tissue infection ( %), conjunctivitis ( %), ear, nose and throat infection ( %), respiratory tract infection ( %), suspected malaria ( %). no comparative data before flooding. bich et al. vietnam, cross-sectional study-rural and urban districts interviewed within mo after flood about social, economic, and health impacts. in each district, a flooded commune and a less affected commune (control commune) were selected. no statistically significant differences in proportion of dengue cases in flood affected and less affected communes. higher proportions of pink eye and dermatitis in severely flood affected communes. in flood affected communes, / urban cases (p < . ) and / rural cases (p < . ) contracted pink eye after flood. in flood affected communes, / urban cases and / (p < . ) rural cases contracted dermatitis after flood. chen et al. taiwan, - routine data-analysis of a database integrating daily precipitation and temperature and an infectious disease case registry. heavy precipitation ( - mm) a significant risk factor for enteroviruses (rr = . ; % ci . - . ) and dengue fever (rr = . ; % ci . - . ). extreme torrential rain (> mm) a significant risk factor for enteroviruses (rr = . ; % ci . - . ) and bacillary dysentery (rr = . ; % ci . - . ). associations between precipitation levels and enterovirus infections, japanese encephalitis (p < . ), and stronger linear relationships between precipitation and bacillary dysentery, dengue fever, leptospirosis (p < . ). marcheggiani et al. italy, - routine data-national statistics collected by italian ministry of health. association between hepatitis a, salmonellosis, infectious diarrhea, leptospirosis, cutaneous and visceral leishmaniasis, legionellosis and flood events from - seemed to exist. milojevic et al. bangladesh, controlled interrupted time series-diarrheal incidence of a cohort of , residents classified as flooded or non-flooded in . after fully controlling pre-flood rate differences and seasonality, no clear evidence of excesses mortality or diarrhea risk during/ after flooding. no evidence of excess risk from acute respiratory illnesses during flood but moderate increase in risk mo after flood (rr = . ; % ci . - . ). su et al. taiwan, routine data-to clarify association between leptospirosis and melioidosis epidemics and flooding. positive correlation for leptospirosis (r = . ; p < . ) and for melioidosis (r = . ; p < . ) with cumulative rainfall. increase in melioidosis cases significantly associated with > mm/day (p < . ). number of leptospirosis cases positively correlated with -h cumulative rainfall (r = . ; p = . ). appendix b. studies assessing the relationship between infectious diseases and flooding: water-borne apisarnthanarak et al. thailand, case report- melioidosis patients located through active case surveillance. cases reported excess flooding of homes and had traditional risk factors for melioidosis. all cases survived. auld et al. canada, outbreak investigation-e. coli o :h and campylobacter outbreak. outbreak occurred several days after heavy rainfall ( -d accumulation - mm). heavy rainfall hypothesized as a causative factor of the outbreak. carrel et al. bangladesh , - longitudinal study- -y data cluster analysis of health surveillance and geographic information system to investigate temporal and spatial distribution of cholera following flood protection interventions. , confirmed cholera cases. two clusters of lower than expected cases, clusters of higher than expected cases found (p < . ). following flood protection interventions, overall decrease in cholera incidence, differences in the geography of high vs. low spatial clusters of cholera, and shifts in location of unusually high spatio-temporal cholera clusters. harris et al. bangladesh hashizume et al. bangladesh, routine data-number of observed cases of cholera and non-cholera diarrhea per week during flood and post-flood periods compared with expected numbers. during flooding, cholera cases . times higher ( % ci - ) and non-cholera cases . times higher ( % ci . - . ) than expected. post-flood period, cholera cases . times higher ( % ci . - . ) and non-cholera cases . times higher ( % ci . - . ). ko et al. taiwan, routine data-melioidosis outbreak. melioidosis cases identified following flooding. onset within d. qadri et al. bangladesh, routine data-diarrheal stools collected from patients during flooding. of stool specimens tested, positive for v. cholerae o ( . %), for shigella spp ( . %), for salmonella spp ( . %). reacher et al. england, historical cohort study-post-flooding survey interview. flooding associated with significant increase in risk of gastroenteritis with depth of flooding (rr = . ; % ci . - . p = . , p for trend by flood depth = . ). schwartz et al. bangladesh , , , routine data-diarrheal patients during the , , and floods compared with non-flood periods. cross-sectional study- , individuals provided flood survey health data. house/yard flooding signficantly associated with gastrointestinal illness (incidence rate ratio = . ; % ci . - . ). volume issue appendix c. studies assessing the relationship between infectious diseases and flooding: rodent-borne amilasan et al. the philippines, hospital-based investigation-investigating risk factors for leptospirosis mortality following flooding. prospective surveillance and retrospective data collection. outbreak of leptospirosis cases, cases died. patients predominately young and male. delayed initiation of treatment, older age, jaundice, anuria, hemoptysis increased risk for death. bhardwaj et al. india, case-control study-identifying risk factors for leptospirosis during flooding. confirmed cases and age and sex matched fever and healthy controls given a questionnaire. chiu et al. taiwan, - routine data-analyze characteristics of patients with laboratory-diagnosed leptospirosis and correlate onset of symptoms with exposure to floodwater. patients identified with history of contact with contaminated soil/water. / patients ( %) suffered from leptospirosis after typhoon. dechet et al. guyana, routine data-laboratory testing on suspected leptospirosis hospitalizations and deaths. confirmed outbreak of leptospirosis after severe flooding. sero-epidemiogical study-evaluated leptospirosis risk in flood-exposed population. / patients exposed to floodwaters exhibited anti-leptospira specific igm antibodies and confirmed positive. re-testing months later found significant antibody titers > against serovar copenhangeni in cases ( . % seroconversion rate). flooding appeared to be sole risk factor, verification not possible due to lack of control group. radl et al. austria, outbreak investigation-leptospirosis. st documented outbreak of leptospirosis in austria. four serologically confirmed cases, all triathlon athletes. triathlon preceded by heavy rainfall ( mm (appendices a, d) older studies have shown associations. in romania, flooded basements were a significant risk factor for wnv in apartment dwellers (p = . ). in , heavy rains in moravia, czech republic resulted in flooding, and mosquito populations in the area amplified immediately. wnv activity was reported in the area. hubálek and halouzka stated environmental factors such as flooding can facilitate the re-emergence of wnv. be overwhelmed by the flood waters. while flooding may initially wash out vector populations, they return when the waters recede. receding flood water can provide ideal breeding habitats. therefore, vector-borne diseases are likely to have mid-term to long-term impacts on health following flooding (fig. ) . vector-borne virus outbreaks are strictly determined by the presence of the pathogen and particular competent disease vectors. the current and future establishment of exotic mosquito species in europe is a cause for serious concern, as the newly introduced species may already be disease vectors or could potentially become vectors. west nile virus (wnv) emerged in europe after heavy rains and flooding, with outbreaks in romania in - , the czech republic in , and italy in . the flood in the czech republic resulted in mass mosquito breeding with a biting frequency peaking at bites per person per minute. specimens from flood-affected residents were examined serologically for mosquito-borne viruses. paired serum samples showed one tahyna virus infection among residents. jiménez-sastré et al. sampled dwellings in tabasco, mexico, post-flood for dengue fever cases and found the geographical distribution of dengue fever cases was associated with the proximity of two permanent bodies of water. chen et al. found heavy precipitation was a significant risk factor for dengue fever (rr = . ; %; ci . - . ). additionally, more non-european appendix d. studies assessing the relationship between infectious diseases and flooding: vector-borne hassan et al. sudan, outbreak investigation-rift valley fever. confirmed human cases including deaths. outbreak followed heavy rainfall with severe flooding. hubalek et al. czech republic, routine data-specimens from residents in flooded area examined serologically for mosquito-borne viruses. antibodies detected after flood for tahyna, sindbis, and batai viruses, with only activity found for tahyna virus among residents. jiménez-sastré et al. mexico, cross-sectional study-convenience sampling of dengue fever in flooded colonies. cases with positive serology of igg ( . %) and cases of positive igm ( . %). geographical distribution associated with proximity to permanent water bodies. tong et al. australia , - routine data-assessment of variability in environmental and vector factors on ross river virus transmission. wu et al. china, - longitudinal study-review of retrospective data to determine intermediate host snail dispersal patterns and acute and chronic infections of schistosomiasis after floods. average number of acute schistosomiasis cases recorded in flood years . times higher than in years with little to no flooding. re-emerging and new snail infested areas in flood years on average . and . times larger than in years with normal water levels. flooding of marshlands identified as main driver for vector dispersal. responsible for local disease transmission, the factors that influence transmission, location of breeding ground, and which measures of control should be implemented. local destruction of breeding sites after flooding has receded is extremely effective, so individuals should remove unused vessels and stagnant water when possible. water storage containers need to be covered to protect from disease vectors, such as egg-laying female mosquitoes. individuals can protect themselves against mosquito bites by using repellents during biting hours, mosquito nets, and screens in doors and windows. individual and community awareness and participation is essential for successfully reducing the risk of infectious diseases following flooding. understanding the social and cultural influences on response behavior in the time of a flood emergency is crucial to inform the design and targeting of warnings and health education messages. some studies showed the frequency of infectious diseases can increase in the weeks to months after flooding, and figure illustrates when infectious disease outbreaks following flood events are likely to occur. however, there remains scientific uncertainty about the strength of association between infectious disease incidence and flooding. floods can cause population displacement and changes in population density, raise concern about waste management and the availability of clean water, as well as affect the availability and access to healthcare services. all of these are risk factors for an infectious disease outbreak. kouadio et al. and watson et al. suggested that unless there is a substantial population displacement, there is minimal risk of infectious disease transmission and outbreaks following flooding. overall, the risk of infectious disease following flooding is context-specific, differs between countries, and is dependent upon a number of synergistic factors. outbreaks of leptospirosis and diarrheal diseases following flooding have been documented in europe , , , , , , , [ ] [ ] [ ] but the evidence of increased incidence of vector-borne diseases following flooding is lacking because the time lag before onset can be several months. past studies have indicated possible associations between vector-borne diseases and flooding in europe. , [ ] [ ] [ ] european residents may be exposed to these risks while traveling. foreign relief workers can potentially introduce infectious diseases into an area affected by flooding and these workers may be susceptible to endemic diseases that are more prevalent because of the flood. surveillance in flood-affected areas is fundamental to understanding the impact of flooding on infectious disease incidence. surveillance and early warning systems may reduce current and future vulnerability. a comprehensive risk assessment could help determine priority diseases for inclusion in the enhanced surveillance system and prioritize prevention and control measures. in addition to surveillance and early warning systems to detect epidemic-prone diseases, assuring access to clean water, proper sanitation, adequate shelter, and primary healthcare services is essential. despite a considerable amount of research on the relationship between infectious diseases and flooding, globally and in summary of possible public health interventions public health interventions include those made before, during, and after flooding to reduce vulnerability to infectious diseases. interventions need to take place at a variety of levels: individual, household, community, regional, national, and international. the public health measures cited in the literature to reduce the risk of infectious diseases as a result of flooding focus on: risk assessments, enhanced surveillance systems, and specific prevention and control measures depending upon the type of infectious disease risk. , a rapid disease risk assessment should be conducted by a representative multi-agency group within the first week of the flood including: data on the flooded region and displaced persons, the main disease threats for the enhanced surveillance system, baseline data collection, and identification of priority interventions. , during a flood event, hand-held devices that allow workers to enter and analyze data in the field can assist the rapid risk assessment. existing disease surveillance systems can be enhanced to target specific diseases or syndromes and to support timely response actions to reduce disease impact and risk of transmission. , public health teams need to establish adequate disease surveillance systems which take into account the inherent disruption of the public health infrastructure that may occur during flooding. an enhanced surveillance system should be adaptable and context-specific, monitor key epidemiological data and compare with baseline data, monitor vulnerable groups, identify any emerging outbreaks, and result in timely public health action. in high-income countries, risk assessments and surveillance systems need to be very refined to detect small differences from baseline incidence data. prevention of infectious diseases following flooding involves maintenance of health services, provision of shelter, clean water supplies, proper sanitation, regular and adequate food supply, and in some cases mass vaccination campaigns and control of disease vectors. , water and sanitation are vital elements in the transmission of water-borne diseases; hence, providing clean drinking water is a priority in the initial days following flooding. clasen et al. found that household interventions were more effective in preventing diarrhea than interventions at the water-source. interventions at the household level reviewed included: chlorination, filtration, solar disinfection, and combined flocculation and disinfection. ejemot-nwadiaro et al. found hand-washing interventions can reduce diarrhea episodes by one-third. rodent control is another prevention measure that needs to be considered during flooding. the local rodent species and their behaviors should be identified, water and food storage containers should be rodent-proofed, and solid waste should be properly stored, collected, and disposed. , according to bhardwaj et al. prompt and vigilant fever surveillance activities in pre-flooding preparedness plans, rodent control programs, and improvement of environmental sanitary conditions may help greatly reduce leptospirosis incidence. vector control can reduce disease transmission by rendering the environment unfavorable for the survival, development, and reproduction of the vector. , establishing surveillance for the introduction of new vector species could contribute substantially to vector-control. an expert should identify vectors • papers on unrelated subject areas; such as, biochemistry, molecular biology, and genetics. personal communications between key informants were conducted in conjunction with the literature review. the context of the questions included the current state of knowledge of the association between flooding and infectious diseases and potential solutions to mitigate the risks. because flooding is a natural disaster and cannot be induced experimentally, the research evidence was unlikely to be the considered 'gold standard' of a systematic literature review or a randomized controlled trial. most of the data were observational, and because of the insufficient numbers of similar studies and variations in outcome reporting, no studies were excluded on the basis of study quality. a formal assessment of bias was not possible for each individual study. it is important for health officials and the public to understand that exacerbation of disease risk factors contribute to infectious disease outbreaks following flooding. population and individual vulnerability and resilience factors can worsen or mitigate infectious diseases following flooding. the community needs to be aware of actions that can facilitate or prevent infectious disease. to mitigate infectious disease risk following flooding, those involved in flood planning, response, and recovery should be aware of the results of this systematic literature review. if climate change causes more floods, then the future health burden of infectious diseases from floods could increase. in europe, maintenance and continuous adaptation and improvement of public health measures is important to sustain the low risk of infectious disease outbreaks following floods. presently, there are clear research needs to improve the understanding of the association between infectious diseases and flooding: • more robust epidemiological studies on infectious diseases covering the pre-, mid-, and post-flood periods. • further research assessing the effectiveness of public health interventions minimizing risk from infectious diseases following flooding. • investigation of infectious disease incidence following smaller flood events. • analysis of the differences between summer and winter flooding on infectious disease incidence. • analysis of the differences between flash and riverine flooding on infectious disease incidence. no potential conflicts of interest were disclosed. this work was carried out within public health england's department of extreme events and health protection, funded partly by the eu project "public health adaptation strategies europe, the body of information still remains fragmentary. many studies attempted to collect data retrospectively, had methodological shortcomings, lacked longitudinal data/baseline health data, control groups for comparison, and measures of clear disease outcomes. the studies included in this review were mainly observational studies with widely varying quality levels and study designs. because it is unethical to conduct experimental studies on this topic, rigorous observational studies must be continue to be undertaken. observational studies can present particular challenges because of the unpredictability of the timing and location of floods. reporting and recall bias was very likely in many studies. additionally, many studies relied on data from disease surveillance systems. obtaining relevant disease surveillance data pre-, mid-, and post-flooding is frequently challenging. population displacement can distort the rates of comparison for infectious disease incidence. the quality and robustness of disease surveillance systems can vary from country to country, and a country with a weak disease surveillance system will probably lack pre-flood baseline data. flood damage to pre-existing public health infrastructure can exacerbate weaknesses in a disease surveillance system. furthermore, it is difficult to attribute an increase in infectious disease incidence solely to a flood event, and therefore this issue may be under-investigated and under-reported. finally, this systematic review is not entirely exhaustive, and there may be many other reports in gray literature, but the quality is likely to be lower than the peer-reviewed published reports identified. the search strategy used was adapted from two studies ( table ) . , all papers with the specified search terms in their titles, abstracts, or keywords were searched for. focused searches of the following databases were conducted: medline, scopus, and pubmed. the cochrane database of systematic reviews was searched for further existing epidemiological reviews, as well as evidence aid. further relevant articles were identified manually from cited references from each selected full-text paper. data from gray literature were not systematically searched, but sources and advice from key experts were discussed in the accompanying text. inclusion criteria • papers published from january to september . ahern et al. included studies associated with infectious disease incidence following flooding up to . • epidemiological studies. • studies conducted in any country, because europe experiences a wide range of climate and geographical variation. • papers in all languages with english abstracts. • all papers where an explicit link is studied between flooding as an exposure and an infectious disease as an outcome. exclusion criteria • papers concerned primarily with mental health effects, flood-related injuries, population displacement, economic costs, and disruption of food supplies. a role of high impact weather events in waterborne disease outbreaks in canada risk factors for typhoid and paratyphoid fever in jakarta, indonesia health impacts of flooding in lewes: a comparison of reported gastrointestinal and other illness and mental health in flooded and non-flooded households outbreak of norovirus infection associated with contaminated flood water extreme precipitation linked to waterborne disease outbreaks. sciencedaily did a severe flood in the midwest cause an increase in the incidence of gastrointestinal symptoms? waterborne epidemics in finland in - a case control study to explore the risk factors for acquisition of leptospirosis in surat city, after flood resurgence of field fever in a temperate country: an epidemic of leptospirosis among seasonal strawberry harvesters in germany in leptospirosis on oahu: an outbreak associated with flooding of a university campus leptospirosis following a flood in the veneto area later leptospirosis after flood in tabasco, mexico strikes, flooding, rats, and leptospirosis in marseille, france climate change, flooding, urbanisation and leptospirosis: fuelling the fire? infectious diseases following natural disasters: prevention and control measures infectious diseases that pose specific challenges after natural disasters: a review global health impacts of floods: epidemiologic evidence climate change and infectious diseases in europe extreme water-related weather events and waterborne disease risks of water-borne disease outbreaks after extreme events influence of environmental factors and human activity on the presence of salmonella serovars in a marine environment systematic review of waterborne disease outbreaks following extreme water events effects of extreme precipitation to the distribution of infectious diseases in taiwan heavy rainfall and waterborne disease outbreaks: the walkerton example factors determining vulnerability to diarrhoea during and after severe floods in bangladesh medicaid outpatient utilization for waterborne pathogenic illness following hurricane floyd flood hazards and health: responding to present and future risks. tyndall centre for climate change research global trends in waterrelated disasters: an insight for policy-makers. the united nations world water assessment program. international center for water hazard and risk management building human resilience: the role of public health preparedness and response as an adaptation to climate change health impacts of floods in europe: data gaps and needs from a spatial perspective major flood disasters in europe future change of precipitation extremes in europe: intercomparison of scenarios from regional climate models no upward trends in the occurrence of extreme floods in central europe summary for policymakers: managing the risks of extreme events and disasters to advance climate change adaptation protecting health in europe from climate change disease emergence from global climate and land use change infectious diseases in the aftermath of monsoon flooding in pakistan infectious diseases of severe weather-related and flood-related natural disasters we would like to acknowledge carla stanke world health organization regional office for king's college london); and brittany scheckelhoff epidemics after natural disasters the threat of communicable diseases following natural disasters: a public health response frequency of infectious diseases among flood affected people at district rajanpur, pakistan flood-associated melioidosis in a non-endemic region of thailand impacts of flood on health: epidemiologic evidence from hanoi spatiotemporal clustering of cholera: the impact of flood control in matlab shifting prevalence of major diarrheal pathogens in patients seeking hospital care during floods in melioidosis outbreak after typhoon, southern taiwan health effects of flooding in rural bangladesh enterotoxigenic escherichia coli and vibrio cholerae diarrhea flooding and communicable disease fact sheet mosquitoborne viruses geographic distribution of dengue fever cases in flooded zones from villahermosa, tabasco, in rift valley fever outbreak in sudan climatic, high tide, and vector variables and the transmission of ross rover virus effect of floods on the transmission of schistosomiasis in the yangtze river valley, people's republic of china risk factors for west nile virus infection and meningoencephalitis, romania west nile fever in czechland nile fever--a reemerging mosquito-borne viral disease in europe public health guide in emergencies communicable disease control in emergencies: a field manual communication, data sharing, and collaboration, at the disaster site. comput in civil eng interventions to improve water quality for preventing diarrhea typhoon-related leptospirosis and melioidosis longitudinal epidemiology of leptospirosis in the czech republic monitoring of the epidemiological situation in flooded areas of the czech republic in year outbreak of leptospirosis among triathlon participants in langau leptospirosis outbreak following severe flooding: a rapid assessment and mass prophylaxis campaign leptospirosis in mumbai: postdeluge outbreak leptospirosis following a major flood in central queensland outbreak of leptospirosis after flood, the philippines leptospirosis after typhoon in taiwan anti-epidemic provision for the population in emergency situations in the krasnodar territory increase of leptospirosis in dengue-negative patients after a hurricane in puerto rico in the health impacts of floods. in: [few r and matthies f] flood hazards and health: responding to present and future risks. tyndall centre for climate change research a review of the invasive mosquitoes in europe: ecology, public health risks, and control options key: cord- - gyy c authors: sanchez-ramos, juan r. title: the rise and fall of tobacco as a botanical medicine date: - - journal: j herb med doi: . /j.hermed. . sha: doc_id: cord_uid: gyy c a forgotten and valuable chapter in the history of tobacco concerns its role as a botanical medicine. for three hundred years following its importation into europe, tobacco came to be considered a universal remedy highly prescribed by physicians. in the early history of tobacco, the literature on its medicinal benefits was voluminous. nonetheless, bitter opposition to its use for non-medicinal purposes began to arise. there was little doubt of its medicinal efficacy at first, but with time, as the concepts and practice of medicine changed, the tide of medical opinion turned against it. medical support for the therapeutic use of tobacco reached its nadir during the mid-nineteenth century, when it was dropped from most medical pharmacoepiae. medical opinion on the health hazards of recreational smoking required another years to arrive at the contemporary opinion that cigarette smoking is the single most important preventable environmental factor contributing to illness, disability and death in the u. s. soon after tobacco was introduced into europe as an ornamental plant, it came to be regarded as a remarkable medicinal plant. spanish sailors and the chroniclers of the indies observed and recorded the widespread use of tobacco. they were impressed by the esteem with which it was held by the natives of the new world. tobacco played a very important role in the mystical, social and medical rituals of the american natives. based on the medical applications of the herb by the natives, european herbalists believed that most herbs of the new world possessed some medicinal virtues. by the end of the th century, tobacco was in widespread use in europe to treat a variety of diseases. some medical authorities popularized tobacco as a panacea for treating over different ailments. over time, excessive use of tobacco led to the first great well-documented "drug" controversy. awareness of the inability to give up smoking of tobacco long after recovery from the illness led some to see the habit as sinful, simply because the individual indulged in the practice for "pleasure". puritans in england saw non-medical use and dependence on daily tobacco smoking as a sign of a weak and immoral character. a more rational view against the medical use of tobacco argued that a single medication could not possibly cure so many different ailments. it was not till the th century that the deleterious health consequences of chronic tobacco smoking became strongly evident and led to efforts to suppress tobacco use. identification of nicotine and its physiological effects led to insights into the neurochemistry of the autonomic nervous system. more recently nicotine and the nicotinic receptors in brain are being explored as agents that might enhance cognition. review of tobacco's history is relevant to the contemporary problem of differentiating socially or medically-approved use from substance abuse and addiction. j o u r n a l p r e -p r o o f methodology the methodology used to prepare this review was based on the study of selected publications on the history of tobacco. many of these books were long out of print but were available at the university of chicago regenstein library. the books selected for study included significant sections on medical use and abuse, as well as the social history of tobacco. primary documents from the early spanish chroniclers and physicians were not available and so the author relied on secondary sources, books written in early to mid- s. from the very outset, tobacco was smoked by the spanish because it was considered pleasurable, but at the same time it was attributed with exceptional medicinal qualities. the j o u r n a l p r e -p r o o f chroniclers of the indies also noted that once spaniards began to smoke, it was difficult to give up the practice (corti ) . in , francis bacon stated this succinctly: "tobacco conquers men with a secret pleasure, so that those who have once become accustomed thereto can later hardly be restrained therefrom (corti ) the use of tobacco for pleasure alone would not have been palatable to the europeans at home, who would have found the habit both primitive and sinful (ortiz ) . interestingly, tobacco was introduced into spain as an ornamental medicinal plant. "pleasure sought tobacco, but medicine justified it for reasons of its own, and sensuality was able to hide behind the cloak of curative science" (ortiz ) in england, smoking became fashionable at a time when puritanism was taking hold. the puritans did not deny tobacco's medicinal qualities but objected when smoking was indulged in for non-medical reasons. they noted that tobacco "drinking" (as smoking was then termed) was not confined to specific doses at certain times of the day like other medicines, and therefore might be harmful, especially to the young (apperson ) . the puritans in the colony of connecticut, in attempting to set controls on the consumption of tobacco, passed laws (around ) prohibiting persons under the age of from smoking, and ordering that no smoker could enjoy his pipe unless he obtained a doctor's certificate (apperson ) . even with a doctor's permission, smokers of the colony at that time were not allowed to take tobacco publicly in the "street, highways, or any barnyards" (apperson ) . during the th century many writers and physicians condemned the use of tobacco for non-medicinal purposes and attempted to differentiate legitimate use from "licentious" abuse. tobias venner j o u r n a l p r e -p r o o f in his "brief and accurate treatise concerning the taking of the fume of tobacco, which very many in these days do too licentiously use" (london, ) denounced the common mode of smoking tobacco which most men took "like tinkers drank ale" (apperson ) . he listed precepts for the correct use of tobacco. for example, that "you drink not between taking of fumes, as our idle and smoakie tobacconists are wont" and "that you goe not abroad into the aire immediately upon taking of the fume, but rather refrain therefrom the space of half an hour, or more, especially if the season be cold or moist" (apperson ). many people associated recreational smoking with idling. in the rules of the grammar school at essex, england, founded in , it was prescribed that "the master must be a man of sound religion, of grave behavior, of sober and honest conversation, no tippler or haunter of alehouses, no puffer of tobacco" (apperson ) . in spite of condemnation of recreational use, the smoking of tobacco was practised more for pleasure than for its medicinal value in western europe and the american colonies. tobacco did continue to be employed as medicine, especially in forms other than smoke, until mid-nineteenth century. from the american civil war to the present, tobacco has been used almost exclusively as a recreational substance. the attacks on its abuse in the late th and early th centuries were linked to temperance movements and based on moral arguments. only in the last years has the opposition to smoking been based on strong medicinal arguments. the last attacks on the use of tobacco re-introduced a moral component to the medical argument: non-smokers are subject to some deleterious health consequences of smoke pollution generated by smokers. the point is made that it is immoral to smoke since innocent non-smoking victims (including children) may be hurt. j o u r n a l p r e -p r o o f it has been suggested that the tobacco epidemic was due to a lack of prior restraints on grounds of convention, religion, morality or law simply because neither the substance nor the technique of smoking was previously known (laufer ) . it was up to medical profession to provide "restraints" in the form of a set of rules for appropriate consumption of tobacco. it should be emphasized, however, that there undoubtedly was a real belief in the medicinal efficacy of tobacco, especially within the context of the fifteenth and sixteenth century notions of health and disease. for example, certain diseases were seen as a disturbance in the balance of four qualities: hot, dry, cold, wet. catarrh (the common cold), particularly prevalent in the northern countries, was believed to be due to excess of cold and wet, so that applications of hot and dry tobacco smoke was seen as beneficial. purgation of the head by nasal irrigations and fumigations, or by provoking sneezing, was commonly practiced. "caput pungia" or clearing of the head was the latin term applied to this practice (ortiz ) . purgation of the gastrointestinal tract by eliciting vomiting or promoting bowel movements were popular medical remedies for which tobacco in one form or another was efficacious (ortiz ) , the practice of medicine from antiquity to the renaissance was based therapeutically on plant-derived substances. during the renaissance, prior to the discovery of tobacco, there was great interest in identifying the lost panacea of antiquity, the sylphium, described in great detail by the ancient physicians, hippocrates, galen and celsus. this plant, indigenous to desert regions of north africa, had been reported to be useful in treating fever, bronchitis, scrofula, tumors, toothache, bites of rabid animals, wounds from poisonous weapons, sore throats, pertussis, pleurisy, icterus and epilepsy . this wondrous plant, still j o u r n a l p r e -p r o o f not unequivocally identified, had disappeared, so that the introduction of tobacco was hailed as a substitute for the long-lost panacea of legend. two other factors helped perpetuate the notion that tobacco was a panacea. spanish sailors and the chroniclers of the indies observed and recorded the widespread use of tobacco and were impressed by the esteem with which it was held by the natives of the new world. tobacco played a very important role in the mystical, social and medical rituals of the american natives. based on the medical applications of the herb by the natives, european herbalists believed that most herbs of the new world possessed some medicinal virtues. a few influential books on the medical benefits derived from tobacco generated a host of literature on the san sancta (holy cure), the panacea of panaceas . tobacco was mentioned for the first time in the very first book written about the discovery of the new world, the diary of columbus. an entry in his diary, dated october , , mentions dry leaves carried by an "indian" in a canoe, who valued the leaves for their healthfulness (corti ) . columbus later wrote, in november , that members of his crew, sent out to explore the island of cuba, saw many people who carried a burning torch to kindle fire and to perfume themselves with a certain herb. later it was learned that the herb was smoked in a rolled cylindrical form (cigar) and employed to lessen fatigue and as a disinfectant (corti ) . on the second voyage, columbus left father ramon pané on the island of hispaniola to convert the taino indians. pané described the use of a snuff, cohoba, derived from an intoxicating plant, by a medicine man in a healing ritual. the "doctor" followed the same diet and assumed the same aspect of a sick person. both doctor and patient would j o u r n a l p r e -p r o o f purge themselves by inhaling the snuff intranasally. the use of cohoba was also referred to by many chroniclers, including oviedo, las casas and columbus himself (corti ) . the identity of cohoba has been disputed, but most agree that the effects of the powder might not be due to tobacco alone, but to the addition of powder derived from grinding products of the hallucinogenic plant piptadenia peregrine (ortiz ) . in , the portuguese explorer cabral reported the use by brazilian natives of a medicinal herb called betum (later identified as tobacco) for a variety of ailments including abscesses, fistulas, sores, and polyps (corti ) . in , the first official chronicler of the indies, oviedo y valdes, published "the general history of the indies" in which he described the use of tobacco as a medicine by the indians, and also that some spaniards on the island used it for treating the disease of syphilis, unknown to europeans until this time (corti ) . oviedo was the first to use the word tabaco correctly in print. tabaco was the word for the instrument with which the natives of hispaniola inhaled the smoke or powder of the herb. the word tabaco (or the anglicized tobacco) came later to mean the plant itself (corti ) . the actual amount of tobacco introduced into europe between and is not recorded, but the growing importance of tobacco is reflected in the literature of the period. between and , the number of books published in europe which referred to the medicinal use of tobacco increased markedly (see table ). the two most influential books on the medicinal use of tobacco were by nicolas "this plant, which is commonly called tobacco, is a very ancient herb and known among the indians, especially those of new spain. after these lands were conquered by our spaniards, they, being taught by the indians, made use of it in wounds suffered in war, healing themselves with it, to the great benefit of all. it was brought to spain a few years ago more to adorn gardens with its beautiful appearance than for the marvelous medical virtues which it has; now we use it more for these virtues than for its beauty, for they are certainly such as to attract admiration its quality is hot and dry in the second degree. it has the virtue of heating and dissolving, with some astringency and invigoration. it glues together and closes up fresh wounds, so they say, at the first application. it cleans and purifies infected sores, and brings them to perfect health, as we shall describe later. and now i shall speak of the virtues of this plant and the things which it is useful for, one after another …." monardes then systematically listed all the ailments which can be cured by either smoking, chewing, or drinking tobacco, or applying hot leaves or tobacco ointments onto skin (ortiz ) . for-example, ailments of the breast are alleviated by tobacco syrup; smoke taken by mouth expels the causes of most complaints. the use of warmed leaves, salves, clysters (enemas) is prescribed for internal congestion, stomach aches, constipation, kidney stones, and flatulence. for ailments of pregnancy and labor pains a leaf of the plant, very hot, is applied to the navel. to expel worms, tobacco is invaluable. tobacco is also recommended for rheumatism, abscesses, toothache, and venomous wounds; furthermore, application of tobacco is sufficient to restrain any flux of blood. monardes advertised tobacco as a household remedy and it was due primarily to his authority that the new herb was accepted by physicians and laymen alike as one of the most popular remedies ). the book on horticulture "maison rustique" by liebault and estienne published in (paris) included a chapter entitled "nicotiane" which says that tobacco was introduced into france by jean nicot and was called by some the "queens herb". nicot sent seeds of tobacco to queen catherine de medici, who later became a great advocate of tobacco, and was supposedly the first promoter of medicinal snuff. catherine treated her ill young son, francois ii with an unction of tobacco. the young prince died with symptoms of poisoning and it was generally believed to be a consequence of the tobacco ointment . in any case, the book by liebault and estienne became very popular among physicians and laymen, containing information about tobacco and its various applications in disease. "tobacco will heal all old sores and cancerous ulcers, ringworms, great scabies, and what evil so ever may be, by stamping the leaves in a clean mortar and applying the herb and juice together upon the sore" the book also mentions a host of other virtues of the plant including its efficacy in treating dropsy . as early as , the plant was called nicotiane in honor of jean nicot, who as was mentioned, introduced the plant into france, but also performed medicinal experiments with the herb, demonstrating its effectiveness in shrinking a cancerous growth on the face ). the bubonic plague was endemic almost every year of the th century in some part of europe. a number of serious outbreaks in great britain popularized the use of tobacco as a disinfectant, documented in in the book by dr. antoine sarracin "de peste commentarius " published in geneva and lyons ). in addition to all of the books by physicians attesting to the wondrous cures produced by tobacco, a great number of poets, historians and botanists bolstered the panacea image of tobacco. of the total of diseases and other conditions reported as treated with tobacco between the years and , were reported as treated with tobacco between the years and . in these years, physicians invented new formulae using tobacco and also found new uses for it, since they also applied it to patients' eyes and ears. j o u r n a l p r e -p r o o f before the year , there were only four medical authorities who warned of possible harmful effects of the herb (stewart ) . by tobacco was at the height of its fame as a medicinal herb, but the first book published about medicinal tobacco in london in (work for chimney-sweepers) emphasized its harmful effects. the author, writing under a pseudonym, "philartes", probably found it expedient to avoid using his real name since his book was exposing the harmful effects of tobacco. he argued that no one remedy could be applied to all maladies any more than one shoe could fit all men's feet. tobacco purged its users too violently and dried up the sperm of a man so that if used too long, "the propagation and continuation of mankind will be abridged". moreover, philartes declared tobacco had a stupefying effect, not unlike opium, and it increased melancholy greatly and wasted the liquid part of the blood and much more (stewart ). this book elicited more books in defense of tobacco, setting the stage for the london tobacco controversy which lasted years (stewart ). in england, as opposed to the continent, tobacco was seen less as a medicinal herb than as a recreational social habit (apperson ) . sir walter raleigh is generally credited with introducing tobacco smoking to queen elizabeth and the english court, thereby making it the latest fashion in london. by the end of elizabeth's reign ( ) smoking was popular among all classes of society: but it was especially the mark of the young man of fashion: "at the end of the th century, london was infested with strutting, affected dandies, and these gallants adopted smoking as something especially devised for them. their extravagances in this art, the elaborate smoking equipment they carried about with them, and their insolent claim that only they knew the correct method of smoking made them the butt of many literateurs." (dickson ) on the continent the use of tobacco by smoking was hardly known. a german visitor to england in could scarcely believe his eyes when he saw everyone smoking even in the theatres (apperson (austin ) . aside from the attacks on the abuse of tobacco, there was another reason for condemning its use. the tobacco trade was largely in the hands of the spanish, the enemies of england, and represented great economic loss for the country. king james raised the duty on tobacco in an attempt to diminish importation. despite the king's opposition in words and deeds, the use of tobacco increased rapidly during his reign. the increased duty imposed by the king suppressed the regular trade and developed a great traffic in smuggling from spain and the colonies and also promoted the cultivation of tobacco in england. the outbreak of the plague again in in london helped overcome the king's opposition. doctors declared that steady smokers were less subject to infection than others and recommended tobacco as a disinfectant, with the result that smoking increased enormously in spite of the king's antipathy (corti ) . by , there were upward of , apothecaries, grocers, chandlers and inn-keepers living by the trade of selling tobacco in and near london(macinnes ). from to , the production of tobacco in the english american colonies increased exponentially from , lbs. per year to , , per year (jacobstein ) . the spread of tobacco to japan, china, turkey and russia is beyond the scope of this essay. it should be noted that the most severe penalties in the form of torture and death failed to suppress the use of tobacco in those countries, and eventually tobacco use became worldwide (brooks , austin . by the beginning of the th century, tobacco was being used more for pleasure than for its medicinal value both in western europe and the american colonies. before tobacco was j o u r n a l p r e -p r o o f to become abandoned as a medicine altogether another twist of fashion propelled it, in the form of snuff, as the primary medicinal form. in , a book had been published in france dealing with the preparation and use of snuff for medicinal purposes (brooks ) . snufftaking became fashionable among the upper classes in france and rapidly disseminated among the upper classes of western europe. the habit took such a hold of the governing classes, the nobility, and clergy in france and england, that it almost supplanted smoking. smoking "was relegated to the middle and lower classes during this period (corti ). one of the books of the time, "grundlicher unterricht" (ulm) by frederick hoffman, physician to the king of prussia, devoted a chapter to the correct use of snuff. he believed that snuff was particularly advantageous in curing head ailments caused by "moist humours" and in the treatment of certain conditions of the eyes and ears . he prescribed snuff powders mixed with balsams and different herbs, which were able to "relieve the nose of germs and offensive odors and also have a beneficial effect in gout" . he also warned that constant, careless use of snuff affected the sense of smell and produced throat ailments and its abuse resulted in deafness, insanity and fatal illness . while hoffman's assertions of the therapeutic value of tobacco was weak, the arguments against its abuse were no better founded . a pupil of hoffman, frederick camel, also published a dissertation in which he analyzed the different qualities of snuff and attempted to explain the action of the different constituents of tobacco. a small controversy arose in europe over snuff, which was used as much for pleasure as for medicine. proponents presented case histories to prove snuff had cured bronchitis, consumption, apoplexy and other diseases. opponents to the use of snuff called snuffers snivellers and snorters, and that they were digging an early grave with their noses. the controversy which ended around did have the effect of reducing snuff taking for both medicine and social purposes, but the habit did not entirely disappear from medical practice until more than a century later (stewart ) . in , linnaeus published his "species plantarum" in which tobacco was classified as a member of the nightshade family (solanaceae) and the modern scientific terms for the chief species of the genus nicotiana, tabacum and rustica were first included . physicians who continued to use tobacco as a medicine found two new applications. dr. tissot suggested introducing tobacco smoke into a patient's lungs to resuscitate the apparently drowned (stewart ) . a second new application was the procedure for giving tobacco j o u r n a l p r e -p r o o f smoke clysters, again for resuscitating drowning victims (stewart ) . by , medicinal tobacco was being abandoned and deleted from some but not all materia medica. several pharmacoepiae continued to include tobacco leaves up until the beginning of the th century. the swiss pharmacoepia still mentioned "folium nicotianae" in . the german pharmacopia mentioned tobacco for the last time in (vanproosdy ). as early as the th century, experiments were carried out with extracts of tobacco "essential oils of tobacco"; its poisonous effects were demonstrated by showing that one drop of tobacco oil would kill a dog or cat . by , louis lauguelin, a french chemist discovered, but was unable to completely isolate the active principal of tobacco, which he called "nicotianine". other chemists continued the work until when posselt and reimann, at lille, france, isolated the constituent of tobacco now called nicotine (volle and koelle ) . with the discovery of this potent poisonous alkaloid, the attacks on the medicinal and recreational use of tobacco were intensified. in , a summation of the effects of tobacco was published by l. b. coles, in the united states. he emphasized the dependence liability of tobacco, noting that tobacco was never taken like other medicines and then lain aside. "a man takes this so-called medicine for forty years perhaps, but gets no cure." (stewart ) he also cited many, many case histories to prove tobacco never cured diseases for which it was prescribed and noted the harmful effects of nicotine. the first pharmacological studies of nicotine were initiated by orfila in , and was followed by a sharp increase during world war ii when widespread adaptation of the cigarette by women was added to large -scale consumption by american troops(surgeon-general's ). it has been noted that since the introduction of tobacco in europe, any major war has invariably been associated with an enormous increase in the prevalence of smoking (corti ) . the deleterious effects of tobacco on health had been suspected, and alluded to, for centuries before appropriate tools for scientific investigation were developed. the relationship between cancer of the lip and tobacco use was noted as early as the th century, but it was not until that the first systematic approach to that association was made(surgeon-general's ). in statisticians began to note increases in the incidence of lung cancer. in the dangers of involuntary (passive) smoking was described: "levels of carbon monoxide which can be reached in cigarette smoke-filled rooms have been shown to decrease the exercise duration required to induce angina pectoris in patients with coronary artery disease. side-stream smoke, which comes from the lighted tip of the cigarette between puffs, has higher concentrations of some of the irritating and hazardous substances than does mainstream smoke (that smoke inhaled by the smoker." (surgeon-general ) the most recent opinion on passive smoking appeared in a prestigious journal of medicine, reporting that chronic exposure to tobacco smoke is deleterious even to the non-smoker, significantly reducing small-airway resistance (white and froeb ) . over the last years, the health hazards associated with cigarette smoking have been communicated to the public by the mass media. according to the report of the surgeon general, the increased awareness by the individual smoker of the deleterious effects of tobacco smoke has resulted in a decrease in the prevalence of smoking in the general population. however, the percentage of teenagers who smoke has not declined in the last decades, and the number of teenage females who regularly smoke has increased(surgeon-general's ). the historical record on tobacco has demonstrated that establishment of the most severe penalties for smoking in the past, including torture and death, failed to suppress smoking in the long run in turkey, russia and japan (brooks ) . it is no surprise, then, to see that the threat of delayed physical harm, in the form of disease, has failed to suppress smoking among the youth of the u.s. today. it is clear that tobacco has reinforcing properties that motivate its user to continue smoking even when aware of the possible health consequences. nicotine appears to be the compound in tobacco which is most likely responsible for these effects. when the nicotine and tar content were varied independently, it was the nicotine content that correlated with ratings of strength and satisfaction(surgeon-general's ). moreover, laboratory research has demonstrated that animals will self-administer nicotine (surgeon-general's ). an approach to this problem has been suggested recently by an english physician(s), j o u r n a l p r e -p r o o f an approach that has a ring of familiarity. they argue that tobacco snuff would be an acceptable and less harmful substitute for cigarette smoking. they note that in the years of tobacco history, during which time tobacco has been chewed, snuffed or smoked, no population gave up one form of tobacco use without replacing it with another. the only time that the british decreased the frequency of smoking was in the th century when they switched to snuff. snuff, they report, produces peak blood levels of nicotine comparable to those produced by smoking tobacco. in addition, there are no products of combustion such as tar carbon monoxide and oxides of nitrogen. the pollutant effects of tobacco smoke would be eliminated by the use of snuff. these physicians postulate a new age for snuff is ahead, predicting that snuff could save more lives and avoid ill-health more than any other rational preventative measure likely to be available well into the st century (russel, jarvis et al. ). in the last few years, a new way to inhale nicotine (e-cigarettes or e-pens) is growing in popularity especially among youth. e-cigarettes are electronic devices that heat a liquid and produce an aerosol or mix of small particles in the air. e-cigarettes can deliver a high level of nicotine. according to one manufacturer, a single refillable cartridge in an e-pen contains as much nicotine as a pack of regular cigarettes. a national health interview survey reported: "overall, . % of adults aged ≥ years had ever used an e-cigarette, and . % currently used e-cigarettes in . adults aged - years were the most likely to have ever used an e-cigarette ( . %); the percentage declined steadily to . % among adults aged ≥ years. adults aged - years ( . %) and - years ( . %) were more likely to be current e-cigarette users than adults aged - years ( . %) and those aged ≥ years ( . %). across all age groups, fewer than one fourth of adults who had ever used an e-cigarette reported being a current user." (mmwr ) an e-cigarette aerosol is not harmless, but it generally contains fewer toxic chemicals than smoke from burned tobacco products, like regular cigarettes. nicotine interacts with a group of receptors that are normally targeted by the neurotransmitter acetylcholine. nicotinic acetylcholine receptors (nachrs) are transmembrane ion channels. when activated, either by acetylcholine or by nicotine, they allow selected ions j o u r n a l p r e -p r o o f to flow across the cell membrane. nachrs are distributed in the autonomic and central nervous systems and at the neuromuscular junction. acetylcholine and nicotine act at these receptors to alter electrochemical properties at a variety of synapses, which can in turn affect the release of several other neurotransmitters. nicotine has been shown to enhance attention, the ability to concentrate on particular stimuli and screen out the rest. researchers at the national institute on drug abuse have shown, using neuroimaging methods, that nicotine activates specific brain areas in subjects performing tasks that demand attention (powledge ) . researchers are beginning to study the efficacy and safety of nicotine patches for treating mild cognitive impairment, thought to be a precursor of alzheimer disease (powledge ) . interestingly, smokers have lower rates of neurodegenerative disorders, and nicotine improves cognitive and motor functioning in people with alzheimer's disease and parkinson's disease (newhouse, potter et al. ). the mechanism is not clear, but it is hypothesized that nicotine modulates release of neurotransmitters depleted in those diseases. nicotine is also being studied for its analgesic actions and for treating obesity. development of synthetic drugs by pharmaceutical companies that mimic nicotine actions at selective receptors may lead to novel therapeutics to enhance cognition, alleviate pain and to promote weight loss. however, there are those who advocate for less expensive nicotine products like a transdermal patch, chewing gum, or nasal spray. these formulations are generally intended for smoking cessation but are widely available, usually without prescription (powledge ). since the late s, the tobacco plant has been used as a natural living laboratory to generate bio-pharmaceutical agents. plant molecular "pharming" or farming (pmp or pmf) is the practice of using plants to produce human therapeutic agents. many therapeutic proteins have been produced in plants, and some of them have are close to commercialization (yao, weng et al. , dirisala, nair et al. . the tobacco plant has the potential to massproduce pharmaceutical products with less cost than traditional methods. the first application of plant pharming was for the generation of human growth factor in tobacco (barta, sommergruber et al. ). tobacco-derived proteins have been tested and used to combat mers-cov and prevents the virus from infecting lung cells (yao, weng et al. ) . other examples of therapeutic agents produced in tobacco include a number of vaccines directed against malaria, anthrax, hepatitis and influenza. in addition to harnessing the power of the plant to produce useful bio-pharmaceuticals, the tobacco plant continues to reveal new molecules that had not previously been identified as biologically active. recently, a plant defensin (nad ), a cationic antimicrobial peptide, was isolated from the flowers of the ornamental tobacco plant (nicotiana alata) (poon, baxter et al. ). nad exhibits potent antifungal activity against pathogenic fungi. the potential of the tobacco plant to yield novel therapeutic agents or facilitate production of antigens and antibodies is an expanding frontier for this versatile plant. in tracing the gradual transformation of medical opinion on the use of tobacco, it is clear that medical opinion evolves with increasing information and technology, but it is also molded by contemporaneous social, economic and political circumstances. although most of the concepts of medicine from before the th century are no longer tenable or valid in modern times, man himself has not changed from a biological point of view. the propensity to ingest plant or chemical substances has been a characteristic of man since before recorded history and will remain with him as long as he lives social attitudes and medical opinion are subject to relatively rapid change. future decisions on the regulation of tobacco and of newer synthetic substances with abuse potential must be approached with this in mind. man will continue to self-administer psychoactive substances. the responses of society and of the medical profession will most likely undergo the transformations described for tobacco. this research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. conflict of interest: the author has no conflicts to declare. j o u r n a l p r e -p r o o f the social history of smoking perspectives on the history of psychoactive substance use the expression of a nopaline synthase -human growth hormone chimaeric gene in transformed tobacco and sunflower callus tissue the mighty leaf; tobacco through the centuries, little, brown and co introduction of tobacco in europe magic plants in primitive medicine use of tobaco among the american indians a history of smoking, harcourt, brace and co panacea or precious bane: tobacco in th century literature recombinant pharmaceutical protein production in plants: unraveling the therapeutic potential of molecular pharming the tobacco industry in the united states introduction of tobacco into europe percentage of adults who ever used an e-cigarette and percentage who currently use e-cigarettes, by age group -national health interview survey effects of nictoinic stimulations on cognitive performance cuban counterpoint phosphoinositide-mediated oligomerization of a defensin induces cell lysis a new age for snuff a history of the medicinal use of tobacco - report on smoking and health report on smoking and health ganglionic stimulating agents. pharmacological basis of therapeutics small airways dysfunction in nonsmokers chronically exposed to tobacco smoke plants as factories for human pharmaceuticals: applications and challenges key: cord- -itdx wqi authors: white, alexandre i r title: historical linkages: epidemic threat, economic risk, and xenophobia date: - - journal: lancet doi: . /s - ( ) - sha: doc_id: cord_uid: itdx wqi nan the art of medicine historical linkages: epidemic threat, economic risk, and xenophobia as a historian and medical sociologist, i have been studying the histories of international responses to epidemic events and what they can tell us about the nature of power, economics, and geopolitics. a historical understanding of the international regulations for containing the spread of infectious diseases reveals a particular focus on controls that have protected north american and european interests. in the past months, there have been xenophobic attacks on people of asian descent connected to coronavirus disease and precipitous losses in global stock exchanges and risk of recession. most reports have treated these as separate phenomena: considering one to be a cultural consequence of epidemic fears run rampant and the other to be the impact of the pandemic on global trade. yet if one pauses to consider the history of the global management of pandemic disease threats, epidemics and global commerce have been inextricably related. part of this history is the role of xenophobic responses to infectious disease threats. the xenophobia that has occurred in relation to the covid- pandemic can be situated in a longer history that dates back to th-century epidemics and the first international conventions on controlling the spread of infectious diseases. while quarantine, cordon sanitaire, and other social distancing practices date back to th-century europe and earlier, by the th century the spread of epidemic diseases emerged as a problem that required an international, coordinated response. european colonial expansion brought smallpox and other diseases to the americas and africa from the time of columbus to the s. these epidemics wrought widespread devastation for indigenous peoples. simultaneously, europeans encountered new diseases in the tropics. colonisation brought a particular encounter with diseases capable of harming europeans. the napoleonic wars were global in nature and also revealed the vulnerability of european powers to diseases emerging from their colonial domains, and the capacity of these diseases to emerge in europe. by the end of the th century, however, the preexisting forms of ad-hoc and uncoordinated quarantine of ships at port by european powers was being tested, especially in the mediterranean. epidemics of plague and cholera that would claim hundreds of thousands of lives in europe-while claiming far more in india and elsewhere-became a concern. but quarantines were costly, and were also an effective tactic for imposing trade tariffs and enacting trade wars under the guise of public health. a new system was needed to better manage the spread of infectious disease. from to , conferences were held to standardise international regulations for the establishment of quarantine and the sanitary management of plague, cholera, and yellow fever. in , the first international sanitary conventions were adopted, codifying the first agreements for the prevention of the international spread of infectious diseases. these conventions aimed to maximise protection from disease with minimum effects on trade and travel. plague, cholera, and yellow fever, became the focus of massive international concern due to their threat to continental europe and the economic threats the diseases posed to global trade. the early international sanitary conventions did not police the spread of these three diseases from europe to other countries or focus on any diseases endemic to europe. the threat of diseases emerging from colonial sites that could disturb systems of trade and travel led to aggressive control of these diseases in sites of epidemic outbreak and aggressive scrutiny of those people deemed to be responsible for disease spread. the importance of colonial trade from asia led to the rise of a particular scrutiny and bias against people of asian descent-especially chinese migrants and indian muslims travelling around the world. in the eyes of colonial health officials and the drafters of the first international sanitary conventions, the spread of cholera and plague was an economic, epidemic, and political risk to the long-term stability of the global economy. the particular anxieties over the threat of plague being spread by the free travel of colonised populations drove the colonial administrators in ceylon (now sri lanka) to prophesise the potential collapse of the tea industry-and by extension their entire colony. because trade with europe was so crucial to the colony, in the late th century the colonial administrators endeavoured to sacrifice all trade with india rather than risk the threat of plague arriving with migrant workers from the subcontinent. in one letter between colonial administrators, it was suggested, in a derogatory way, that if even a single person from india or east asia entered ceylon without being exposed to sanitary surveillance "there would have been great peril to the colony for these coolies being free immediately on landing (in ceylon) to spread over the island would scatter the seeds of disease as they went". such xenophobic sentiments were shared elsewhere. the heightened scrutiny and bias against non-europeans who were blamed for spreading disease have historically resulted in aggressive racist and xenophobic responses carried out in the name of health controls. in in cape town, south africa, an epidemic of bubonic plague resulted in the quarantine and forced removal of most of the city's black african population to a racially segregated quarantine camp. this camp and practice of eviction can be viewed as part of the blueprint for future forced removals and a precursor to racially segregated south african townships before and during apartheid. similar scrutiny was a feature of the policing of the hajj. under the international sanitary conventions from to , muslim pilgrims travelling from india were perceived in europe as a threat because of their potential to meet and spread disease to european muslims during the hajj, who would then return to europe by passage through the suez canal. quarantines and controls were enacted for muslims pilgrims who travelled both from india to mecca and back to europe after the pilgrimage. the disease surveillance and sanitary system that governed the hajj has historically been one of the largest of its kind in the world. concerns about the economic risks of disease spread were not limited to european empires, and neither were the xenophobic practices associated with those concerns. the usa has a history of anti-chinese sentiment in response to epidemics. historian james mohr has described how in honolulu, doctors, colonial administrators, and the general us colonial population lamented the outbreak of bubonic plague in because it prompted fears that the city would become associated with asia, where plague was then present. as plague spread in honolulu and countries around the world closed their borders or quarantined all vessels arriving from its port, the honolulu city administrators embarked on a full quarantine of the city's chinatown, allowing no one to leave. these quarantines imposed considerable hardships on those within, limiting employment, movement, and access to supplies. the area of quarantine encompassed chinese and non-us properties immediately near the harbour, but avoided buildings and businesses that were owned by white americans and immediately connected to sites of quarantine. ultimately, the public health authorities burned contaminated buildings, but fires spread beyond their control and consumed most of chinatown in flames. similar anti-chinese responses occurred in san francisco during the plague epidemic of - , when chinese-specific quarantines were enacted. my own research suggests that the concern for the trading relationships central to us economic growth were pivotal to us congress endorsing the creation of who. in a report accompanying the resolution that ultimately heralded us support for who, it stated that: "particularly in our shrinking world, the spread of disease via airplane or other swift transport across national boundaries gives rise to ever present danger. thus to protect ourselves that we must help wipe out disease everywhere…the records of our export trade show that countries with relatively high living standards buy most of our goods. if the rest of the world continues in illhealth and abject poverty our own economy will suffer." in , the un and world health assembly transferred responsibility for the international sanitary conventions to who in its charter. the international sanitary conventions were reformed and ultimately renamed under who to the international health regulations in , which were revised to their current form in . more recently, nations have aligned infectious disease control policy alongside concerns for national security. in the current pandemic of covid- , we also see the links between epidemic risk, xenophobic responses, and the global economy. verbal and physical attacks on people of asian descent and descriptions of the disease as "the chinese virus" are all connected in this long legacy of associating epidemic disease threat and trade with the movement of asian peoples. we have seen huge sell-offs on asian stock markets and distinct drops in share prices in european and us financial markets. what was once an initial economic concern for global trade as it related to china has now had effects on all scales of the economy from small businesses to the fortune and potentially on a scale we have not seen since the worst financial crises of the th century. when we think about the framing of disease threats, we must recognise that the history of international infectious disease control has largely been shaped by a distinctly european perspective, prioritising epidemic threats that arose from colonial (or now post-colonial) sites that threatened to spread disease and affect trade. covid- is a serious and dangerous pandemic, but we must ask ourselves who our responses are designed to protect and who are they meant to vilify? in a pandemic, the best responses are those that protect all members of the population. a eurocentric or us-centric view that excludes or stereotypes others will do much more harm than good. as the epicentre of the epidemic shifts for now to europe and the usa and as global responses intensify, we should be prepared for more economic risk and confront racist or xenophobic responses for what they are-bigoted opinions with no basis in public health or facts. center for medical humanities and social medicine, johns hopkins university and johns hopkins school of medicine, baltimore, md - , usa alexandrewhite@jhu.edu plague and fire: battling black death and the burning of honolulu's chinatown contagion: how commerce has spread disease global risks, divergent pandemics: contrasting responses to bubonic plague and smallpox in cape town security, disease, commerce: ideologies of postcolonial global health the evolution, etiology and eventualities of the global health security regime two regimes of global health the politics of securing borders and the identities of disease campbell l. chinese in uk report "shocking" levels of racism after coronavirus outbreak. the guardian, feb , tavernise s, oppel jr ra. spit on, yelled at, attacked: chinese-americans fear for their safety.the key: cord- - la hkzv authors: kauhala, kaarina; kowalczyk, rafal title: invasion of the raccoon dog nyctereutes procyonoides in europe: history of colonization, features behind its success, and threats to native fauna date: - - journal: curr zool doi: . /czoolo/ . . sha: doc_id: cord_uid: la hkzv we aimed to review the history of the introduction and colonization of the raccoon dog nyctereutes procyonoides in europe, the features behind its successful expansion and its impact on native fauna. the raccoon dog quickly colonized new areas after being introduced to the european part of the former soviet union. today it is widespread in northern and eastern europe and is still spreading in central europe. features behind its success include its adaptability, high reproductive potential, omnivory, hibernation in northern areas, multiple introductions with > individuals from different localities, and tendency to wander enabling gene flow between populations. firm evidence of the raccoon dog’s negative impact on native fauna, such as a reduction in bird populations, is still scarce. raccoon dogs may destroy waterfowl nests, although a nest predation study in latvia did not confirm this. predator removal studies in finland suggested that the raccoon dog’s impact on game birds is smaller than expected. however, raccoon dogs may have caused local extinction of frog populations, especially on islands. raccoon dogs may compete with other carnivores for food, for example for carrion in winter, or for the best habitat patches. in northern europe potential competitors include the red fox vulpes vulpes and the badger meles meles, but studies of their diets or habitat preferences do not indicate severe competition. the raccoon dog is an important vector of diseases and parasites, such as rabies, echinococcus multilocularis and trichinella spp. and this is no doubt the most severe consequence arising from the spread of this alien species in europe. invasive species have many ecological effects and may threaten biological diversity (e.g., ebenhard, ; hulme, ; vilà et al., ) . alien species may alter habitat, and predate on or compete with native fauna or be important vectors of diseases and parasites. they may also hybridize with native species and thus affect their genetic variability. besides ecological effects, they may have considerable economic impacts on invaded areas (vilà et al., ) . there are alien mammal species in europe, of which are considered established, i.e. they form self-sustaining populations (genovesi et al., ) . these include several carnivore species, such as the american mink neovison vison, raccoon procyon lotor and raccoon dog nyctereutes procyonoides. they were brought to europe because of their valuable fur or as pets and either escaped or were intentionally introduced into the wild (genovesi et al., ) . these carnivores are widespread in europe, occurring in over european counties. the raccoon dog is one of the most successful alien carnivores in europe. it has spread rapidly into many european countries after being introduced by russians during the first half of the th century (e.g., lavrov, ; lever, ; helle and kauhala, ) . the raccoon dog has been suspected of causing damage to native fauna through predation, but firm evidence of this is scarce (lavrov, ; nasimovič and isakov, ; kauhala, ) . raccoon dogs may also compete with native medium-sized carnivores, such as the eurasian badger meles meles and the red fox vulpes vulpes (jędrzejewska and jędrzejewski, ; kowalczyk et al., ) . furthermore, the raccoon dog is an important vector of zoonoses and parasites, such as rabies echinococcus multilocularis and trichinella spp (e.g., oivanen et al., ; deplazes et al., ; holmala and kauhala, ; romig et al., ) . its role as a vector of diseases and parasites is likely to cause considerable ecological and economic impacts and may also cause health problems to humans. our aim was to review the published literature on the history of the introduction and colonization of the raccoon dog, the features behind its success and its ecological effects in europe. the raccoon dog originates from the far east. six subspecies are usually distinguished: n. p. procyonoides (gray, ) in most of china and northern vietnam, n. p. orestes (thomas, ) in the mountainous region of yunnan in china, n. p. koreensis (mori, ) in korea, n. p. ussuriensis (matschie, ) in the amur and ussuri regions of siberia and eastern china, n. p. viverrinus (temminck, ) in japan (except hokkaido) and n. p. albus (beard, ) in hokkaido (ellerman and morrison-scott, ; ward and wurster-hill, ) . the climate in the original distribution area varies from the subtropical regions of japan, northern vietnam and southern china to a harsh continental climate with cold winters in mongolia and southeast siberia. accordingly, raccoon dogs in different areas have adapted to different climates, habitats and diets, which can be seen in their body size, fat reserves, thickness of fur, and their behavioral and dental characteristics (kauhala and saeki, a) . a total of about individuals of the ussuri raccoon dog n. p. ussuriensis were introduced, mainly to european parts of the former soviet union, between and (lavrov, ). this subspecies is now widespread in northern and eastern europe (mitchell-jones et al., ; kauhala and saeki, b) . its original range in south-east siberia covers the valleys of the amur and ussuri rivers and the khankai lowland, the shores of the sea of japan and also areas as far inland as komsomol'sk (novikov, ) . in its native range the winters are cold with thick snow cover, and raccoon dogs are forced to hibernate. it has thick winter fur and accumulates large fat deposits in autumn to survive through the harsh winter (stroganov, ) . the ussuri raccoon dog was thus pre-adapted to survive in areas with long winters in northeast europe. its thick fur was the reason that russians introduced it into the western parts of their country. russians first bred the animals in fur farms and then released them deliberately so as to have a new valuable fur animal in the wild. the first introductions in or ( pregnant females) were made to transcaucasia, abkhazia, southern ossetia and karatalinia (lever, ) . in many areas, especially on the asian side of the caucasus, the populations did not flourish but remained small or vanished completely. more raccoon dogs were released in the mid- s e.g., in leningrad, novgorod and kalinin provinces, in north caucasus, ryazan province south of moscow, kirgizia and ukraine ( fig. ; lavrov, ) . raccoon dogs were introduced to astrakhan between and and to moldavia between and (lever, . they were also released in estonia in the s, in pskov in and in the karelian isthmus near finland in (lavrov, ) . one hundred raccoon dogs were released in belarus in (lever, ) . some individuals were also introduced further north, to the kola peninsula in and to archangel in - (lavrov, ). many introductions made to the european part of the soviet union were successful and the populations started to increase rapidly. populations spread at a rate of km per year (and even up to km per year) from the introduction sites (lavrov, ). the first wandering raccoon dogs were seen in finland in the s and s (siivonen, ; suomalainen, ; fig. ) . the raccoon dog started to truly colonize finland in the mid- s, but there was a time-lag of about years until rapid population increase started in the mid- s. the phase of rapid population growth lasted for another decade and by the mid- s most of southern and central finland was inhabited (helle and kauhala, ) . after this phase of increase the population growth seemingly ceased and numbers fluctuated for - years until they started to increase again. the raccoon dog population is still increasing, and today the raccoon dog is the most common medium-sized carnivore in finland (kauhala, ) . the hunting bag increased from in / to , in (finnish game and fisheries research institute, ). raccoon dogs were found all over estonia in the s (lavrov, ) . their numbers remained low, however, because of numerous wolves canis lupus and lynx lynx lynx, the natural enemies of raccoon dogs in estonia. in contrast, wolves and lynx were very scarce in finland in the s and s (ermala, ) , which may have contributed to the rapid spread of raccoon dogs in the country. raccoon dogs were found all over lithuania in the late- s and thus colonized the country in about years (lavrov, ; fig. ) . in latvia raccoon dogs were observed or hunted as early as . the first raccoon dogs were seen in sweden in (notini, ) but after that raccoon dogs were observed only occasionally in norrbotten, until they started to spread a few years ago (p.-a. Åhlèn, pers. com.). the reason for this long time-lag between the first observations and the rapid population increase in sweden is not known. in norway (finnmark) the first records of raccoon dogs are from (wikan, ) . there were no other observations in norway until winter / when a few raccoon dogs were shot in central norway (r. andersen, pers. com.). they most probably invaded central norway via sweden. raccoon dogs were first noticed in poland in and in east germany in (dehnel, nowak and pielowski, ; nowak, ) . fifteen years later, i.e. by the end of the s, almost all of poland, with the exception of higher parts of the mountains in the south, was occupied by the species (fig. ) . nowadays the raccoon dog is among the most common carnivores in some areas of the country (jędrzejewska and jędrzejewski, ) . over , raccoon dogs are caught in poland annually, and the hunting bag increases from year to year. in germany, the raccoon dog population remained sparse until it started to increase in the s, thirty years after the first observations, especially in eastern parts of the country (ansorge and stiebling, ) . the hunting bag has increased exponentially since the early s in germany (drygala et al., a, b) , and in brandenburg (eastern germany) alone the hunting bag increased from in / to (baagøe and jensen, ) . the first observations of raccoon dogs were made in eastern and central europe between and (nowak and pielowski, ; artois and duchêne, ; nowak, ; lever, ; weber et al., ; fig. ). for instance, in france the first observation of the species was made in or and the first case of reproduction was observed in (léger and ruette, ) . in northern italy raccoon dogs were seen and photographed in (p. genovesi, in litt.) , showing that the species has managed to cross the alps. today the raccoon dog is also found occasionally in the netherlands, moldova, slovenia, croatia, bosnia-herzegovina, and serbia. it has also been seen once in macedonia (Ćirović and milenković, ; mitchell-jones et al., ; Ćirović, ) . one raccoon dog was run over by car in se spain in (anon, ). the northern limit of the raccoon dog's distribution is determined by climate. it can live in areas where the mean annual temperature is above °c, the thickness of snow cover is < cm, the snow cover lasts < days and the length of the growing season for plants is at least days (lavrov, ) . today the northern limit of its permanent distribution lies at the arctic circle (helle and kauhala, ) . raccoon dogs will possibly widen their distribution area northwards due to climate change. increased spring precipitation in the form of snow at higher latitudes may, however, compensate for the effect of global warming (melis et al., ) . one of the main factors responsible for the successful expansion of raccoon dogs in europe was mass introduction over a wide area coupled with a large amount of genetic variation. together with their natural tendency to disperse and high migratory ability this allowed raccoon dogs to invade neighboring areas in a relatively short time. more research on the colonization process should be done, because the exact details are still poorly known. genetic data on raccoon dogs is still scarce. so far, populations from several locations in finland and germany have been investigated by pitra et al. ( ) . reconstructed phylogenies reveal two major clades in european raccoon dogs, which diverged approximately , years ago. in total, nine haplotypes were found in raccoon dogs in europe with a sequence divergence of . %- . % (mean . %). as suggested by pitra et al. ( ) , a combination of factors including multiple translocations with use of individuals from different geographical areas, secondary contact and admixture of two co-occurring separate maternal lineages with divergent evolutionary histories are probably the main determinants of the genetic variability of raccoon dogs in europe. it was probably a sequential, two-step process that included reduction in genetic variation due to the founder effect and population bottlenecks during initial introductions in the european part of the former soviet union in - , followed by an increase in genetic variation by hybridization of individuals from multiple native-range sources representing divergent haplogroups (pitra et al., ) . however, according to ansorge et al. ( ) there was no indication of the founder effect or inbreeding in the european populations, indicated by the same level of variability that can be seen in the native amursk population. additionally, phylogenetic analysis indicates different invasion corridors of the species in the western range of raccoon dog distribution in central europe, as earlier suggested by ansorge et al. ( ) , with the secondary contact zone between previously geographically and genetically different source populations in germany (pitra et al., ) . an important factor behind the raccoon dog's success is the very high plasticity of the species. they are true omnivores and eat anything they can catch (reviewed in sutor et al., ) . in białowieża forest, the index of food niche breadth for raccoon dogs was . , nearly twice as high as in the next species with the widest niche -the red fox ( . ; jędrzejewska and jędrzejewski, ) . the diet of raccoon dogs varies between areas and seasons, according to the availability of different food sources (e.g., ivanova, ; nasimovič and isakov, ; sutor et al., ) . in many areas, small mammals form the bulk of their diet in all seasons (bannikov, ; nasimovič and isakov, ; kauhala et al., a; bao et al., ; sutor et al., ) . carrion may reach up to % of biomass consumed during harsh winters (jędrzejewska and jędrzejewski, ; sidorovich et al., ) . frogs, lizards, invertebrates and birds are also frequently consumed (e.g., barbu, ; jędrzejewska and jędrzejewski, ; sutor et al., ) . raccoon dogs eat berries and fruit, especially in late summer and autumn because they serve as an important food source when raccoon dogs fatten themselves before entering winter dormancy (e.g., nasimovič and isakov, ; kauhala et al., a; kauhala, ; sutor et al., ) . the preferred habitats of raccoon dogs are wet open habitats: damp meadows and forests with sparse canopy but abundant undergrowth, marshlands, river valleys and gardens. however, they may occupy various habitats from continuous forests to open agricultural landscapes and suburban areas (jędrzejewska and jędrzejewski, ; drygala et al., c) . however, habitat preferences at the western and southern edge of the distribution area are poorly known. the raccoon dog has a high reproductive capacity; higher than expected for a medium-sized carnivore species (kauhala a ). this has also contributed to its success. mean litter size is - in areas with favourable conditions, both in native and introduced ranges (judin, ; helle and kauhala, ; ). the maximum litter size at birth in a sample of adult females from southern finland was . the maximum number of embryos was , and that of corpora lutea was . raccoon dogs are monogamous and the male participates in pup-rearing by warming and guarding the pups when the female is foraging (ikeda, ; yamamoto, ; kauhala et al., b; drygala et al., a) . females can thus spend a lot of time foraging and produce enough milk for a large litter. the raccoon dog's opportunistic diet further contributes to the large litters and also survival rate of juveniles. the survival rate is highest when the crop of berries is good . the mean annual mortality rate of juveniles during their first year of life is as high as % - % in southern finland (helle and kauhala, ) . raccoon dogs thus produce many pups, but most of them die early in their life, and the mortality rate of juveniles is the major mortality factor of the species. the mortality rate is lowest (ca. %) among middle-aged ( - year old) raccoon dogs and increases after years of age. only one per cent of individuals reach the age of years, with the maximum life span being about years . raccoon dogs generally reach sexual maturity at the age of months, but the reproductive value is highest among - -year old females which thus produce most of the pups in the population . in europe, raccoon dogs are found from the warmer conditions of hungary and the balkans to the much harsher conditions of northern europe (kauhala and saeki, b) . in cold climates raccoon dogs hibernate during winter. during hibernation their body temperature is . - . °c lower than during summer. this habit is unique among canids, and may also have contributed to the successful spread of raccoon dogs in northern europe (mustonen et al., ) . in winter, raccoon dogs settle in shelters which protect them against cold and predation (kowalczyk and zalewski, ) . in poland, active badger setts are most often selected by raccoon dogs. badger setts can also be used as breeding dens (kowalczyk et al., ) . hibernation usually lasts from november until march (in finland), but when the winter is mild raccoon dogs may be active even in mid-winter. they usually sleep when the air temperature is < - °c, snow depth > cm and day length < h . most raccoon dogs are active when the temperature is above zero, there is no snow and day length is > h. for instance, in germany raccoon dogs do not usually hibernate (drygala et al., b) . raccoon dogs are very well adapted to a long period of food deprivation in winter . they fatten themselves during autumn and almost double their body weight between early summer and late autumn (korhonen, a, b; kauhala, ; mustonen et al., ) . fattening in autumn and sleeping in winter are regulated by hormonal changes . thyroid hormone levels are low during winter and the animal thus adapts its general metabolism to the availability and requirements of energy (korhonen, ). in fur farms, raccoon dogs lose their appetite when air temperature decreases to - °c, which indicates an endogenous behavioural pattern: when it is too cold raccoon dogs stop eating and hibernate. another feature behind the success of raccoon dogs is their tendency to wander (nasimovič and isakov, ) . after introduction in europe, raccoon dogs wandered as far as km in a year (nasimovič and isakov, ) or km within three years (nowak, ) . adults may disperse in a colonizing population (sutor, ) whereas in stable populations only juveniles usually disperse (nasimovič and isakov, ; kauhala et al., b; kauhala and helle, ) . the mean dispersal distances, estimated on the basis of home range sizes, were km for females and km for males in south-east finland, with the mean maximum distances being km and km respectively . the maximum straight line distance in a couple of months was km in southern finland (kauhala and helle, ) . in north-east germany, the mean and maximum dispersal distances of both sexes were . km and km respectively (drygala et al., ) . very little is still known about dispersal routes and more research on the subject is required. the successful expansion of raccoon dogs in europe was also possible due to the secretiveness of the species and low persecution at the beginning of invasion. raccoon dogs are nocturnal animals, utilising mainly wet habitats covered with dense vegetation and showing inactivity in winter. these facts decrease their vulnerability to persecution kowalczyk et al., ) . in many countries the species was only persecuted once it had successfully established its population. in some areas hunters are not very interested in hunting raccoon dogs because the fur of wild animals has low value. population density varies according to the structure of the landscape. in finland, described an inverse relationship between home range size and the proportions of meadows and gardens in the home range. habitat richness (number of habitat patches per ha) also affected home range size: home ranges were small in areas where the landscape was a small-scale mosaic consisting of meadows with abundant undergrowth, gardens where raccoon dogs could find fruit and berries and small patches of mixed forests . because home range size and population density tend to be negatively correlated in monogamous canids with exclusive home ranges (trewhella et al., ; contesse et al., ; woodroffe et al., ) , population density can be estimated from home range size. the maximum density is then two adults in each home range in pup-rearing season when overlap of home ranges is smallest (kauhala et al., b) . for instance, in the 'best' areas of southern finland home ranges are only ha and raccoon dog density can be up to two adults per km , whereas in poorer areas with large spruce forests pup rearing home ranges are about ha and the corresponding density is < . adults per km . in northern germany pup rearing home ranges are about ha (drygala et al., b) and the density would thus be up to one adult per km . the area is a mosaic of mixed forests, wetlands and maize fields. as the raccoon dog population in germany is still increasing and spreading, population density may also increase. in forests of suwałki landscape park, nw poland, raccoon dog density was estimated to be only . individuals per km (goszczyński, ) . in białowieża primeval forest (poland) density was . - . ind./km , and mean home range size . km (jędrzejewska and jędrzejewski, ; kowalczyk et al. unpublished) . hunters in particular have suspected that raccoon dogs destroy the nests of game birds (lavrov, ). according to naaber ( naaber ( , , raccoon dogs robbed % of waterfowl nests in some areas of estonia. ivanova ( ) found remains of birds (mainly water birds) in % of raccoon dog scats collected in a river valley in voronez. when the raccoon dog population increased rapidly in russia, it was thought to be very harmful but, according to lavrov ( ) , this was not based on fact. raccoon dogs were accused of causing the decline of grouse populations even in areas where raccoon dogs did not occur (lavrov, ). even today robust scientific studies clearly demonstrating that raccoon dogs cause damage to native birds are scarce. birds eaten by raccoon dogs are mainly passerines (kauhala, ; sutor et al., ) . they are more important for raccoon dogs when voles are scarce than during vole peak population times (ivanova, ; judin, ; kobylińska, ) . it is not known whether raccoon dogs have caused a decline in passerine populations. the occurrence of birds in the diet increases with latitude, i.e. birds are consumed especially in northern europe (sutor et al., ) . the increase of carnivory with increasing latitude has also been detected among other omnivorous mammals (vulla et al., ) . according to diet studies ( data sets from different parts of native and introduced ranges) it is unlikely that raccoon dogs affect game bird populations in general. this is because, excluding some finnish data, there were remains of waterfowl or grouse in only - % of the feces or stomachs of raccoon dogs (kauhala, ) . although raccoon dogs may prey on ground-nesting birds such as waterfowl (barbu, ; włodek and krzywiński, ; schwan, ; sutor et al., ) , they probably consumed many of the non-passerine birds as carcasses (novikov, ; barbu, ; woloch and rozenko, ; kauhala and auniola, ) . waterfowl, especially female eiders somateria mollissima, occurred commonly in the feces of raccoon dogs in the sw archipelago of finland (kauhala and auniola, ). however, a viral disease killed many brooding eiders during the years ( ) ( ) when the data were collected and raccoon dogs probably found most of the eiders as carcasses. raccoon dogs also catch sick or injured birds left behind by hunters (samusenko and goloduško, ; pavlov and kiris, ; barbu, ; naaber, ; viro and mikkola, ; kauhala et al., a) . remains of egg shells, including those of domestic poultry, occurred in - % of the samples (kauhala, ) . in most studies, they are not mentioned at all. it is thus hard to know the extent of egg consumption by racoon dogs. opermanis et al. ( ) found, however, that raccoon dogs destroyed only . % of waterfowl nests in a wetland area of latvia. amphibians (e.g., rana spp., bufo spp., bombina spp. and triturus cristatus) commonly occur in the diet of raccoon dogs in spring and summer (e.g., ivanova, ; lavrov, ; barbu, ; viro and mikkola, ; kauhala et al., a kauhala et al., , a jędrzejewska and jędrzejewski, ; sutor et al., ) . both adult frogs and tadpoles are easy prey for raccoon dogs and this may cause a decline in frog populations, especially on islands and in other fragmented or isolated areas (kauhala and auniola, ; sutor et al., ) . frogs were scarce in the diet of raccoon dogs in the outer archipelago in southern finland, although they occurred commonly in the diet on the mainland (kauhala and auniola, ) . it is possible that raccoon dogs had already caused a decline in the frog populations of the archipelago. predator removal studies do not provide firm evidence of the harmfulness of raccoon dogs to game bird populations. studies in finland indicated that the breeding success of ducks improved in only one study area in northern finland where raccoon dogs occurred only occasionally even at the beginning of the experiment (kauhala, ) . the most frequently removed predators in the area were red foxes and pine martens martes martes. in southern finland where raccoon dogs are common, the breeding success of dabbling ducks was positively correlated with a raccoon dog index. furthermore, the breeding success of ducks improved in the predator protection area of southern finland during the experiment (kauhala, ) . in the predator removal area chick production declined at the end of the study with a simultaneously increasing fox population. the most frequently removed predators in this area were raccoon dogs, which may have resulted in an increase in fox populations which, in turn, may have affected the breeding success of ducks. the raccoon dog index also correlated positively with the reproductive success of black grouse in southern finland (kauhala et al., ) . another predator removal study in finland indicated, however, that raccoon dog removal might have had some effect on the breeding success of ducks (väänänen et al., ) , but the change was not significant. furthermore, chick production of, for example, mallards anas platyrhynchos and coots fulica atra, increased at first but then declined after the second year of raccoon dog removal. this happened simultaneously with the decline in the raccoon dog index. these results resemble those of the predator removal study described above and probably relate to the interactions between different predators. on the other hand, when different areas were compared there was a negative relationship between the breeding success of mallards and raccoon dog abundance index, so more research is needed on this topic in order to understand these contradictory outcomes. raccoon dogs consume carrion during all seasons if available, but carcasses are especially important for them in winter when other food sources are scarce (jędrzejewska and jędrzejewski, ; sidorovich et al., sidorovich et al., , . raccoon dog scavenging was recorded on % of carcasses available in białowieża forest (poland; selva et al., ) . according to sidorovich et al. ( ) raccoon dogs compete with native carnivores for carcasses in belarus in late winter. this competition can be so severe that the increasing raccoon dog population appears to have caused a decline in native carnivore populations, including the red fox, brown bear ursus arctos and pine marten. the polecat mustela putorius has probably suffered most from competition with raccoon dogs (sidorovich et al., ) . this information is, however, based only on correlative data and firm evidence is lacking. however, in białowieża forest, the rate of food niche overlap was very high ( %) among raccoon dogs and polecats in spring and autumn (jędrzejewska and jędrzejewski, ) . the polecat population has also decreased in finland during recent decades. the probable reasons for this include habitat changes and competition with other carnivores (liukko et al., ) . in northern europe, the red fox and the badger might compete directly or indirectly with raccoon dogs for food, habitats or den sites. correlative data from finland showed that when raccoon dogs were heavily hunted and their population decreased, the fox population started to increase (kauhala, ) . this may be a coincidence, but it can also indicate that raccoon dogs and red foxes compete for some resources in finland. in southern finland, there was some overlap in the diet of raccoon dogs, badgers and foxes but differences also existed: the badger consumed more invertebrates and the fox more mammals and birds than the raccoon dog (kauhala et al., a) . furthermore, female foxes in finland have become more carnivorous after the arrival of the raccoon dog, as revealed by a study on dental morphology (viranta and kauhala, ) . this case of character displacement points to the conclusion that foxes and raccoon dogs have competed for food resources in finland. however, in winter when food is scarcest both raccoon dogs and badgers hibernate and, hence, no competition for food between the raccoon dog and other carnivores exists in this season in northern areas. in north-eastern poland, the diet of raccoon dogs overlaps % with red foxes and % with badgers in spring and summer. in winter, diet overlap between raccoon dogs and red foxes increases to %, when both species utilize more carrion. other species that raccoon dogs may compete with are semi-aquatic species (american mink - % and river otter lutra lutra - %; jędrzejewska and jędrzejewski, ) . a habitat preference study from southern finland indicated that the habitat preferences of raccoon dogs and badgers differed to some extent: raccoon dogs favored meadows (including clear-felled areas) and open woodlands with abundant and tall undergrowth as well as gardens, whereas badgers favored forests with a thick canopy but sparse undergrowth . management of forests using clear felling (common in finland) may thus benefit raccoon dogs at the expense of native badgers. both species were, however, flexible in their habitat use and when the most favored habitats were not available they used the same habitats, such as fields . whether they compete in these circumstances for the best habitat patches is unknown and certainly requires further research. in north-eastern poland the habitat niche of raccoon dogs overlapped % with that of the fox and % with that of the polecat (jędrzejewska and jędrzejewski, ) . raccoon dogs commonly use badger setts kowalczyk et al., ) . raccoon dogs thus benefit from the occurrence of badgers in the area. the habit of using badger setts has probably facilitated the invasion of raccoon dogs in europe (kowalczyk et al., ) , because deep and complex badger setts might offer refuge against the cold and predation (kowalczyk and zalewski, ) . common use of burrows may lead also to intra-guild predation. in białowieża forest, the killing of raccoon dog pups by badgers was recorded. raccoon dogs may also influence badger breeding success, as no concurrent breeding of badgers was recorded in badger setts in which raccoon dogs bred (kowalczyk et al., ). raccoon dogs as vectors of diseases and parasites although the red fox has been the main terrestrial wildlife rabies vector in europe since the nd world war (e.g., anderson et al., ) , the significance of the raccoon dog as a vector of rabies has recently increased who, ). seventythree percent of the observed rabies cases were in raccoon dogs during an epizootic of sylvatic rabies in finland in - (nyberg et al., westerling, ; westerling et al., ) . in the baltic states as well, the raccoon dog is an important secondary host of rabies: the number of observed rabies cases in raccoon dogs in was in estonia and in lithuania (who, ) . the corresponding figures for fox cases were and . in lithuania, the prevalence of rabies in raccoon dogs increased almost . times from . % in to . % in . % in (mačiulskis et al., . in russia, belarus and ukraine rabies also occurred in raccoon dogs in (who, ) . in poland, the raccoon dog is the second (after red fox) most important vector of rabies among wild animals. north-eastern poland ( , km ), cases of rabies were recorded in raccoon dogs (siemionek et al., ) . when oral vaccination was used, the number of rabies cases in raccoon dogs in poland declined to − in the whole country (smreczak et al., (smreczak et al., , (smreczak et al., , smreczak and Żmudziński, ) . the role of the raccoon dog as a vector of rabies may further increase in europe, because the raccoon dog population is still growing and spreading (ansorge and stiebling, ; drygala et al., a, b) . the total number of reported wildlife rabies cases (excluding bats) in europe in was , of which were in raccoon dogs (who, ) . bait vaccinations against rabies have proved to be effective and have resulted in many rabies-free countries in europe (wandeler, ; artois et al., ; pastoret et al., ) . the increasing raccoon dog population may, however, alter the situation: the current strategies to control wildlife rabies may not be effective enough in a community of two important vector species; the red fox and the raccoon dog singer et al., ) .the hibernation of the raccoon dog may further complicate the situation (schneider et al., ) . indeed, a modelling study showed that epizootics in the community of two species were stronger than expected for single species (singer et al., ) . rabies could persist in the community, even if the disease was not spreading in an individual vector species due to low density. in the community of two vector species raccoon dogs were usually the major rabies host, and the number of cases in fox populations depended on raccoon dog density. when raccoon dog density was high, invasive raccoon dogs could even outcompete native foxes (singer et al., ) . additionally, badgers may act as a spill-over species and suffer from rabies epizootics. other viruses also dangerous to humans, including sars (severe acute respiratory syndrome) and avian h n viruses have been found in raccoon dogs in china (guan et al., ; changchun et al., ; qi et al., ) . raccoon dogs have additionally fallen victim to canine distemper virus (cdv) in japan (machida et al., ; aoyaki et al., ) . cdv may have the most far-reaching consequences of all infectious agents for free-living carnivores (deem et al., ) . data from germany indicates the possible transmission of cdv between wild carnivores and the domestic dog canis familiaris (frölich et al., ) . the prevalence of the virus was much higher in urban and suburban foxes than in rural ones. to our knowledge there is no data showing the role of the raccoon dog as a vector of cdv in the carnivore community (including domestic dogs canis familiaris), but this possibility cannot be ruled out. alveolar echinococcosis caused by echinococcus multilocularis is a dangerous emerging zoonosis in europe. the parasite can even cause lethal diseases in humans (eckert et al., ; kern et al., ; moks et al., ) . the red fox has been the definite host in central europe, but recently cases have been detected in raccoon dogs too (thiess et al., ; machnicka-rowinska et al., ; deplazes et al., ; kapel et al., ) . prevalence in foxes is high ( %− %) in the core area of this zoonosis . small mammals, mainly rodents, are the intermediate hosts of the parasite (schantz et al., ) . e. multilocularis is spreading in europe and new endemic areas have been detected in recent years (eckert et al., ) . e. multilocularis has even invaded cities (hofer et al., ; deplazes et al., ) . the parasite is found in denmark, the netherlands, belgium, france, germany, poland, czech republic, slovakia, switzerland, austria, northern italy, slovenia and lithuania (romig et al., ; vergles rataj et al., ) . e. multilocularis has reached as far as latvia and estonia in the north: prevalence in foxes was . % in latvia and . % in estonia (moks et al., ; bagrade et al., ) . the parasite is so far absent in finland (oksanen and lavikainen, ) . the reason behind the spread of e. multilocularis in europe is probably the growing fox and raccoon dog populations romig et al., ) . the raccoon dog is highly susceptible to e. multilocularis infection and may provide an additional pool of definitive hosts in europe (romig et al., ) . in poland prevalence in raccoon dogs was % (machnicka-rowińska et al., ) . due to high densities of the species in some areas of the country, it is a serious source of infection. in northern brandenburg, germany, prevalence in raccoon dogs was . %- . % (s. schwarz et al., unpubl. data). the parasite is an increasing public health concern, because efficient control measures are not available (eckert et al., ) . however, baiting foxes in an urban area of zurich using baits with praziquantel (an antihelminthic) has decreased the prevalence of e. multilocularis in the city (hegglin et al., . sarcoptic mange, a zoonosis caused by a parasite sarcoptes scabiei, is an important mortality factor of raccoon dogs both in native and introduced ranges (kauhala, b; shibata and kawamichi, ; kowalczyk et al., ) . raccoon dogs may also transmit the parasite to other animals including foxes, lynx and even brown bears (mörner et al., ) . mange has caused significant declines in red fox populations in, for example, sweden, in the city of bristol, uk (lindström et al., ; harris and baker, ) and also temporarily in finland (k. kauhala, pers. obs.) . the occurrence of infected raccoon dogs in the area may increase the risk of serious epizootics among foxes, because both species may use badger setts as den sites kowalczyk et al., ) . also, badgers may be infected on rare occasions (collins et al., ) . trichinella spp. are parasitic nematodes that cause trichinellosis (gottstein et al., ) . the disease is common in carnivores, especially scavengers, all over the world. foxes are the most common reservoirs of sylvatic trichinellosis in europe, although in finland the raccoon dog is another important reservoir (pozio, ; oivanen et al., ) . sylvatic trichinosis is more common in northern europe than in central and southern parts of the continent, because the human impact on natural ecosystems is less intense in the north (pozio, ) . domestic trichinellosis occurred only in two countries in the european union, finland and spain, in the s (pozio, ) . the raccoon dog may be an important reservoir species in finland, because it carries the most intense infections and is the only species that hosts all four trichinella spp. (t. spiralis, t. nativa, t. pseudospiralis and t. britovi) that occur in finland (oivanen et al., ) . the prevalence and risk of infection in wild animals (e.g., foxes) is lower in northern than in southern finland, probably due to the sparse raccoon dog population in the north. the prevalence in foxes has increased simultaneously since the s along with the increase in the raccoon dog population in finland (oivanen et al., ) . prevalence in foxes is much higher ( %) in estonia where raccoon dogs are more common than in sweden ( %) where raccoon dogs are sparse (oivanen et al., ) . these facts point to the conclusion that the role of the raccoon dog as a reservoir of trichinella spp. is remarkable (oksanen et al., ; oivanen et al., ) . the raccoon dog is one of those invasive species which extended its range quickly after introductions and invaded neighboring areas. by the s, raccoon dogs had colonized over . million km of europe (nowak, ; novak and pielowski, ; kauhala and saeki, b) and in many areas became the most numerous of carnivores (jędrzejewska and jędrzejewski, ; sidorovich et al., ; . the success of the raccoon dog invasion in europe was enabled thanks to an exceptional combination of factors including: widely distributed and multiple introductions, great migratory ability and the high reproductive capacity of the species, plasticity of food habits, hibernation in areas where climate is harsh and its general adaptability to different climatic and environmental conditions, and the admixture of individuals from divergent matrilineages (e.g., lavrov, ; helle and kauhala, ; kauhala a kauhala , b kauhala et al., , kowalczyk et al. , pitra et al., ; sutor et al., ) . few projects have been conducted in europe on the ecology of the species, so little is still known on the impact of raccoon dogs on native fauna. it seems that in many areas raccoon dogs fit very well into the local communities and successfully coexist with native medium-sized carnivores. locally, the raccoon dog may be an important threat to populations of waterfowl and amphibians. in protected areas, intensive and long-term control should be conducted to preserve local fauna. the raccoon dog is a very important vector of rabies, sarcoptic mange, trichinellosis and echinococcus multilocularis. this is no doubt the most severe consequence of the colonization of this alien species in europe. since it is continuing its expansion as well as increasing in numbers in some areas where the population has 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to a new competitor? food composition of the raccoon dog nyctereutes procyonoides gray, in finland carnivory is positively correlated with latitude among omnivorous mammals: evidence from brown bears, badgers and pine martens the effect of raccoon dog nyctereutes procyonoides removal on waterbird breeding success control of wildlife rabies: europe nyctereutes procyonoides first records of raccoon dog nyctereutes procyonoides (gray, ) in switzerland rabies in finland and its control - historical perspective of rabies in europe and the mediterranean basin. paris: the world organisation for animal health distribution of rabies in europe raccoon dog found dead in sör-varanger : a new norwegian mammal biology and behavior of raccoon dogs nyctereutes procyonoides in poland acclimatization of the raccoon dog in southern ukraine infectious disease: infectious disease in the management and conservation of wild canids male parental care in the raccoon dog nyctereutes procyonoides during the early rearing period we are grateful to dr. amy eycott for her linguistic revision of our manuscript. we thank four anonymous reviewers for their critical comments on the manuscript. key: cord- -jcsfbxgu authors: vogel, hans-arthur title: the nature of airports date: - - journal: foundations of airport economics and finance doi: . /b - - - - . - sha: doc_id: cord_uid: jcsfbxgu this chapter presents the historic development of global air transportation. as it is the main function to accommodate this traffic growth, airports have advanced in response to it. first, their role within the air transport system will be described. a picture of their social, environmental, economic and political impact will be given next. this chapter’s feature is on airport products and services. the nature of airports chapter outline . introduction . the role of airports within the air transport system airports are complex systems, providing infrastructure and services for the operations of aircraft and handling of passengers and cargo. this requires an adequate airfield, including a runway, aircraft parking apron, and terminal facilities for passengers, cargo, general aviation, and aircraft maintenance as well as supporting fixtures for access circulation/car parking, utilities, and other nonaeronautical use facilities. all of them are multifaceted in nature, while the commonality is that they have long lead times to plan and develop and are costly to build and maintain. this very nature of the airport business is a major determinant of the financial performance. another equally important factor is the demand side. airports have developed in response to the overall traffic growth, providing infrastructure and services to their airline customers. the success of aviation and the significant growth rates associated with that is causing an equally significant problem in terms of lacking infrastructure on the ground and in the air. various countries strongly support the industry on the whole, in order to participate in its benefits, for example, economic development and generation of employment. the population in other countries, however, is more critical regarding the environmental effects-especially when living in the vicinity of an airport. these notable differences are partially driven by their individual historical development in parallel to traffic growth and are, to a certain extent, addressing the challenges arising from these, in turn. as evidenced by the partial statistics on commercial aviation's long-term development in table . , it is a continuing success story and has been resilient vis-à-vis oil and/or gulf crises, other acts of war and terrorist attacks, severe acute respiratory syndrome (sars) and the like as well as economic recessions. during the second decade of this century, air transportation is performed by approximately , scheduled airlines with , aircraft in use, air navigation services, and more than , airports (fonseca de almeida, ). according to icao ( ), . billion passengers and . m tons of cargo were handled in . in general, commercial airports have developed in response to the fast growth of the world's airline industry, which in turn is significantly correlated with the annual growth of the gross domestic product (gdp). it is essential to bear this in mind for the rest of the book, since the airport business is fundamentally driven by the numbers or traffic volume. airport operations and management are an important part of the air transport value chain. many other industries would be pleased to cope with the problems associated with the lasting growth (and, in a few regions, maturity) of aviation. some of the ensuing issues, however, are far from being solved and may pose a severe threat. lacking infrastructure on the ground and in the air results in capacity constraints in general and congested hub airports in particular. traffic growth, however, has actually developed significantly differently across the regions. fig. . displays the regional passenger structure based on icao data. a clear trend of airport passengers in relative terms with regard to asia becomes visible, while north america falls behind and europe remains relatively stable. the underlying traffic shift is also reflected by the long-term volumes in passengers, aircraft movements and cargo handled. in spite of worldwide economic uncertainty and political instability in many countries, airports accommodated almost . billion passengers in . as the passengers are being counted at both the departing and arriving airport, the numbers are about double those of icao and the international air transport association (iata). while the total passenger number has almost tripled since , the regional distribution during this period is rather different-with direct implications for the affected airports. the demand for transportation in general, and for air transportation in particular, is primarily dependent on the status and growth of the economy, growth of the population, disposable income per capita and the resulting propensity to travel. the effects of different market maturity and the shift of the center of economic growth from north america (nam) and europe (eur) toward asia-pacific (asp) is illustrated by fig. . . although the middle east (mea) exhibits the highest overall growth rate for the period under scrutiny, it needs to be noted that this is due to the rather low traffic volume in base year . latin america-caribbean (lac) and africa (afr) have grown at par with and slightly higher than global average, respectively. in addition to the long-term development of the passenger segment, fig. . illustrates the development of the freight market during the last decade. after significant growth, volumes appear to stagnate after the effects of the most recent global financial crisis had been made up for in . roughly two-thirds of air cargo are accommodated by the belly hold of passenger aircraft. after inspecting historical data and identifying an overall trend, the future outlook needs to be analyzed in order to fully comprehend the fundamentals driving the airport business. table . displays the expected compound annual growth rate (cagr) or mean annual growth rate of the passenger sector over the specified period. based on rounded billion travelers expected to have flown in , iata projected this figure almost to double to . billion in . this is equivalent to a cagr of . % on average. other traffic projections, for example, airbus ( ) or boeing ( ) foresee healthy growth rates in a corridor between % and %, more toward the higher end regarding the short to medium range and toward the lower end for the longer term. airports council international (aci, ) is forecasting an even higher rate of . % for passengers (and . % for air cargo as well as . % for aircraft movements) in the long term up to . based on the regional trend described above, this scenario results in a tremendous change in passenger market shares, as displayed in fig. . . the uneven regional growth rates (cf. fig. . ) are set to continue, primarily due to market maturity and gdp growth. while this will provide superior growth perspectives to airports in the asia-pacific region, the overall outlook is very positive across the board. regardless of the slightly different projections, volumes will more or less double during the next years. against this background, iata is expecting that almost all of the world's top airports require major infrastructure expansion during this period. moreover, there could be more slot coordinated airports within years' time already. that is in addition to the level and level airports (with some peak congestion) as of november . all regions are concerned by this challenge, although europe is in the limelight of this infrastructure shortage (garcia, ; gittens, ; clark et al., ) . in order to accommodate for this growth scenario, adequate infrastructure is required both in the air and on the ground-substantially beyond current plans to expand capacity. otherwise, eurocontrol ( ) is afraid that according to their most likely scenario, there will be around . million flights more in demand than can be accommodated by , and million passengers will be unable to fly. it also means that the number of airports operating near capacity during most of the day, as it is the case at london heathrow (lhr), for example, will rise from six in summer to then sixteen. . the social, environmental, economic, and political impact of airports although airports are difficult neighbors due to their environmental impact which will be analyzed in section . . , they are an important economic factor for the cities and regions they serve. in addition to providing access to the global air transport system thus supporting connectivity, they also generate direct, indirect, and induced economic activities and employment (mcgraw, ) . the direct effects may be measured in employment and income resulting from the local airport operations, including the operator itself, other service providers, agencies, and the airlines. while indirect impacts refer to employment and economic activities linked to supplying the air transport industry, induced effects comprise employment and activity supported by the spending of air transport employees, for example, suppliers of goods and services purchased by employees. usually, their combined effect is being measured by the economic multiplier. the multiplier concept incorporates the spendings of direct employees as well as employees of supplying companies. finally, airports also support attracting and sustaining business development outside of air transport. these spin-off effects primarily materializing in the tourism and travel and trade industries are termed to be the catalytic impact (aci europe, ; air transport action group, atag, ). in their most recent study on the benefits of aviation, the atag ( ) reports the overall economic impact of aviation to have been around usd . tn in , supporting . % of the global gdp, with . million jobs dependent on aviation and . million thereof directly in aviation on a global scale. furthermore, they estimated direct employment to have been , with airport operators and another . million with a retail and car rental company or government agencies such as customs on-airport. according to aci ( ), the data concerning its airports revealed a ratio of for total employees on the airport site versus employees of the airport operator and a rule-of-thumb industry benchmark of eight airport employees per , passengers on average. significant regional variations need to be noted though for both, since the employment structure is affected by different operational, managerial and ownership models. these differences also apply to the total income of usd . bn generated by aci airports globally. for europe alone, intervistas ( ) has quantified the overall economic impact of airports in terms of , , total jobs and gdp of eur . bn or . % of the regional gdp, including catalytic effects. another local example is the impressive overall total economic impact of aviation on the dubai economy in , which is estimated to be usd . bn, comprising a "core" impact of usd . bn and "tourism" benefits of usd . bn. this is equivalent to . % of dubai's total gdp and was sufficient to support , jobs or % of the dubai's total employment (oxford economics, ) . it needs to be noted, however, that other industries certainly do generate employment, attract additional businesses (including air traffic/airports) and prompt multiplier effects as well. also, impact studies are descriptive in nature and less qualified as a basis for decision-making than costÀbenefit analyses. the latter address the question whether or not a project or sector is beneficial and also account for environmental implications-revealing favorable results for air transport in general (jorge-calderón, ). still, airports are now integrated into their region's socioeconomic engine with considerable economic and social benefits. these have frequently been capitalized on by politics, specifically where airports are in government ownership. quite often, however, the positive effects are overshadowed by the undisputed negative environmental impact, especially on residential areas in the vicinity of airportsÀwhile the value of commercial property in aviation dependent use is enhanced (cohen and brown, ). in recent years, airport planning and development increasingly tend to be a controversial issue. airports have to deal with numerous local issues regarding noise, air quality, waste management, and other environmental concerns, as well as the policies resulting from these matters. eurocontrol ( ) explains the various environmental topics connected to aviation. with air transportation serving the growing needs for the traveling public, aviation, at the same time, encumbers costs or detriments onto society and nature. these main adversities, harming the environment, are identified as aircraft noise, air pollution, climate change, third party risks, and aviation emissions. aircraft noise is a fundamental harm to people living close to the airport, complaining about noise disturbances, especially during nighttime periods. the "balanced approach" presents a means to undertake noise management procedures at airports and implicates the reduction of noise at the source, land-use planning and management measures, noise mitigation procedures, and operational restrictions. the most remarkable aviation emissions responsible for local air pollution are oxides of nitrogen and carbon monoxide. the encroachment of the environment often induces environmentalists and public campaigners to protest against airports, because of possible airport expansion projects or because of the two basic aviation disturbances of noise and gas emissions. these groups have the ability and power to bring about very damaging repercussions to airports, which can lead to night curfews being enforced at airports. one example of the growing public campaigns and citizens' initiatives is the monday demonstrations inside the terminal of the frankfurt airport in against the airport and its generation of noise. being a good neighbor, however, is vital to get planning approval for potential expansion projects. noise insulation of neighboring houses, technological advances such as new aircraft engine technology as well as renewable energies are further mitigations-usually implying financial burdens for the industry. new aircraft engine technology enables the airports' surrounding area to be less harmed by aircraft noise, invoking fewer noise complaints. renewable energies are further technological advances airports can make use of, in order to be part of the move of "going green." due to the large area that airport infrastructure demands, regenerative energy sources, like solar energy devices, can be mounted either to the spacious rooftops or onto the airport's open land masses. additionally, airports can possibly opt for installing wind turbines and use them as regenerative energy sources. such endeavors also would favor the social and environmental influences of airports, as sustainability on the one hand fabricates a positive image of the airport for the public, and simultaneously is welcomed by environmentalists (federal aviation authority, faa, a,b; pagliarello, ) . two initiatives support the efforts of "going green": aci's "carbon accreditation programme" and eurocontrol's "collaborative environmental management specification" (cem). the former was successfully implemented in europe a number of years ago and went global in november . the program certifies airports at four different levels of accreditation covering all stages of carbon management: mapping, reduction, optimization, and neutrality. as of spring , more than airports in more than countries across all regions have actually reached the fourth stage of carbon neutrality. the cem, on the other hand, was only launched in and is limited to europe, but includes aircraft operators, air navigation service providers, and trade associations in addition to airport operators. its objective is to facilitate the already existing activities of these core operational stakeholders by increasing their awareness of the various interdependencies. this, in turn, is to support sustainable airport development as an essential element for improving air transport movements capacity and flight efficiency (bates, ; eurocontrol, ). due to their significant importance for the economic development of a region and/ or an entire country, airports have frequently been subject to political activities. a prime example for the instrumental character of airport development-actually aviation on the whole-is the new dubai world central al maktoum airport, but also the expansion projects of neighboring abu dhabi (and to a certain extent also doha), where these investments are perceived to be a token of preparing the economies for the postÀoil future. similarly, the bric countries have an overriding interest in developing their airports' system, as ground infrastructure may not be comparable to north america or europe. but governments of the developed nations also follow a similar agenda in supporting the competitiveness of their economies. in europe, the european commission (ec)-in its capacity as an economic regulator and competition authority-has come up with several directives and regulations to create a level playing field for airlines and a more efficient use of scarce capacities to the benefit of the traveling public. additional comprehensive measures were adopted to address the capacity shortage at europe's airports and improve the quality of services offered to passengers under the umbrella of the "better airports package" (ec, ) . more recently, the ec ( ) introduced their "new aviation strategy for europe," which is supposed to foster innovation and generate growth for european business, while letting passengers benefit from increasing connectivity and safer, cleaner as well as cheaper flights. (additional aspects of aviation/airport policy will be considered in feature . .) from a commercial perspective, the two main groups of airport users are the airlines, representing the primary customers (b b) and the travelers or consumers using the dedicated facilities (b c). for the airlines, airports are instrumental for offering their product by providing the required infrastructure to operate aircraft and service their customers being passengers and cargo shippers. these genuine airline customers are airport users or consumers at the (continued) same time. this also holds true for meters and greeters as well as employees. the airline business requires adequate airport access as well as facilities and services at competitive fees and charges, plus a growth perspective for future development. in order to address the airlines' demand for adequate capacity and facilities to operate their business, airports provide the required infrastructure and offer a range of services. these represent the main sources of their revenue. at most airports aeronautical charges include the categories summarized by table . . furthermore, a number of airports impose peak charges and/or noise surcharges (or discounts, as applicable), as a constituent of the landing charges. more rarely, additional charges fall due for aircraft emissions and the usage of centralized infrastructure, such as baggage sorters and underground fueling system. ground handling services are not necessarily provided by the airport operator but frequently by third parties. the latter case will then generate commercial income based on a concession fee paid by the handling agent. also fuel charges are usually not collected by the airport but levied by the fuel companies. government taxes bypass the airport operator in general. while chapter , measuring the financial position, will give an example of a table of charges and chapter , regulatory regime, will add pricing aspects, it is worthwhile stating two relevant principles stipulated by icao's ( ) "policies on charges for airports and air navigation services": first, the "user pays principle," which means to say that users should bear the full and fair cost for the provision of required infrastructure; second, airport charges are essentially cost based (leighfisher, ) . the airlines' customers-the passengers consuming at the airport-have a different perspective. today's savvy travelers increasingly expect both air carriers and airports to understand their preferences and provide personalized offers, advice, and guidance for their door-to-door journeys. empowered consumers will be loyal to those addressing their needs for information, control, and individual service. this, for sure, includes easy access to and processing at the airport for boarding their flight (ascend, ) . in order to address this demand, airports provide the required infrastructure and offer a wide range of services and amenities. the latter are frequently provided by third parties instead of the airport operators themselves. for running their businesses on the airport premises, these concessionaires have to pay a percentage fee on their turnover on top of a fixed rental fee. the major services are summarized by table . , representing sources of commercial income for the airport operator generated on the landside, primarily driven by passenger volumes. it needs to be noted that airport employees also make use of several services and contribute to the generation of commercial revenue. the same applies to (continued) airlines (primarily on the airside) generate aeronautical revenue, commercial or nonaeronautical revenue results from activities on the landside of the airport where passengers consume. global market forecast airports council international (aci) the impact of an airport smoothing the airport experience À . boeing, . current market outlook À . boeing commercial airplanes the fight for slots the effect of international airports on commercial property values: case studies of the airport business. routledge specification for collaborative environmental management (cem) environmental issues for aviation challenges of growth-european aviation in . eurocontrol, brussels. european commission (ec), . airport package. com ( ) final. ec, brussels. european commission (ec), . an aviation strategy for europe. com ( ) final. ec environment and energy research & development federal aviation authority (faa) a future perfect? trends and challenges for the aviation industry. th airline marketing workshop forecast reveals air passengers will nearly double to . billion. iata, montreal, press release . international civil aviation organization (icao), . icao database-air transport statistics. icao, montreal. international civil aviation organization (icao), . icao's policies on charges for airports and air navigation services economic impact of european airports-a critical catalyst to economic growth aviation investment-economic appraisal for airports, air traffic management airlines and aeronautics airport design and operation, second ed review of airport charges the heterogeneous impact of airports on population and employment growth in cities the continuing development of airport competition in europe quantifying the economic impact of aviation in dubai the evolving challenge of noise authorities and airlines renting floor space for operations and back offices, parking facilities, as well as associated utilities. major characteristics of concession contracts will be introduced in chapter , measuring the financial position.as with any other business, meeting customer needs and expectations is key to operating an airport successfully. this appears to be mandatory, as copenhagen economics (ce, ) confirmed by oxera ( ) found that: these findings apply primarily to small , million passengers per annum (mppa) and medium sized airports, while larger ones . mppa are affected more by competition for transfer passengers. in general, airports are competing for any additional traffic in terms of passengers and cargo, particularly for: g passengers in a shared local market, g connecting passengers, and g airline services on new and existing routes (oxera, ) .although the focus of this research was on europe, it can be concluded from the wide-spread granting of commercial incentives to airlines across regions that airport competition has become a worldwide phenomenon in the meantime. various enticements have actually developed into a major tool of airport marketing, in addition to putting their products to the shop-window at the different "routes conferences." feature . will discuss the competitive situation in the sector in more detail. this chapter presented the historic development of global air transportation. as it is their main function to accommodate traffic, airports have advanced in response to it. traffic volume and structure, however, are not under full control of airport management but subject to overall economic, political and regional developments. an overview of airports' social, environmental, economic, and political impact was given. environmental concerns as well as changing customer demands and consumer behavior pose new problems in the digital age. addressing these is an ongoing and costly endeavor.this chapter's feature introduced to airport products and services. basically, two main types can be differentiated. while products and services delivered directly to key: cord- -om xc bs authors: berhan, yifru title: will africa be devastated by covid- as many predicted? perspective and prospective date: - - journal: ethiop j health sci doi: . /ejhs.v i . sha: doc_id: cord_uid: om xc bs nan since the novel coronavirus disease (covid- or sars cov- infection) has been declared as pandemic, several mathematicians and statisticians have developed different trajectory curves for africa, with the assumption that the virus can have an exponential pattern of transmission. according to economic commission for africa, k- . million covid- related deaths may occur in africa ( ) . a large body of literature and international media have also predicted that africa is going to be flooded, much higher than europe and the united states of america (usa). for ethiopia alone, some estimated - million with full mitigation and - million people without mitigation actions can get infected. when the author of this perspective sees such an easy to do, but hard to conceive figures, he likes to join the closed loop forum and express what his thought is. as of st april , close to k confirmed cases and + deaths are reported from african countries, while the global figure climbs to more than two and a half million and individual countries in the west are reporting the highest ever cases ( k- k+) and deaths ( k- k+) in less than three months ( ) . the hardest hit countries being the most capable to tackle such kind of infectious outbreak, and the extremely contagious nature of this virus is the puzzle and unprecedented phenomenon. virtually, countries of the globe do not look like they are ordered by the burden of this infection; the actual magnitude of case and death load in each looks as if they are ordered by their economic power and financial muscle. the bottom line is that this infection has been exponentially spreading, and becoming highly prevalent and fatal in the richest countries. that is not yet happening in countries within the tropical climate zone. will it be like that in the weeks or months to come is the core question of this perspective. some may argue that the developed countries testing capacity is what has inflated the case load, citing usa and germany as an example. yes, the high test uptake has helped the developed countries to identify as many cases as possible in a short period of time. rising in the last three months in the western countries of the temperate climate zone was not only case load, but also the staggering mortality figure and the severely morbid cases (hospitalization for pneumonia, icu care, dialysis, and blood transfusion), which are the two key measurements to show how severe the actual magnitude of the covid- is. a very important argument is; had the covid- transmission been as contagious as in europe and usa, by this time, every health facility in africa and other tropical countries could have been flooded with severely ill patients and deaths. but, that is not the case in any of african and tropical countries. the other side of the coin is; the overwhelming cases and deaths experienced in europe and usa is despite the fact that they started to report covid- confirmed cases almost same time or later than many of the countries in the tropical climate zone. up to now, the proportion of mortality in the majority of covid- reporting countries is in the lower range (< %) ( ) . the relatively high case fatality rates among countries with larger case load are reported from europe and one north african country (algeria). this observation may lead to pose questions on the predilection of the transmission and the survival of the virus particle outside the human body at different climate zone, as discussed below. on blanket view of the global distribution of the infection, relatively low case and death load is observed across africa, south middle east, south and southeast asia and latin america. since the beginning, the epicenter has moved from east to west along the temperate climate zone, and causes incomparably massive casualties. even in africa, the relatively hardest hit countries are still outside the tropical zone (algeria, egypt, morocco and south africa). countries in the tropical zone of asia and latin america, with relatively high case load, are not yet as hot spot as western countries in the temperate zone, despite the proportional duration of exposure; the cumulative number of deaths is incomparably low. the mathematical modeling result for the stated period using hypothetical numbers and the reported data from several tropical countries is far apart. brazil looks an exception, probably due to the rainy season or high tourist flow just around the outbreak. further, this is despite the fact that some african countries has started reporting covid- cases even earlier than some western countries with high case load. many authors have underscored the high mobility of the global population for the rapid spread of covid- in hot spot areas. but, the number of cases in many of the african countries is large enough to result in exponential transmission of the virus and be able to make hot spot. age and sex strata are some of the factors determining the prognosis, but not that much strong to justify the exponential transmission. hereunder, some more critical appraisal is presented. what can we learn from history to upkeep the above argument? with our limited knowledge, what history tells us may be in line with what we are observing the covid- pandemic at this juncture. as read from chronicles of influenza and other coronaviruses pandemics, the biology of sars cov- may have something to do with the climate to have exponential or restricted rate of transmission. it is not debatable that sars cov- is the seventh well known new coronavirus that infects humans (after sars-cov, mers-cov, hku , nl , oc and e) ( ). sars-cov and mers-cov are also new coronaviruses detected in humans in and , respectively, and are highly fatal ( ) . the mean global case fatality rates of sars cov- , sars cov and mers cov are %, % and %, respectively ( , ) . the last four coronaviruses usually cause mild upper respiratory tract infection, with the exception of oc , which once had caused an outbreak of severe pneumonia in france ( ) . like sars cov- , sars cov originated in china (guandong province), and was subsequently able to disseminate to europe and america, almost similar with the current trend. sars cov has become pandemic by reaching to countries in different continents, while the epicenter was in hong kong, with a total , infections and fatalities in a year period globally ( ). asian and european countries are the ones which are still sporadically reporting sars cov infection. the dissemination of sars cov to countries in the tropical zone along the globe, however, was minimal or none at all. another important milestone that consolidates the origin of the previous and current sars is the emergence of another new coronavirus in (named sads cov) from china near the origin of sars cov, which killed k piglets ( ) . the point is; the spread of mers cov and sars cov was predominantly in asia and europe. probing the history of influenza pandemics and the tropical epidemics can also give some clue on the likelihood distribution and proportion of cases and deaths of the current pandemic. since the time of hippocrates ( - bc), infectious disease pandemics had ravaged millions of human lives. some of the attributed etiologies for the outbreaks had international and regional propensity. yersinia pestis, which caused the 'black death' of - million people and the typhus fever which killed more than million in europe alone during the second world war are bacterial etiology, and were not having continental or national boundary. neisseria meningitides (the one causing meningitis outbreak along the meningitis belt), malaria, yellow fever, cholera, shigellosis, dengue fever are still common causes of outbreaks in the tropical climate zone. seasonal influenza outbreaks due to h n , h n and h n have been predominantly occurring in the northern hemisphere. the implication is that geographical and climate change may influence the microorganisms' survival outside the human body, and may determine the incubation period of the pathogen in the human body. influenza outbreaks occurred in europe and usa during cold and low humid weather (usually starting in winter and subsiding in spring), while meningitis and cholera outbreaks occurred in the tropics during hot weather and rainy season (usually preceding flood), respectively. although there is a long list of highly catastrophic influenza pandemics at different period of human history, it is worth mentioning those in the late th , early and second half of the th century and early in this century. among others, like the current pandemic, the 'russian flu'/h n ( - ) and 'hong kong flu' pandemics/h n ( ) ( ) ( ) which each killed one to four million people, and 'asian flu' pandemic/h n ( ) ( ) which killed million people originated from asia and massively spread to europe and america. 'spanish flu'/h n ( ) ( ) ( ) , which originated from spain, and killed - million people spread globally. another 'russian flu' pandemic/h n erupted in - and killed around k people worldwide ( ) . an important observation was that, like the currently observed covid- pandemic, the morbidity and mortality of the aforementioned influenza outbreaks were not that much spreading and killing outside the temperate zone, at least in africa. the first 'russian flu', for instance, reached in northern african countries, including egypt and algeria, but the case load and mortality were not as high as the european countries. in england alone, more than , people died of 'russian flu' in just one year. the 'asian flu' pandemic had also reached to many parts of africa, but was not highly catastrophic as it was in the northern hemisphere. the spanish flu was a bit exceptionally highly fatal in many parts of the world. it was estimated that about % of africans died. even then, in south africa (temperate zone) the estimated mortality ( k) was -fold higher than ethiopia ( k- k), which is somehow in line with the current pandemic ( ) . as a continuation of the old pandemics, the seasonal outbreaks and casualties of influenza in europe and usa are still devastating. according to the centers for disease control and prevention (cdc) of usa report, the - influenza outbreak killed k people in the usa alone, which was higher than the influenza related deaths ( k) in - season ( ) . the global estimate of deaths due to seasonal influenza was between k- k ( ). most of these deaths due to seasonal influenza occur in north asia, europe and north america. the swine flu pandemic that originated from mexico was the third h n influenza pandemic ( - ) that resulted in about k- k fatalities predominantly in north and south america, west europe, south and southeast asia, and australia ( ) . interestingly, among african countries, only egypt, algeria and south africa were part of the swine flu pandemic. the who annual estimate of mortality due to seasonal influenza is also a quarter to half a million. the bottom line is that, with the exception of the spanish flu, neither of the influenza pandemics seriously affected the african continent. the purpose of citing the above mortality figures is to show that there are infectious disease conditions which follow seasonal changes and are not proportionally distributed across the globe. the common causes of infectious outbreaks in the tropics and temperate zone are not same. otherwise, the influenza viruses and coronaviruses are biologically, pathogenically and epidemiologically completely different. what is probably in-common in the two groups is their potential to cause pneumonia and ability to expose to secondary bacterial infection. from previous coronavirus outbreaks (sars cov, mers cov) and influenza outbreaks as a proxy, one may extrapolate that the tropical zone may not be hit by covid- as hard as the temperate zone. the explosive nature of the covid- spread to every corner of the six continents, however, may make it incomparable in all parameters with the previous coronavirus and influenza outbreaks. notwithstanding this thought, the already observed rate of spread in the tropics is not as skyrocketing as the temperate zone, despite the virus lands almost two months back in many countries. in other words, the cases and deaths will likely increase, but not with flooding nature as seen in the temperate zone. as noted earlier, the number of confirmed cases may be underestimated due to lack of adequate testing. however, the seriously ill and death rates cannot be underestimated. let alone the covid- like outbreak, we know how many hospitals are overwhelmed when there is an outbreak of smaller scale. therefore, the severe morbidity and mortality indicators so far reported in the two zones have shown a remarkable disparity. overall, the cumulative cases and deaths will as well increase in africa, and it may even last longer than other types of pandemics, but the chance of exponential increment looks less likely. as sars cov, covid- is likely to be endemic in asia, europe and north america. among others, the very crowded day and night social life and the poor personal and environmental hygiene in this zone can be thought as creating a very conducive environment for the spread of covid- and any other communicable diseases. the high prevalence of malnutrition, malaria, tuberculosis, stress and non-communicable diseases (including diabetes and hypertension) may also make the majority of the people at higher risk for death. it is probably with this background why many are predicting the worst in africa. there is also a different assumption that the majority of african people and many more in the tropics are already exposed to several viral and bacterial infections (the justification for the planned bcg trial), which could help them to have a herd immunity to be protected from closely related pathogens. however, this theory may not be that much valid as the observed case fatality rate among covid- infected persons is not different from other parts of the world. if that is not the case, why the european or the american type of cases flooding into hospitals and overwhelming deaths are not yet observed in africa, in particular, and other countries in the tropics? one may argue that the carriers of this virus are still few in the respective countries. as the international travel of the people in the region is relatively limited, yes, that is partly true. however, it is also hard to accept that many of the first carriers of the virus in asia, europe and usa had a chance to travel to china/wuhan and around; quite significant number of community transmission was noted in europe and usa. it is also not wise to think that the number of the first carriers of this virus was too few to transmit the virus in africa as the transmission is presumed to have an exponential pattern ( for , then for , for and the like). nigeria (the first most densely populated african country with highly mobile urban population) reported the first case on february th , but its case load and deaths after nearly two months are and , respectively ( ). the second most densely populated african country and owner of the famous ethiopian airlines (ethiopia), which has been flying to international destinations till march th / at which time restriction was made to countries, has reported its first case about five weeks back; so far, has cases and deaths. egypt (the third most densely populated african country with large tourist flow before the outbreak and large number of its citizens working in europe) reported the first case one week earlier than italy, but the magnitude of cases and deaths are totally incomparable (italy's deaths are nearly times of egypt). the case load curves of many african countries are also waxing and waning type; a steady type of increment is not yet observed in the last - months, which is against with an exponential spread. this may not be solely explained by the preventive measures implemented, as there were several inconsistencies and breaches in many parts of africa. some also argue that the absence of community transmission is what has contributed to the low case load in africa and elsewhere with few cases. it is true that the majority of the transmissions occur in the community in europe and usa. however, it is still difficult to take it as a major reason for the low case load in several countries after reporting their respective first case nearly two months back, and with limited containing and mitigating actions. if we take ethiopia as an example, the wisdom of the author is that the covid- was imported probably several weeks before the quarantine was initiated for those who were coming from abroad. ethiopian airlines have been flying to more than countries in the world (including china at destinations). therefore, as the very recently confirmed case reports showed, the assumption is that the virus carriers are already within the community, and probably in many other african countries too. the recently reported eight cases in ethiopia came from the community with no contact history. the majority (> %) of the reported cases had an incubation period for more than two weeks, which is in contrast to the experience in the temperate zone. in literature, with few exceptions ( - days), the incubation period is less than two weeks. this is probably another research area on the impact of the climate on the multiplication of the virus in the human body and its survival outside the human body. although it is too early to deduce, the author's assumption is that africa and many of other countries in the tropical zone are less vulnerable to coronavirus and influenza virus infections, primarily because of the weather condition. until proved otherwise, this is probably because of the lower survival of the coronaviruses and influenza viruses in the external environment here in the tropics, whereby the humid weather condition is probably hostile to the virus to live outside the human body, thereby having a limited chance of proliferation and transmission from one person to another one unless it gets access as early as possible it is out. this hypothesis is going to be tested soon, at least for sars cov- . in , chan and colleagues reported that sars cov viability was rapidly lost (> log ) at higher temperatures and higher relative humidity ( ) . thus, in europe, usa and north asia, in particular, sars cov and sars cov- may live longer in the cold seasons outside the human body and be able to proliferate fast in the human body and infect as many people as possible. furthermore, in europe, sars cov- is reported as staying viable up to -day outside the human body. had this been the case here in africa and other places in the tropics, by this time, the covid- related admissions to hospital and deaths could have been overwhelming. with this regard, ethiopia and many african countries may as well benefit from ultraviolet radiation (uvr) b exposure. it is well proven fact that ozone depletion, prolonged sunlight exposure, higher altitude and latitude increase the uvr b exposure, of which ethiopia specifically has double advantage to be protected from covid- like epidemics (high altitude and prolonged sun light exposure). living organisms in general and microorganisms in particular are at higher risk for uvr b effect. uvr b is known to kill viruses by chemically modifying their genetic material (dna and rna viruses). during rainy or cloudy season, %- % of uvr b type is blocked, which may be one of the possible reasons for low incidence of covid- in the african region at this dry moment ( , ) . although it is unlikely to be the reason for all, one cannot ignore the timely actions of many of the african governments' role in implementing many of the preventive measures, including lockdown in a few countries. in many places, the public response to the call was also appreciable. here in the ethiopian capital, contact tracing, handwashing and preparations with available resource for the worst ahead are very impressive and commendable. streets are not that much crowded with pedestrians, and traffic jams have significantly decreased, which all have probably played some role in reducing the exposure. here and there handwashing service and practice was looking as the campaign is active, but could not be long-lasting in many places. what is likely to happen next? in the author's opinion, the case load is very likely to keep on increasing in all parts of africa with a bit higher than the current pace; particularly, if the complacence of the people grows along with the slow increment of the cases and the deaths, the risk of transmission of this virus may be a bit higher than the current trend. whatever the risk of transmission is, the cumulative figure is very unlikely to be in several millions as many predicted. the argument is that since the majority of the african population lives in scattered rural area, with the current awareness and the weather condition as described above, the risk of a large area spread in short a while is less likely. the expectation is that, before the spread of this virus reaches a larger scale, the two-three waves of the outbreak will be over. then after, sporadic cases will keep on emerging until the season is favorable for the virus's spread. similar spread and trend is expected in the majority of tropical countries as learnt from the previous pandemics. if that is not the case, this virus will not have a pattern similar to other infectious outbreaks (ascending, flattening and descending pattern). if the latter is true, africa will not be an exception; years long outbreak can occur elsewhere and the destiny will be unpredictable. the experience in the last three months, however, has shown that covid- outbreak is almost similar with previous pandemics; some countries like china and south korea are already entertaining the second wave after coming from apex to close to the baseline. therefore, the first scenario is; like many of other viral infections, those infected with covid- will develop humoral immunity and be protected from reinfection. as the majority of the population becomes immune (herd immunity) in due course, the chance of outbreak and the incidence rate will be less and less. the coming generation as well will be exposed in their earlier age and similarly develop the herd immunity. the possibility of developing a vaccine is within the domain of this assumption. the second scenario is reinfection. naturally, the majority of viral infections do not recur (with exception of those integrating their genome to the human genome, like hiv, human papilloma virus). covid- antigen, however, may not stimulate the human immune system to develop antibody against reinfection. this is much worrying as it may herald the difficulty to develop vaccine. researchers are soon to rule in or rule out whether the first or the second scenario is true. anecdotal evidence from china and south korea shows the possibility of reinfection, but that needs to be verified whether it is reinfection, reactivation or false positive result of the earlier test. african government and health stakeholders should not develop complacence with the slow rate of increment or reduction from recorded apex. apart from the seasonal nature, the character of infectious outbreaks is having two-three waves of mass infection; the latter waves are usually severe, for which complacence takes the major share. as the rainy and cold seasons are coming along the equator, second and third waves may be harder than before. seriously ill patients in hundreds to thousands are not manageable in an african setting. therefore, the already in action preventive interventions have to be maintained or strengthened till this outbreak is declared over (particularly contact tracing, avoiding or minimizing physical contact, hand washing, social distancing and universal mask use when exposure to other persons or patients is inevitable). the lockdown for africa, in particular, is a very controversial and challenging action. the author's opinion is that, as far as the social distancing and other preventive actions are in place, the lockdown action is not a wise decision for africa. the living style in the village and at the household level is already congested type; it is not uncommon to find dozens of people living and sleeping in a room. if lockdown is implemented, it should be complemented by mass testing, which is not economically and technically feasible for africa. therefore, phase by phase, the workforce has to resume the daily activities with stringent application of physical distancing and universal mask use. then after, students may be allowed to attend class on shift base (may be odd/even number on a day) with good advice and in-school close monitoring of the physical distancing. otherwise, the economic and social devastating effect of this virus to the african continent in general and poor countries in particular may not be tolerable and easily reversible. it may even result in social unrest and political crisis. therefore, we should not further delay the resumption of economically rate limiting sectors. if things go significantly in the wrong direction, preventive actions can be retightened as many countries are doing. in the author's opinion, whatever the consequence of this pandemic is in africa or elsewhere, it is another turning point in human history after the spanish flu and the second world war, by bringing about an extraordinary change in the political, economic and social landscape across the globe. from social interaction, international connectedness and travel perspective, i do not think that i am wrong if i say that covid- has dramatically changed the so called "world is a village" to 'world is an individual'. the economic crisis described by many, as the deep recession looming, may also hit hard africa and other low income countries with fragile economy. beyond controlling the outbreak, the big lesson for the world is to get ahead better prepared to manage such scale of outbreaks, and to make a significant paradigm shift in resourcing future researches to prevent and treat infectious outbreaks. for decades, communicable diseases are left to low income countries (particularly to sub saharan africa) with limited effort to develop vaccines and antimicrobials in resource rich countries. in short, the lesson acquired from covid- pandemic is expected to be the legacy for the generation to come. specific to africa, it is not arguable that covid- is a practical test that has clearly shown how much the health facilities are scarce and ill-equipped to handle such scale of public health emergency. when nations in africa are aware of that the expected covid- caseload is projected to be in several hundred thousand at a time, they also realized that available hospital beds in each big town are only a few hundred or less. similarly, the available health facilities and the health force to provide intensive care to critically ill patients are either non-existent or rudimentary. it is ahead a very disturbing experience for many of them. as an example of status indicator, the two countries with large population size (nigeria and ethiopia) are each able to test < , individuals in nearly two months. some african countries reported zero, , and the like number of ventilators at the national level while the demand is in thousands. this is in contrast to the first and second world where the testing and the basic life support capacity is extraordinary. in one of his briefings, his excellency andrew cuomo, the new york state governor requested the federal government to supply k ventilators while he has k at hand. the author is not sure whether the nations in africa in total have this number of ventilators. it is, therefore, covid- is a learning curve for african governments in the tropical zone to revise their health policy and get better prepared for similar or larger outbreaks in the years to come. covid- is not only a deep wake up click, but also a great 'opportunity' to mobilize the human force and financial resource to catch up in a short period of time with affordable cost. around two decades back ( ), african leaders signed the abuja declaration, which was stated as african countries should allocate % of their annual budget for health services ( ). in practice, however, the majority could not make it even %. that is why the health system and health facilities in africa remained crippled despite the staggering case load in every referral hospital. as a result, african countries are enforced to export the financially capable patients (including leaders) to middle east and asia with a yearly increasing number that has exploited the country's scarce resource. in the era of covid- , however, no way, nowhere to go. this is another reality, what makes covid- a breathtaking phenomenon. neither the economic nor the military power enables the abler to escape this invisible disease by traveling somewhere else. invariably, the covid- victim or susceptible individuals worldwide are getting help only from the nearby hospitals. luckily, the hospitals and treatment centers in these poor countries are not yet overwhelmed by covid- cases. if the worst comes (cases flooding like the europe and usa), there is an extremely low chance of getting medical care in africa. whether we like it or not, it will be a natural death and survival ('survival of the fittest'), like in the time of the old pandemics. african vips and well to do's will not be an exception. it is from this bad experience, what african leaders and every one of us need to take a big lesson to get prepared ahead for the worst to come (taking covid- as 'a blessing in disguise'). in general, covid- is another 'red flag' for humankind. in other words, the recent 'red flag' for humankind is the emergence of four highly fatal coronavirus strains (sars cov, mers cov, sads cov and now sars cov- ) in less than two decades with extremely fast global dissemination of sars cov- in three months and the lack of treatment or vaccine for either. related to this, the sporadically exploding highly fatal viral hemorrhagic fevers in the tropical zone (like ebola and marburg viruses) with on and off migration to other countries and again with no treatment or vaccine are a previously well noted 'red flag' for humankind. above all, the emergence of four new coronaviruses as a human pathogen in the first quarter of the st century is a 'red flag' for the emergence of another new coronavirus in the years to come, whose effect and destiny cannot be predicted. could the climate change have an influence in the mutation of these new coronaviruses and probably many more is not yet well substantiated. overall, the earlier appearance of the third generation of diseases implies that the human battle with the emerging viruses and bacteria will be tougher than before. covid- in africa: protecting lives and economies a novel coronavirus from patients with pneumonia in china clarivate analytics solution. diseases briefing: coronaviruses. . accessed on an outbreak of coronavirus oc respiratory infection in normandy, france fatal swine acute diarrhoea syndrome caused by an hku -related coronavirus of bat origin reviewing the history of pandemic influenza: understanding patterns of emergence and transmission. pathogens are we prepared for the next pandemic? estimated influenza illnesses, medical visits, hospitalizations, and deaths and estimated influenza illnesses, medical visits, hospitalizations, and deaths averted by vaccination in the united states influenza vaccines: ummet needs and recent developments the effects of temperature and relative humidity on the viability of the sars coronavirus ultraviolet radiation: how it affects life on earth abuja declaration on hiv/aids, tuberculosis and other related infectious diseases sars = severe acute respiratory syndrome mers = middle east respiratory syndrome sads = swine acute diarrhea syndrome key: cord- -x i x v authors: gensini, gian franco; yacoub, magdi h.; conti, andrea a. title: the concept of quarantine in history: from plague to sars date: - - journal: j infect doi: . /j.jinf. . . sha: doc_id: cord_uid: x i x v the concept of ‘quarantine’ is embedded in health practices, attracting heightened interest during episodes of epidemics. the term is strictly related to plague and dates back to , when the rector of the seaport of ragusa (then belonging to the venetian republic) officially issued a -day isolation period for ships, that became days for land travellers. during the next years similar laws were introduced in italian and in french ports, and they gradually acquired other connotations with respect to their original implementation. measures analogous to those employed against the plague have been adopted to fight against the disease termed the great white plague, i.e. tuberculosis, and in recent times various countries have set up official entities for the identification and control of infections. even more recently ( ) the proposal of the constitution of a new european monitoring, regulatory and research institution has been made, since the already available system of surveillance has found an enormous challenge in the global emergency of the severe acute respiratory syndrome (sars). in the absence of a targeted vaccine, general preventive interventions have to be relied upon, including high healthcare surveillance and public information. quarantine has, therefore, had a rebound of celebrity and updated evidence strongly suggests that its basic concept is still fully valid. the concept of 'quarantine' is radically embedded in local and global health practices and culture, attracting heightened interest during episodes of perceived or actual epidemics. the term, however, evokes a variety of emotions, such as fear, resentment, acceptance, curiosity and perplexity, reactions often to be associated with a lack of knowledge about the origins, meaning, and relevance of quarantine itself. historically quarantine has been defined as the detention and segregation of subjects suspected to carry a contagious disease. more recently, the term quarantine has come to indicate a period of isolation imposed on persons, animals or things that might spread a contagious pathology. nowadays the word quarantine should be used to refer to compulsory physical separation (including restriction of movement) of groups of healthy individuals who have been potentially exposed to a contagious disease. the term 'isolation' must be kept separate from the term quarantine, since the former denotes the separation and confinement of subjects already known to be infected with a contagious disease to prevent them from transmitting disease to other people; the latter, essentially the same procedures but with suspected transmitters of disease. from ancient times different populations have adopted varying strategies to prevent and contain disease. one of these is exactly what we would now call isolation. the old testament evidences how individuals affected by diseases were separated from others, and people with leprosy, as leviticus informs, had to live isolated all their lives. in the new testament, too, leprosy continues to be considered a reason for social discrimination, and is represented as curable only through the phenomenon of a divine intervention. the isolation, temporary or otherwise, of sick people has thus always been extensively used as one of the approaches to limit the spread of disease. another strategy was the establishment of a time limit to the manifestation of diseases. in the v century b.c. hippocratic teaching had established that an acute illness only manifested itself within forty days. the case of plague was representative with respect to this; since a disease manifesting itself after days could not be acute, but chronic, it could not be plague. in the ancient past the term pestis (plague) was used in a broad way to indicate every epidemic characterised by high mortality, and magical practices were implemented to fight different diseases since the idea of preventive instruments (such as quarantine) was still not present. with regard to the real plague (the disease caused by yersinia pestis), one may remember the first great pandemic wave of the greek -roman period, and the recurrent epidemics throughout europe in the vi and vii centuries a.d. against acute, fatal diseases such as bubonic plague attempts were made by healthy communities to prevent entry of goods and people from infected communities. in the vii century a.d. armed guards were stationed between plague-stricken provence and the diocese of cahors. particularly virulent was the impact of the disease on the whole of europe in the middle of the xiv century, when the plague spread from southern europe to germany and russia, causing the death of more than % of the european population. medieval laws, renaissance health achievements and xvi -xviii centuries overview the concept of (modern) preventive quarantine is strictly related to plague and dates back to , when the rector of the seaport of ragusa, today called dubrovnik (croatia), officially issued the socalled 'trentina' (an italian word derived from 'trenta', that is, the number ), a -day isolation period. ships coming from infected or suspected to be infected sites were to stay at anchor for thirty days before docking. this same period of time became days for land travellers, probably because the shorter period was not considered sufficient to prevent the spread of disease, and precisely from the italian number forty ('quaranta') comes the term quarantine. furthermore, the chief physician of ragusa, jacob of padua, also advised establishing a place outside the city walls for the treatment of sick (or suspected to be infected) citizens. the imposition to remain - days in an isolated site was determined not only by health reasons, but also by economic necessity, since the quality and safety of the trade network needed to be protected from the black death. the attention dedicated by the ragusan rulers to the plague was, therefore, responsible for the creation of the first 'official' quarantining as a legal system aimed at defending both health and commercial aspects. the following were the main tenets of the law of ragusa: visitors from areas where plague was endemic would not be admitted into ragusa until they had remained in isolation for a month; whoever did not observe this law would be fined and subjected to a month of isolation; no one from ragusa was allowed to go to the isolation area; people not assigned by the great council to care for quarantined persons were not allowed to bring food to isolated people. in venice set up one of the first known 'lazaretto' (quarantine station) on an island near the city, and the venetian system became a model for other european countries. during the next years similar laws were introduced in italian ports (pisa) and in french ones (marseilles), and they gradually acquired other connotations with respect to their original implementation in the context of the middle ages. one such connotation was the institution of a social body to provide the necessary isolation structures (dispositions, facilities, implementation of the laws themselves); another, of more intellectual and medical content, was the gradual acquisition of the essential mechanisms of contagion. in effect, even during the early renaissance, physicians did not have a clear idea of infectiousness, though many waves of epidemics had succeeded one another in the course of the previous centuries. it was only during the xvi century that girolamo fracastoro defined and empowered the concept itself, through the hypothesis that small particles were able to transmit disease. this led the medical profession to integrate previously adopted remedies, simple and insufficient, with more precise quarantine interventions (even if not at an international level) that, however, became the remote bases for modern epidemiology and health sciences. in the xvi century the quarantine system was expanded through the introduction of bills of health, a type of certification that the last port visited by travellers was free from disease. a clean bill, with the visa of the consul of the country of arrival, entitled the ship to the use of the port without quarantine. in the course of the xviii century the practice of quarantine had become, on the one hand a notable nuisance, and on the other, a source of abuse. with regard to the former point, the periods of quarantine were variable across different countries, so that there was no certainty concerning the time needed to implement the quarantine itself. as consequence, not only delay, but perplexity was caused to travellers. with regard to the latter question, instances of bureaucratic and restrictive implementation of quarantine regulations were rife, and the disinfection of correspondence was used as an excuse for political espionage. the upshot of this diffused dissatisfaction with quarantine measures was the emergence of the awareness of the need for a shared standardisation, which, in turn, led to the call for xix century international conferences. from a scientific-epidemiological point of view the concept of quarantine had come to be defined quite precisely in the course of the xix century, but the contemporaneous health organisation was not systematic and capillary enough to confront bursts of epidemics across europe in an organic way. the mid-xix century cholera epidemics, for example, evidenced the scantiness of international uniformity in quarantine practices. even if france had proposed, already in , a meeting for the discussion of the international standardisation of quarantine, it was only in that the first international sanitary conference took place in paris. collaboration at the international level was hard to achieve since quarantine policies mirrored not only health organisation views, but also national trade protection issues that varied from state to state. open negotiation on quarantine was strongly limited by economic and political agendas, as documented by the rome conference, where a proposal regarding the inspection of quarantine of ships from india, using the suez canal, produced a violent discussion between britain and france based not on health questions, as much as on the extent of british dominance over the canal. with regard to the united states of america, protection against imported pathologies had always been retained a local issue, and so handled by the single states. only sporadic attempts had been performed to impose quarantine requirements until repeated and serious yellow fever epidemics led to the passing of federal quarantine legislation by congress in , a set of laws that paved the way for federal involvement in quarantine activities. in the arrival of cholera from abroad prompted a reinterpretation of these laws so as to endow the federal government with more authority in the imposition of quarantine requirements. it was only in that, after a number of conferences held in the second half of the xix century, an agreement was achieved both in europe and in the united states, concerning the notification of disease and other issues. after this achievement conventions and regulations began to be ratified regarding, in particular, relevant principles for the standardisation of quarantine measures. in the united states, as local authorities realised the benefits of federal involvement, local quarantine stations were gradually turned over to the government; in europe established periods of detention were fixed with special reference to cholera, yellow fever and plague. it is interesting to observe how measures analogous to those employed against the plague have been adopted to fight against the disease that, not by chance, has been termed the great white plague: we refer to tuberculosis (tb). before the tubercle bacillus was recognised as the causative agent of the disease, sanatoria had been set up as the only remedy for sufferers from tuberculosis; this may be considered as an application of the broad concept of 'preventive-therapeutic' quarantine. sanatoria constituted a simple and inexpensive tool to break the chain of transmission of the disease, since they guaranteed isolation. they, therefore, had a precise role in controlling tuberculosis, and it is for this reason that, between and , sanatoria spread across the whole of europe and north america. even during the s, although streptomycin was already on the market ( ), tb hospitals were considered important for tuberculosis therapy as sites dedicated to the isolation of tb patients, as recommended by quarantine practice. in the scenario of contagious diseases of the past, the so-called 'health officers' deriving partly from medieval and renaissance predecessors and partly from figures created by the schools of hygiene, acquired fundamental importance. among their various functions were those of furnishing the single national health systems with appropriate corporate entities and legislative organisms, as well as obviously caring for the health of the whole population. in many european countries, including italy, these 'officers' represented, even in the second half of the xx century, the basis of all public health organisation devoted to the monitoring and control of infectious diseases. in the first years of the xx century, a deep medicalization of quarantine measures occured. in the term 'lazaretto' (used especially for plague) was substituted by that of 'health station', since in europe, particularly in france and in italy, the distinction among sick, suspectedly sick, and healthy people, began to acquire a real medical value. four years later an international office of public health was established, and more than twenty nations adhered to it in less than years. variola and typhus were added to the three (plague, cholera and yellow fever) historical quarantining diseases in , and years later this same international office imposed a set of quarantine rules targeted to all kinds of travellers (by land, sea and air). when the world health organisation replaced the international office of public health the expression 'quarantining diseases' disappeared, and pathologies controlled by international health laws (such as plague, cholera and yellow fever) or pathologies under surveillance (such as poliomyelitis, recurrent fever and typhus) appeared. in the face of this resurgence of attention towards infectious diseases, tuberculosis was again made the object of specific measures, which, however, served to monitor and control other diseases. consequent to the high transmission and seriousness of tuberculosis in the europe of the nineteenth century, various countries set up official entities for the identification and control of infections. in the united kingdom a government-funded agency, the medical research council (mrc), was created in in the hope of finding scientific solutions to the illness. its activity was specifically directed to research. with reference to the other side of the atlantic, in the twentieth century ( ) quarantine measures became the task of the national communicable disease centre, at present called the centre for disease control (cdc) and prevention, an organisation, already equipped, in the sixties, with more than quarantine stations located at every port and international airport, and, in the seventies, shifting its field of action from routine inspection to problem management, intervention and regulation. more recently ( ) the proposal of the constitution of a new european monitoring, regulatory and research institution was made, since the already available system of surveillance, set up in europe to control the onset of epidemics, came up against an enormous challenge in the global emergency of the severe acute respiratory syndrome (sars). in the absence of a targeted vaccine, general preventive interventions had to be relied upon, including high healthcare surveillance and public information. quarantine has, therefore, had a rebound of celebrity, as witnessed by the 'fact sheets' prepared and published by the cdc, in which one may read that 'quarantine is medically very effective in protecting the public from disease'. the 'modern' quarantine for sars is a -day period (the incubation period of sars is in fact - days) and, like the quarantines of the past, has been applied to persons who have been exposed to the disease and who may be infected, while, once again, isolation has been implemented to separate healthy people from sick ones. as mentioned above, the health emergency of sars has constituted a real challenge for health systems. however, it has also put into discussion the real effectiveness of quarantine measures, for, precisely as for every other health intervention, quarantine has limits of application of which the medical and social community should be perfectly aware. a recent paper proposing a compartmental model for the geographical spread of infectious diseases shows how this scheme may be adopted to address the effectiveness of human quarantine. the model itself was applied to data deriving from a canadian historical record regarding the time period of the so-called spanish influenza pandemic ( - ) . information on the daily mobility patterns of subjects engaged in the fur trade throughout central canada before, during and after the epidemic were used to establish whether rates of travel were affected by informal quarantine policies, and then the same methodology was adopted to analyse the impact of observed differences in travel on the diffusion of the epidemic. this same model has suggested that quarantine effectiveness varies depending on when the limitation on travel between communities is applied, and on how long it lasts. an operative template of such a type appears particularly interesting from our historical-scientific point of view since it links historical features to current scientific epidemiological evidence. similar to other effective health measures, quarantine is not a panacea, and has its limits. this is highlighted by the recent risk of bioterrorism, where a potentially large and diverse number of agents may be implicated. in addition, other recent epidemics, such as the acquired immuno deficiency syndrome (aids), cannot be considered quarantine-able not only because of medical but also because of ethical and legal issues. however, good quality evidence overall suggests that the basic concept of quarantine is still fully valid, and that the implementation of correct quarantine procedures must be tailored according to single health, social and geographical conditions. , , large-scale quarantine following biological terrorism in the united states the origin of quarantine quarantine and isolation. th ed. the new encyclopaedia britannica the black death past and present. . some historical problems a state of deference: ragusa/dubrovnik in the medieval centuries storia della medicina dall'antichità a oggi trade and health policies in ragusa-dubrovnik until the age of george armmenius-baglivi history of the concept of quarantine plague, policy, saints and terrorists: a historical survey a short history of quarantine (victor c. vaughan) politics of quarantine in the th century international law and infectious diseases the evolution of the concept of 'fever' in the history of medicine: from pathological picture per se to clinical epiphenomenon (and vice versa) compliance, coercion, and compassion: moral dimensions of the return of tuberculosis international sanitary regulations. rd annotated ed. world health organization guideline on management of severe acute respiratory syndrome (sars) severe acute respiratory syndrome. fact sheet: isolation and quarantine simulating the effect of quarantine on the spread of the - flu in central canada plague as a biological weapon: medical and public health management. working group on civilian biodefense quarantine and the problem of aids some historical comments on quarantine: part one some historical comments on quarantine: part two the authors would like to thank professor luisa camaiora, b.a., m.phil., for her correction of the english. key: cord- - ehuuvnx authors: götzinger, florian; santiago-garcía, begoña; noguera-julián, antoni; lanaspa, miguel; lancella, laura; calò carducci, francesca i; gabrovska, natalia; velizarova, svetlana; prunk, petra; osterman, veronika; krivec, uros; lo vecchio, andrea; shingadia, delane; soriano-arandes, antoni; melendo, susana; lanari, marcello; pierantoni, luca; wagner, noémie; l'huillier, arnaud g; heininger, ulrich; ritz, nicole; bandi, srini; krajcar, nina; roglić, srđan; santos, mar; christiaens, christelle; creuven, marine; buonsenso, danilo; welch, steven b; bogyi, matthias; brinkmann, folke; tebruegge, marc title: covid- in children and adolescents in europe: a multinational, multicentre cohort study date: - - journal: lancet child adolesc health doi: . /s - ( ) - sha: doc_id: cord_uid: ehuuvnx background: to date, few data on paediatric covid- have been published, and most reports originate from china. this study aimed to capture key data on children and adolescents with severe acute respiratory syndrome coronavirus (sars-cov- ) infection across europe to inform physicians and health-care service planning during the ongoing pandemic. methods: this multicentre cohort study involved participating health-care institutions across european countries, using a well established research network—the paediatric tuberculosis network european trials group (ptbnet)—that mainly comprises paediatric infectious diseases specialists and paediatric pulmonologists. we included all individuals aged years or younger with confirmed sars-cov- infection, detected at any anatomical site by rt-pcr, between april and april , , during the initial peak of the european covid- pandemic. we explored factors associated with need for intensive care unit (icu) admission and initiation of drug treatment for covid- using univariable analysis, and applied multivariable logistic regression with backwards stepwise analysis to further explore those factors significantly associated with icu admission. findings: individuals with pcr-confirmed sars-cov- infection were included, with a median age of · years (iqr · – · ) and a sex ratio of · males per female. ( %) had pre-existing medical conditions. ( %) individuals were admitted to hospital. ( %) individuals required icu admission, ( %) mechanical ventilation (median duration days, iqr – , range – ), ( %) inotropic support, and one (< %) extracorporeal membrane oxygenation. significant risk factors for requiring icu admission in multivariable analyses were being younger than month (odds ratio · , % ci · – · ; p= · ), male sex ( · , · – · ; p= · ), pre-existing medical conditions ( · , · – · ; p= · ), and presence of lower respiratory tract infection signs or symptoms at presentation ( · , · – · ; p< · ). the most frequently used drug with antiviral activity was hydroxychloroquine ( [ %] patients), followed by remdesivir ( [ %] patients), lopinavir–ritonavir (six [ %] patients), and oseltamivir (three [ %] patients). immunomodulatory medication used included corticosteroids ( [ %] patients), intravenous immunoglobulin (seven [ %] patients), tocilizumab (four [ %] patients), anakinra (three [ %] patients), and siltuximab (one [< %] patient). four children died (case-fatality rate · %, % ci · – · ); at study end, the remaining were alive and only ( %) were still symptomatic or requiring respiratory support. interpretation: covid- is generally a mild disease in children, including infants. however, a small proportion develop severe disease requiring icu admission and prolonged ventilation, although fatal outcome is overall rare. the data also reflect the current uncertainties regarding specific treatment options, highlighting that additional data on antiviral and immunomodulatory drugs are urgently needed. funding: ptbnet is supported by deutsche gesellschaft für internationale zusammenarbeit. in late december, , who was notified of an unusual cluster of pneumonia cases in wuhan, china. the disease, later termed covid- , spread quickly beyond the borders of china, with the first cases in europe being recorded on jan , . subsequent investigations identified a novel betacoronavirus now designated as severe acute respiratory syndrome coronavirus (sars-cov- ). currently, there are no antiviral treatment options with proven efficacy, but several randomised controlled trials are investigating agents such as hydroxychloroquine, lopinavir-ritonavir, favipiravir, and remdesivir (eg, nct , nct , and nct ). other trials are focusing on immunomodulators, including tocilizumab and anakinra (eg, nct and nct ). to date, data on covid- in children and adolescents remain scarce, despite the number of confirmed covid- cases now exceeding million globally. , most published data originate from china, which cannot necessarily be extrapolated to children in europe and elsewhere. [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] also, existing papers from china contain very few clinical data on children, and most lack details regarding supportive measures required by children with covid- . similarly, recent epidemio logical reports from europe and north america contain little clinically relevant information. , determining the level of support required by children is essential for paediatric service planning during the ongoing covid- pandemic. by use of a well established research network, predominately comprising paediatric infectious diseases specialists and paediatric pulmonologists, the aim of this study was to rapidly capture key data on covid- in children in europe on a large scale, to aid physicians in europe and in other geographical locations with service planning and allocation of resources. for this cohort study, european members of the paediatric tuberculosis network european trials group (ptbnet)-which currently includes clinicians and researchers, most of whom are based at tertiary or quaternary paediatric infectious diseases or paediatric pulmonology units, across paediatric health-care institutions in european countries [ ] [ ] [ ] [ ] [ ] [ ] -were invited to contribute cases of confirmed sars-cov- infection that had been managed at or managed remotely by their health-care institution (including individuals admitted to other hospitals or identified during community screening) before or during the study period. any individual aged years or younger with sars-cov- infection confirmed by rt-pcr was eligible for inclusion. a standardised data collection spreadsheet was used by collaborators to record data from their centre. all data were reviewed by three of the investigators (fg, bs-g, and mt), and any inconsistencies and other data queries were clarified with the reporting collaborators. units that did not see any cases before or during the study period were asked to report the absence of cases fulfilling the inclusion criteria at the end of the study period. the study was done over a · -week period, from april to april , . the study was reviewed and approved by the ptbnet steering committee, and the human research ethics committees of the university of bochum, germany ( - -br), the hospital gregorio marañon, spain (ceim hgugm- / ), and the city of vienna, austria (ek - -vk). the study was conducted in accordance with the declaration of helsinki and its subsequent evidence before this study we searched medline on may , , through the pubmed interface to identify publications describing clinical studies in children with covid- . to ensure a broad search, the search terms used were "(child or children or pediatric or paediatric) and covid- ". no additional limits were set. this search yielded papers: case reports or case series; epidemiological reports; guidelines and consensus statements; reviews, perspectives, or editorials without original data; and letters; were unrelated to children with covid- . papers presented original data, but exclusively in adults. only ten papers reported clinical studies in children with covid- : eight papers originated from china, one from spain, and one from italy. the study by tagarro and colleagues was reported in letter format, and only included children with confirmed severe acute respiratory syndrome coronavirus (sars-cov- ) infection in madrid. the study from italy by parri and colleagues was also reported as a letter and included cases across several italian hospitals. however, the study only featured a single patient who required mechanical ventilation, and consequently very few data on children with covid- at the severe end of the disease spectrum. to our knowledge, this study is the first multinational, multicentre study in children with covid- , and provides a detailed overview on sars-cov- infection in children in europe during the initial peak of the pandemic, which was facilitated by a collaboration of units across european countries. the study has several key findings. first, the data show that covid- is generally a mild disease in children, including infants. second, the study found that a substantial proportion ( %) of children develop severe disease, requiring intensive care support and prolonged ventilation. several predisposing factors for requiring intensive care support were identified. third, the study confirms that fatal outcome is rare in children. there was considerable variability in the use of drugs with antiviral activity as well as immunomodulatory medication, reflecting current uncertainties regarding specific treatment options. this study confirms previous reports from china suggesting that the case-fatality rate of covid- in children is substantially lower than in older adult patients. however, some children develop severe disease and require prolonged intensive care support, which should be accounted for in the planning of health-care services and allocation of resources during the ongoing pandemic. finally, the findings highlight that data on antiviral and immunomodulatory drugs are urgently needed from well designed, randomised controlled trials in children, to enable paediatricians to make evidencebased decisions regarding treatment choices for children with severe covid- . amendments. no personal or identifiable data were collected during the conduct of this study. a confirmed case was defined as a patient in whom sars-cov- was detected in any clinical sample (respiratory tract, blood, stool, or cerebrospinal fluid) by rt-pcr. pcr testing was done as part of routine clinical care, and therefore done according to local testing guidelines in place at the time. date of symptom onset was defined as the day when the first symptom or sign occurred, and date of diagnosis as the day when sars-cov- was first detected. pyrexia was defined as a body temperature at least · °c. the index case was defined as the most likely source case based on history; if multiple family members were affected, the person who displayed symptoms first was recorded. diagnosis of upper respiratory tract infection was based on clinical signs and symptoms, encompassing any of the following: coryza, pharyngitis, tonsillitis, otitis media, or sinusitis. lower respiratory tract infection was based on clinical signs and auscultation findings. inotropic support was defined as administration of dopamine, dobutamine, epinephrine, or norepinephrine by continuous infusion. non-parametric two-tailed mann-whitney u tests were used to compare continuous variables and χ² or fisher's exact tests to compare categorical variables, as appropriate. in children younger than years, age was calculated as fraction of a whole year ( days); from years of age, age was rounded to the nearest year. the % ci around the case-fatality rate (cfr) was calculated with the wald method. normality of data distribution was assessed with the shapiro-wilk test. the clinical endpoint was the need for admission to an intensive care unit (icu; either neonatal or paediatric intensive care). the association of baseline characteristics and clinical findings with icu admission was initially evaluated using univariable logistic regression. subsequently, multivariable logistic regression analysis with the backward stepwise method was used to explore variables that were independently associated with icu admission. only variables that were significant in univariable analyses were introduced into the model. factors associated with drug treatment for covid- were also explored with univariable analysis. all probabilities are two tailed. p< · was considered statistically significant. all analyses were done with prism (version . ; graphpad, la jolla, ca, usa) and spss (version . ; ibm, armonk, ny, usa). the funders had no role in the study design, data collection, data analysis, data interpretation, or writing of the manuscript. the corresponding author had full access to all the data and had the final responsibility for the decision to submit for publication. cases of sars-cov- infection were reported from health-care institutions located in european countries: austria, belgium, bulgaria, croatia, denmark, estonia, germany, greece, hungary, ireland, italy, lithuania, norway, portugal, slovakia, slovenia, spain, sweden, switzerland, turkey, and the uk (figure ). three cases did not meet the inclusion criteria (one -year-old individual and two individuals diagnosed with covid- based on serological testing, but pcr negative). five participating units in the netherlands, moldova, ukraine, and russia reported not having encountered any cases. individuals with pcr-confirmed sars-cov- infection were included in the final analyses. ( %) were contributed by tertiary or quaternary health-care institutions, whereas ( %) had been diagnosed in secondary and ( %) in primary health-care settings. the median age of the study population was · years (iqr · - · ), ranging from days to years (table) . age was non-normally distributed (w= · ; p< · ), with ( %) participants younger than months (figure ). the sex ratio was · males to every female. the most common source of infection was a parent, considered the index case in ( %) individuals; for ( %) individuals, the most probable index case was a sibling. in the remaining ( %) individuals, the index case was a person outside of the immediate family or unknown. ( %) individuals were admitted to hospital and ( %) required admission to an icu for additional support, corresponding to % of those admitted to hospital. ( %) individuals had no pre-existing medical conditions. among the remaining ( %) individuals, the most common conditions were chronic pulmonary disease ( individuals, of whom had asthma and six bronchopulmonary dysplasia), followed by malignancy ( individ uals, of whom had leukaemia or lymphoma and had solid tumours), neurological disorders ( individuals, of whom nine had epilepsy and eight had cerebral palsy), congenital heart disease ( individuals), chromosomal abnormalities (ten individuals, of whom eight had trisomy ), and chronic kidney disease (nine individuals; table). ( %) individuals had two or more pre-existing medical conditions. ( %) individuals were receiving immunosuppressive medication at the time of covid- diagnosis (table) . three ( %) had a previously diagnosed immunodeficiency, comprising common variable immunodeficiency, congenital neutropenia, and schimke immuno-osseous dysplasia. ( %) individuals were receiving chemotherapy at the time of their diagnosis or had received chemotherapy in the preceding months. three ( %) had previously undergone human stem cell transplant. pyrexia was the most common sign at presentation, observed in ( %) individuals (table). approx imately half had signs or symptoms of upper respiratory tract infection and approximately a quarter had evidence of lower respiratory tract infection; ( %) had gastrointestinal symptoms. ( %) individuals with gastrointestinal symptoms had no respiratory symptoms; the majority ( %; n= ) of these individuals had pyrexia. ( %) individuals were asymptomatic. dates when sars-cov- infection was confirmed by rt-pcr in the study population are summarised in figure . the median interval between symptom onset and diagnosis was days (iqr - ; range - ); in the baseline characteristics in the entire cohort and by requirement of icu admission majority (n= ; %) of cases, the interval was no more than days. in eight cases, sars-cov- infection was confirmed before any signs or symptoms were presentmainly neonates born to sars-cov- -positive mothers and household members of symptomatic adults with confirmed covid- . a chest x-ray was done in ( %) patients. of those, ( %) had changes consistent with pneumonia (table). ten ( %) had changes suggestive of acute respiratory distress syndrome (ards), all of whom required mechanical ventilation. in ( %) patients, additional viruses were detected in respiratory samples, comprising enterovirus or rhinovirus (n= ), influenza virus (n= ), parainfluenza virus (n= ), adenovirus (n= ), respiratory syncytial virus (rsv; n= ), bocavirus (n= ), and coronavirus nl , coronavirus hku , coronavirus oc , and human metapneumovirus (n= each). in patients one virus was detected in addition to sars-cov- ; in six patients, two additional viruses were detected simultaneously; and in one patient, three were detected. patients with one or more viral co-infections were more likely to have signs or symptoms of upper or lower respiratory tract infection at presentation compared with those in whom no additional viral agent was identified (appendix p ). furthermore, individuals with viral co-infection were significantly more likely to require icu admission, respiratory support, or inotropic support. ( %) individuals did not require respiratory support at any stage. ( %) patients required oxygen support: ( %) were started on continuous positive airway pressure (cpap) and ( %) on mechanical ventilation (including who had been managed with cpap initially). the median duration of mechanical ventilation was days (iqr - ; range - ). one (< %) patient was started on extracorporeal membrane oxygenation. ( %) patients required support with inotropes. when comparing individuals by their requirement of icu admission, we found that patients who required icu admission were younger than those who did not (ie, individuals in the community and those admitted to hospital but not needing icu support), but this was not statistically significant (table; figure ). in univariable analysis, being younger than month of age, male sex, pre-existing medical conditions, pyrexia, signs or symptoms of lower respiratory tract infection, radiological changes suggestive of pneumonia or ards, and viral coinfection were associated with icu admission (table) . in multivariable analysis, the factors that remained associated with icu admission were being younger than month (odds ratio [or] · , % ci · - · ; p= · ), male sex ( · , · - · ; p= · ), signs or symptoms of lower respiratory tract infection at presentation ( · , · - · ; p< · ), and presence of pre-existing medical conditions ( · , · - · ; p= · ). the most commonly used drug with antiviral activity was hydroxychloroquine, used in ( %) patients, followed by remdesivir, which was used in ( %) patients. lopinavir-ritonavir was used in six ( %) patients and oseltamivir in three ( %), two of whom had influenza virus co-infection. three ( %) patients received two drugs with antiviral activity and one (< %) patient received three; all four patients had ards on chest x-ray. no patient received chloroquine, favipiravir, zanamivir, or ribavirin. with regard to immunomodulatory medication, ( %) patients received systemic corticosteroids, seven ( %) intravenous immunoglobulin, four ( %) tocilizumab, three ( %) anakinra, and one (< %) siltuximab. in univariable analysis, factors associated with treatment initiation of drugs with antiviral or immunomodulatory activity comprised pre-existing malignancy (or · , % ci · - · ), cardiac disease ( · , · - · ), or respiratory disease ( · , · - · ); immuno suppressive therapy at presentation ( · , · - · ) or recent chemo therapy ( · , · - · ); radiological findings suggestive of pneumonia ( · , · - · ) or ards ( · , · - · ); and viral coinfection ( · , · - · ; all p< · ; appendix p ). four patients, all older than years, had a fatal outcome (cfr · %, % ci · - · ), with death occurring at , , , and days after symptom onset. two patients had no known pre-existing medical conditions; one had a cardiorespiratory arrest before arrival at the hospital and resuscitation was unsuccessful and the other died while being mechanically ventilated in icu. the third patient had undergone human stem cell transplant months earlier. the fourth patient was managed palliatively (without intubation), due to the severity of their pre-existing medical conditions. the remaining patients were alive when the study closed. ( %) individuals never developed clinical symptoms. in ( %) individuals, all symptoms had resolved without apparent sequelae, whereas ( %) were still symptomatic or were requiring respiratory support when the study closed. to our knowledge, this is the first multinational, multicentre study on paediatric covid- , and also the largest clinical study in children outside of china to date. the inclusion of such a substantial number of cases was made possible by involving a large number of specialist centres across europe via a well established collaborative paediatric tuberculosis research network, allowing this study to provide one of the most detailed accounts of covid- in children and adolescents published to date. it is important to highlight that this study has primarily captured data from children and adolescents who were seen or managed within the hospital setting, and that the majority of participating units were part of tertiary or quaternary health-care institutions. consequently, the study population is likely to primarily represent individuals at the more severe end of the disease spectrum. notably, a recent letter summarising pcr-confirmed cases in wuhan suggests that close to % of children and adolescents with sars-cov- infection are asymptomatic. at the time our study was conducted, testing capacity for sars-cov- in many european countries was lower than clinical demand, and therefore many children with symptoms consistent with covid- in the community were not tested and consequently not diagnosed. nevertheless, our data indicate that children and adolescents are overall less severely affected by covid- than adults, particularly older patients. previous, large-scale data suggest that the cfr in adults older than years is close to %, potentially due to immuno senescence. it is reassuring that our data show that severe covid- is uncommon in young children, including infants, despite their immune maturation being incomplete, , with only few requiring mechanical ventilation. it was striking that all children who died in our cohort were older than years. the centers for disease control and prevention (cdc) reported confirmed cases of covid- in individuals younger than years in the usa as of april , , representing only · % of the total number of recorded cases (n= ). the australian health protection agency has reported that children accounted for only % of confirmed covid- cases in australia. unfortunately, in the cdc report, clinical data were only available in a small proportion of patients (n= ; %). in concordance with our observations, fever and cough were the predominant clinical features at presentation (present in % and % of individuals, respectively), with similar rates observed in a study from italy. in our cohort almost a quarter of patients had gastrointestinal symptoms, some of whom had no respiratory symptoms, and a substantial proportion of children were entirely asymptomatic. the cdc report also mentions three deaths, but it is unclear how many patients were still hospitalised by the time of publication, so it is difficult to come to firm conclusions regarding the cfr in us children. our data indicate that the cfr in children and adolescents across europe is less than %. considering that many children with mild disease will never have been brought to medical attention, and therefore not diagnosed, it is highly probable that the true cfr is substantially lower than the figure of · % observed in our cohort. this hypothesis is further supported by an epidemiological study from china, in which the cfr in individuals aged years or younger was only · % (one death in confirmed cases). furthermore, our data indicate that sequelae related to covid- are likely to be rare in children and adolescents. however, after the closure of our study, reports of a hyperinflammatory syndrome affecting children that is temporally, and potentially causally, associated with sars-cov- infection have emerged, which has sub sequently been named paediatric inflammat ory multisystem syndrome temporally associ ated with sars-cov- (pims-ts; sometimes known as mic-s). , further research will be required to characterise this emerging disease entity in detail, and determine the longterm outcome of affected children. importantly, our data show that severe covid- can occur both in young children and in adolescents, and that a significant proportion of those patients require icu support, frequently including mechanical ventilation. a small study from madrid also found that four ( %) of children with sars-cov- infection required admission to icu. in our cohort, being younger than month, male sex, presence of lower respiratory tract infection signs or symptoms at presentation, and presence of a pre-existing medical condition were associated with increased likelihood of requiring icu admission. our results also show that the majority of children who are intubated due to respiratory failure require prolonged ventilation, often for week or more. this contrasts with observations in children with rsv infection who, on average, only require mechanical ventilation for - days, but is not dissimilar to observations in children with influenza. this has important implications for service planning, as although the overall demand for icu support might be lower in children than in adults, each patient is likely to occupy icu space for an extended period of time. at this time of intense strain on health-care services worldwide, it is vital that adequate resources are allocated to paediatric services to sustain the provision of high-quality care for children. the observation that, in our study, individuals with viral co-infection (ie, infected with sars-cov- and one or more other viral agents) were more likely to require icu support than those in whom sars-cov- was the only viral agent identified might have implications for the winter period - , when the incidence of other viral respiratory tract infections, including rsv and influenza virus infections, is bound to increase. this could result in a greater proportion of paediatric patients with covid- requiring icu support than in the cohort described here, as the influenza season - was already over in europe before the study commenced. our data also reflect the uncertainties regarding drug treatment options for covid- . in some countries, including spain and italy, national guidelines were encouraging the use of hydroxychloroquine for selected cases, as reflected in our data, while in other countries, recommendations were more guarded regarding the use of antiviral agents in the absence of robust human data. an expert consensus statement from the usa has emphasised that antiviral treatment should be reserved for patients at the severe end of the disease spectrum, ideally within a clinical trial. overall, the expert panel appeared to favour the use of remdesivir over other agents, based on the currently available data from invitro and animal studies, including in non-human primates, and recent data from compassionate use in humans. , the panel members' opinion was split regarding the use of lopinavir-ritonavir, given the disappointing results of a recently published randomised controlled trial. the main limitation of this study relates to the number of variables for which data were collected. in the context of the ongoing covid- pandemic, to ensure high levels of participation and avoid diverting substantial time away from clinical front-line duties, a decision was made not to collect detailed data on laboratory parameters or icu interventions. a further limitation was that a variety of inhouse and commercial pcr assays were used across different participating centres, precluding an assessment of diagnostic test performance. also, the number of children receiving antiviral or immunomodulatory treatment was too small to draw meaningful conclusions regarding their effectiveness, which will be addressed by the aforementioned randomised trials. a further limitation is that different countries were using different thresholds to screen for sars-cov- at the time the study was done, with some recommending screening of all children admitted to hospital or conducting community screening, whereas others were using more selective testing strategies. despite those limitations, to our knowledge, this study provides the most comprehensive overview on covid- in children and adolescents to date. in conclusion, our data, originating from a large number of specialist centres across europe, show that covid- is usually a mild disease in children, including infants. nevertheless, a small proportion of children and adolescents develop severe disease and require icu support, frequently needing prolonged ventilatory support. however, fatal outcome is rare overall. our data also reflect the current uncertainties regarding specific treatment options, highlighting that more robust data on antiviral and immunomodulatory drugs are urgently needed. mt conceived of the study. fg, bs-g, sbw, mb, fb, and mt designed the study. fg, bs-g, and mt cleaned and analysed the data, constructed the figures, and wrote the first draft of the manuscript. all authors contributed data to the study, contributed to the data interpretation, critically reviewed the manuscript, and approved the final manuscript for submission. fg has received funding from gilead for research related to hepatitis e. bs-g and mt have received assays free of charge from cepheid for tuberculosis diagnostics projects. mt has received assays at reduced pricing or free of charge from cellestis/qiagen for tuberculosis diagnostics projects, has received support for conference attendance from cepheid, and is currently receiving funding from biomérieux as an investigator of an ongoing tuberculosis diagnostics study. uh reports personal fees from cepi for being a member of the speac-cepi meta-data safety monitoring board for covid- vaccine trials, outside of the submitted work. the other authors declare no competing interests. michael buettcher (lucerne children's hospital, lucerne cantonal hospital references who. novel coronavirus ( -ncov) situation report coronaviridae study group of the international committee on taxonomy of viruses. the species severe acute respiratory syndrome-related coronavirus: classifying -ncov and naming it sars-cov- who. novel coronavirus ( -ncov) situation report severe and fatal covid- occurs in young children characteristics of pediatric sars-cov- infection and potential evidence for persistent fecal viral shedding novel coronavirus pneumonia emergency response epidemiology team. the epidemiological characteristics of an outbreak of novel coronavirus diseases (covid- ) in china clinical characteristics and intrauterine vertical transmission potential of covid- infection in nine pregnant women: a retrospective review of medical records clinical characteristics of a case series of 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remdesivir for patients with severe covid- therapeutic options for the novel coronavirus ( -ncov) a trial of lopinavir-ritonavir in adults hospitalized with severe covid- we express our gratitude to all colleagues and research personnel involved in the data collection for this study, as well as the members of the human research ethics committees and institutional review boards that have kindly fast-tracked this study. we are also grateful for the kind support of the clinical microbiology & infectious diseases department and the covid- group at hospital general universitario gregorio marañón, madrid, spain. this project did not receive specific funding. ptbnet is supported by the deutsche gesellschaft für internationale zusammenarbeit. bs-g is funded by the spanish ministry of health-instituto de salud carlos iii and co-funded by the european union (feder; contrato juan rodés, grant jr / ). an-j was supported by "subvencions per a la intensificacio de facultatius especialistes"-departament de salut de la generalitat de catalunya, programa peris - (slt / / ).editorial note: the lancet group takes a neutral position with respect to territorial claims in published maps and institutional affiliations. key: cord- - npcun p authors: nan title: note from the editors: don’t stop thinking about tomorrow date: - - journal: euro surveill doi: . / - .es. . . . sha: doc_id: cord_uid: npcun p nan as we are now starting a new decade and thinking about tomorrow, we would like to take stock of selected events in . one memorable event was the worldwide movement of young people for the climate. even if not directly related to infectious disease prevention and control, it reminded us of our collective obligation to the upcoming generations. disease prevention is about improving future health outcomes. continuous vigilance and surveillance are necessary elements in ensuring the best possible protection of the heath of the population as a whole. pathogens continue to evolve in their ability to cause human disease. this was demonstrated by the recent detection of pneumonia cases of unknown origin in wuhan, china since mid-december, for which an unknown, novel corona virus has been preliminarily determined as the cause [ , ] . an example of how pathogens are able to escape tools and technologies developed to control and stop their spread is antimicrobial resistance (amr). amr has been a worldwide concern for some time already and has featured prominently in eurosurveillance. in , we covered various aspects of amr such as the emergence of multidrug-resistant neisseria gonorrhoeae related to international travel [ ] , an outbreak of extensively drug-resistant klebsiella pneumoniae in a german hospital [ ] , and the surveillance of antimicrobial consumption and prescribing for example in belgium, israel and switzerland [ ] [ ] [ ] . another aspect driving spread and severity of communicable diseases is human behaviour. the continued spread of measles in europe over the past decade has been facilitated by insufficient vaccine coverage in specific population groups or regions. over the past year, vaccine hesitancy and mandatory vaccination were covered in several eurosurveillance articles [ ] as were interventions to improve confidence in vaccines, for example, motivational interviews conducted with parents of newborns on maternity wards in canada resulted in lower hesitancy and greater intention to vaccinate [ ] . as usual, food-and waterborne diseases, hiv/aids and blood-borne diseases, emerging and vector-borne diseases, influenza and other respiratory diseases were the subject of several articles in the categories, 'outbreak reports' and 'surveillance articles'. these two article types have different structures and collectively replaced the former category 'surveillance and outbreak reports' at the beginning of . the associated new instructions for authors have led to greater consistency and completeness of information in submissions in these article categories. a special issue published in january illustrated how advanced diagnostics support public health policy development [ ] . we also published articles on less frequently encountered topics such as a skin rash outbreak traced to a portable floating tank [ ] and urban brown rats as the possible source of multidrug-resistant enterobacteriaceae and meticillin-resistant staphylococcus [ ] . in , we published articles ( rapid communications, regular articles and other items such as editorials, letters and meeting reports). the acceptance rate of % was similar to previous years. as a reflection of the european focus of eurosurveillance, the vast majority of published articles were from europe, even though % of accepted articles in were from non-european countries. we will continue to welcome contributions from around the globe that are relevant for public health in europe in the year ahead. our rapid communications on ongoing or emerging threats were published within to weeks of submission, creating awareness and providing evidence to support rapid public health action. some examples of the rapids we published included the worsening epidemiological situation of carbapenemase-producing enterobacteriaceae in europe [ ] , a case of extensively drug-resistant typhoid fever imported from pakistan to denmark [ ] and the detection of a chlamydia trachomatis variant escaping detection by a widely used assay in finland that was found in other european countries thereafter [ ] [ ] [ ] . an activity close to our heart is the eurosurveillance lunchtime seminar that is organised every year on the margins of the european scientific conference on applied infectious disease epidemiology (escaide). the seminar about pointof-care testing (poct) and its impact on surveillance of communicable diseases and public health was well received and we look forward to publishing a respective special issue sometime in early spring. the call for the next special issue on food as a vehicle for amr will be launched in the second half of . other activities by the eurosurveillance editors comprised several workshops on publication ethics, tools to increase transparency in scholarly communications, and on how authors can improve their chances of getting published. last but not least, we started to post educational article-related quizzes on twitter. all this could not have been achieved without the involvement of so many amazing supporters and constructive critics: our editorial board members, colleagues at the european centre for disease prevention and control (ecdc), public health experts and scientists in the field of infectious diseases and other disciplines in europe and elsewhere who respond when we ask for assistance and who remain unnamed here. we owe you a heartfelt thank you! we also thank our publisher, the ecdc, and its director who provide us with continued funding and editorial independence. we also value the contributions of our reviewers who go the extra mile, often on short notice and in their spare time, to help us select the right articles and guide authors in how they can improve their manuscripts. we are indebted to each of them. to acknowledge the ca experts who reviewed for us in , we are publishing a list with their names in this issue [ ] and sent certificates to all those who supported us with more than one review. in his new year message, united nations (un) secretary-general antónio guterres pointed out that we enter the new decade "with uncertainty and insecurity", but he also stated that there is hope, addressing young people as "the greatest source of that hope" as they demand a role in shaping the future and encouraging them to challenge those in charge by "speaking out", "thinking big", "pushing boundaries" and "keep[ing] up the pressure". he also noted that the un will be launching a blueprint for further action for the sustainable development goals [ ] . also, the president of the european commission ursula von der leyen's agenda for europe contains an "aspiration of living in a natural and healthy continent" and a "world full of new technologies and age-old values" [ ] . sustainability and evolution within scholarly communication are important to us editors. together with our contributors and supporters, we are constantly working to maintain eurosurveillance as a useful means to provide sound and trustworthy evidence for communicable disease prevention and control also in the future. in , we will discuss with our editorial board our strategy and goals for the years to ; we envisage to further advance to follow new developments and meet the demands of our diverse audience to the best of our abilities also in the time to come. to get a better idea of the various needs and interests, we launch a satisfaction survey today. the results should inform our strategy by identifying areas of particular interest to our audience. we hope that many of you will respond and help us shape the future of the journal, so that eurosurveillance continues to be interesting for readers, attractive for authors and useful for strategic and day-to-day public health decision-making. pneumonia of unknown cause -china. geneva: who who statement regarding cluster of pneumonia cases in wuhan collection: emerging multidrug-resistant neisseria gonorrhoeae related to international travel. stockholm: ecdc extensively drug-resistant klebsiella pneumoniae st outbreak, north-eastern germany antibiotic consumption in belgian acute care hospitals: analysis of the surveillance methodology, consumption evolution to and future perspectives antimicrobial use trends antimicrobial use in acute care hospitals: national point prevalence survey on healthcare-associated infections and antimicrobial use special edition: tackling vaccine hesitancy and improving immunisation delivery promoting vaccination in maternity wards ─ motivational interview technique reduces hesitancy and enhances intention to vaccinate, results from a multicentre non-controlled pre-and post-intervention rct-nested study advanced diagnostics to inform public health policy an outbreak of skin rash traced to a portable floating tank in norway urban brown rats (rattus norvegicus) as possible source of multidrug-resistant enterobacteriaceae and meticillin-resistant staphylococcus spp worsening epidemiological situation of carbapenemase-producing enterobacteriaceae in europe, assessment by national experts from countries ceftriaxone-resistant salmonella enterica serotype typhi in a pregnant traveller returning from karachi chlamydia trachomatis samples testing falsely negative in the aptima combo test in finland finnish new variant of chlamydia trachomatis escaping detection in the aptima combo assay also present in Örebro county the 'finnish new variant of chlamydia trachomatis' escaping detection in the aptima combo assay is widespread across norway eurosurveillance reviewers in un) regional information centre -europe. un secretary-general's new year's message. brussels: un. political guidelines for the next european commission - . a union that strives for more. my agenda for europe. brussels: european commission this is an open-access article distributed under the terms of the creative commons attribution (cc by . ) licence. you may share and adapt the material, but must give appropriate credit to the source, provide a link to the licence and indicate if changes were made.any supplementary material referenced in the article can be found in the online version. key: cord- - dpnmswf authors: de zwart, onno; veldhuijzen, irene k.; elam, gillian; aro, arja r.; abraham, thomas; bishop, george d.; richardus, jan hendrik; brug, johannes title: avian influenza risk perception, europe and asia date: - - journal: emerg infect dis doi: . /eid . sha: doc_id: cord_uid: dpnmswf during autumn , we conducted , interviews in european and asian countries. we found risk perceptions of avian influenza to be at an intermediate level and beliefs of efficacy to be slightly lower. risk perceptions were higher in asia than europe; efficacy beliefs were lower in europe than asia. during autumn , we conducted , interviews in european and asian countries. we found risk perceptions of avian influenza to be at an intermediate level and beliefs of efficacy to be slightly lower. risk perceptions were higher in asia than europe; efficacy beliefs were lower in europe than in asia. t he possibility of an influenza pandemic presents a major public health challenge. since , outbreaks of avian influenza (ai) have occurred in asian, european, and african countries. as of august , , the total number of cases was and the number of deaths was ( ) . a crossover of current human influenza virus with the avian h n virus could result in a virus capable of human-tohuman transmission and the start of a new pandemic. despite extensive media attention for avian influenza, knowledge about risk perception of ai is scarce. we therefore explored the conditions for effective nonmedical interventions. if an influenza pandemic occurs, public health authorities will be dependent on the willingness and ability of the public to adhere to recommendations regarding personal hygiene, vaccination and prophylaxis, quarantine, travel restrictions, or closing of public buildings ( , ) . adherence, however, cannot be assumed. evaluation of the outbreak of h n ai in the netherlands in showed that adherence to antiviral therapy and behavioral measures, such as wearing face masks and goggles, was low ( ). our ability to promote health-protective behavioral change depends on our knowledge of determinants of such behavior ( ) . the protection motivation theory posits that health-protective actions are influenced by risk perceptions ( ) ( ) ( ) . risk perceptions are defined by the perceived seriousness of a health threat and perceived personal vulnerability. however, the protection motivation theory explicitly states that higher risk perceptions will only predict protective behavior when people believe that effective protective actions are available (response efficacy) and that they have the ability to engage in such protective actions (self-efficacy). we investigated risk perceptions and efficacy beliefs related to ai of a random sample of persons in areas. random digital dialing was used to select the samples, and data were collected by using computer-assisted telephone interviewing. interviews were conducted from september through november , , in european countries (denmark, the netherlands, united kingdom, spain, and poland) and east asian areas (singapore; guangdong province, people's republic of china; and hong kong, special administrative region, people's republic of china). at the time the telephone survey was conducted, on october , , the media announced the introduction of ai in europe. we therefore ensured that at least interviews were conducted in each country after october , . the questionnaire focused on risk perception of ai and other infectious diseases, precautionary behavior, and use of information sources; it was based on our earlier study of risk perception of severe acute respiratory syndrome (sars) ( ) . respondents first received a brief explanation of ai. in line with the protection motivation theory ( ), a measure of risk perception was constructed by multiplication of seriousness (scale - ) and vulnerability (scale - ). to make the scores comparable, the seriousness score was first divided by . to normalize the skewed distribution of the new variable, a square-root transformation was performed, which resulted in a measure of risk perception on a scale from (low) to (high). a total of , respondents were interviewed; participation rates varied from . % in asia to . % in poland. most respondents were female (table ) . european respondents were significantly older than asian respondents (mean age and years, respectively, range - years, t = . ; degrees of freedom [df] = , ; p< . ). overall, % of respondents thought they were likely or very likely to become infected with ai if an outbreak occurred in their country. this perception varied from % in denmark and singapore to % in poland and spain. risk perception scores varied significantly across countries; the highest mean score was in poland and the lowest was in denmark (table ) . higher scores were observed in europe than in asia (t = . ; df = , ; p< . ), and differences between individual countries within europe were significant. multivariate analysis showed that country, sex, and age group remained inde-pendent significant factors and showed a significant interaction between country and sex and between country and age group (figure) . in all countries, except singapore, risk perception was higher among women than men, but this difference was smaller in asian than in european countries. the effects of age also varied by country; mean risk perception levels were higher in older age groups in europe but not in asia. response efficacy and self-efficacy also varied across countries; levels were highest in china and lowest in the netherlands (table ). mean response efficacy and self-efficacy were significantly higher in asia than in europe (response efficacy t = − ; df = , ; p< . ; self-efficacy t = − ; df = , ; p< . ). response and self-efficacy were inversely associated with risk perception (p = . and p< . , respectively). multivariate analysis also showed that country, but not sex or age, was significantly associated with response efficacy. country, sex, and age group were all significantly associated with self-efficacy. self-efficacy levels were lower for women compared with men and for the youngest age group compared with older respondents. risk percep- tion and efficacy levels before and after the introduction of avian influenza in europe did not differ significantly. our study showed that risk perceptions for ai appear to be at an intermediate level and that efficacy beliefs are slightly lower. both differ according to country or region. no evidence was found that the introduction of ai in europe in october influenced perceptions of risk or efficacy. fielding et al. have reported on risk perception of ai in hong kong with a focus on live chicken sales ( ) . although our results are difficult to compare with theirs, our study appears to indicate a higher feeling of vulnerability, with . % of hong kong respondents thinking it likely or very likely that they would become infected with influenza during an outbreak. takeuchi's interviews on food safety practices of consumers in thailand found high levels of knowledge of ai but lower levels of risk perception and behavior change ( ) . if we compare our results with those from several studies on perception of risk for sars, we find that perception of risk for sars in some of the asian countries was relatively low compared with that in the united states ( ) . in the netherlands, however, perception of risk for sars was low, whereas our present study indicates that it is high for influenza ( ) . the lower level of risk perception for ai in asia may be related to the proximity to the current outbreak and the experience with the sars epidemic. these experiences may have resulted in the notion that new epidemics of infectious diseases can be controlled. also, despite the fact that the first cases of h n influenza among humans in asia were reported in , a larger outbreak did not ensue. accordingly, risk perception research has shown that the public may be more optimistic when familiar risks are perceived to be largely under volitional control ( , ) . our study has several implications for public health policy and research. although in all countries an influenza pandemic is perceived as a real risk, the level of self-efficacy appears to be rather low. when developing preparedness plans for an influenza pandemic, specific attention should therefore be paid to risk communication and how perceived self-efficacy can be increased; otherwise, adherence to preventive measures may be low. world health organization. cumulative number of confirmed human cases of avian influenza a/(h n ) reported to who nonpharmaceutical interventions for pandemic influenza, international measures nonpharmaceutical interventions for pandemic influenza, national and community measures avian flu epidemic : public health consequences. bilthoven: national institute for public health and the environment (rivm) and institute for psychotrauma health promotion planning, an educational and ecological approach the precaution adoption process factors in risk perception cognitive and physiological processes in fear appeals and attitude change: a revised theory of protection motivation sars risk perception, knowledge, precautions, and information sources, the netherlands. emerg infect dis avian influenza risk perception, hong kong avian influenza risk communication emerg infect dis the public's response to severe acute respiratory syndrome in toronto and the united states the social amplification of risk and risk communication the british foot and mouth crisis: a comparative study of public risk perceptions, trust and beliefs about government policy in two communities interventions for hiv, sexually transmitted infections, and viral hepatitis. key: cord- - rxradwz authors: kohl, claudia; kurth, andreas title: european bats as carriers of viruses with zoonotic potential date: - - journal: viruses doi: . /v sha: doc_id: cord_uid: rxradwz bats are being increasingly recognized as reservoir hosts of highly pathogenic and zoonotic emerging viruses (marburg virus, nipah virus, hendra virus, rabies virus, and coronaviruses). while numerous studies have focused on the mentioned highly human-pathogenic bat viruses in tropical regions, little is known on similar human-pathogenic viruses that may be present in european bats. although novel viruses are being detected, their zoonotic potential remains unclear unless further studies are conducted. at present, it is assumed that the risk posed by bats to the general public is rather low. in this review, selected viruses detected and isolated in europe are discussed from our point of view in regard to their human-pathogenic potential. all european bat species and their roosts are legally protected and some european species are even endangered. nevertheless, the increasing public fear of bats and their viruses is an obstacle to their protection. educating the public regarding bat lyssaviruses might result in reduced threats to both the public and the bats. the european continent is inhabited by hibernation. many bat species migrate over vast distances while others are rather territorial. all bats in europe utilize echolocation to navigate. contrary to the worldwide efforts in protecting bats, they have been increasingly gaining attention as potential reservoir hosts of some of the most virulent viruses we know. various publications reviewed bats globally as carriers and potential reservoir hosts of human-pathogenic and zoonotic viruses [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] , while hardly anything is known about human-pathogenicity of european bat viruses apart from lyssaviruses. in this review, we discuss a selection of viruses as possible threats posed by european bats to the public from our point of view. a summary of viruses that have been detected in european bats is given in table at the end of the manuscript. a more comprehensive and up-to-date list of bat-associated viruses can be found online at the database of bat-associated viruses (dbatvir) [ ] . european bat lyssaviruses (family rhabdoviridae) are the most important zoonotic bat-borne viruses in europe and have been comprehensively reviewed by banyard et al. in this special issue on bat viruses (title: lyssavirus infections of bats: emergence and zoonotic threat) [ ] . therefore, we will provide a short overview. [ , ] nyctalus noctula rhinolophus ferrumequinum hungary pcr [ ] myotis myotis germany pcr [ ] astroviridae myotis myotis germany pcr [ ] mamastrovirus italy pcr [ , ] the postulates drafted by jacob henle and robert koch in the late th century constitute a framework regarding the principles of cause-and-effect in microbiology [ ] . back then, it was comparatively straightforward to limit cause-and-effect to four postulates, although viruses had not yet been discovered nor was molecular biology developed ( table ). all of the postulates are hard to fulfill for viruses, as they do not grow on nutrient media, but require living cells for replication. when looking for viruses on a molecular level, it is necessary to consider that only the first postulate can be accomplished. studies identifying a host-pathogen relationship solely at the molecular level do not take into consideration that detection does not equal etiology. even though polymerase chain reaction (pcr) screening and metagenomic studies are indispensable and valuable tools, virologists should stay close to the henle-koch postulates when assuming a possible virulence of viruses detected in bat hosts. a plethora of coronaviruses has been detected in bats, mostly belonging to the alphaand betacoronaviruses [ , ] . the genus alphacoronavirus hosts human-pathogenic strains (i.e., human cov e and nl ); however, in this review, we will focus on selected highly human-pathogenic betacoronaviruses and their european bat virus relatives [ ] . from november until july the world was confronted with the first pandemic of the new millennium, caused by a novel coronavirus (cov) inducing the severe acute respiratory syndrome in humans (sars) [ ] [ ] [ ] . the pandemic spread from its origin, a wet-market in the guangdong province in china, through countries on five continents resulted in more than infected humans of whom more than eventually died [ , ] . the search for the animal reservoir began, identifying masked palm civets and bats as possible sources. subsequently, a plethora of diverse coronaviruses of distinct groups have been detected in various bat species around the world via molecular-biological techniques. in , another human-pathogenic coronavirus, called middle east respiratory syndrome coronavirus (mers-cov), began spreading from the arabian peninsula, so far resulting in globally laboratory-confirmed cases of infection with mers-cov, including at least deaths [ ] . dromedaries and bats are suspected as reservoirs for mers-cov [ ] . recent findings support the plausibility of dromedaries as reservoir species [ ] . although numerous studies in european bats report the presence of sars-like-cov and mers-like-cov sequences [ , [ ] [ ] [ ] ] , no final conclusion can be drawn regarding their zoonotic potential. a related virus detected in bats cannot necessarily be considered as zoonotic. a few alterations in the sars-cov spike protein enabled its binding to the host receptor ace- , thus sars-cov became capable of infecting humans [ ] . so far, the sars-like cov detected in european bats lack these alterations and thus are not predicted to be capable of infecting humans. although virus strains might be similar or related on a nucleic acid level, the distinct function of proteins is crucial when determining the host range. therefore, mere similarity is not sufficient to examine the potential of viruses to infect humans or even predict their virulence. it took ten years from the emergence of sars-cov for the first bat cov to be isolated from rhinolophus bats in china, that displayed the human ace- receptor, which enabled the virus to infect human cells [ ] . these findings provide evidence for the reservoir theory. from the european perspective, nevertheless, no sars-like cov or mers-like cov has been isolated from any european bat, nor has any transmission of sars-like cov or mers-like cov to humans been reported. the case of mers-cov is slightly different, as a sequence of base pairs with % identity to mers-cov was detected in a bat (taphozous perforates-the species identification performed was not beyond doubt, as it was based on exclusion criteria (no cytochrome b sequence of taphozous perforates is available in genbank [ ] )) in saudi arabia [ ] . this finding initiated a controversy among leading cov experts, as the journal nature recently reported [ ] . they discussed that the complete genome sequence of mers-cov obtained from the bat should confirm that the virus was indeed identical and not coincidentally just a short conserved region of the virus genome. furthermore, a prevalence study might provide insights into the distribution of mers-cov in bat populations. although taphozous perforates are not abundant in europe, climate change and environmental factors may have an effect on the future distribution of this bat species (figure ) [ ] . the case of mers-cov emergence impressively demonstrates the necessity of virus discovery and prevalence studies. with the first sequence of mers-cov that became available, bats were suspected as reservoir hosts, not only because mers-cov is a sars-cov relative, but also because previous bat virus discovery studies had provided eligible sequences of bat cov to genbank, allowing for correlations with the novel mers-cov. recently, a quasi-species of mers covs was recovered from nasal swabs of dromedaries of the kingdom of saudi arabia [ ] . the mers cov consensus genome variants from dromedaries and humans are indistinguishable, supporting the plausibility of dromedaries in the role of transmission [ ] . in , the first reported outbreak of filovirus, named lloviu virus (llov), in a european bat population occurred in france, spain, and portugal [ ] . several colonies of schreiber's bats (miniopterus schreibersii) suddenly declined due to an unknown disease. llov was found in animals that showed signs of viral infection, but not in healthy bats co-roosting in the caves (myotis myotis). llov is distinctly related to filoviruses found in african bats and was classified in as type species of the novel genus cuevavirus [ ] . unfortunately, the lack of successful isolation of llov prohibits the experimental infection of schreiber's bats to clarify whether llov is the first filovirus capable of inducing disease in bats. this would challenge the hypothesis of bats as potential reservoir hosts for other filoviruses like ebola and marburg virus. schreiber's bats are distributed in distinct lineages throughout oceania, africa, southern europe, and south-east asia (figure ) [ ] . they are thought to transmit and maintain llov across different lineages throughout their habitats, although no studies are available to prove this hypothesis. consequently, the sole demonstration of a novel filovirus sequence does not provide evidence of a possible public health threat. following the henle-koch postulates, the virus should be isolated and further characterized to draw conclusions on the evolution of filoviruses in their respective bat host. as most filoviruses are described as highly pathogenic for humans, the occurrence of llov should be carefully monitored by prevalence studies in the highly abundant miniopterus schreibersii (figure ). in , three distinct paramyxoviruses were detected in german bats, two of which were related to the proposed genus jeilongvirus (myotis mystacinus, pipistrellus pipistrellus) and one was related to the genus rubulavirus (nyctalus noctula) [ ] . another study published in the same year described another different paramyxoviruses in bats from germany (myotis bechsteinii, m. daubentonii, m. myotis, and m. mystacinus) and bulgaria (myotis alcathoe and m. capaccinii), all of which belong to the genus morbillivirus [ ] . none of the novel bat paramyxoviruses are closely related to viruses of the highly pathogenic genus henipavirus or other human-pathogenic paramyxoviruses [ , ] . there is no evidence to suggest that any of these novel paramyxoviruses are capable of infecting humans. similar to the case of the llov filovirus, virus isolates and prevalence studies in both humans and bats could improve knowledge and clarify their zoonotic potential. few studies have documented the negative results from pcr testing of european bats for other human-pathogenic viruses. for instance following generic pcr screening for flavi-, hanta-and influenza-a viruses in european bats in [ ] , testing of another central european bats for influenza-a viruses [ ] and testing european bats for hepadnaviruses in did not lead to the detection of any viral nucleic acids [ ] . pcr screening of european bats for orthopoxviruses has not revealed any known or novel virus sequences [ ] . so far, the only virus isolates (beside lyssaviruses) obtained from european bats are one bunyavirus, one adenovirus and orthoreoviruses [ , , , ] . these represent the only isolates that would allow for further characterization and potential clarification of their zoonotic potential. nevertheless, recombinant viruses, constructed on sequence information, are also valuable tools to study prevalence and pathogenicity in vitro. toscana virus (tosv) was isolated from a bat's brain in , while simultaneously tosv was isolated from sandflies in the laboratory [ ] . as tosv has never been reported in bats afterwards and no hemagglutination-inhibiting antibodies has been initially found in the bat, there is a reasonable chance that this tosv isolation may have been a cross-contamination [ ] . bat adenovirus (bat adv- ) was isolated from a bat's intestine in [ ] , and the whole genome was obtained and circumstantially analyzed [ , ] . bat adv- displays a monophyletic relationship to the adenoviruses of canids (cadv). moreover, open trading frames (orf) in the bat adv- genome and the cadv are identical and not present in other members of the mastadenoviruses. the closely related canine adv contribute to the severe kennel cough syndrome in canids and show an unusually broad host range [ ] . this provides evidence suggesting an ancestral inter-species transmission of mastadenoviruses between bats and canids. like in the case of rabies virus, which is prevalent in both bats and terrestrial mammals (e.g., dogs, raccoons, skunks, and foxes) of the americas, a continuing exchange and transmission between bats and canids or other terrestrial animals might be possible [ ] . there is no evidence of a zoonotic potential of bat adv- . in , three novel orthoreoviruses were isolated from plecotus auritus and myotis mystacinus in germany [ ] . a subsequent pcr screening obtained identical viral sequences also in other bat species: pipistrellus pipistrellus, pipistrellus nathusii, pipistrellus kuhlii, and nyctalus noctula. at the same time, a group in italy detected further orthoreoviruses in myotis kuhlii, rhinolophus hyposideros, tadarida teniotis, and vespertilio murinus [ ] . summing up the data for the reovirus isolates from germany and italy, a close relationship was revealed to the genus mammalian orthoreovirus (mrv), in particular to an orthoreovirus obtained from a dog (strain t /d ) with hemorrhagic enteritis in italy [ , , ] . no ancestral relationship was assumed here, but rather an opportunistic -behavior‖ of the novel closely related mrvs, as they were detected in various different bat species. moreover, the newly isolated mrvs are phylogenetically related to viruses capable of inducing severe meningitis in humans [ ] . recently, a study published by steyer et al. described the detection of an mrv from a child hospitalized with acute gastroenteritis in slovenia [ ] . the causative agent was determined to be an mrv with the highest similarity of . %- . % in the respective segments to a bat mrv (t /bat/germany/ / ) [ ] . this might indicate a human-pathogenic potential of strain t /bat/germany/ / . as the case of sars-cov has shown that even small changes in the genome are important for determining the host range, this has to be determined for the bat mrvs in further studies. interestingly, no contact was reported between the infected child and bats, but contact to a domestic dog was assumed [ ] . the isolated viruses will allow for a seroprevalence study (cross-reactivity and cross-neutralization with other strains) in humans, which shall be initiated to examine the prevalence of specific antibodies to bat mrvs in germany and italy (where these viruses have been found) to clarify their zoonotic potential. this is especially interesting as asian bat orthoreoviruses of the genus pteropine orthoreovirus have already been linked to potentially zoonotic respiratory diseases in humans [ , ] . rhabdoviruses of the genus lyssavirus that have been detected in europe are considerably harmful and truly zoonotic agents, inevitably causing the death of unvaccinated humans if not treated in time before onset of the rabies disease [ ] . even though bat-transmitted lyssaviruses have a fatality rate of virtually % and are suspected to be transmissible by bat biting and scratching, the reported total number of human fatalities in europe is low (n = - since ) [ ] [ ] [ ] . all described hosts of european bat lyssaviruses (eblv- and eblv- ) are synanthropic, hence sharing their habitats with humans [ ] . eblv- has been predominantly detected in eptesicus serotinus and e. isabellinus in europe, both living in buildings, roofs, and attics usually in the southern regions of europe (e. serotinus until ° north, e. isabellinus in southern portugal-e. isabellinus is a north african population of e. serotinus that is controversially but not concludingly discussed as a novel species [ ]), and male bats are reported to co-roost with multiple bat species [ ] . eblv- was also detected in v. murinus, m. schreibersii, m. myotis, m. nattereri, r. ferrumequinum, and t. teniotis. whether these bat species constitute accidental hosts infected by spillover from co-roosting e. serotinus species, or whether they are additional reservoirs, has not yet been determined [ ] [ ] [ ] [ ] ] . two human cases described by johnson et al. were confirmed as infected with eblv- , which is prevalent in european m. daubentonii and m. dasycneme [ , ] . m. daubentonii is prevalent in north-eastern europe and is frequently found co-roosting with p. pipistrellus and m. nattereri, whereas m. dasycneme is found throughout europe and in the mediterranean, co-roosting with m. capaccinii. so far, none of the co-roosting bats have been reported to carry eblv- [ ] . however, spillover transmission to other animals (stone-marten, sheep, and cat) was described for eblv- [ ] [ ] [ ] . overall, lyssaviruses prevalent in european bats pose a risk to public health, and preventive measures have already been implemented by many european countries for decades (e.g., surveillance, vaccination plans, and post exposure prophylaxis) [ ] . especially the high-risk occupational groups (i.e., bat workers, bat carers in bat bat hospitals) are at increased risk. however, lyssavirus prevalence in european bats is very difficult to determine and results are very heterogenic [ ] . the lyssavirus prevalences are considerably low, but changes of behavior as a result of a lyssavirus infection may be more likely to bring bats into contact with humans. however, it is necessary to balance the risk with the total number of fatal human cases during the last years (five cases in million people living in greater europe) [ ] . accordingly, the risk is relatively low and would probably fall to zero if people were educated appropriately. direct contact (bites and scratches) with certain bat species might be risky and require post exposure prophylaxis. only few of the european bat species are known to be reservoirs of eblv- and eblv- , but all of the european species are endangered or close to extinction. relocation or culling of bat colonies, in spite of being an obvious solution from the viewpoint of the general public, increases the risk of lyssavirus exposure and transmission and should not be considered [ ] . only education can channel public fear to avoid further threats to the bats and the general public. alexander von humboldt discovered the latitudinal gradient in species diversity as early as [ ] : the richness of species is subject to a global diversity gradient, abating from the species-rich tropics toward the higher latitudes [ ] . bats influence this gradient significantly. more than bat species have been described worldwide. although they are abundant worldwide except for the polar regions, a steep diversity gradient is present from the tropics towards the poles [ ] [ ] [ ] [ ] . are fewer viruses prevalent in european bats because of the lower abundance of species in the more temperate europe? and is the zoonotic risk posed by bats decreased accordingly? only few studies on the biogeography of microorganisms are available. these studies indicate that the latitudinal diversity gradient has either no or a top-down effect on microbial diversity [ ] [ ] [ ] [ ] [ ] . two studies hypothesized that the local diversity and dispersal of viruses is very high, though overall, the viral diversity is limited on the global scale [ , ] . therefore, no assumptions can be made regarding the viral diversity in species abundant in temperate climates. as the total number of abundant species might not be essential, the change in biodiversity might play a role. the effect of decline in biodiversity on the emergence of diseases is subject of numerous publications [ ] [ ] [ ] [ ] [ ] [ ] [ ] . basically, there are arguments in favor of two controversial theories; reduced biodiversity could either increase (dilution effect) or decrease the risk of disease transmission. for almost half of the zoonotic diseases that have newly emerged by spillover since , a preceding change in land-use, agriculture, and wildlife hunting was reported [ ] . all of the above-mentioned effects contribute to changes in biodiversity and increased contact situations between human and animal hosts, also in europe. once spillover in novel hosts has occurred, a high density of the novel host population eventually facilitates the establishment in the novel niche. thus, human overpopulation and a decreased biodiversity might be mutual factors promoting the establishment of emerging infectious diseases. in conclusion, the baas becking hypothesis from might still be appropriate: -everything is everywhere, but the environment selects‖ [ ] . until now, lyssaviruses have been the only proven zoonotic viruses in european bats and may cause rabies in humans. however, only few bat species are known to transmit lyssaviruses in europe, and the number of human cases is rather low. nevertheless, education of the general public should be intensified to avoid easily preventable infections. although viruses with zoonotic potential have been detected in european bats, no clear assumption can be made without further studies. sero-prevalence studies should be conducted on the orthoreoviruses isolated from european bats, especially as a closely related virus was detected in a diseased child in slovenia [ ] . other bat viruses detected by using molecular techniques should be isolated (e.g., mers-like cov or bat bunyavirus) to allow for characterization and follow-up sero-prevalence studies. in general, bats are special reservoir hosts because of their biological features, long-time co-evolution and high diversity of viruses that can be found. furthermore, there is neither a clearly decreased risk in the emergence of zoonotic viruses in temperate climates compared to the tropics nor a decreased risk in regions of lower biodiversity. in conclusion, many drivers of emergence in the tropics also have validity in europe. however, european bats are endangered species, and some of them are threatened by extinction. although lyssaviruses are prevalent in european 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transmission of infectious diseases biodiversity loss and emerging infectious disease: an example from the rodent-borne hemorrhagic fevers biodiversity loss and the rise of zoonotic pathogens pangloss revisited: a critique of the dilution effect and the biodiversity-buffers-disease paradigm a meta-analysis suggesting that the relationship between biodiversity and risk of zoonotic pathogen transmission is idiosyncratic host range and emerging and reemerging pathogens population biology of multihost pathogens geobiologie of inleiding tot de milieukunde the authors are grateful to ursula erikli for copy-editing and the two anonymous reviewers for their valuable comments. both authors reviewed the literature and wrote the manuscript. the authors declare no conflict of interest. key: cord- -qxkxjxsz authors: pensaert, maurice b.; martelli, paolo title: porcine epidemic diarrhea: a retrospect from europe and matters of debate date: - - journal: virus research doi: . /j.virusres. . . sha: doc_id: cord_uid: qxkxjxsz abstract a retrospect is given on the emergence of porcine epidemic diarrhea (ped) during the early seventies in europe. while, at first, it appeared as a disease affecting feeder pigs, fattening- and adult swine, it later also became pathogenic for neonatal and suckling pigs hereby drastically increasing its economic impact. isolation of the causative virus revealed a new porcine coronavirus, the origin of which has never been clarified. pathogenesis studies with the prototype strain cv showed severe villous atrophy in neonatal pigs and the virus-animal interactions showed many similarities with transmissible gastro-enteritis virus (tgev), another porcine coronavirus. disease patterns in field outbreaks showed muchvariation but, while farm related factors played a role, possible genetic variations of virus strains in europe have not been examined and are thus unknown. cv in experimental pigs caused diarrheal disease and mortality rates similar to those later encountered in asia and more recently with the “original” us strains even though genomic typing of the prototype european strain have shown that it belongs to the s-indel strains. in europe, ped has become endemic during the eighties and nineties and subsequently regressed so that, after , swine populations in many countries have largely become seronegative. sporadic outbreaks have recently reappeared showing a large variety of clinical outcomes. one" or also "tge " and both these denominations referred to its clinical similarity to tge, a common cause of viral diarrhea in pigs in europe at that time. an important difference with tge was, however, that neonatal pigs were not affected. since these denominations were considered unsatisfactory from a scientific point of view, the name of the new syndrome was quickly changed to "epidemic diarrhea-ed". the first ed outbreak occurred on a farm in the spring of and the second months later, at a distance of miles from the http://dx.doi.org/ . /j.virusres. . . - /© elsevier b.v. all rights reserved. former. suckling piglets were not affected but pigs of weeks and older and also adults showed an acute diarrhea lasting one week. the outbreak lasted - weeks on the farm. during the autumn of and also the following winter, several new outbreaks were reported. a clinical diagnosis and possibility for differentiation from tge was thus based on the high morbidity in fatteners and adult animals in the absence of disease in neonatal and freshly weaned pigs. in most of these diarrheal cases, tgev was excluded by laboratory examination. the fact that ed was observed on farms with a recent history of a tge outbreak, and thus in tgev immune animals, increased the conviction that tgev was not involved. during , ed spread rapidly between pig farms, particulary fattening herds. mortality was rare and the effect of an outbreak was estimated at about weeks feed cost. a similar disease pattern was observed during the early seventies in belgium and a rapid spread occurred to neighbouring countries in western europe. here also, suckling pigs were not affected and remained free of diarrhea even when their mothers suffered from a watery diarrhea during several days. some neonatal pig mortality could occur by starvation because the sick mothers often suffered from agalactia. an additional sign observed in belgium and later also reported in gemany, but not mentioned in england, was that some fatteners were found dead, particularly towards the end of the fattening period, and this occurred repeatedly in some farms but not in others. a mortality rate as high as % could be encountered. this was not due to dehydration accompanying the diarrhea but animals suddenly died from acute back muscle necrosis. while the clinical link with an ed infection was clear, the pathogenetic background has never been revealed. belgian pigs were highly stress positive at that time and a severe belly ache often observed in adult animals during an outbreak of ed may have been a trigger. in general, as no baby pig mortality occurred due to the ed agent, not very much attention was given to this new diarrheal syndrome and the etiology was not intensively investigated. however, it was assumed that a viral agent was involved since bacteriological examination of faecal material did not reveal a specific bacterial cause. none of the known porcine viruses could be associated and a new virus was, therefore, suspected. much changed in when wood ( ) from the veterinary investigation centre in norwich (england) described a new diarrheic syndrome. it differed from ed in that it now affected pigs of all ages, including neonatal and suckling pigs. mortality was variable, restricted to young piglets and averaged around %. this new disease now resembled tge more closely than ed did, but tgev was again excluded using direct immunofluorescence on intestines and applying established serological techniques available for detection of anti-tgev antibodies. now, a differentiation with tge on a clinical basis only became difficult, often impossible. this new syndrome was called ed to differentiate it from the ed where no baby pigs were involved. ed was economically much more important than ed . ed also quickly spread to the european continent and was recognised in belgium in . reports from other countries including the netherlands, germany, france, bulgaria, hungary and switzerland, followed soon. in belgium, mortality rates in neonates on breeding farms varied considerably. they could be as high as % (large variation from to %) and the average was %. variation in mortality in neonatal pigs was litter bound, not explained at that time, but also farm bound where it appeared to be associated with farm size (still many small family farms at that time), farm struc-ture (one or several farrowing units), number of neonatal pig litters present at the start of the outbreak, number of pregnant sows due to farrow within one week of the appearance of disease signs and possibly other factors. differences in virulence of virus isolates was not given any attention. this new evolution to ed with the involvement of baby pigs and its larger economic impact yielded better opportunities for collecting material for etiological studies, for experimental reproduction of the disease and for the development of virological and serological techniques. in , chasey and cartwright ( ) reported the detection of virus like particles, and pensaert and debouck ( ) described the isolation of a new coronavirus-like agent (cvla) from diarrheic pigs, with both research groups succeeding in reproducing diarrhea in experimental pigs. soon after the isolation of this new coronavirus, extensive pathogenesis studies were performed in colostrum deprived pigs with one of the belgian isolates, designated coronavirus cv , (isolated in month of ) which became the prototype strain for pedv in europe (debouck and pensaert, ; debouck et al., ) . ed was soon named "porcine epidemic diarrhea" (ped) caused by ped virus (pedv) a denomination which still stands at present. from the early studies with pedv in neonates (debouck and pensaert, ; debouck et al., ) it was soon clear that the pathogenesis resembled very much that of tgev. experience gathered from research with tgev helped much in the approach to study this new enteric disease. lack of success to cultivate the virus in cell cultures forced to produce clean virus stocks by oral inoculation of colostrum deprived pigs, performing surgery h later and rinsing the in vivo produced virus from the lumen of the infected small intestines during h while keeping the pig in the incubator (debouck and pensaert, ) . such "clean" pig adapted virus stocks served for experimental pig inoculation experiments and to produce an hyperimmune serum for the preparation of a conjugate for an immunofluorescence (if) conjugate to detect the virus in tissues. serological tests were developed to detect antibodies by elisa and to study possible relationship with other coronaviruses by immuno-electron microscopy . genome analysis of the ped isolate(s) was not available at that time. by immuno-electron microscopy and if, pedv was not related to any of the known porcine coronaviruses (tgev, haemagglutinating encephalo-myelitis virus) . some discrete relationship with members of the genus alpha-coronavirus was later demonstrated using other and more sensitive tests. the origin of pedv was thus unknown and no potential parent coronavirus could be indicated. an elisa test was soon used for routine serology . a crucial question was whether or not the ed agent and ed /pedv were related or whether ed /pedv was totally new. infectious material containing the ed agent from earlier outbreaks was not available. a retrospective serological survey was carried out on sow sera that had been collected in slaughterhouses in belgium starting in and thus prior to the emergence of ed in on the european continent. antibodies to pedv were not found in sera collected in but were present in % of the sows collected in , in % of the sows in and in % of the sows in . these results indicated that the coronavirus ped had been responsible for first ed outbreaks, for the ed outbreaks and thus it can be accepted that pedv emerged in but later widened its host tropism from growing and adult swine towards neonatal pigs. this finding was interesting from an evolutionary point of view. thus, pedv that presumably started as a cause of diarrhea in in feeders, fatteners and adult swine, had suddenly acquired tropism for neonatal pigs and now became a rather devastating disease. but even after the emergence of ed /pedv, some outbreaks on breeding-finishing farms still did not involve neonatal pigs. while it was assumed that both ed and pedv were co-circulating in the swine population, it is also possible that some farms had experienced an earlier ed infection and that immune sows protected their offspring against pedv by lactogenic immunity while groups of fattening pigs had become susceptible. it must, however, be mentioned that cross-protection between ed and pedv has never been studied. also, after a first epidemic phase of the new pedv, the virus often persisted on breeding-finishing farms in weaned and feeder pigs (endemic ped). the sow population was immune, protecting its offspring, while feeder pigs became susceptible after loosing their maternal protection. the highly variable and mixed clinical picture was, at that time, ascribed to the possible co-circulation of the original ed agent and its presumed variant pedv in the population. genome analysis was not available and ed infectious material is also now no longer available to retrospectively examine this issue. ed /pedv is likely a variant of ed . that variants of pedv relatively easy emerge is not unusual as animal coronaviruses are known to easily undergo genetic alterations. recombination and insertions and deletions have repeatedly been demonstrated in pedv by genome analyses of isolates during more recent outbreaks in asia and in the usa (fan et al., ; li et al., ; jarvis et al., ; vlasova et al., ; oka et al., ) . even now ( ) in recent cases of ped in europe, varying types of clinical manifestations, either with or without affection of neonatal pigs, are observed (see later). the question on the origin of pedv (and thus of its presumed ancestor ed agent) in is unanswered. there are no indications for a possible evolution from another known so called "parental" coronavirus, even after comparative studies with the known coronaviruses using detailed genome analyses of different genes including the s gene. so far, only discrete antigenic relationship involving the n protein but without any cross protection was detected with some of the other animal members of the genus alphacoronavirus such as feline infectious peritonitis virus (fipv), tgev, porcine respiratory coronavirus (prcv), canine coronavirus (ccov) and mink coronavirus (mcv). by the use of monoclonal antibodies to the n proteins of the human alphacoronaviruses nl and e, no cross reactivity was detected with pedv (sastre et al., ) . the only alphacoronavirus in which also the m proteins cross reacts with pedv is mcv (have et al., ) . the nucleotide sequence of the pedv nucleocapsid gene and of typical coronavirus motifs show that pedv, within the region of the genome sequenced, shows indeed greatest homology to the human e, tgev, prcv, fipv, ccov and feline enteric coronavirus (fecv) (bridgen et al., ) . it is interesting to mention that, similar to pedv, several of the other alphacoronaviruses, including the human e, tgev, prcv, ccov, fecv and fipv use the cellular receptor aminopeptidase n (apn) for virus entry into cells in their host (weiss and navas-martin., ) and this seems to be a common evolutionary characteristic. still, the genetic and antigenic diversity between pedv and the other alphacoronaviruses is very largealso, no cross-reactivity has been reported between pedv and the coronaviruses belonging to the beta, gamma or delta genera.the genomic data presented above and the use of the same cellular receptor suggest a common origin of some of some of these alphacoronaviruses. a carrier-wild animal species as source of the virus, as often described with other coronaviruses, cannot be excluded. soon after its detection, experimental studies in neonatal pigs revealed that target cells of pedv were limited to the epithelium covering the intestinal villi and the pathogenesis was thus highly similar to that of tgev (debouck and pensaert, ; debouck et al., ) . cv virus infection in the villous enterocytes in neonatal pigs caused rapid cell desquamation throughout the small intestine within - h after inoculation which was somewhat slower than observed with tgev. still, the villous atrophy induced by pedv was so abrupt and extensive that rapid and severe dehydration occurred leading to death in neonatal pigs. due to this similarity in pathogenesis with tgev, much of the scientific knowledge acquired on tge diagnosis, −immunity, −prevention could be almost invariably applied to ped. an apparent difference with tgev, probably of minor importance from a clinical point of view, was that epithelial cells on colonic villi were also infected but desquamation was not observed. still now, it is a question if this colonic site of replication contributes to disease severity. ped diarrhea in fatteners and sows is often accompanied by an apparent belly ache, a clinical sign not seen with tge, and the question arises if the colon infection may contribute to this clinical manifestation. results of pathogenesis studies obtained in caesarean derived, colostrum deprived neonatal pigs upon inoculation with the european prototype strain cv of the seventies, were practically identical to those observed more recently in asia and in the usa epidemics with the so-called "original us pedv strains" stevenson et al., ; kim and chae, ) . a point of debate in the pedv evolution, particularly since its occurrence in asia and its emergence the usa, is the arising of pedv genetic variants influencing virulence. the history in europe, here presented, allows to assume that ed /pedv was a variant of ed which had acquired tropism for intestinal enterocytes in neonatal pigs. this new tropism expanded and increased the virus virulence since a vulnerable age became affected and piglets mortality became an important economic aspect of the disease. currently, two major pedv variants are described in the usa upon routine genome analyses of usa isolates. the first, also called "original us pedv ", appears to be "highly virulent" while the second, the so called s-indel strains, standing for insertions and deletions in the s gene of the virus, are associated with mild(er) clinical outbreaks. similar genotypic variants have been detected in asia, the s-indels already before and the highly virulent since . when adopting this genomic identification, it appears that cv is classified as a s-indel isolate apparently belonging to a different cluster compared to the us indels (carvajal et al., ) . considering the pathogenesis and virulence of the european prototype strain cv of the seventies as evaluated by the sites and degree of replication and the degree of villous atrophy, no real difference exists with the more recent highly virulent (original us pedv) isolates from the usa. for example, the pig adapted c when experimentally inoculated in neonatal piglets, caused villous atrophy with villous length reduction from the normal value of - m to as low as - m throughout the small intestine and within - h after the start of the diarrhea coussement et al., ) . much depends on how virulence of pedv is determined. if virulence of a pedv isolate is considered merely from the point of view of virus-neonatal pig interaction with parameters such as duration of incubation period, rapidity and severity of enterocyte desquamation, degree and extent of atrophy of villi, production of virulent virus quantities and severity of diarrhea, then cv can be classified as highly virulent despite its identification with s-indel isolates. that s-indels isolates do not systematically mean low virulence was recently shown in a us study (chun-ming et al., ) in which litters of - days old suckling pigs were inoculated with the s-indel iowa strain in the presence of their ped negative mothers. the severity of clinical signs and the mortality of the pigs varied between the liters (from % to %). severe clinical signs were observed in of the litters. two of the sows developed diarrhea. it was observed that, despite similar background of sows and environment in this experiment, the severity of disease was rather variable. it appeared that the pigs' body weight at birth and the sows health conditions and lactation were influential factors. in the same experiment mentioned above (chun-ming et al., ) , one litter was also inoculated with an original us pedv strain of high virulence. it was concluded that virulence of the s-indel isolate was generally lower based on the longer incubation period, the shorter duration of diarrhea, more limited regions of virus infection, overall lower pig mortality ( % vs % for "original") and some other additional parameters. the sites and extent of the deletions or insertions and the seqence differences in the s gene may play an important role. in a recent publication (chen et al., ) the pathogenicity differences between u.s.pedv prototype strains and a s-indel-variant stain were compared in conventional neonatal pigs under experimental infections and enteric disease, as evidenced by clinical signs,fecal virus shedding, gross and histopathological intestinal lesions, were significantly lower for the s-indel strain.however,the molecular basis for the virulence differences were not elucidated. since the early beginning in europe, it was clear that ped disease can show much variability even in different litters of pigs particularly when suckling their mother. such differences and the high variation in pig mortality in different litters (from to %) was an observation also made in the seventies in europe when the first epidemic occurred and the reason was never unravelled. even more variability is experienced when virulence and severity of ped disease is related to the interaction virus-farm population and thus in field outbreaks. the result of a ped outbreak will be much more difficult to predict, to evaluate and to define since, next to possible virulence differences of the isolates and next to variation among litters in suckling pigs, many additional factors play a role in determining the clinical outcome of the infection. they include immune status of sows, dose of virus exposure on the farm, herd size and pig farming management and others, all of which may be interacting in a different way. moreover, the procedures applied for intentional infection (feed back) of the sow population to speed up the induction of immunity to be passively transfered to the litter could be considered as a potential cause of worsening of the clinical status of the suckling pigs. in fact, that practice can also be a source of other pathogens for gilts/sows and/or for newborn piglets. it is thus possible that, particularly in a fully susceptible pig population and even with pedv strains of similar virulence, the mortality rates and losses are much higher in some continents or regions or farms with extensive and highly industrialised pig farming. the overall health status of the population apparently also plays an important role. while genomic changes surely will occur in ped virus isolates, it is advised to be careful when associating them with virulence changes. when a different clinical picture is observed on farms, it is often too hastily concluded that variants with varying virulence have arisen based on genome analysis only and without testing for virulence factors in experimental pigs. while genome analysis is certainly useful and may be directional, repeated comparative animal inoculation experiments with so called new isolates, clinically denominated as candidate "virulence-variants", need to be carried out in a standardized way before solid conclusions about virulence are made. this is indicated by the large variations very often observed with one and the same isolate. the neonatal, non suckling pig, preferably colostrum deprived, is reliable and even essential for this purpose. parameters as duration of incubation period, a timewise follow up of site and degree of villous affection in the small intestine are needed and must be repeated before calling a pedv isolate a variant with impact on virulence. it should be stressed that pig adapted virus strains should be used as it is known that major genomic modifications can arise when pedv is cell culture passaged, as well in porcine as in non-porcine cells, such as in vero cells. the epidemiology of ped in europe has been and still is quite puzzling. pedv outbreaks in the late seventies and early eighties occurred both on breeding and fattening swine farms. acute outbreaks with neonatal pig mortality were encountered in the breeding-fattening farms which became infected for the first time. pedv often became endemic. in farrowing-finishing farms, successive groups of pigs became infected upon weaning and after losing their lactogenic protection from their immune mothers, so that the virus could persist. whether the virus persisted or not after the original outbreak was somewhat unpredictable, as it could also disappear from the farm. the farm size (number of sows) and its structure (number of units) played a role. also ped persistence regularly occurred in fattening farms using the system of continuous introduction of feeder pigs originating from numerous and different breeders. a typical case of persistent diarrhea caused by pedv lasting months on a breeding-finishing farm was described in the netherlands (pijpers et al., ) and this was a feature regularly observed in europe in the eighties. recent experience in the usa ( ) ( ) ( ) , has shown that management practices adopted in the epidemic phase of the infection can turn ped to a endemic/enzootic and long lasting form (jung and saif, ) . pedv infections were a regular cause associated with viral diarrheal picture in weaned and feeder pigs. in a serological study in belgium in , pedv was associated with diarrhea in out of groups of feeder pigs after arrival in fattening farms (callebaut et al., ) but, the virus remained prevalent in the swine populations of western europe during the eighties. a serosurvey in belgian sows using sera collected in slaughterhouses, and thus mostly originating from different farms, showed pedv antibodies % in and % in . similar percentages of sows were positive in germany (on regional locations), france, spain, the netherlands and bulgaria while no antibodies were found in scandinavia, northern ireland, usa or australia . in , antibodies were detected in sera received from taiwan (the first evidence of the presence of pedv in asia). as the eighties advanced, fewer outbreaks on breeding farms were seen even though the virus was still detected but the general economic impact of ped had become lower. in belgium in , groups of feeder pigs from commercial finishing herds, using the all in-all out production system, were examined for serocoversion to pedv and tgev. none of the groups seroconverted to tgev while seroconverted to pedv with diarrhea observed in all (van reeth and pensaert, ) . in an hungarian study published in , . % of faecal samples from weaned pigs with diarrhea tested positively for pedv (nagy et al., ) . during the nineties, an acute ped outbreak which was described in spain involving a fattening unit of pigs with diarrhea starting in - weeks old pigs in one barn affecting pigs from to kg and subsequently spreading to the other barns (carvajal et al., ) . an isolated outbreak was described, in in england, in a large finishing herd where weaners were brought in over a month period and positive sows were found in the breeding herds supply-ing the weaners (pritchard et al., ) . but, no further epidemic of ped occurred despite a very low pedv seroprevalence as only . % of fatteners from different finishing units were positive for antibodies to pedv(may -january . interest from a disease and economic point of view became very low in europe and no further research was performed on ped. practically no serosurveys were carried out. a serological survey in sows from farrow to finish herds carried out in belgium in revealed that gilts were positive for pedv antibodies in only of the considered farms, and in , fattening farms were examined for pev antibodies and none were positive (pensaert, unpublished) . it appeared that pedv, except for a focal case, was disappearing from the european swine population towards the turn of the century. for this reason, no attention or follow up was given anymore to this viral infection while its field of interest had fully moved to asia. however, a somewhat atypical ped outbreak occurred unexpectedly in the po valley in northern italy in , (martelli et al., ) . it occurred between may and june in an area densely populated with pigs. the outbreak started with four cases occurring in fattening farms from may to july. no clinical cases were detected during august and september. in october, two new cases appeared: the first in a fattening unit and the second in the nursery of a three-site production unit. the disease spread during the winter of - , affecting more than farms including fattening units as well as farrow-to-finish or farrow-to-weaner farms. some pedv positive farms were still detected between mid- and the end of , but the disease progressively disappeared (sozzi et al., ) . from - , only sporadic outbreaks were observed in grower and finisher herds (efsa, ) . this epidemic in italy in - inclined us to forecast a new episode of ped epidemics in europe but it did not occur. recently and due to an increased attention following the epidemic in the usa, single or limited ped outbreaks have sporadically been diagnosed in europe. one case in ukraine, (dastjerdi et al., ) occurred in a -sow farm ( farrowings a week) and mortality in pigs less than days old approached %. the virus was closely related to "original us" strains reported form north america (sequence identity of . %). isolates from other cases reported from belgium (theuns et al., ) , holland (van der wolf et al., ) , france (grasland et al., ) , germany hanke et al., ) and portugal (mesquita et al., ) and italy were, on the basis of genetic sequence, closely related to each other. when sequenced, they were classified as s-indel strains, and the german isolate showed . % identity to the oh strain isolated in the usa in january . the size and clinical disease in these outbreaks were very variable. the outbreak involved in belgium: fattening farm (no mortality), in france: farrow to finish farm (mortality % in pigs at one week and % at weaning), in germany: farms ( fattening with . % and % mortality, breeding with % and no mortality, respectively) and in portugal where it started in one farm (with pig mortality, but not further defined) and where the virus spread to other pig farms during a period of months. from these data, it can be seen that, again, there was much and unexplained variation in ped clinical disease and outcome. except for the possibility of the outbreak in ukraine, it is very doubtful that the other european isolates have anything to do with those involved in the us epidemic. similar focal cases must have occurred in europe before the us outbreak but were, most likely, neither recognized nor diagnosed nor reported as ped. s-indel strains have been present in europe as cv appears to be the earliest known representative (carvajal et al., ) . it is remarkable that, in many european countries, no large epidemic occurred despite several indications that the breeding population in their densely populated swine raising regions is negative for antibodies to pedv and thus presumably fully susceptible. it is difficult to understand why a virus such as pedv has gradually regressed in the swine population in europe in the absence of any special control measures. vaccination has not been applied and no control programmes have been installed. the puzzling aspect is that, during the last decennia, pedv was and still is focally present in europe and did not cause an epidemic despite the high numbers of susceptible-seronegative farms and despite the very dense swine populations in some regions. one would expect that a virus such as pedv, which replicates to very high titers in swine and which can easily and rapidly spread from one swine farm to another, would be able to maintain itself in the swine population. as previously explained, once an outbreak has occurred on a breeding farm, pedv virus could persist easily when successive litters of pigs, after losing their lactogenic protection at weaning, become a susceptible target for infection. in fact, persistence for a virus such as pedv would be almost as a "natural" feature similar to the endemic character observed with other porcine enzootic enteric viruses such as swine rotaviruses, swine enteroviruses and others. tgev cannot serve as an example here because, in europe, it has largely been eliminated from the swine population due to the emergence, in the early eighties, of the closely related porcine respiratory coronavirus (prcv). prcv is a tgev deletion mutant which has acquired respiratory tropism and shows an epidemiological advantage of rapid aerogenic spreading while causing a protective immunity to tgev. endemic prcv has thus "replaced" tgev in europe. it would be interesting to study the mechanisms behind the regression/waning of pedv in europe. could it be that the virus has a non swine ancestor which has temporarily become adapted to swine but which is not really swine-borne? such evolution would not be unique for animal coronaviruses. could it be that the virus can maintain itself in the population only when present at a sufficient high dose allowing it to continue the infection chain but once reaching a low level quantity,e.g on a farm basis, is not longer able to do so? the waning of pedv has apparently not occurred in parts of asia within its - decennia of presence on that continent to the same degree as it did in europe, and it will be intriguing to closely follow the epidemiological course and evolution of pedv in the usa, once the epidemic phase has passed. surveillance and control of ped coronavirus in pig in italy seqence determination of the nucleocapsid protein gene of the porceni epidemic diarhoea viris confirms that this virusis a coronavirus relatyed to human coronavirus e 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coronavirus. microbiol an apparent new syndrome of porcine epidemic diarrhea key: cord- -z h sc authors: semenza, jan c; ebi, kristie l title: climate change impact on migration, travel, travel destinations and the tourism industry date: - - journal: j travel med doi: . /jtm/taz sha: doc_id: cord_uid: z h sc background: climate change is not only increasing ambient temperature but also accelerating the frequency, duration and intensity of extreme weather and climate events, such as heavy precipitation and droughts, and causing sea level rise, which can lead to population displacement. climate change-related reductions in land productivity and habitability and in food and water security can also interact with demographic, economic and social factors to increase migration. in addition to migration, climate change has also implications for travel and the risk of disease. this article discusses the impact of climate change on migration and travel with implications for public health practice. methods: literature review. results: migrants may be at increased risk of communicable and non-communicable diseases, due to factors in their country of origin and their country of destination or conditions that they experience during migration. although migration has not been a significant driver of communicable disease outbreaks to date, public health authorities need to ensure that effective screening and vaccination programmes for priority communicable diseases are in place. population growth coupled with socio-economic development is increasing travel and tourism, and advances in technology have increased global connectivity and reduced the time required to cover long distances. at the same time, as a result of climate change, many temperate regions, including high-income countries, are now suitable for vector-borne disease transmission. this is providing opportunities for importation of vectors and pathogens from endemic areas that can lead to cases or outbreaks of communicable diseases with which health professionals may be unfamiliar. conclusion: health systems need to be prepared for the potential population health consequences of migration, travel and tourism and the impact of climate change on these. integrated surveillance, early detection of cases and other public health interventions are critical to protect population health and prevent and control communicabledisease outbreaks. travel medicine will increasingly see the health consequences of significant changes associated with global change, particularly climate change and socioeconomic development. together these changes mean more opportunities for people to travel to pathogen-endemic countries and for pathogens to be imported to new locations, with the potential for unexpected communicable disease cases and outbreaks. moreover, people who migrate or are displaced can also be at increased risk for chronic disease and mental health issues. thus, travel medicine needs to take a broader perspective than just asking patients where they are going or where they have been, considering how the ongoing and projected shifts in the magnitude and pattern of disease could affect the health and well-being of individuals and populations. modifications to the approaches used by health systems to manage adverse health outcomes are needed to ensure health care providers have the most up-to-date information. migration describes the movement of a person away from their usual residence whereas travel describes a person who passes from place to place, for any reason. migration and travel have shaped the history of humanity and enriched societies economically, socially and culturally. multiple and interacting factors drive migration in particular. climate change, including increasing climate variability, can be one of these factors. we discuss the potential impacts of climate change on migration and travel and the implications for travel medicine and public health practice. following a brief review of climate change, we discuss the potential health implications of migration and travel and the way in which they are affected by climate change and provide suggestions for health systems to better manage the potential impact of climate change, migration and travel on population health. the intergovernmental panel on climate change special report on warming of . • c concluded that human activities have caused ∼ . • c of global warming since pre-industrial times and that, if it continues to increase at the current rate, warming is likely to reach . • c between and . the special report concluded that climate change is increasing, and will continue to increase, land and ocean temperatures and the frequency, intensity and duration of heat waves in most land regions (high confidence). it also concluded that climate change will continue to increase the frequency and intensity of heavy precipitation events globally and the risk of drought in the mediterranean region specifically (medium confidence). climate change is a long-term process, but the extent to which individual weather events are influenced by climate change can increasingly be estimated. , migration the greatest human migration started or years ago when homo sapiens left africa for other parts of the world - ; a series of 'mega-droughts' may have contributed to this. [ ] [ ] [ ] migration has continued since and has become a defining characteristic of our times, affecting every inhabited continent. migrants may move internally, settle in neighbouring countries or move to other continents. currently, europe, north america and oceania are the main destinations for migrants although, overall, europe and asia have received the greatest number of migrants in recent decades. migration has political, social, economic, cultural, environmental and public health implications. migrants generally contribute more in taxes and social contributions than they receive in benefits. [ ] [ ] [ ] [ ] but migration can also pose chal-lenges, particularly when there is a rapid influx of large numbers of people. the international importance of migration was recognized in by the united nations general assembly when the agenda for sustainable development was adopted; of the sustainable development goals (sdgs) directly or indirectly relate to migration (table ). in , the united nations general assembly adopted the new york declaration for refugees and migrants to support a comprehensive approach to migration. these international accords were also thematically linked to other major international agreements, including the sendai framework for disaster risk reduction and the paris agreement under the united nations framework convention on climate change. , the drivers of migration are complex and include political, economic, social, cultural and environmental factors (figure ). these same factors can determine whether migration is permanent or temporary. the drivers of migration can be grouped into five categories - : ) push factors that force people to migrate including war, unemployment, food scarcity, over-population or prosecution. ) pull factors that attract people to a new destination including work and educational opportunities, political or religious freedom. ) network drivers that facilitate the migration process such family ties, social support, kinship, safety and feasibility of transport. ) national policies that allow or prohibit migration. ) personal aspirations and motivations. these drivers are often interconnected and situation specific ( figure ). they can also interact with climate change, which can itself be a trigger for migration ( figure ). , although environmental drivers do not appear to have been the most significant contributor to international migration to date, , migration in response to the consequences of climate change can be a pragmatic adaption strategy that balances the risks of staying and the risks of moving. , [ ] [ ] [ ] [ ] for example, for the tonga-speaking people in southern zambia, migration is an adaptation strategy to climate variability when the availability of water affects both agricultural production and livestock survival. additional warming of . • c is projected to further exacerbate climate-related drivers of migration; studies suggest that an increase in extreme weather and climate events and disasters associated with climate change could trigger an increase in migration. [ ] [ ] [ ] [ ] climate change impacts on migration and health. the complex and multiple drivers of migration mean that it is difficult to attribute specific migrations to climate change (figures and ) . as a result, projections of migration associated with climate change vary widely, ranging from million to million, with these numbers based on extrapolations. , in , a world bank report on the impact of climate change on migration estimated that by -in just three regions-climate change could force more than million people to move within their countries. table summarizes the world bank findings from three case studies in sub-saharan africa (ethiopia), south asia (bangladesh) and latin america (mexico). evidence for the possible role of climate change on migration comes from different sources (figure and ) . these include studies of the extent to which 'temperature and precipitation' are associated with out-migration. for example, in recent decades, temperature had a statistically significant effect on out-migration from agriculture-dependent countries. there is a nexus between climate change and migration in that temperature and precipitation are positively associated with migration: a • c increase in average temperature in the sending country is associated with a . % increase in bilateral migration flows; an additional millimeter of average annual precipitation is associated with an increase in migration of . %. another study suggests that an increase in precipitation anomalies from the long-term mean may also be associated with an increase in out-migration. under a moderate climate change scenario, if global mean temperature rises by • c, tropical populations would have to move considerable distances in order find places where temperatures are similar to those in places they currently live in and to preserve their annual mean temperatures. 'extreme weather events' linked to climate change, such as heat waves, droughts, storms, floods and wildfires, cause shortterm population displacement ( figure ). in , disastersmost of which were related to extreme weather-displaced . million people in countries ( figure ). in , california only low-income countries show marked increases in population under spp . b the higher number of climate migrants under the more climate-friendly scenario in ethiopia is in part driven by the regional climate models, which project lower water availability by in general compared with the other two scenarios (pessimistic reference and more inclusive development scenarios), which are coupled with higher emissions. experienced the most destructive wildfire season on record with more than , people being evacuated from their homes. a number of factors led to these fires, including accumulated natural fuel and compounding atmospheric conditions that were linked to climate change. based on the experience of other events in the usa, some people will eventually return to their communities, but others will permanently relocate. for example, following hurricane katrina, it was estimated that between % and % of the population returned, with young adults being more likely to have moved further away. , in , after hurricane andrew in florida, % of displaced residents relocated within the same county, % moved within the state and % moved out of state. in some cases, extreme weather events can cause longerterm migration. for example, an increase in the frequency and intensity of droughts in tanzania has killed livestock and forced the maasai people to migrate from rural to urban settings, with documented implications for their mental health. similarly, prior to the syrian migrant crisis in , the fertile crescent was affected by a severe and sustained drought associated with anthropogenic increases in greenhouse gas emissions and this, combined with unsustainable agricultural and environmental practices, contributed to internal migration, political instability and conflict and eventually to an exodus of one million migrants to europe. 'river flooding and erosion' has adversely affected agriculture in bangladesh and resulted in population migration to india ( figure ). climate change models project an increased frequency and likelihood of severe storms, with implications for sea level and flooding, in the ganges-brahmaputra-meghna delta, and this is likely to displace a large number of people. in pakistan, the adverse economic impact of heat waves on agricultural and non-agricultural activity has increased outmigration. in contrast, flooding in pakistan was not associated with significantly increased migration, possibly due to the larger scale of the response by relief agencies to floods compared with heat waves. in other regions, food scarcity due to flooding has contributed to internal migration. in in mali, flooding destroyed fields, damaged grain stores and impeded livestock production and, as a result, an estimated . million people are food insecure and internally displaced. 'gradual changes' due to climate change, such as changing rainfall patterns, rise in sea level, increased salinization and decreased soil fertility, can also be a driver for migration ( figure ). practice. migration has implications for health and public health practice. , migrants can be exposed to health risks in their country of origin and country of destination (figure ) ; they may be particularly at risk during their journey, due to lack of shelter, exposure to harsh climatic conditions, heat and overcrowded, inadequate transit and detention centres. public health interventions need to target migrants in all of these settings, and especially during migration, in order to minimize associated health risks (figure ) . sudden displacement because of a disaster or other event can be very stressful and manifest in post-traumatic stress disorders, depression or anxiety that can continue for months or even years. other factors that can affect the mental health of migrants include family separation, acculturation, job insecurity, restricted mobility, dangerous border crossings, stigmatization and marginalization. stress is associated with higher rates of depression and anxiety disorders in the short term and with cardiovascular disease in the longer term. [ ] [ ] [ ] epidemic intelligence data from the european centre for disease prevention and control (ecdc) suggests that migration is a relatively infrequent driver of communicable disease threat events in europe, compared with travel and tourism. , there was no evidence during the migrant crisis in europe that migrants posed a risk to european union citizens from communicable diseases, and despite the barriers to accessing immunization that migrants experience, the contribution of migrants to the current measles outbreaks in europe is minimal. however, migrants may be at increased risk of communicable disease due to exposure or conditions during migration and in the country of destination (table ) . , , , [ ] [ ] [ ] [ ] for example, there is evidence that tuberculosis transmission occurs on migration routes to europe, including during long-term stays in refugee camps. overcrowded and inadequate refugee camps, detention centres and housing can spread vectors (e.g. lice and fleas) that transmit diseases such as relapsing fever, trench fever and epidemic or murine typhus. poor and overcrowded living conditions can also increase the risk of respiratory diseases, such as seasonal influenza. migrants living in overcrowded conditions with poor sanitation may also be at risk of cholera outbreaks. overcrowding, poor sanitation and limited access to health services can also facilitate the emergence of antimicrobial resistance (amr) among migrants, particularly refugees and asylum seekers. migrants may be at increased risk of communicable disease in their country of destination due to factors including lack of vaccination, low socioeconomic status and poor living conditions and limited access to health care (table ) . recent evidence from the european union (eu) and the european economic area (eea), based on cd cell counts and hiv-rna trajectories from seroconversion also suggests that migrants may be at risk of hiv transmission in their country of destination; two-thirds of a sample of hiv-positive migrants from sub-saharan africa, latin america and the caribbean acquired their hiv infection in the country of destination. essential public health measures include ensuring adequate living conditions, access to health care in refugee camps, detention centres, screening for communicable diseases and assessment offer serological screening and treatment (for those found to be positive) to all migrants from countries of high endemicity in sub-saharan africa and focal areas of transmission in asia, south america and north africa. offer serological screening and treatment (for those found to be positive) for strongyloidiasis to all migrants from countries of high endemicity in asia, africa, the middle east, oceania and latin america. offer vaccination against mmr to all migrant children and adolescents without immunization records as a priority. offer vaccination to all migrant adults without immunization records with either one dose of mmr or in accordance with the mmr immunization schedule of the host country. offer vaccination against diphtheria, tetanus, pertussis, polio and hib a (dtap-ipv-hib) to all migrant children and adolescents without immunization records as a priority. offer vaccination to all adult migrants without immunization records in accordance with the immunization schedule of the host country. if this is not possible, adult migrants should be given a primary series of diphtheria, tetanus and polio vaccines. see table for details. cxr means chest x-ray; ltbi, latent tb infection; tst, tuberculin skin test; igra, interferon-gamma release assay; mmr, measles/mumps/rubella. source: ecdc. public health guidance on screening and vaccination for infectious diseases in newly arrived migrants within the eu/eea. https://ecdc.europa.eu/sites/portal/files/documents/public% health% guidance % on% screening% and% vaccination% of% migrants% in% the% eu% eea.pdf. vaccination against hib is only recommended to children up to five years of age. of vaccination status on arrival in countries of destination (table ). available evidence shows that it is cost-effective to screen child, adolescent and adult migrants for active and latent tuberculosis, hiv, hepatitis c, hepatitis b, strongyloidiasis and schistosomiasis (table ) . targeted hiv prevention, testing and treatment programmes are also required in countries where migrants are at risk of hiv acquisition after arrival. there is also a clear benefit from ensuring that migrants are included in vaccination programmes and providing catch-up vaccinations where needed (table ) . particular attention should be given to vulnerable children, women and the elderly, who might also suffer from non-communicable diseases, such as cardiovascular diseases, diabetes, cancer, chronic lung diseases, mental health and trauma. sudden migration can result in complications from noncommunicable diseases if treatment and care are discontinued or if access to medications is interrupted. these conditions can cause a life-threatening deterioration and acutely exacerbate preexisting conditions in the event of sudden migration (table ). travel, including for business and tourism, has increased dramatically in recent decades. globally, in , commercial airlines carried more than billion passengers; this is projected to have risen to . billion in and to continue to increase in the coming years. air travel contributes to greenhouse gas emissions and, hence, to climate change. at the same time, the effects of climate change on tourism assets, such as biodiversity, coral reefs, glaciers and cultural heritage, are leading to an increase in 'last chance' travel to destinations before they are further degraded. [ ] [ ] [ ] for example, in the southern hemisphere, sea level is projected to rise by - cm by the end of this century, submerging much of the maldives. in northern latitudes, climate change is already having an adverse impact on the winter tourism industry in lapland and may make it impossible to maintain its snowcovered winter wonderland in future. in many ski resorts, artificial snowmaking, which has high energy costs, is increasingly being used to supplement natural snow, to improve reliability and to extend the season. climate change can be a factor in creating conditions suitable for vector-borne disease transmission. importation of pathogens from endemic areas can then result in the subsequent spread of these diseases under suitable climatic conditions. extended seasonal transmission seasons due to climate change can also increase the window of opportunity of pathogen importation. climatic suitability, including lower and upper temperature thresholds, affects the growth, abundance and survival of mosquito vectors such as aedes aegypti and aedes albopictus that can transmit dengue, zika and chikungunya. in europe, a warmer climate appears to be associated with more frequent outbreaks of dengue and chikungunya are projected to become more suitable for onward transmission of the chikungunya pathogen. climate change may have contributed to the explosive spread of zika in brazil. the epidemic was preceded by 'record warmest' climatic conditions, accompanied by a severe drought. the utilization of home water storage containers during the drought might have provided breeding sites for aedes mosquitoes and increased exposure to mosquitoes. virus importation into a susceptible population could then have triggered the epidemic. precipitation, another important environmental factor affected by climate change, also influences the availability of conditions suitable for mosquito vectors. for example, heavy rainfall increases the abundance of a. albopictus and, hence, the risk of transmission of dengue and chikungunya. climate change can increase the risk of other vector-borne diseases, including tick-borne and rodent-borne infections, and can also influence the range, seasonality and incidence of water-borne diseases such as cholera. , global air travel may facilitate the spread of 'resistant pathogens'. for example, it is thought to have facilitated the rapid dissemination of methicillin-resistant staphylococcus aureus from the uk and north america across europe and then to asia. vancomycin-resistant enterococci and klebsiella pneumoniae carbapenemase-producing k. pneumoniae followed a similar trajectory. the burden of antibiotic resistance in destination countries can also be exacerbated by climate change, because an increase in ambient temperature is associated with a significant increase in antibiotic resistance for common pathogens, including k. pneumoniae and s. aureus. it is hypothesized that temperature accelerates horizontal transfer of resistance genes or the uptake of genetic material. ambient temperature may also facilitate environmental growth of resistant strains and enhance transmission from food, agriculture and environmental sources. climate change impacts on travel: implications for public health practice. air travel can facilitate the spread of communicable diseases around the globe. passenger volume has been identified as a significant driver of the importation of viremic passengers. , flights directly connect millions of passengers between europe and asia, africa, north america and south america, with many of these locations 'hot spots' for the emergence of communicable diseases. a disease outbreak in one part of the world can quickly spread to another part via air travel. , for example, in-flight transmission of severe acute respiratory syndrome (sars) in resulted in the rapid spread of sars-associated coronavirus (sars-cov) around the world. international air travellers departing from mexico in unknowingly carried and disseminated the novel influenza virus a(h n )v around the world. similarly, air transport networks contributed to the spread of middle east respiratory syndrome from saudi arabia in , chikungunya dispersion in the americas in , ebola from west africa in and zika spread in the americas in . [ ] [ ] [ ] [ ] more specifically, air travel can increase the risk of importation of pathogens from endemic areas into regions with competent mosquito vectors and suitable climatic and environmental conditions for vector-borne diseases. dengue, a mosquito-borne viral disease, is a significant public health concern, threatening almost half of the world's population. table . vaccinations to be offered to migrants in the absence of documented evidence of prior vaccination within the eu/eea priority vaccinations mmr administer to individuals ≥ months of age. two doses of mmr a should be administered at least month apart but preferably longer according to national guidelines. measles vaccine provided before months of age does not induce protection in all and should be repeated after months of age. loss of access to medication or devices, loss of prescriptions, lack of access to health care services leading to prolongation of disruption of treatment degradation of living conditions loss of shelter, shortages of water and regular food supplies and lack of income add to physical and psychological strain interruption of care due to destruction of health infrastructure, disruption of medical supplies and the absence of health care providers who have been killed, injured or are unable to return to work interruption of power supplies or safe water life-threatening consequences, especially for people with end-stage renal failure who require dialysis source: http://www.euro.who.int/en/health-topics/health-determinants/migration-and-health/migrant-health-in-the-european-region/migration-and-health-key-issues# transmission occurs largely in tropical and sub-tropical regions, but outbreaks have occurred in europe around the mediterranean where a. albopictus is present. infected air passengers from endemic areas can arrive in europe during their viremic period, be bitten by local mosquito vectors and transmit the dengue virus locally and trigger an outbreak due to a warming climate. other means of transport are also implicated in the spread of disease-causing pathogens. for example, ballast from cargo ships played a role in moving pathogenic vibrios to new locations that were environmentally and climatically suitable, even in northern latitudes. travel and tourism can also facilitate the importation of pathogens from developed countries with low vaccination coverage, to developing countries with high rates of susceptible individuals due to lack of health care access. , responding to the public health challenges associated with travel and climate change requires robust national surveillance systems, including effective tracking of vector location and disease importation. integrated surveillance of invasive and endemic mosquito species is crucial for effective prevention and control of vector-borne diseases. early detection of outbreaks can be aided by seasonal surveillance in areas where competent vectors are active and in close proximity to airports with a large influx of passengers from endemic areas. for example, the risk of dengue importation can be described by a model that relates air travellers from dengue-affected areas to dengue importation. this approach can delineate in space and time where the risk is the highest, and target seasonal surveillance to high-risk areas, for early case detection and intervention. an important consideration when projecting risk of disease transmission associated with climate change and travel is that the timing of risks may be under-estimated, i.e. transmission may occur sooner than models suggest. for example, the modelled future environmental suitability of a. aegypti in the contiguous usa in the period - projects potential suitability in southern areas of mid-western states, such as illinois, indiana and ohio. however, breeding colonies of a. aegypti were found in ontario in southern canada in , indicating that the risk of transmission of diseases such as dengue fever and zika may occur earlier than the projections suggest. the importation and spread of tropical pathogens in temperate regions due to climate change is another aspect to consider for public health practice. it is a potential threat to the safety of the blood supply and, hence, of blood transfusions, particularly with respect to pathogens for which there are no diagnostic tests. [ ] [ ] [ ] [ ] [ ] expansion of areas with an increased risk of communicable diseases due to climate change also increases the risk of blood bank contamination with communicable pathogens as a higher number of prospective blood donors are exposed to potential infections for a longer period, e.g. if climate change alters the length of the annual mosquito activity season. moreover, the asymptomatic phase of many infections, even if it is relatively short, increases the potential for transmission by transfusion. climate change projections of the probability of infection should therefore be used for preparedness activities. in addition, certain pathogens, such as the west nile virus, can persist in stored blood components and subsequently cause infection through intravenous application. pathogen reduction technology that inactivates pathogens in donated blood is a strategy that could be used for pre-emptive risk reduction. the world is warmer today than in pre-industrial times, and warming is projected to continue. the frequency, duration and intensity of extreme weather events have increased, with implications for migration in particular. global warming is associated with migration from farming communities and from small islands and coastal areas. evidence of climate change impacts on migration in other settings is less clear. the combined impact of travel and climate change can favour the importation, establishment and spread of tropical diseases in temperate regions. these developments require public health action, including targeted and culturally appropriate interventions and novel technologies, to prevent and control emerging health threats associated with the interaction between climate change, migration and travel. it calls for training of health care professionals to provide appropriate health care (prevention, screening, and treatment) for migrants and for risk assessment of diseases among travellers/ tourists. adequate living conditions, screening and vaccination programmes, and medical interventions for migrants can prevent outbreaks of communicable diseases and the spread of resistant pathogens. assessment and interventions also need to encompass chronic conditions, mental health and trauma due to migration. targeted hiv prevention, testing and treatment programmes are also required in countries where migrants are at risk of hiv acquisition after arrival. effective national surveillance systems that include tracking of vector location and disease importation can inform targeted prevention and control interventions. novel approaches including modelling the arrival of air passengers into environmentally and climatically receptive areas, to improve assessment of the risk of importation of pathogens from endemic areas, and assessment of climatic suitability, can inform seasonal surveillance or active case finding. specific measures may be required to ensure blood safety, including pathogen reduction technology, where there is a risk of the importation and spread of tropical pathogens in temperate regions. the authors report no financial interests or connections, direct or indirect or other situations that might raise the question of bias in the work reported or the conclusions, implications or opinions stated-including pertinent commercial or other sources of funding for the individual author(s) or for the associated department(s) or organization(s), personal relationships or direct academic competition. j.c.s. wrote the first draft of the paper. both authors approved the final paper. herein are the authors' own and do not necessarily state or reflect those of ecdc. ecdc is not responsible for the data and information collation and analysis and cannot be held liable for conclusions or opinions drawn. we should like to thank wei-yee leong from the lee kong chian school of medicine, nanyang technological university, singapore for her help with the figures. none declared. an ipcc special report on the impacts of 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population changes on human exposure to the virus vector mosquito aedes aegypti county health unit. aedes aegypti mosquito climate change projections of west nile virus infections in europe: implications for blood safety practices blood supply under threat emerging infectious threats to the blood supply emerging infectious diseases that threaten the blood supply current perspectives in transfusion-transmitted infectious diseases: emerging and re-emerging infections emerging infectious disease agents and their potential threat to transfusion safety we would like to thank the editor and the three anonymous reviewers for detailed and constructive feedback on the manuscript. we also appreciated the insightful comments and suggestions from teymur noori, pontus naucler and senia rosales-klintz at ecdc. the views and opinions expressed 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- -o zspgrk authors: ippolito, g.; fusco, f.m.; caro, a. di; nisii, c.; pompa, m.g.; thinus, g.; pletschette, m.; capobianchi, m.r. title: facing the threat of highly infectious diseases in europe: the need for a networking approach date: - - journal: clin microbiol infect doi: . /j. - . . .x sha: doc_id: cord_uid: o zspgrk in recent years emerging and re-emerging infections, as well as the risk of bioterrorist events, have attracted increasing attention from health authorities because of the epidemic potential that renders some of them a real public health challenge. these highly infectious diseases (hids) are occurring more and more frequently in europe, and despite the many initiatives in place to face them, many unsolved problems remain, and coordinated efforts for dealing with hids appear mandatory. whereas uncoordinated measures would lead to only partial and poor responses to these emerging threats, networking represents a valuable approach to these diseases, in order to: (i) ensure a rapid and effective response; (ii) stimulate complementarity and prevent duplication; (iii) promote international cooperation, exchange of experience, good practice and protocols; and (iv) support the less prepared countries in the european community. despite hopes to the contrary, infectious diseases appear far from being defeated and continue to claim the attention of public health authorities. particularly in recent years, yet to be fully understood changes in the environment, increased movement of goods and persons, and the local influence of global warming and other phenomena concerning vectors and hosts, seem to have promoted and accelerated changes in the presentation of old infectious diseases and the development of new ones [ ] [ ] [ ] . the relevance of the 'emerging and re-emerging' infectious diseases, usually defined as 'infections that have newly appeared in a population or have existed previously but are rapidly increasing in incidence or geographic range', is further noted by the who in its recent world health report [ ] . the who stressed that infectious diseases are spreading faster and emerging more quickly than ever before. some emerging and re-emerging diseases represent a real challenge because of their epidemic potential. recently, many global alarms involving infectious diseases-such as the anthrax crisis in the usa, the emergence of sars, the pandemic threat posed by the highly pathogenic avian influenza a (h n ), and the cases of imported or autochthonous viral haemorrhagic fever (vhfs) in europe-have highlighted the need to improve preparedness for these highly infectious diseases (hids), also in order to increase certain aspects of what is perceived in many areas as an issue of collective and national security [ ] . emerging hids are of particular concern because they usually hit relatively unprepared public health systems, and appropriate diagnostic tests, vaccines, drugs, containment and mitigation measures are frequently not available or not immediately so. a similar situation could occur if a pandemic strain of influenza virus emerges: several surveys conducted in european countries and in the usa have revealed many gaps in their preparedness plans, in particular in terms of making such plans truly operational, in stepping up prevention measures against seasonal influenza, in ensuring essential services, in enhancing collaboration with adjacent countries, and in extending and better directing influenza research [ ] [ ] [ ] . research on emerging infectious diseases has been funded since the inception of the european union (eu) framework programmes (fp) for research in . in the eu developed recommendations for early diagnosis and management of bioterrorism-related infections, with the aim of providing member states with a common basis for dealing with these diseases [ ] . among activities/projects covered in the fp - , more than half are focused on various aspects of influenza, which makes the commission's fps arguably the single largest funding source for influenza research in europe. the other topics covered include: vhfs, sars, transmissible spongiform encephalopathies, food-and water-borne diseases, other zoonoses, as well as issues such as preparedness and capacity building for different diseases in a more generic fashion. in total, both influenza research and research on other emerging infectious diseases have received more than € million of eu funding each since . a complete searchable list and short descriptions of all projects, grouped into different categories (as well as a downloadable pdf version) is available online [ ] . concurrent with the increasing awareness of the threat of a new influenza pandemic, the current fp - introduces for the first time a specific area dedicated to 'potentially new and re-emerging epidemics', specifying that its 'focus will be on confronting emerging pathogens with pandemic potential including zoonoses'. the term 'potentially new and re-emerging epidemics', which is uncommon in the scientific literature, refers mainly to those emerging viral diseases of current or future relevance for europe. this new mandate to cover research systematically in the area of emerging epidemics establishes a focal point within the fp from which calls for proposals in this area can be strategically planned. the past calls in the area of emerging and re-emerging infectious diseases were frequently published ad hoc, in response to specific threats, and the lack of a dedicated area was responsible for the limited coordination and long-term planning. the new mandate in fp specifically dedicated to diseases should overcome these problems. although research on influenza will continue to receive support in view of the magnitude and likelihood of an influenza pandemic, future calls will increasingly build a strategic european research capacity for other emerging and re-emerging hids. a definition of hids and the agents/diseases included are summarized in table . several cases of these diseases have been reported in europe since : cases of sars were imported in eight countries, and approximately imported confirmed or suspected cases of vhfs have been reported, mainly lassa fever [ ] [ ] [ ] [ ] . very recently, two isolated cases of lassa fever have been diagnosed in london in travellers who returned to the uk from nigeria and mali [ , ] , and several cases of autochthonous crimean-congo haemorrhagic fevers have been reported in the european region (in turkey and in some states in the balkans) and in some countries within the eu (bulgaria and greece) [ , ] . no human cases of highly pathogenic influenza a (h n ) virus have occurred in europe, but two suspected cases were managed in the netherlands and belgium, and public health authorities in greece faced a pseudo-outbreak [ ] [ ] [ ] . moreover, several recent cases of cowpox infections have been reported recently in europe: confirmed cases in germany, one suspected case in the netherlands, five confirmed and seven suspected cases in france. although human cowpoxvirus infections are not classified as hid, these cases are worth mentioning here as an example of how an unexpected agent can disseminate rapidly. some of the cases described above were proven to be caused by the same virus, indicating exposure to a common source of infection related to an international trade in pet rats by a czech rat breeder [ ] . two cases of human infection with an orthopoxvirus, similar to but distinct from cowpox, have been identified in north-eastern italy in two veterinary doctors who had been exposed to infected cats [ ] . this finding, and the fact that the two infections occurred independently of one another, underscore the need to enhance awareness of zoonotic poxvirus transmission (possibly endemic) also in regions where this problem has not been addressed so far, e.g. the southern alps. almost all of the cases requiring isolation were first admitted to a general hospital without adequate isolation capabilities, and later transferred to a high-level isolation unit. despite the fact that no outbreaks occurred in europe, these experiences exposed weaknesses in terms of recognition, public health response, and diagnostic and clinical management. indeed, despite the wide availability of national and international plans and guidelines, their application in 'real-life' scenarios remains poor. not surprisingly, public health policies and diagnostic and clinical approaches to hids differ widely among european countries, and a common platform that would enable scientists to respond in a quick and powerful manner is still lacking. hids require multidisciplinary expertise. experts in microbiology (especially virology), public health, epidemiology, infectious diseases, and communication need to work together to respond to such incidents. for hids in particular, because of the rarity of their occurrence, strong collaboration and exchange of data, and attention to lessons learned from previous episodes, are advisable. for these reasons, creating new networks and enhancing those functioning well should be strongly promoted, in order to: ensure a rapid and effective response to health threats deriving from natural infection by or deliberate release of hid agents; stimulate complementarity and prevent duplication; promote international cooperation, exchange of experience, good practice and protocols; support the less prepared countries in the european community. a continuous effort is necessary for sustaining and promoting research on hids, whether basic or translational, in order to promote the increase of general knowledge concerning on these issues and to support the development of new tools for facing them in an effective manner. the development and refinement of new diagnostic tests, new therapeutics and innovative vaccines is mandatory as never before. the use of networking and international partnership could represent the successful strategy in this context. the traditional boundaries between basic science and clinical medicine should be dropped, and through effective networks the few hid events that occur worldwide should be studied thoroughly. a network of top-quality scientists and clinicians will provide the complementarity required for the development of these new approaches. moreover, improved funding for research on hids could come from the involvement of networks in the private sector, which could be encouraged to invest in this area because of the epidemic potential and the possible large-scale economic consequences. early recognition and prompt reaction to hids rest upon adequate preparedness, which should include the availability of adequate infrastructures and specific training for healthcare workers. several differences exist among european countries, due to government policies, as well as to pre-existing conditions, and these may result in delayed and dissimilar public health interventions and non-standardized training programmes. a better coordination of public health approaches to hids may lead to standardization of interventions and protocols, such as the prompt isolation within structures with adequate technical and logistic features, to the development of a common core-curriculum, and substantial improvement in the application of international health regulations. moreover, from a practical perspective, a network involving the main public health institutes may play a key role in the management of: a returning hid patient travelling through more than one country (e.g. in the case of one or more connecting flights), in order to coordinate public health interventions; an hid patient admitted in a country without adequate healthcare settings for isolation (in this case, a cross-border transport by ground or air may be the most appropriate solution); multi-country outbreaks. due to the current perceived international security threats, several eu member states are considering establishing biosafety level (bsl)- diagnostic facilities. to improve and sustain the existing initiatives and networks aimed at promoting collaboration among the existing bsl- laboratories appears mandatory, as well as to provide assistance, through these networks, to other european countries not equipped with such sophisticated and costly facilities [ ] . moreover, among the critical points identified in the context of the laboratory diagnosis of hid agents are the scarcity of biological samples to validate the diagnostic methods and the fact that few commercial diagnostic tests are available for these pathogens. thus, a well-functioning network is essential for: the sharing of diagnostic and research experience of the currently operating bsl- european laboratories, as well as diagnostic protocols, samples, reagents, and personnel for training; the review of current laboratory diagnostic capability for hid agents; the development of new hazard-free diagnostic tests suitable to be transferred to other non-bsl- laboratories; the standardization of procedures for biosafety and biosecurity. intra-hospital procedures for clinical assistance and infection control for hid cases represent 'the core' of managing these diseases, and represent effective measures for hid containment. on the other hand, hospitals may play an important role in the amplification of an outbreak if infection control measures are inconsistently applied. consequently, common protocols for infection control and biosafety during the clinical and diagnostic management of hids patients, based on the available evidence and on 'reallife' experiences, are strongly advisable [ ] [ ] [ ] [ ] . moreover, in order to offer to these patients the best available standards of care, a set of specific skills is required, and thus, given the scarcity of these events, a functioning network for expert consultation, second opinion, and scientific support is needed. as more and more persons, animals and goods move within europe, the need for improved and coordinated responses to hids continues to grow. furthermore, it is increasingly recognized that hids can pose a significant threat to each country's national security. innovative research and coordinated efforts, through the establishment of well-functioning networks, are the only way to deal with these issues, in order to improve preparedness and to react quickly: in short, to be 'prepared for the unknown'. a key role may be played by the european centre for disease prevention and control, whose mission is, among others, to 'coordinate the european networking of bodies operating in the fields within the centre's mission' [ ] . uncoordinated measures can lead to only partial and poor responses, and different approaches to similar health threats in various eu countries are likely to negatively affect the compliance by health professionals, and the perception of the population. although well-functioning networks are already in place, many gaps still exist, as well as opportunities for future collaboration. fortunately, new scientific developments, and new perceptions of these health threats, make this field one of the most stimulating research areas with a direct impact on the health of millions of people. global trends in emerging infectious diseases climate change and infectious disease: a dangerous liaison? european lab network prepares for high-risk pathogen threat world health organisation: geneva infectious diseases and national security how prepared is europe for pandemic influenza? analysis of national plans challenges remain in preparedness european centre for disease prevention and control gouvras g task force on biological and chemical agent threats, public health directorate, european commission, luxembourg. bichat clinical guidelines for bioterrorist agents european commission quality assurance for the diagnostics of viral diseases to enhance the emergency preparedness in europe no authors listed e-alert july: case of lassa fever imported into germany from sierra leone marburg hemorrhagic fever -the netherlands ex uganda a fatal case of lassa fever in london the first case of lassa fever imported from mali to the united kingdom crimean-congo hemorrhagic fever in greece: a public health perspective probable cases of crimean-congohaemorrhagic fever in bulgaria: a preliminary report management of potential human cases of influenza a/h n : lessons from belgium a dutch case of atypical pneumonia after culling of h n positive ducks in bavaria was found infected with chlamydophila psittaci a pseudo-outbreak of human a/h n infections in greece and its public health implications european centre for disease prevention and control. cowpox in germany and france related to rodent pets cat-to-human orthopoxvirus transmission, northeastern italy networking for infectious-disease emergencies in europe risk management of febrile respiratory illness in emergency departments the initial hospital response to an epidemic framework for the design and operation of highlevel isolation units: consensus of the european network of infectious diseases infection control in the management of highly pathogenic infectious diseases: consensus statement from the european network for infectious diseases the authors wish to thank c. schmaltz (european commission, research directorate general, brussels) for the data about eu-funded research projects, and for his invaluable suggestions and critical reading of the manuscript. all authors declare no dual or conflicting interests. key: cord- -frlc authors: sanchez-lorenzo, a.; vaquero-martinez, j.; calbo, j.; wild, m.; santurtun, a.; lopez-bustins, j.-a.; vaquero, j.-m.; folini, d.; anton, m. title: anomalous atmospheric circulation favored the spread of covid- in europe date: - - journal: nan doi: . / . . . sha: doc_id: cord_uid: frlc the current pandemic caused by the coronavirus sars-cov- is having negative health, social and economic consequences worldwide. in europe, the pandemic started to develop strongly at the end of february and beginning of march . it has subsequently spread over the continent, with special virulence in northern italy and inland spain. in this study we show that an unusual persistent anticyclonic situation prevailing in southwestern europe during february (i.e. anomalously strong positive phase of the north atlantic and arctic oscillations) could have resulted in favorable conditions, in terms of air temperature and humidity, in italy and spain for a quicker spread of the virus compared with the rest of the european countries. it seems plausible that the strong atmospheric stability and associated dry conditions that dominated in these regions may have favored the virus's propagation, by short-range droplet transmission as well as likely by long-range aerosol (airborne) transmission. the world is currently undergoing a pandemic associated with the severe acute respiratory syndrome coronavirus (sars-cov- ), which is a new coronavirus first noticed in late in the hubei province, china , . the virus has a probable bat , respiratory virus infections can be transmitted via direct and indirect contact, or by means of particles (droplets or aerosols) emitted after a cough or sneeze or during conversation by an infected person. the large particles (> μm diameter) are referred to as respiratory droplets and tend to settle down quickly on the ground, usually within one meter of distance. the small particles (< μm in diameter) are referred to as droplet nuclei and are related to an airborne transmission. these particles can remain suspended in the air for longer periods of time and can reach a longer distance from the origin . these small aerosol particles are inhalable and can penetrate all the way down to the alveolar space in the lungs , where cell receptors for some infectious respiratory viruses are located, including . 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 preprint this version posted may , . . https://doi.org/ . / . . . doi: medrxiv preprint the angiotensin converting enzyme ii (ace ) used by sars-cov- to infect the individual . airborne transmission has been suggested to play a key role in some diseases like tuberculosis or measles, and even in coronaviruses [ ] [ ] [ ] . a recent study has described that the sars-cov- virus can remain viable at least up to hours in airborne conditions . respiratory droplets and aerosols loaded with pathogens can reach distances up to - meters under some specific conditions such as a turbulence gas cloud emitted after a cough of an infected person . a study performed in wuhan, the capital of the hubei province, has shown that the sars-cov- virus could be found in several health care institutions, as well as in some crowded public areas of the city. it also highlights a potential resuspension of the infectious aerosols from the floors or other hard surfaces with the walking and movement of people . another study has also shown evidence of potential airborne transmission in a health care institution . recent studies have pointed out a main role of temperature and humidity in the spread of covid- . warm conditions and wet atmospheres tend to reduce the transmission of the disease [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] . for example, it has also been pointed out that the main first outbreaks worldwide occurred during periods with temperatures around - ºc, never falling below ºc, and specific humidity of - g/kg aproximately . the first major outbreak in europe was reported in northern italy in late february . following that, several major cases have been reported in spain, switzerland and france in early march, with a subsequent spread over many parts of europe. at present ( th march ) italy and spain are still the two main contributors of cases and deaths in the . 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) the copyright holder for this preprint this version posted may , . . https://doi.org/ . / . . . doi: medrxiv preprint continent, with major health, political and socio-economic implications. the main hypothesis of this work is that the atmospheric circulation pattern in february has helped to shape the spatial pattern of the outbreak of the disease in europe. the main atmospheric circulation pattern during february was characterized by an anomalous anticyclonic system over the western mediterranean basin, centered between spain and italy, and lower pressures over northern europe centered over the northern sea and iceland ( figure , figure s ). this spatial configuration represents the well-known north atlantic oscillation (nao) , in its positive phase, which is the teleconnection pattern linked to dry conditions in southern europe whereas the opposite occurs in northern europe . figure s show maps for february for several meteorological fields that provide clear evidence of the stable atmospheric circulation in southern europe, with a tendency towards very dry (i.e., lack of precipitation) and calm conditions. as suggested in an earlier analysis , the sars-cov- virus seems to be transmitted most effectively in dry conditions with daily mean air temperatures between around ºc and ºc, which are the conditions shown in figure for the major part of italy and spain. by contrast, northern europe has experienced mainly wet and windy conditions due to an anomalous strong westerly circulation that is linked to rainy conditions. these spatial patterns fit with the well-known climate features associated over europe during positive phases of the nao . the arctic oscillation (ao), which is a teleconnection pattern very much linked to nao, . 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) the copyright holder for this preprint this version posted may , . we argue that this spatial configuration of the atmospheric circulation might have played a key role in the modulation of the early spread of the covid- outbreaks over europe. it is known that some cases were reported already in mid-january in france, with subsequent cases in germany and other countries . thus, the sars-cov- virus was already in europe in early , but it may only have started to extend rapidly when suitable atmospheric conditions for its spread were reached. it is possible that these proper conditions were met in february, mainly in italy and spain, due to the anticyclonic conditions previously mentioned. the link between the covid- spread and atmospheric circulation has been tested as follows. we have extracted the monthly anomalies of sea level pressure (slp) and hpa geopotential height for february over each grid point of the capitals of the european countries ( figure s ) with the highest number of covid- cases reported so far (see data and methods). figure (top) shows that there is a statistically significant . 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 preprint this version posted may , . . https://doi.org/ . / . . . doi: medrxiv preprint (r = . , p< . ) second order polynomial fit between the anomalies of the hpa and the total cases per population. italy, spain, and switzerland, which are the only countries with more than , cases/million inhabitants in our dataset, clustered together in regions with very large positive anomalies of hpa geopotential heights. for the total number of deaths the fit is also statistically significant for a second order polynomial regression (r = . , p< . ), and it shows clearly how italy and spain are out of scale compared to the rest of the european countries. similar results are obtained using slp fields (not shown). these results evidence that it seems plausible that the positive phase of the nao, and the atmospheric conditions associated with it, provided optimal conditions for the spread of the covid- in southern countries like spain and italy, where both the start and the most severe impacts of the outbreak in europe were located. to test this hypothesis further we have also analyzed the covid- and meteorological data within spain (see data and methods, figure s ). the results show that mean temperature and specific humidity variables have the strong relation with covid and fit with an exponential function ( figure ). they indicate that lower mean temperatures (i.e., average of around - ºc) and lower specific humidity (e.g., < g/kg) conditions are related to a higher number of cases and deaths in spain. nevertheless, it is worth mentioning that both meteorological variables are highly correlated (r = . , p< . ) and are not independent of each other. the temperatures as low as - ºc are only reached in a few regions such as madrid, navarra, la rioja, aragon, castille and leon and castilla-la mancha. these areas are mainly located in inland spain where drier conditions were reported the weeks before the outbreak. the rest of spain experienced higher temperatures and consequently were out of the areas . 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 preprint this version posted may , . . https://doi.org/ . / . . . doi: medrxiv preprint of higher potential for the spread of the virus, as reported so far in the literature [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] . in addition, higher levels of humidity also limit the impact of the disease, and therefore the coastal areas seem to benefit from lower rates of infection. thus, in the southern regions of spain (all of them with more than ºc and higher levels of specific humidity) we found lower rates of infection and deceases. this is in line with the spatial pattern in italy, with the most (least) affected regions by covid- mainly located in the north (south). in contrast, when the whole of europe is considered on a country by country basis (see above and figure ), we find the opposite, a clear gradient with more severity from north to south as commented previously. the spatial pattern of covid- described above has some intriguing resemblances with the influenza pandemic, which is the latest deadly pandemic in modern history of europe. the excess-mortality rates across europe in the flu also showed a clear northsouth gradient, with a higher mortality in southern european countries (i.e., portugal, spain or italy) as compared to northern regions, an aspect that is not explained by socio-economic or health factors . in spain, a south-north gradient is also reported in the flu after controlling for demographic factors . the central and northern regions of spain experienced higher rates of mortality, and this has been suggested to be linked to more favorable climate conditions for influenza transmission as compared to the southern regions . interestingly, the slp anomalies of the months before the major wave of this pandemic (which occurred in october-november ) shows a clear south-north dipole with positive anomalies in southern europe centered over the mediterranean, and negative ones in northern europe ( figure s ). in other words, the nao was also in its positive phase just before the major outbreak of the influenza pandemic. this resembles the spatial . 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 preprint this version posted may , . . https://doi.org/ . / . . . doi: medrxiv preprint patterns described above for the current covid- outbreak, both in terms of the spatial distribution of the mortality of the pandemic over europe as well as in prevailing atmospheric circulation conditions before the major outbreak. these intriguing coincidences need further research in order to better understand the spatial and temporal distribution of large respiratory-origin pandemics over europe. taking into account these results, we claim that the major initial outbreaks of covid- in 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 , . although the outbreak of a pandemic is controlled by a high number of biological, health, political, social, economic and environmental factors, with complex and non-linear interrelationships between them, the results of this study indicate that an anomalous atmospheric circulation may explain why the covid- outbreak in europe developed more easily (or faster) in the south-west (mainly north of italy and inland of spain). specifically, the extreme positive phase of the ao and nao during february could have modulated the beginning of the major outbreaks of covid- in europe. this detected anomalous atmospheric pattern, which produces dry conditions over southwestern europe, may have provided optimal meteorological conditions for the virus propagation. in the context of anthropogenic climate change, it has been shown that in future emissions scenarios a poleward expansion of the hadley cell is expected , which in turn is in line with a tendency to increase the frequency of positive phases of the nao ( figure s ). this should be taken into account for planning against future epidemics and pandemics that arise from respiratory viruses. interestingly, the conditions during the last major pandemic experienced in europe (the spanish flu in ), seem to resemble the current spatial pattern of affectation with more cases in the south of europe as compared to the north. equally, the dominant atmospheric situation was strongly affected by anticyclonic (cyclonic) conditions in the south (north) 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. the copyright holder for this preprint this version posted may , . . 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 preprint this version posted may , . . 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. the copyright holder for this preprint this version posted may , . . 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 preprint this version posted may , . . 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 preprint this version posted may , . ncep/ncar , era and era c atmospheric data are used in this manuscript. the maps and data have been retrieved by using the tools and websites referenced in the main text, and more details about the spatial and temporal resolution, vertical levels, assimilation schemes, etc. can be consulted in their references. in brief, an atmospheric reanalysis like those used here is a climate data assimilation project which aims to assimilate historical atmospheric observational data spanning an extended period, using a single consistent assimilation scheme throughout, with the aim of providing continuous gridded data for the whole globe. the artic oscillation (ao) index has been extracted from the climate prediction center of the national oceanic and atmospheric administration (noaa). the ao index is constructed by projecting the daily hpa height anomalies poleward of °n onto the loading pattern of the ao, this latter being defined as the leading mode of empirical orthogonal function (eof) analysis of monthly mean hpa height. more details and data: https://www.cpc.ncep.noaa.gov/products/precip/cwlink/daily_ao_index/ao.shtml. covid- data on country basis were obtained on march th , from the website https://www.worldometers.info/coronavirus/, which it is mainly based on the data provided by the coronavirus covid- global cases by the center for systems science and engineering (csse) at the johns hopkins university. data from spain on regional scale . 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 preprint this version posted may , . we have extracted the monthly anomalies of sea level pressure (slp) and hpa geopotential height for february over each grid point of the capitals of the european countries. we have selected the slp and hpa fields in order to summarize the meteorological conditions over each location, as it is known that several meteorological variables can be involved in the transmission of respiratory viruses , . with this approach we also avoid the lack of properly updated data for all potential meteorological variables involved in the covid- spread, which needs further research as soon as the pandemic ends and a more reliable and complete database of both covid- impact and meteorological data can be compiled . for spain, several meteorological variables with high-quality records were obtained from the spanish meteorology agency (aemet) based on surface observations for each of the capital cities of the provinces inside each autonomous region. specifically, monthly averages for february of -m temperature, -m maximum temperature, -m minimum temperature (°c), air pressure (hpa), wind speed (km h − ), specific humidity (g kg - ), relative humidity (%), total precipitation (mm) and days of more than mm of precipitation. an arithmetic average has been calculated for the autonomous regions with more than one province. we have checked coupled model intercomparison project phase (cmip ) simulations for two future scenarios (rcp . and rcp . ) at the end of the th century. . 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) the copyright holder for this preprint this version posted may , . . 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) the copyright holder for this preprint this version posted may , . . https://doi.org/ . / . . . doi: medrxiv preprint clinical features of patients infected with novel coronavirus in wuhan , china a pneumonia outbreak associated with a new coronavirus of probable bat origin identifying sars-cov- related coronaviruses in malayan pangolins the role of particle size in aerosolised pathogen transmission : a review covid- ): how covid- spreads recognition of aerosol transmission of infectious agents : a commentary evidence of airborne transmission of the severe acute respiratory syndrome virus aerosol and surface stability of sars-cov- as compared with sars-cov- turbulent gas clouds and respiratory pathogen emissions: potential implications for reducing transmission of covid- aerodynamic characteristics and rna concentration of sars-cov- aerosol in wuhan hospitals during covid- outbreak transmission potential of sars-cov- in viral shedding observed at the university of the role of absolute humidity on transmission rates of the covid- outbreak role of temperature and humidity in the modulation of the doubling time of covid- cases. under rev the ncep / ncar -year reanalysis project era : fifth generation of ecmwf atmospheric reanalyses of the global climate influenza virus transmission is dependent on relative humidity and temperature the effects of weather and climate on the seasonality of influenza: what we know and what we need to know . 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 preprint this version posted may , . . 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)the copyright holder for this preprint this version posted may , . . https://doi.org/ . / . . . doi: medrxiv preprint key: cord- -ogb xg authors: palomino, juan c.; rodríguez, juan g.; sebastian, raquel title: wage inequality and poverty effects of lockdown and social distancing in europe date: - - journal: eur econ rev doi: . /j.euroecorev. . sha: doc_id: cord_uid: ogb xg social distancing and lockdown measures taken to contain the spread of covid- may have distributional economic costs beyond the contraction of gdp. here we evaluate the capacity of individuals to work under a lockdown based on a lockdown working ability index which considers their teleworking capacity and whether their occupation is essential or closed. our analysis reveals substantial and uneven potential wage losses across the distribution all around europe and we consistently find that both poverty and wage inequality rise in all european countries. under four different scenarios ( months of lockdown and months of lockdown plus months of partial functioning of closed occupations at %, % and % of full capacity) we estimate for european countries an average increase in the headcount poverty index that goes from . to . percentage points and a mean loss rate for poor workers between % and . %. the average increase in the gini coefficient ranges between . % to . % depending on the scenario considered. decomposing overall wage inequality in europe, we find that lockdown and social distance measures produce a double process of divergence: both inequality within and between countries increase. the dramatic and unprecedented intensity of the shock due to the covid- pandemic has highlighted the importance of measuring the economic consequences of "social distancing". the lockdown measures implemented in many countries around the world will likely have a significant negative impact on their gdp. thus, the global economy is expected to shrink by % this year. asia will not have economic growth for the first time in years, the economies of the us and europe are projected to contract between % and % (imf, ) , and the global job losses are estimated to be over million (ilo, ) . however, the effect of the pandemic will not only take place at the aggregate level and is likely to have distributional implications (furceri et al., ) . the social distancing imposed by governments to limit the spread of the pandemic has caused an asymmetric effect on the labour market: discounting essential occupations like health services and food sales, only the jobs not closed by the lockdown that can be done from home ("teleworkable") will be not impeded. this asymmetry of the supply shock implies that the economic costs of social distancing could be significant, not only in terms of negative gdp growth rates but also in terms of higher wage inequality and poverty rates. in this paper, we analyse the potential effects of social distancing on wage inequality and poverty in absence of any compensating public policy across europe. recent studies have provided estimates of the supply shock caused by the emergency regulation imposed to contain the spread of covid- (dingel and neiman, ; hicks, ) . they have evaluated the possible economic consequences of social distancing -without considering the subsequent effects that may occur on the demand side-by calculating to what extent occupations can be performed from home (teleworking). mongey et al. ( ) find that workers with less ability to work from home have been indeed more unable to follow the 'stay at home advice' -using geolocation data-and that they have suffered higher unemployment increases. studies focused on the demand side have shown that, due to fear of infection, economic activity dropped and individuals changed their consumption habits even before lockdown was formally imposed (goolsbee and syverson, ) . in a more comprehensive analysis, del rio-chanona et al. ( ) provide quantitative predictions of supply and demand shocks associated with the covid- pandemic. these studies, mainly focused on the u.s. economy, have analysed the consequences of social distancing in the job market, at the occupation and industry levels, without delving into the study of poverty and inequality. we find two exceptions. first, irlacher and koch ( ) obtain a substantial wage premium (higher than %) in a mincer regression for german workers performing their job from home, and a lower share of teleworkable occupations in poorer german regions. second, brunori et al. ( ) study the short-term effects that two months of lockdown have had on the italian income distribution. by using a static microsimulation model, they find a non-negligible increase of poverty and inequality in italy. to estimate the impact of social distancing on wage inequality and poverty across europe, we concentrate on the legal restrictions (supply side) due to the closure of non-essential occupations and workers not being able to perform their activities at home during the lockdown period. additionally, we consider a range of scenarios with further partial closures of certain activities, caused by mandatory capacity limitations and by the change in individual consumption habits to prevent contagion. despite its relevance, our analysis does not consider additional indirect effects in supply (as shortages propagate through supply chains) and in demand (when the loss of labour income for some workers further reduces consumption). these effects are difficult to estimate at this early stage, and the legal and voluntary restrictions imposed to prevent the spread of the pandemic already provide a clear framework to study the consequences for inequality and poverty of having a particular productive structure. under a lockdown, the asymmetry of the restrictions may affect economies in a different way just because their productive structure is not the same: countries who are specialised in outdoor and non-essential activities like tourism will, in principle, suffer more from the lockdown and the capacity limitations. we thus restrict ourselves to measuring the potential impact on wage inequality and poverty of enforced and voluntary social distancing. in general, if occupations with higher wages are more teleworkable, we should observe an increase in wage inequality due to lockdown and the implementation of social distance measures within each country analysed. however, whether this happens, and the intensity of this change, will depend on the structure of the economy and the extent of essential and closed occupations under the lockdown. the wide set of european countries in our sample -with a variety of productive structures-will also allow us to test if different productive structures imply different potential effects on wage inequality and poverty under lockdown and social distancing. note that if that is the case, inequality would not only increase within countries, but also between nations, which could exacerbate the problem of cohesion in europe. the first step to measure the changes in wage inequality and poverty across europe due to lockdown is to calculate the index of teleworking at the occupational level. dingel and neiman ( ) found that percent of jobs in the united states can be done entirely from home. what is the share of occupations that allow teleworking in europe? following these authors, we use fifteen questions from the occupational information network (o*net) database such as, 'is the work done outdoors?' or, 'does it require significant physical activity?' to calculate the probability of teleworking for each occupation. we then use the european union labour force survey (eu-lfs) occupational structure to translate these probabilities into the european context. finally, we match the eu-lfs occupation teleworking index and the european union statistics on income and living conditions (eu-silc), which provides detailed information on wage at the individual level. after this process, we have for every worker in the eu-silc database the individual index of teleworking (according to her occupation) and the wage. a lockdown implies that some activities -like healthcare or food chain related jobs-will become essential while others will be closed. when the occupation is essential, workers will be not affected by lockdown regardless of their capacity to work from home. when a certain economic activity is closed -like hospitality-working is not at all possible. for the remaining economic activities, only teleworking is allowed. consequently, during the lockdown we need to adjust our index of teleworking for the workers whose occupation is essential or closed, to obtain an individual measure that summarizes the capacity of each worker to keep active under the lockdown. we will call this measure lockdown working ability (lwa) index. the next step is to estimate the wage loss due to the lockdown. because not all workers are able to perform their job at home and some activities are closed or limited (or less demanded to avoid infection), there are potential wage reductions for a significant part of the labour force. to simulate these wage losses, we consider four possible scenarios: two months of lockdown and two months of lockdown plus six months of only partial functioning of the closed activities at %, % and % of capacity. in addition, we consider in appendix e another three scenarios where partial functioning of closed occupations −at %, % and % of full capacity− lasts for nine months. with these proposals we intend to measure not only the effect of the lockdown, but also the impact of the de-escalation period imposed to contain the spread of covid- . although each european country may have followed slightly different lockdown and deescalation strategies, the core of the social distancing enforcing policies has been similar in most of them. for that reason, and to ensure that in our analysis differences across countries are mainly due to their productive structure, we simulate the same scenarios for all european countries. the last step is to measure the changes in wage inequality and poverty across countries, and the variation of wage inequality between and within-countries due to the lockdown. for this task, we first compute the lockdown incidence curve (lic), which represents the relative change in the wage of individuals ordered by centiles, and the related changes in the mean 'growth' rate of the poor (ravallion and chen, ) and headcount poverty index. then, we use the gini coefficient and the mean logarithmic deviation (mld) to calculate the changes in wage inequality. the first measure is a popular index of inequality which is widely used in the literature, while the second measure fulfils some properties which are necessary for our analysis of inequality decomposition. in particular, the mld is the only inequality index that is additively decomposable into a between-group and a within-group component (bourguignon, ; shorrocks, ) and has a path-independent decomposition (foster and shneyerov, ) . our results show that poverty increases for the headcount index and the mean loss rate of the poor in all countries for all simulations, although these changes vary greatly with the country and simulation under consideration. for the four simulated scenarios, we estimate for european countries an average increase in the headcount poverty index that goes from . to . percentage points and a mean loss rate for the poor that goes from % to . %. likewise, wage inequality increases for the gini coefficient in all countries for all simulations. for example, the average increase in the gini coefficient varies between . % and . % for europe as a whole. we thus find that poverty and inequality changes are sizeable in all countries and they increase with the duration of the lockdown. when we decompose overall inequality in europe, both within countries and between countries inequality increase, producing a double process of divergence in wage inequality in europe. but this increase in wage dispersion is not symmetric, and the within-countries inequality component increases more than the betweencountries inequality component. thus, the increase in the within-countries inequality component ranges from . % to . %, while the change in the between-countries inequality component goes from . % to . %, depending on the scenario under consideration. the observed increases in poverty and inequality are in general greater in eastern and southern countries than central and northern countries and are inversely related to the lwa index. to further understand these differences across european countries we need to analyse separately the three components of the lwa index: teleworking and essentiality (which increase the working ability of occupations during the lockdown), and closure (which implies a lower working ability during the lockdown and subsequent de-escalation periods). we observe that the occupational and industry structure of eastern european countries presents, in general, medium average levels of closure, but low average levels of essentiality and teleworking. on the contrary, northern and central european countries show large values of essentiality and teleworking, and low average levels of closure. meanwhile, workers in southern european countries have medium average levels of essentiality, rather low levels of teleworking and, especially, the highest average levels of closure, due to the large preponderance in their productive sector of activities that imply the agglomeration of large groups of people like recreation or hospitality. the rest of the paper is structured as follows. in section we present the lwa index and the methodology applied to calculate the wage losses and changes in inequality and poverty. in section we highlight the main results obtained for europe. finally, section concludes. to analyse the working ability of individuals during the lockdown, we need first to estimate occupational teleworking. for this task we use three different databases (see appendix a). first, we make use of teleworking information acquired using key attributes and characteristics of occupations from the american o*net database (dingel and neiman ) . second, we use the latest wave of eu-lfs ( release) -with detailed employment and occupational information for european countries-to accurately obtain occupational teleworking information for the european occupational categories. finally, this information is combined with the rich socioeconomic data -crucially, salaries-from the wave of eu-silc ( release). this strategy, which is explained in detail in appendix a, allows us to calculate the teleworking capacity of european workers. however, teleworking capacity is not the only determinant of workers ability to effectively work and keep their wage during the lockdown period. we need to consider that some having calculated the teleworking index and identified the essential and closed occupations, we construct the lockdown working ability (lwa) index. this measure summarizes the capacity of individuals to work under a lockdown taking into account not only the value of their occupation's teleworking index, but also if such occupation is essential ( ) or closed ( ). the central idea is that workers in essential occupations can work during the lockdown regardless of whether the occupation can be teleworked or not. on the contrary, workers in closed activities cannot work at all to the extent that their overall activity has been closed. in all remaining cases, working capacity will depend on the share of that occupation that can be teleworked. formally, the first step in constructing the lwa index requires to split the population of workers into three groups according to the occupation of each worker ∈ { , , … , }. if the individual has an occupation that is neither essential nor closed, the value of her index will be equal to the value of her index of teleworking, ∈ [ , ]. if the person has an essential job ( = ), we will compute the lwa index as is the essentiality score given to the occupation of the individual. thus, for partially essential occupations ( < < ), the non-essential share of the occupation ( − ) can work during lockdown only to the extent that it is teleworkable. finally, if the person has a job that is closed ( = ), we will calculate the lwa index as = ( − ) , where ∈ ( , ] is the close score given to the closed occupation of the individual. in partially closed occupations ( < < ), the non-closed share of the occupation ( − ) can work to the extend that is teleworkable. in summary, the lockdown working ability index is calculated as follows: for all ∈ { , , … , }. as shown in figure , the average lwa index varies significantly across european countries: our lwa index varies significantly not only by countries but also by gender, type of contract −permanent or temporary−, type of work −full or part time−, and level of education (see table ). according to their lwa index, women jobs are less affected by social distancing than men jobs in all european countries. interestingly, the biggest difference between both sexes is found in the nordic countries: norway ( points), denmark ( points the next step is to calculate the potential wage loss due to the lockdown for every individual in the population. following the facts observed in europe during the pandemic, we adopt four possible scenarios. as a lower bound, we assume a simple scenario: two months of lockdown (case i). here we suppose that occupations can be developed at full capacity ( %) after the lockdown. next, we assume two months of lockdown and six months of partial functioning of closed occupations at % (case ii), % (case iii) and % (case iv) of full capacity. the rationale for these scenarios is that governments may not allow a fully functioning of closed occupations after the lockdown to avoid a new outbreak of the virus and that individuals may voluntarily choose to stay home, which reduces their consumption, to avoid infection (goolsbee and syverson, ) . for example, some activities like arts, entertainment, recreation, restaurant, hotel and transportation are still under a large negative shock in production and consumption. consequently, to be more informative we have adopted a range of capacity constraints that goes from % to % of full capacity for a period of six months. in addition, given the uncertainty about the duration of legal and voluntary restrictions, in appendix d we have further replicated our results for another three scenarios where partial functioning of closed occupations −at %, % and % of full capacity− lasts for nine months instead of six. we simulate the same scenarios for all countries so that differences across countries are mainly due to their distinct productive structures, isolating our analysis from the influence of particular mitigation measures adopted by each european government. using the lwa index, we calculate the wage loss ( ) experienced by every individual during the lockdown according to the four simulated scenarios described. for the first case (i) the equation we estimate is the following: where − is the annual wage of individual in period − (before the lockdown) and represents the duration of the lockdown in annual terms, i.e., = . because measures the capacity of individual to work under a lockdown, the term − represents the incapacity of worker to perform their job under a lockdown. consequently, the wage loss the duration of the lockdown in many european countries has been approximately of two months. for example, the lockdown went from the rd of february to the th of may in italy, from the th of march to the th of may in spain, and from the th of march to the th of may in france. for these activities chetty et al. ( ) have found, as of july th , a decrease in spending compared to the pre-lockdown levels in the range of between . % and . % in the us. based on weekly credit card expenditure data, bbva research ( ) has found, as of july th , a negative interannual growth rate for these spending groups ranging between % and % in spain. experienced by workers under a lockdown is the proportion of annual wage they lose due to their inability to work during the shutdown period. for the cases (ii), (iii) and (iv) we apply the same equation ( ) unless the individual has a closed occupation, in which case, we need to additionally consider the wage loss due to the partial closure of %, % or % of their occupation for six (or nine) additional months. for these scenarios the relevant equation is: where = { = ≠ is the indicator function, represents the duration of the partial closure ( or ), and is the proportion of closure ( . for case (ii), . for case (iii) and . for case (iv)). to give the intuition of expressions ( ) and ( ), we provide an example. suppose we are interested in calculating the wage loss for three workers with different occupations under a lockdown of months and a posterior partial closure of some activities of % (keeping % of capacity) for months. the first worker is a physician, the second works as a clerk and the third one is a waiter. their pre-lockdown ( − ) annual salaries are − , − and − , respectively. the occupation of the first worker is essential with = so we apply equation ( ) to calculate her wage loss: = − · · = , i.e., the doctor does not lose earnings during the pandemic. the second worker has an administrative occupation that in our example is neither essential nor closed so her index is equal to the value of her index of teleworking, for example, . . then, according to equation ( ) her wage loss will be = − · · ( − . ) = − · . . finally, the occupation of the third worker is closed with = so the value of her index is . in this case, we apply equation ( ) closely related to the lic we have the mean loss rate for the poor, a measure that reveals the average wage loss for workers below the poverty line. let ( ) denote the headcount index defined as the proportion of workers whose salary is less than , where is the poverty line (set at % of the median wage). then, the mean loss rate for the poor ( ) is defined as the area under the lic up to the headcount index divided by the headcount measure, which can be expressed as: when < for all < ( ) one can conclude that the lockdown was poverty-augmenting. in addition to representing the lics for the set of european countries and compute the above unfortunately, the gini index is not additively decomposable into a between-group and a within-group component. its decomposition includes also a residual term which cannot be assigned to either component. for this reason, we use the mld index in the last part of our analysis, where we decompose the overall estimated change of inequality in europe into its between-countries and within-countries components. the mld belongs to the generalized entropy class, which is the only class of inequality indices that is additively decomposable into a between-group and a within-group component (bourguignon, and shorrocks, ) . moreover, the mld has a path-independent decomposition, so the result of the decomposition is independent of which component (between-group or within-group) is eliminated first (foster and shneyerov, ) . the mld ( ) is defined as: where is n-coordinated vector of ones. expression ( ) provides a breakdown of overall wage inequality into between-group and within-group terms. the between-group component ( , , … , ) is the level of wage inequality that would arise if each worker in a country enjoys the mean wage of the country, and the within-group component ∑ ( ) = is the weighted sum of wage inequalities within different countries. how large are the wage losses experienced by workers during the lockdown? are they evenly distributed? a visual approximation to the wage loss across the wage distribution can be achieved by looking at the lic curves. in figure we represent the lics for some european countries under two months of lockdown (case i). we highlight the lic for two extreme cases, romania, and cyprus, where the main wage losses take place at the upper and lower part of the wage distribution ( figure , panel a) and for germany, the uk and france (figure , panel b) , where wage losses tend to decrease with the percentile that the worker occupies. in our two-month lockdown scenario, wage losses are already sizeable and can be superior to % at some parts of the distribution in some countries, varying significantly with the centile of the workers. also, we find that the shape of the distribution of wage losses is similar for the rest of scenarios and the main difference lies only in the larger size of the wage drops. we formally capture the potential impact of social distancing on poverty with two measures: the mean loss rate for the poor ( ) and the changes in the headcount poverty index ( ). table (columns to ) shows the values of for the four simulations under consideration, which indicate that the lockdown is poverty-augmenting in the four scenarios for all european countries. under the most conservative scenario, a two-month lockdown, we find a mean loss rate for the poor of % for europe on average. if we consider an additional -month period of partial functioning of closed activities at % of full capacity (scenario iv), the mean loss rate for poor workers in europe increases up to % ( % if the period of partial functioning lasts for nine months). by countries, the highest loss rate for the poor is found in cyprus (between . % and . %), while the smallest one happens in romania (between . % and . %). the share of workers under the poverty line also increases significantly for the four simulated cases in all european countries (see table , columns - ). for europe on average, this increase varies between . percentage points under two months of lockdown and . percentage points if we consider an additional six months during which closed activities are partially functioning at %. these values imply that −in absence of compensating policies− the percentage of poor people in europe (those with earnings below % of the pre-lockdown median in the country) may substantially increase even if lockdown does not last long. if closed the contribution of growth and redistribution to poverty reduction over the period to in countries, including europe, is estimated in bluhm et al. ( ) . the relationship between the components of social mobility (growth, dispersion and exchange mobility) and inequality is estimated for countries of the european union in prieto et al. ( ) . the headcount poverty index gives additional relevant information about the consequences of the pandemic for poverty since this index is not necessarily consistent with the lic (essama-nssah and lambert, ). eastern and southern countries than central and northern countries. thus, we find that the highest increase in poverty according to the headcount poverty index is in croatia (between . and . points). on the contrary, the smallest percentage increase in poverty according to the headcount index happens in switzerland for case i ( . points) and denmark for cases ii ( . points), iii ( . points) and iv ( . points). if we look at the relationship between these changes in the headcount poverty index and the average lwa we find a negative correlation with = . for the first scenario ( figure , panel a) and = . for the fourth scenario ( figure c , panel a, in appendix c). when we consider the gini of lwa within countries instead of the average lwa the correlation becomes positive with = . for the first scenario (figure panel b) and = . for the fourth scenario ( figure c , panel b, in appendix c). the uneven distribution of potential wage losses across the distribution is prone to have an impact on wage inequality as well. european countries already have important differences in pre-lockdown inequality (table , pre-lockdown wage inequality ( = . ) . other countries with low levels of inequality before the lockdown are sweden, czechia, belgium and norway, all of them with a gini index slightly below . . on the other extreme of the spectrum, we find the countries with the highest level of pre-lockdown wage inequality: bulgaria, ireland, the uk and spain, all of them with a gini index above . . when comparing wage inequality after the lockdown with the baseline, it is observed that absolute and relative changes in inequality are sizeable and increase in all countries with the duration of the partial closure of some activities (table ) . for example, the relative increase of the gini coefficient, at scenario (i), ranges from . % (the netherlands) to . % (cyprus). at the more severe scenario (iv), relative increases in inequality range from . % in france to . % in cyprus (if the period of partial functioning lasts nine months these rates become % in france and % in cyprus). a scrutiny of the absolute changes in the gini coefficient −which makes the change scale independent of the previous level of inequality− reveals that cyprus is again the european country where inequality increases the most for the four simulation cases (between . and . gini points) followed by ireland (between . and . points). on the other hand, the smallest absolute change in inequality is found in norway ( . points) for scenario (i), in norway and france for scenarios (ii) ( . points) and (iii) ( . points), and in france and denmark for scenario (iv) ( . points). these variations in inequality also tend to be related with the lwa index. in figure given the link between the values of the lwa index and the increases in wage inequality (and poverty), it is not surprising that the observed changes are in general greater in eastern and southern countries than central and northern countries. as mentioned before, northern and central europe present large average levels of essentiality and teleworking, and low average levels of closure. meanwhile, eastern europe shows the opposite pattern, i.e., low average levels of essentiality and teleworking, and medium-high average levels of closure. the partial closure of activities that imply the agglomeration of large groups of people like tourism significantly penalises southern europe, whose countries tend to have the highest average closure scores. while some tertiary jobs like administrative, programmers and accountants are not affected by partial closures, others are strongly impacted by the measures to fight covid- and the fears to table . wage inequality changes in europe. note: cl , cl and cl refer to partial closure for months at %, % and % of full capacity, m is months, and ∆ a g and ∆ r g are the absolute and relative changes in the gini index. bootstrapped standard errors are in parenthesis. be infected: hospitality, restaurants, arts and entertainment. for this reason, the impact on inequality and poverty is also related to the share of these specific tertiary occupations. our findings show an increase in inequality for all european countries but, would inequality changes be different enough to increase inequality between countries? the answer is yes, although they are smaller than the inequality changes occurring within countries. in table we show the results of the decomposition of wage inequality for all european workers. our simulations show an increase in overall inequality in workers' salary of . % in europe ( . to . ) according to the mld index under a lockdown of two months. for the same scenario, the changes in the between-and within-countries inequality components are . % (from . to . ) and . % (from . to . ), respectively. for two months of lockdown and six months of partial functioning of closed activities at % of capacity (scenario iv) we find the following increases in inequality for europe on average: . % in overall inequality, . % in between-countries inequality and . % in within-countries inequality. when the period of partial functioning of closed activities at % of capacity lasts nine months the corresponding increases are: . % in total inequality, . % in between-countries inequality and . % in within-countries inequality. both components of overall inequality increase, but the within-countries inequality component increases significantly more than the between-countries inequality component in all scenarios. that is, cohesion between european countries decreases with the lockdown, though the main change in wage inequality happens within european countries. with the partial closure of some activities, changes get larger and the double process of wage divergence (between and within countries) deepens. the emergency measures adopted to contain the spread of covid- all around the world are largely based on social distancing and closure of high-risk productive activities. the paralysis of production imposed by the contention measures during the lockdown and the capacity limitations driven by official restrictions and by consumers precautionary behaviour will thus have an uneven impact on workers from different occupations and industries. our analysis reveals a sizable potential increase in poverty and inequality across europe. table . the between-and within-countries inequality components in europe. note: ∆ a is the absolute change in wage inequality and ∆ r (%) is the relative change in wage inequality. standard errors are in parenthesis. poverty will increase under our simulations in all countries. under the most conservative scenario, a lockdown of two months, we estimate a mean loss rate for the poor of % and an increase in the headcount index of . percentage points on average in europe, with the change ranging from . points (switzerland) to . points (croatia). likewise, wage inequality increases under a lockdown of two months, being the change in the gini coefficient equal to . % for europe on average, with changes ranging between . % (netherlands) and . % (cyprus). considering a more severe scenario with months of partial closure at % of full capacity after a two-month lockdown, we estimate a mean loss rate of . % for the poor workers in overall europe, a rise of . percentage points in the headcount poverty index and a gini increase of . % on average for europe. our results also highlight that lockdown measures are likely to worsen cohesion in europe both between countries and, especially, within countries. our simulations show that between-countries inequality will increase in europe between . % and . %, while within-countries inequality will increase between . % and . %. in general, we find a greater increase of both poverty and inequality in eastern and southern europe than in northern and central europe. workers tend to have a lower and more unequally distributed ability to work under the shutdown and social distancing in the economies of eastern and southern europe than in the northern and central european countries. these differences across european areas get larger with the severity of the measures to fight and prevent covid- infection. impacto de la covid- sobre el consumo en españa en tiempo real y alta definición poverty accounting decomposable income inequality measures distant and unequal. lockdown and inequalities in italy how did covid- stabilization policies affect spending and employment? a new realtime economic tracker based on private sector data supply and demand shocks in the covid- pandemic: an industry and occupation perspective how many jobs can be done at home? tax progression and inequality of income distribution measuring pro-poorness: a unifying approach with new results path independent inequality measures will covid- affect inequality? evidence from past pandemics decreto-legge febbraio , n. . retrieve at: www fear, lockdown, and diversion: comparing drivers of pandemic economic decline occupational exposure to social distancing: a preliminary analysis using o*net data ilo monitor nd edition: covid- and the world of work world economic outlook update working from home, wages, and regional inequality in the light of covid- what is pro-poor growth poverty equivalent growth rate which workers bear the burden of social distancing policies? a study on the relationship between economic inequality and mobility measuring pro-poor growth global inequality when unequal countries create unequal people the class of additively decomposable inequality measures an economic definition of poverty an axiomatic characterization of the watts index key: cord- -bgcqkz p authors: yamamoto, naoki; bauer, georg title: apparent difference in fatalities between central europe and east asia due to sars-cov- and covid- : four hypotheses for possible explanation date: - - journal: med hypotheses doi: . /j.mehy. . sha: doc_id: cord_uid: bgcqkz p the comparison of the numbers of cases and deaths due to sars-cov- / covid- shows that people in central europe are much more affected than people in east asia where the disease originally occurred. trying to explain this difference, this communication presents four hypotheses that propose the following reasons for the observed findings: ) differences in social behaviors and cultures of people in the two regions; ) possible outbreak of virulent viruses in central europe due to multiple viral infection, and the involvement of immuno-virological factors associated with it, ) possibility of corona resistance gene mutation occurring among east asians as a result of long-term co-evolution of virus and host, and ) possible involvement of hygienic factors. direct or indirect supportive evidences for each one of our hypotheses are presented and experimental approaches for their evaluation are discussed. finally, we suggest that the dynamics of the pandemic also shows that the problems of the new coronavirus can be overcome due to people's awareness of the epidemics, rational viral diagnostics and a high level of medical care. the new coronavirus sars-cov- , causing an infectious disease named covid- has caused a major pandemic with more than million people infected and more than , already dead [ , ] . its momentum is disrupting the economy, society, and healthcare systems, filling hospitals with patients, emptying public spaces, and drawing people away from work and friends. due to the test strategy used in nearly all countries, "people infected with sars-cov- " or simply named "covid- cases" are usually people with clinical symptoms or contacts to infected people. the number of infected people without clinical symptoms is therefore unknown. further testing, including antibody tests, will most likely reveal that much more people around the world have been infected than the number of defined cases of covid- . this may upset modern societies on a scale never seen before. on the other side, it may be assumed that these infected people might contribute to herd immunity and slow down further spread of the virus, provided their antibody response is longer lasting and has neutralizing potential. these aspects need further experimentation and proof. in the st century, information (including scientific and technological knowhow) circulates around the world instantly. the world has entered an era where the traffic of people, economic goods, money, but also viruses and other microbes seems to be nearly unlimited. therefore, after the outbreak of the new coronavirus epidemics in china, the transport of the virus to other parts of the world, particularly to europe, was fast and efficient. of particular note is the striking difference in the extent of medical impact caused by sars-cov- in eastern asia versus central europe [ , ] . this difference is prominent, when i) the number of infected persons with clinical symptoms, ii) the ratio between infected people with clinical symptoms and the total population of the countries, iii) the number of deaths, or iv) the death ratios of infected people with symptoms are compared between eastern asia and central europe. in this communication, we compared selected countries from central europe and east asia with respect to the medical impact of sars-cov- and covid- . based on this analysis, we propose four hypotheses that might explain the observed differences. for each one of these hypotheses, we present direct or indirect evidences to support them. none of these hypotheses by itself can explain the observed differences. rather, the mechanisms defined in individual hypotheses seem to interact and thus cause the overall effect observed. we are aware that additional mechanisms, not covered by our analysis, may also contribute to the pandemics. for the analysis of the difference regarding the number of infected people and the death tolls due to covid- between central european and east asian countries, we have chosen italy, spain, france, germany and uk from central europe and china, south korea, japan, and taiwan from south east asia. mongolia and north korea were excluded, since not sufficient information was available from both countries. for comparison, the united states, which have the highest number of infected and dead people due to covid- , were included into our analysis. table first shows the populations and gdps, in order to help estimating the scale, medical level, and affluence scale of the selected countries. it is obvious that east asia is one of the most densely populated areas in the world. it can also be seen that there is not much difference with respect of the gdps, except for china. however, china's gdp has grown rather rapidly in recent years, and it is certain that it will reach the economic level of the other countries sooner or later. european countries ranged from to per million people, whereas those of east asian countries were in the range of ~ . the ratio between the two was about . these numbers depend on the number of tests performed in individual countries, as well as on differences in the test strategy, resulting in a certain degree of uncertainty. to get a more precise picture of comparison, covid- -related deaths per nation's total population (per million people) were calculated based on the total population of each country. as seen in table , the numbers of central european countries were in the range of - deaths/million people, with the only exception being germany's lower number of . in contrast, deaths/million people in east asian countries were in the range of . - , i. e. they were nearly times lower than the values found for central european countries. importantly, also the death rate of infected people seems to be much lower in east asian countries, compared to the central european countries (except germany). the relatively lower number of infected people as well as covid- -associated deaths in germany seems to be due to strong differences in the percentage of infected people with clinical symptoms between the south and north of germany (table ) . it seems that measures taken after the first cases in bavaria (a large state in the south east of germany, which was first hit by the pandemics) were successful to prevent a strong spreading on the long run. germany had the advantage to be affected by covid- later than china and italy. getting valuable information from other countries was essential for slowing down and partially restricting the pandemics in germany. furthermore, the relatively high availability of equipment for intensive care reduced the death rate of infected people. importantly, the picture of inhomogenous distribution of the disease and associated deaths as seen for the whole of germany is also seen when the spreading of infections and deaths is analyzed within bavaria, the state being affected the most ( table ). the detailed analysis of cases and deaths in districts points to hotspots of infection and death, from which the neighbouring areas seem to be reached out. this results in an overall picture with a relatively high number of cases and deaths in the hotspot (tirschenreuth) that far exceeds the average number of cases / population and deaths / population of total germany. the immediate neighbouring districts in the north and south show about half the cases / population and less than half the deaths / population than the hotspot, whereas districts distant of the hotspot are characterized much lower numbers. this picture points to strong initial effects from local infection events, but, importantly, it also indicates that further spreading had obviously been prevented through adequate measures. since the data on the number of covid- -caused deaths in each country gave reliable data that showed strong differences between east asian and central european countries, we tried to explain these differences by four intercalated hypotheses. given the host-virus relationship, it is necessary to consider factors affecting both virulence of the pathogens and the resistance of the hosts to virus infection. several aspects might be involved in the difference. for example, lippi et al. investigated potential reasons for the noticeable difference in covid- -associated mortality rates between asian and european populations from clinical and demographic aspects in italy versus china [ ] . these authors confirmed that a higher burden of comorbidities, male sex, and older age may be considered substantial determinants of enhanced risk of death in italy compared to china. similarly, in new york city where the highest number of deaths is recorded compared to other states in the united states, factors such as high population density, the possible super spreaders of virus, the degree of poverty between races, and the lack of insurance have become important issues [ ] . hypothesis # is based on the difference in social behavior and customs of people in each area, i.e. in europe and south east asia. this might explain the difference to some extent. when comparing the lifestyles of european countries with that of asia, the first noticeable difference is the closeness of direct human contact. in asia, bowing is the mainstream greeting, and even with the spread of western culture, shaking hands is still not very common. of course, besides handshaking, there can be no hugs or kisses that are popular in western culture (if any, those are performed only after building a very close relationship). it is easy to imagine that these common actions in western societies help to spread respiratory viruses like sars-cov- very efficiently. these differences between europeans and asians, considered from a perspective of the social science might be very important in the progress of the pandemic. there is also a marked difference in obesity between westerners and asians, mainly due to differences in food culture. in addition, people wear shoes indoors in western societies, while it is strictly forbidden to do so in east asia. although the weight of this habit in preventing virus infection is not clear at this moment, this difference indicates that asians very clearly distinguish between outdoor and indoor in daily life. the habit of wearing a mask in case of a cold or fear of it also seems quite asian-specific. thus, it is very likely that differences with respect to these actions play an important role in the spread of infection. social distancing has been proven to avoiding new corona infections, and is a drug-free means of controlling de novo infections. shaking hands, kissing, and hugging are not allowed during social distancing. in favour of our hypothesis # , the switch from european style of close contact to the asian style during social distancing is regarded as an essential part of successful slowing down and preventing further infections with sars-cov- . potential effects of repeated infection on the severity of the clinical outcome, contributions of antibody-mediated enhancement of infection to the severity of disease, as well as genetic changes of the virus due to mutation of its rna genome might be underlying the observed effects. in italy, the death toll from the new coronavirus was , by the april , the third highest in the world after the united states and spain. of these, more than , people were confirmed to be infected among medical staff. this finding shows that inadequate protection of medical staff from infection is a major issue. many of the doctors who died were practitioners. they were fighting the new coronavirus without adequate protective equipment (sometimes due to unavailability of material) or underestimation of the contagiousity of the new virus, driven by the strong wish to help their patients. thus, it is highly likely, especially during the medical collapse, that these doctors will have got infections repeatedly from the infected patients one after another. so the question is what would be severe disease [ ] . mice developed higher viral loads, more severe lung pathology, and greater inflammatory responses and generated only limited influenza a virus-specific b and t cell responses. although several pathways could contribute to higher viral loads in mice that received influenza a virus repeatedly, the authors suggested the possibility that the inflammatory response elicited by the first dose of influenza a virus damaged the mucosal barrier, thus allowing the virus given as a second or third dose to penetrate more deeply into the lungs. higher viral loads will lead to the induction of stronger cytokine storms. these data are in agreement with clinical findings in humans, where high-risk individuals were exposed to multiple small doses of hbv, as well as in the woodchuck model, in which animals were repeatedly exposed to small quantities of infectious hbv [ ] . in both cases, viral infection was molecularly evident and there were detectable virus-specific cd -t cell responses but undetectable virus-specific antibody responses. as to repeated infections, another possibility is also considered that is involvement of the antibody-dependent enhancement (ade), which is a well-known phenomenon in the field of viral immunology. first, let's assume the situation of the individual who received a coronavirus infection followed by a second one. one week or so after initial infection, antibodies against the virus are elicited, and the second virus reacts with this antibody causing more serious effects. this phenomenon to increase viral infectivity and virulence has been observed with many viruses including several coronaviruses, hiv, zika virus and mosquito-borne flaviviruses (dengue virus and yellow fever virus). indeed, olsen and colleagues have shown antibody enhancement of infection with one of the animal coronaviruses, feline infectious peritonitis virus by a subset of specific monoclonal antibodies, especially those directed against specific sites on the spike protein [ ] . similarly, wang et al. generated monoclonal antibodies against sars-cov spike proteins and found that these antibodies promoted sars-cov infection [ ] . ade these aspects may be particulary relevant for a limited number of people such as medical staff. therefore, in addition to that, the emergence of more virulent virus due to mutation of the virus during the course of superinfection might also be assumed. rna viruses are, in general, highly susceptible to mutations, and the base substitution rate, which indicates the degree of change, is estimated to be + x - nucleotide substitutions per site and per year on average in case of transmissible gastroenteritis virus (tgev), an enteropathogenic coronavirus. this rate falls in the range reported for other rna viruses [ ] . in addition, it is also known that coronavirus changes considerably easily due to gene recombination or part of gene loss (deletion). for example, the new strain of canine respiratory coronavirus identified in is reported to be a recombinant of the existing canine and bovine coronaviruses [ ] . in addition, it has been known that the deletion of part of the spike gene has caused the emergence of a prcv from the ancestral porcine gastroenteritis virus [ ] . it is possible that the doctor who actually examined many infected patients could be exposed to the coronavirus repeatedly, and among the multiple virus strains infected, more virulent virus strains suitable for spread may be selected and prevailed, at least initially. according to the classical models of virulence evolution of the virus, multiple infections select for raised virulence. to explain why so many people are dying of covid- in new york city, sequence analysis of the viral genome has been performed. according to zimmer, the virus mainly came from asia through a small number of infected individuals in california, while in new york, more than people initially brought the virus mainly from europe, suggesting as if the european type viruses are more virulent in its pathogenicity and infectivity than the asian type [ ] . a number of studies have supported that through collective actions leading to common good production and immune system impairment, viral cooperation can lead to increased levels of virulence. researchers around the world have already infecting vero-e cells [ ] . based on more molecular virological studies, tan et al. proposed that sars-cov- can be divided into two major lineages (l and s). intriguingly, the s and l lineages can be clearly defined by just two tightly linked snps at positions , (orf ab: t c, synonymous) and , (orf : c t, s l). orf ab encoding replicase/transcriptase is essential for viral genome replication and might also be important for viral pathogenesis [ ] . however, there was no evidence so far that this mutation produced a more virulent form of the virus. moreover, the data examined up to now are still very limited, and follow-up analyses of a larger set of data are needed to have a better understanding of the evolution and epidemiology of sars-cov- . thus, further virological studies must focus on the relationship between differences in nucleotide sequences and infectivity/ pathogenicity of viruses since there is no firm evidence, so far, of the existence of european strains of the coronavirus or its pathogenicity being more virulent than the asian strains. human hosts and their virus have co-evolved for millions of years, during which viruses have adapted to defense system of its host by regulating pathogenic mechanisms. therefore, the possible genetic change and resulted selection of people living in east asia should also be considered from an evolutional perspective. thus, the difference in viral susceptibility and mortality of east asian people to sars-cov- could also be explained if people living in east asia may have evolved to be more resistant to viral infections, including those of novel corona viruses. in east asia, especially in china, agriculture started about , years ago, maybe , years ahead of europe. this led to an explosive increase in population, urbanization, and population density with the supply of abundant food. as a matter of course, acute viral infections such as measles, rubella, mumps, which could not be established until then, are believed to have taken roots in the human population (in the case of measles, it requires a population more than , to settle). unlike today, asia had long been much richer than europe before the industrial revolution. under the over-crowded and chaotic conditions, east asians must have experienced overwhelmingly with many plagues including several zoonoses due to the encounter with strange animal species. it is natural to consider that such epidemics are related to the change, choice, and evolution of the people who live there. east asians may have evolved to become more resistant against infectious agents in general including coronavirus. it is possible that difference of the past plagues could contribute to a difference in the susceptibility (and thus, pathogenicity) between europeans and asians against present new corona. present covid- is apparently derived from bats directly or via vector animals, and its appearance is closely related to chinese food culture. given this, it is not strange to consider the possibility that this area had been hit by coronavirus infections similar to this time before long ago. in fact, the country experienced similar endemics, sars and mers only and years ago, respectively. this suggests that coronavirus infection itself is one of the most likely candidates for east asian selection and evolution among the past plagues. although humans are a fairly homogeneous group of species as viewed from the genome, the diversity of the genome is well maintained. it avoids all human species from suffering the same disease and is a means of survival as a species, even if some disease prevails. although plague and people have been closely linked, one of the causes of human diversity is infectious disease. many genetic diseases are unfavorable to survival, but in some cases they are also advantageous for survival, and in some cases mutations have given the power to survive from the diseases that have hit the ground in the past. in east asia, where agriculture was established early on and urbanization has been achieved, plagues have been rushing to people in a messy environment since ancient times. we believe that it should be worth considering that individuals with advantageous gene mutations have been selected in relation to various epidemics, and have reached the present day. several genes may be involved in the genetic predisposition to covid- , and the combination of multiple genes may be important for the severity of the infection. among them, human leukocyte antigen (hla) polymorphisms are associated with susceptibility to various diseases such as autoimmune diseases and infectious diseases. the composition ratio of hla types varies greatly depending on the country and ethnic group. since hla is a protein of the immune system that is responsible for antigen presentation, hla has been attracting attention in relation to disease susceptibility. ellinghaus and colleagues performed gwas on patients in italy and spain [ ] . but, it was found that certain hla types are unlikely to be associated with exacerbation of the novel coronavirus at least in italy and spain. nevertheless, since hla types, which are present only in japan and other asian countries, may show resistance to the novel coronavirus, further analysis is necessary. the human angiotensin-converting enzyme (ace ) gene on chromosome has an insertion (i) or deletion (d) of a base pair (bp) alu repeat sequence in intron [ ] . therefore, in the i/d polymorphism, there are three different genotypes, ii, id and dd. ace is a metalloproteinase, which is a type i transmembrane glycoprotein. this protein plays an important regulatory function in the renin-angiotensin-aldosterone system (raas) and can convert angiotensin i (angi) vasoconstrictor, which is inactive, to angiotensin ii (angii). angii is the core product of the raas system, and causes various biological reactions through the angiotensin receptors (at and at ) while ace (angiotensin invertase ) is a homologue of ace and is well known as a receptor for sars-cov- . however, the original role of ace is to digest angii into ang - polypeptides, and protect the heart, vasodilate, resist growth, and resist proliferation. also, the activity of bradykinin can be enhanced by ace . very recently, we showed a strong negative correlation that the numbers of sars-cov- infected cases and deaths due to viral infection decreased with increasing ace ii genotype frequency [ ] . the serum ace level was significantly higher in those with the dd genotype compared with those with either the id or the ii genotype [ ] , and viral infection may lead to suppression of ace function and causes ace /ace imbalance responsible for ras over-activation and pulmonary shut-down [ ] . this can further reduce the effects of ace , which counteracts the pathophysiological effects of ang ii produced by ace , and may worsen the pathology. in patients with the d allele, especially those with the dd genotype, higher risk of morbidity and mortality from sepsis, acute respiratory distress syndrome (ards) and certain heart, lung and kidney conditions probably due to inflammation, vasculopathy and coagulopathy induced by angii [ ] is reported. thus, the ace /ace imbalance predicts that covid- patients with the d allele of ace , especially the dd genotype, have a higher severity and prevalence of covid- . further evidence for our hypothesis is provided by results obtained through the study of other viral systems. there are a few lucky people who have escaped infection while being exposed to hiv- . individuals homozygous for ccr -Δ show perfect resistance to hiv- [ ] . infection with yersinia pestis or smallpox virus were suggested as potential selective pressures favoring ccr -Δ [ ] . only european or central asians have this characteristic and in norway, ccr -Δ allele frequencies reaches nearly %. since aids, smallpox and plague are, by nature, independent infectious diseases that should be completely unrelated, it is very intriguing if these infectious diseases are linked by this mutant gene. indeed, in , lalani et al. showed that poxviruses, can exploit chemokine receptors, especially ccr to infect some cell types, notably migratory leukocytes [ ] . this further suggests a need searching for polymorphism and virological studies to see if there is a difference in the function of the ace gene as a sars-cov- entry receptor between asians and europeans. besides, several other examples are available in the resistance to certain type infections and genetic mutations. relationship between sickle cell anemia and malaria is well known [ ] . although less dramatic, it is speculated that the relationship between typhoid fever and cystic fibrosis, which is a recessive genetic disease commonly found in europeans, is similar. there is also information regarding the relationship between human abo blood type and disease, while ab type is strong against cholera and o type is resistant to tuberculosis [ ] . however, our hypothesis suffers from the lack of analogous data available in other viral infections. in other words, if this theory is relevant, we should realize earlier that there is a difference in susceptibility and pathogenicity between western and asian people even in the case of other viral infections before this corona pandemic. still, it is not impossible to explain with a claim that there was no report from the past because there was no appropriate viral pandemic involving europe and east asia in the past. if there is, it may be the spanish flu occurred at the beginning of the last century or some influenzas after that. however, in the case of spanish flu, it was before the identification of the influenza virus, and it was a special event taking place towards the end of world war i in europe, so it is quite difficult to compare the difference in the pathogenicity of the influenza virus in both areas. or is the new coronavirus indeed the first case to show such ethnic differences in terms of pathogenicity? it is hoped that this point will be answered when data in the comparative studies on new coronavirus infections in the united states, where many european and asian immigrants live, will be accumulated in the very near future. in relation to this natural selection of human traits about viral resistance, there are also some records on the relationship between hygienic condition and resistance to infectious diseases. it is generally accepted that asia used to have a denser human population and to have lower hygienic conditions than europe. is corona's low pathogenicity for east asians not related to the situation of asia being less-hygienic than in europe? a similar paradoxical seeming suggestion has been raised for childhood leukemia: the more often a child is infected during the first year of life, the less likely it seems to develop leukemia. epidemiological studies performed by kinlen [ ] , and greaves and wiemels [ ] separately showed that high socioeconomic status and lack of contact with multiple infections early in life could be a risk factor. based on these observations, zur hausen and de villiers made the following proposal by assuming the existence of a fairly universal lesser-known tumor virus such as ttv. many viral infections during pregnancy and perinatal have a negative effect on the persistence and increase of this oncovirus. intermittent viral infections, by inducing interferon, significantly reduce tumor virus load and reduce the risk of viral chromosomal alterations, prerequisites for malignant transformation [ ] . very recently, katoh et al. reported a possible association between lower rate of fatality induced by coronavirus and immunization rate against encephalitis [ ] . artificial vaccines against japanese encephalitis (je) may result in relatively lower mortality rate in some countries. je immunization is widespread or included in national programs in many asian countries including china, south korea, japan, and taiwan. in all of these countries, the fatality rate due to covid- is very low when compared with countries that don't immunize against je. also, a similar hypothesis has been proposed that the inoculation of bcg vaccine may be effective against infectious diseases caused by the new coronavirus [ ] . it is thus very intriguing to find out the reason why recipients are cross-protected against covid- conferring lower fatality rate in the countries where immunization is performed against some infectious diseases such as encephalitis or tuberculosis. it will be important to explore the underlying mechanism, such as whether this can be explained by mere nonspecific activation of immunity. as the aspect of nonspecific activation of immunity is considered as one possible mechanism that counteracts sars-cov- infection as well as the death rate of infected patients, it might seem worthwhile to ask the question whether the lower rate of infection and mortality due to sars-cov- in germany, compared to other european countries, might be connected to differences in vaccination coverages. unfortunately, such an analysis is difficult and has severe inherent limitations, as there is a very high degree of variability of vaccination coverage in germany with respect to age, sex and geography [ ] . this does not allow to consider germany as one entity, but rather would require to focus on many different regions and groups, for which it seems difficult to obtain the required complete set of data. however, when the influence vaccination coverage for risk groups is compared between european countries [ ] germany is only on place among -certainly not in favour for a more advanced immunization profile of the country. furthermore, the analysis of the national vaccination calendars of france, united kingdom, italy, spain, sweden, portugal and germany [ ] shows a large overlap of essential immunizations in these countries -a finding that is not in favour of assuming a specific aspect of immunization in germany that might have a particular negative impact on sars-cov- infections and disease. there is no doubt that central europe is much more affected by sars-cov- and covid- than east asia. the strong difference between east asia and central europe cannot be explained by eventual differences in the frequency of testing, as this would only affect the number of detected cases per inhabitants, but not the number of deaths. we are convinced that the behavioral difference in human contact in both areas of the world can be considered to have a very important influence on the spread of the sars-cov- , as seen by the impressive positive effect of social distancing on the control of covid- in europe. this shows that hypothesis # seems to be relevant to a significant degree for the differences between east asia and central europe. however, hypothesis # cannot explain the complete picture observed, as it would only have an impact on the number of cases in relation to the population, but not on the death rate of cases. as the death rates per cases are also lower in east asia compared to central europe, mechanisms suggested in hypothesis # - might also contribute to the overall effect. in addition, mechanisms not included into our hypothesis might play essential roles and await to be defined in the future. essential parts of our hypotheses for which we have no direct supportive information so far can be experimentally verified or falsified in the future. these so far unresolved aspects are i) the possible existence of more virulent strains of sars-cov- in europe, ii) the effects of repeated infections, possibly in combination with iii) ade, iv) polymorphism of ace or some other genes such as tmprss [ ] and ace [ , ] , and their relation to the function of viral receptor. covid- positive cases are already over . million even at this point in total while number of people infected with sars coronavirus- was only about , . considering its near-future expansion in developing areas such as africa and south america, the new coronavirus may reach an even stronger impact than sars-cov- . moreover, this coronavirus is very easy to mutate due to its original properties. taking these facts into account, this sars-cov- has the potential to persist in every corner of the world, has a great possibility of finding and adapting to the best environment in various climates and people's lives, and becoming established in human society. however, the pandemics have taught us some essentials for counteracting in the future. at the beginning of the outbreak of covid- in europe, the initial response, especially the delay in response to outbreaks (clusters), demographics, social behavior and lower testing capacity, etc. were sometimes very problematic in response to covid- . these experiences allowed states that were hit later by the pandemics, like germany, to adjust countermeasures. in germany, the federal and local governments have been involved in the fight against covid- from an early stage, and especially with an emphasis on looking for signs of early onset, pcr testing of very large numbers of samples for free, and isolation of defined cases. the medical system had time to be prepared and intensive care beds equipped with artificial respirators were reserved for covid- and increased in number. the needed specialized staff was trained. social distancing guidelines were introduced and widely followed. this resulted in slow-down of the pandemic. therefore, we can be confident, that even if european corona strains were more virulent than asian strains, or if europeans were more susceptible to coronaviruses, the authors declare no conflict of interest. world health organization. naming the coronavirus disease (covid- ) and the virus that causes it covid- : what is next for public health? who scientific and technical advisory group for infectious hazards clinical and demographic characteristics of patients dying from covid- in italy versus china why are so many people dying of covid- repeated low-dose influenza virus infection causes severe disease in mice: a model for vaccine evaluation repeated exposure to trace amounts of woodchuck hepadnavirus induces molecularly evident infection and virus-specific t cell response in the absence of serological infection markers and hepatitis monoclonal antibodies to the spike protein of feline infectious peritonitis virus mediate antibody-dependent enhancement of infection of feline macrophages antibody-dependent sars coronavirus infection is mediated by antibodies against spike proteins genetic evolution and tropism of transmissible gastroenteritis coronaviruses discovery of a novel canine respiratory coronavirus support genetic recombination among betacoronavirus complete genomic sequence of human coronavirus oc : molecular clock analysis suggests a relatively recent zoonotic coronavirus transmission event most new york coronavirus cases came from europe, genomes show. the new york times patient-derived mutations impact pathogenicity of sars-cov- on the origin and continuing evolution of sars-cov- . national science review genomewide association study of severe covid- with respiratory failure online ahead of print sequence variation in the human angiotensin converting enzyme sars-cov- infections and covid- mortalities strongly correlate with ace i/d genotype an insertion/deletion polymorphism in the angiotensin i-converting enzyme gene accounting for half the variance of serum enzyme levels covid- and individual genetic susceptibility/receptivity: role of ace /ace might the double x-chromosome in females be protective against sars-cov- compared to the single x-chromosome in male? implications of the angiotensin converting enzyme gene insertion/deletion polymorphism in health and disease: a snapshot review homozygous defect in hiv- coreceptor accounts for resistance of some multiply-exposed individuals to hiv- infection evaluating plague and smallpox as historical selective pressures for the ccr -delta hiv resistance allele use of chemokine receptors by poxviruses sickle cell disease and malaria morbidity: a tale with two tails blood type biochemistry and human disease epidemiological evidence of an infectious basis for childhood leukaemia origins of chromosome translocations in childhood leukaemias virus target cell conditioning model to explain some epidemiologic characteristics of childhood leukemias and lymphomas cross-protection induced by encephalitis vaccines against covid- might be a reason for relatively lower mortality rate in some countries is bcg vaccination causally related to reduced covid- mortality? online ahead of print vaccination coverage in german adults influenza vaccination coverage among high risk groups of european countries how much money is spent on vaccination across western european countries sars-cov- cell entry depends on ace and tmprss and is blocked by a clinically proven potease inhibitor covid- infections are also affected by human ace d/i polymorphism the data show that the two most southern states, bavaria and baden-württemberg have much more cases of covid- and covid- -related deaths (both in absolute numbers and per people) than the two northern states within bavaria, there are very strong differences between tirschenreuth (one of the hotspots of covid- in germany, located in the north east of bavaria on the border to the czech republic) and its directly neighbouring districts wunsiedel compared to districts that are more distant to the hotspot (oberallgäu in the north west corner, main-spessart in the south west corner and regensburg in the center of bavaria). taken together, these data show the high efficiency of sars-cov- for spreading from a site of initial infection, but also the efficiency of adequate countermeasures taken the authors state no conflict of interests. key: cord- -b y n authors: de zwart, onno; veldhuijzen, irene k.; elam, gillian; aro, arja r.; abraham, thomas; bishop, george d.; voeten, hélène a. c. m.; richardus, jan hendrik; brug, johannes title: perceived threat, risk perception, and efficacy beliefs related to sars and other (emerging) infectious diseases: results of an international survey date: - - journal: int j behav med doi: . /s - - - sha: doc_id: cord_uid: b y n purpose: to study the levels of perceived threat, perceived severity, perceived vulnerability, response efficacy, and self-efficacy for severe acute respiratory syndrome (sars) and eight other diseases in five european and three asian countries. method: a computer-assisted phone survey was conducted among , respondents. the questionnaire focused on perceived threat, vulnerability, severity, response efficacy, and self-efficacy related to sars and eight other diseases. results: perceived threat of sars in case of an outbreak in the country was higher than that of other diseases. perceived vulnerability of sars was at an intermediate level and perceived severity was high compared to other diseases. perceived threat for sars varied between countries in europe and asia with a higher perceived severity of sars in europe and a higher perceived vulnerability in asia. response efficacy and self-efficacy for sars were higher in asia compared to europe. in multiple linear regression analyses, country was strongly associated with perceived threat. conclusions: the relatively high perceived threat for sars indicates that it is seen as a public health risk and offers a basis for communication in case of an outbreak. the strong association between perceived threat and country and different regional patterns require further research. severe acute respiratory syndrome (sars) and avian influenza are two examples of recent emerging infectious diseases that may cause severe threats to population health, large economic losses, as well as fear and dread [ , ] . the behavior of the general population or specific risk groups can play an important role in both the spread and control of infectious diseases. the sars epidemic showed the impact of worldwide travel on the rapid spread of an epidemic, as well as the possible merits of strict hygiene and quarantine measures in halting that epidemic [ ] . in case of an infectious disease pandemic, public health authorities will be dependent on the willingness and ability of the general public to adhere to recommendations regarding personal hygiene, vaccination and/or prophylaxis, quarantine, travel restrictions, or closing down of public buildings such as schools [ , ] . compliance with recommended precautionary behaviors is not self-evident [ ] . specific attention to factors influencing behavioral change during outbreaks of infectious diseases is, therefore, necessary. one of the factors that may influence willingness and motivation to adopt precautionary behaviors is risk perception [ ] [ ] [ ] [ ] , i.e., the perceived personal vulnerability or likelihood of a disease or health threat. perceived vulnerability, combined with perceived severity, can be regarded as perceived threat. people are expected to have the highest perceived threat of sars if they think that an infection with sars is likely and will have serious health consequences. however, risk perception is certainly not the only determinant of protective behavior. protection motivation theory suggests that response efficacy (i.e., the extent to which people believe that available protective actions against sars are effective) and self-efficacy (i.e., the extent to which people believe they have the ability to engage in such protective actions) are two other key predictors of protection motivation [ ] . risk perceptions are often biased. unrealistic optimism about risks is often observed toward familiar risks that are perceived to be largely under volitional control. people perceive their relative risk compared to others of the same gender and age as lower. a pessimistic bias, i.e., perceptions of risk that are (much) higher than actual risk, is more likely for new risks that are perceived as uncontrollable. the latter might be the case with new emerging infectious diseases, like sars [ ] [ ] [ ] [ ] . while in some fields, such as environmental risks, risk perception has been studied intensively, not much is known about risk perception of recently emerging infectious diseases. related to emerging infections diseases, first, explorative and descriptive studies are needed to increase our insights in perceived threat, risk perception, and efficacy beliefs. such studies can inform more focused and theory-driven investigations. during and in the aftermath of sars, several of such exploration studies have been conducted, but these studies did not include international comparisons across a range of different countries. these studies showed that the risk of sars was perceived differently across the globe and was not directly linked to the proximity of the outbreak. risk perception of sars in some of the asian countries was relatively low compared to risk perception in the usa [ ] [ ] [ ] but similar to levels reported for the netherlands [ ] . one study focused on differences in psychosocial factors predicting preventive behavior in four affected regions [ ] . ji and colleagues compared optimism related to sars in china and canada and concluded that both groups demonstrated unrealistic optimism, while at the same time they were overly pessimistic about their own chances of getting infected [ ] . a limited number of studies have looked at risk perception of avian influenza with different results varying from high perceived risks to low risk perception [ ] [ ] [ ] [ ] . a dutch study showed high levels of risk perception of avian influenza in case of an outbreak and indicated that almost % of respondents had taken some sort of precautionary measures [ ] . there are few international comparative studies that analyze differences in perceived threat, risk perception, and efficacy beliefs between (infectious) diseases and conditions and differences between countries [ ] [ ] [ ] [ ] . it is generally unknown whether risk perceptions of emerging infectious diseases are perceived in similar ways across countries. because there was a large difference between how sars has affected southeast asia and europe, one might hypothesize that this would mean a higher risk perception of sars and possibly other infectious diseases in countries in southeast asia. if international differences in risk perceptions of sars exist, the question is whether such differences are specific for sars, whether we see the same for risk perception of avian influenza (as most cases have also occurred in southeast asia), or whether they may indicate a more general trend in risk perceptions. the present study explored perceived threat, risk perception, and efficacy beliefs related to sars in random samples of the population of eight countries in europe and asia. to explore if country differences were specific for sars, perceived threat, risk perception, and efficacy beliefs related to avian influenza and other (infectious) diseases were also investigated. this study had the following specific objectives: -to study levels of perceived threat, vulnerability (or risk perception), severity and comparative vulnerability for sars in denmark, the netherlands, poland, spain, the uk, china, hong kong, and singapore; -to compare perceived severity, vulnerability, and threat of sars with other diseases and conditions, i.e., avian influenza, common cold, diabetes, hiv, high blood pressure, tuberculosis, food poisoning, and a heart attack; -to study differences and associations between these factors across the eight countries and between europe and asia. because data collection for the present study took place in the autumn of , i.e., years after the sars epidemic, it was not possible to collect information on specific precautionary behaviors. furthermore, specific results on risk perception of avian influenza and related efficacy beliefs have been reported elsewhere [ ] . data were collected using computer-assisted telephone interviewing in the native languages by native speakers of each country, coordinated by a dutch company that specializes in international telephone survey research, using random digit dialing (rdd). for the asian countries, the dutch company was assisted by an asian agency. if unanswered, numbers were tried again up to five times and, when possible, call back appointments were made. interviews were conducted from september to november in eight different countries, five in europe representing regions in north, west, south, and east europe (denmark, the netherlands, great britain, spain, and poland) and three regions in east asia (singapore, province of guangdong china, and hong kong). in china, the survey was conducted in the province of guangdong. during the period of data collection, no cases of sars were reported. respondents aged to years were eligible for participation. the questionnaire was based on a previously developed sars risk perception questionnaire [ ] and focused on risk perception and severity of sars, avian influenza, and other (infectious) diseases, efficacy beliefs and use of information sources and took, on average, min to complete. the questionnaire was first developed in english, translated into dutch, and subsequently pretested in great britain and the netherlands using cognitive interviewing. further translations were made into danish, spanish, polish, mandarin, and cantonese; all translations were conducted by professional translators and checked by native speakers, including members of the project team. the questionnaire started with basic demographic questions, including urbanization and level of education (see table for categories). respondents were then presented with the following diseases or conditions: diabetes, a common cold, hiv, high blood pressure, sars, tuberculosis, heart attack, flu from a new virus, and food poisoning. these illnesses and conditions were included as these are both infectious and noninfectious diseases, some more common and familiar, and some with more serious consequences, thus giving a range of options for comparisons. for sars and flu, the respondents first received a brief explanation (for sars, "sars is a severe acute breathing related illness caused by a previously unknown virus"; for flu, "a new type of flu virus can arise from avian flu, it causes serious illness and spreads easily in the population"). respondents were then asked about: . severity ("how serious (on a scale from to ) would it be for you if you got [disease] in the next year?"); . vulnerability ("how likely do you think it is that you will develop or contract a [disease] in the next year; very unlikely ( ) to very likely ( )); . comparative vulnerability ("how likely do you think it is that you will develop or contract [disease] in the next year compared to other [women/men] of your age in [own country]; much less likely ( ) to much more likely ( )). the questionnaire continued with two questions focusing on knowledge of sars (name symptoms, whether sars is a communicable disease). for sars, flu from a new virus, and common cold, the following additional questions were included: response efficacy ["to what extent do you think people can take effective actions to prevent getting sars/flu from a new virus/common cold in case of an outbreak"; outbreak was included for sars and flu from a new virus; not at all ( ) to very much ( )]; self-efficacy ["how confident are you that you can prevent getting sars/flu from a new virus/ common cold in case of an outbreak"; not confident ( ) to very confident ( )]. the order of these three diseases was chosen randomly by the computer. the questionnaire continued with questions on use of sources of information during the sars outbreak, trust in these sources, and preferences for ways of communication during future outbreaks. respondents where then presented with scenarios and asked about possible preventive actions. results of this have been reported elsewhere [ ] . the questionnaire concluded with some general background questions on perceived general health, perceived happiness, whether respondent had been vaccinated against influenza, and about employment status, education level, and religion. (the questionnaire is available online at http://www .eur.nl/fgg/ mgz/sarscontrol/questionnaire_risk_perceptions_survey. htm.) respondents indicating they never heard about sars ( . %) were excluded from the analyses. furthermore, "don't know" answers on the questions about risk percep-tion were treated as missing values and, therefore, also excluded from the analysis. on average, . % of respondents did not know how to rate sars severity and . % could not rate their vulnerability to sars. for the different countries, mean scores and standard deviations (sd) were calculated for severity, risk perception, perceived threat (see below), and comparative vulnerability of eight different diseases or conditions. in line with the protection motivation theory, one measure was defined as "perceived threat"; it was constructed by multiplication of the measures of perceived severity (scale - ) and vulnerability (in case of an outbreak in the country for sars and flu from a new flu virus; scale - ). to make the scores comparable, the severity score was first divided by two. to normalize the skewed distribution of the new variable, a square root transformation was performed that resulted in a measure of perceived threat on a scale from (low) to (high). a sars knowledge score (scale - ) was calculated based on whether the respondent could name a symptom of sars and whether the respondent knew sars was a communicable disease. differences in background characteristics (gender, age group, area, and level of education) and risk perceptions between the samples in europe and asia were explored with chi-square tests or (paired) student's t tests, of which the p value and the effect size r are reported. an r below . indicates low effect size, . - . indicates medium effect sizes, and higher than . indicates large effect size. to test for important correlates of sars-related risk perceptions, four multiple linear hierarchical regression models were applied with perceived severity, vulnerability, threat, and comparative vulnerability as dependent variables. the independent variables were included in blocks with country (dummy coded) in the first block, sex, age, highest education, and urbanization in the second block, and the amount of information during the sars outbreak and the sars knowledge score in the last block. as we did not want to choose one country as a reference group, we ran the models by leaving out the intercept. in doing so, the regression coefficients for the countries do not represent the difference in mean compared to the reference group but the actual (corrected) mean value of the respective dependent variable. the r , a measure of the proportion of variance in the dependent variable that is explained by the independent variables in the model, is given for each hierarchical step in the models. the models were applied to the total population and the model for perceived threat was also applied to the separate countries. in the european countries, % of the numbers created by rdd were nonexistent and % of the numbers could not , , , total % participation rate --- gender male female age group - - table ). for the interviews conducted by the asian agency, no response rates are available. in total, , respondents were interviewed. data on background variables in the different participating countries are provided in table . most respondents in all countries were female ( % in the total group). european respondents were significantly older than asian respondents (p < . , r = . ). substantially more respondents in asia lived in a city, as both hong kong and singapore were included (p< . , r= . ). asian respondents were higher educated than european respondents (p< . , r= . ). sars was rated as the third most severe problem among the diseases and conditions included, hiv as the most serious problem and common cold as the least serious (see table ). compared to flu from a new flu virus, sars was rated more serious in all countries (overall= . versus . (scale - ), p< . , r= . ; country-specific test results not shown). perceived vulnerability, risk perception, for common cold was the highest, . , and for hiv the lowest, . (scale - ). for sars, the risk perception levels differed in case of an outbreak in or outside the country. it was among the highest with . in case of an outbreak in the country, while in case of an outbreak outside the country it was . (p< . , r= . ). the vulnerability for an outbreak of flu from a new flu virus was higher than for sars both in case of outbreak inside the country ( . versus . , p< . , r= . ) and outside the country ( . versus . , p< . , r= . ). this finding was true for all countries (separate test results not shown). perceived threat of sars in case of an outbreak in the country was among the highest of the diseases with a mean score of . (scale - ); perceived threat of hiv ( . ) and a common cold ( . ) were the lowest. perceived threat of sars and flu from a new flu virus in case of an outbreak were similar in most countries, but in denmark, china, and hong kong, sars was perceived more threatening than flu from a new flu virus (p< . , r= . ; p< . , r= . ; and p= . , r= . , respectively). the level of perceived threat varied across countries. perceived threat of sars was the highest in poland and the lowest in singapore. in fig. , the results of perceived threat of sars, flu from a new virus, high blood pressure, and diabetes are presented. although levels of perceived threat varied between countries, the pattern of perceived threat differences between the different diseases and conditions was the same in all countries with perceived threat of sars and avian flu being the highest and diabetes the lowest. the comparative vulnerability of sars in case of an outbreak outside the country was . (scale - ), indicating that that people thought it slightly less likely that they would contract sars compared to the average other ( table ). for flu from a new flu virus, perceived severity was higher in europe, . to . in asia (p< . , r= . ) as was perceived vulnerability, . to . (p< . , r= . ). in comparing europe to asia, there is not one pattern for all diseases, some are perceived more severe in europe (heart attack, hiv), others in asia (food poisoning, common cold) nor is there for perceived vulnerability. of the respondents in the asian countries, more than % could name symptoms of sars; this percentage was just over % in european countries. the proportion who knew sars was a communicable disease varied between % in spain and % in denmark. the mean knowledge score was . (range - ) in europe and . in asia (p< . , r= . ). self-efficacy was lower than response efficacy for both sars and a common cold in all countries, but the difference was larger for sars. both response efficacy and selfefficacy for sars were higher in the asian countries compared to the european countries (p< . , r= . and p< . , r= . , respectively; see fig. ). the regression models for perceived severity, vulnerability, threat, and comparative vulnerability for all countries combined are presented in table . country was significantly associated with perceived threat, vulnerability, severity, and comparative vulnerability. besides country, a higher perceived severity of sars was significantly associated with female gender, lower level of education, and a higher sars knowledge score. a higher perceived vulnerability for sars was significantly associated with lower level of education. all the variables that were significantly associated with severity and vulnerability were also significantly associated with perceived threat. comparative vulnerability was significantly associated with gender and amount of information. comparative vulnerability in women was lower than in men and lower in respondents that received more information about sars. the models for each outcome variable explained less than % of the variance ( table ). the proportion of the variance explained by country was higher than that for the other potential correlates in the models. analysis per country (table ) showed that perceived threat of sars was higher in respondents with lower levels of education in poland, great britain, and spain, while it was higher among the higher educated in singapore. singapore was the only country where age was independently associated with perceived threat. level of urbanization was a significant correlate in poland only with living in less urban areas associated with a lower threat. in the netherlands and denmark, perceived threat was higher in respondents who received higher amounts of information about sars, and in great britain, it was higher in respondents with a higher knowledge score. the model for the total population explained . % of variance of which . % was accounted for in a model with only the country variable (table ). in the separate models by country, the explained variance was less than % in all countries. the present study shows that perceived threat of sars in case of an outbreak in the country was higher than that of other diseases and conditions included in this study. perceived vulnerability of sars was at an intermediate level compared to other diseases while perceived severity was high. perceived threat for sars varied between countries in europe and asia with perceived severity higher in europe and perceived vulnerability higher in asia. perceptions of vulnerability compared to other people for sars was relatively small and comparable to other diseases. response efficacy and self-efficacy for sars were higher in asia compared to europe. our study has several limitations, especially related to the means of data collection. firstly, the response rate varied substantially between countries from . % to . % with low response rates in the participating asian fig. mean perceived threat of sars and flu from a new flu virus in case of an outbreak, high blood pressure and diabetes by country. the asterisk indicates that the difference in mean perceived threat between sars and flu is statistically significant countries in particular. this may have led to nonrepresentative samples, and the differences in response rates may partly explain the reported differences in risk perceptions and other variables. these differences in response rates and the low rates in some of the participating countries limit the generalizability of our data, and the results should, therefore, be interpreted with caution. secondly, because of the lack of an existing validated questionnaire for perceived threat and risk perception of infectious diseases suitable for telephone administration in large samples, the questionnaire was specifically developed for the project reported in this paper based upon an earlier questionnaire used during the sars outbreak [ ] . our study design, aiming to include a large number of respondents from a range of different countries and regions, using telephone surveying as the means of data collection, combined with the financial and time pressure restraints, enabled the inclusion of only a limited number of items per construct. this may have reduced the reliability of our measures, especially toward possible underlying cultural differences in constructs. furthermore, extensive pretesting of the survey questionnaire with cognitive interviewing was restricted to two european countries. we, therefore, do not know whether all concepts used were understood in the same way in all participating countries. on the other hand, we did contextualize our risk perception questions by including a setting (in case of an outbreak), time frame (next months), and focusing on the risk of the individual (instead of population)-all issues known to be important for measuring risk percep- the present study also has its strengths. it is among the first large-scale comparative studies into perceived threat and risk perception of emerging infectious diseases, and in fact, unique in the number of countries represented. perceived threat for sars, as well as avian influenza, were among the highest and at the same level as for, for example, a heart attack. this indicates that these potential problems were taken very seriously by the general public. because few comparative studies into perceived threat of sars and other newly emerging infectious diseases have been conducted, it is difficult to interpret the differences between countries and continents. comparing our results with data from several earlier studies on risk perception of sars in the usa, canada, the netherlands, singapore and hong kong has its limitations, as these studies were done in during the sars epidemic, whereas in our study, we asked respondents to envisage a new outbreak [ ] [ ] [ ] [ ] . for example, in , risk perception of sars in some of the asian countries was relatively low compared to risk perception in the usa. ji et al., in their study on optimism across cultures, have pointed out that unrealistic optimism concerning sars was higher among chinese than among canadians [ ] . they interpreted this being in line with the chinese and east asians in general holding a cyclical perception of events, so that a negative event may be seen as antecedent to a positive outcome. the higher level of severity of some diseases in europe (sars, flu from a new virus, hiv, tuberculosis) may indicate that more unfamiliar diseases are perceived more severe. the higher perceived vulnerability for some diseases (sars, tuberculosis, hiv) in asia may be based upon the fact that these are indeed more prevalent in these regions. the observation that, compared to europe, efficacy beliefs for sars were more positive in asia and that people felt more able to control sars, may be explained in the same way. alternatively, it may also be that the more direct and closer experience with the disease in asia and the experience of outliving and overcoming the outbreak have increased self-efficacy and response efficacy beliefs in asia. preventive measures in asia were also more visible and might have been more reassuring to the public [ ] . also, efficacy beliefs related to a common cold and flu from a new virus were higher in asian countries where the latter may be explained by the fact that, despite the first cases of avian influenza among humans in asia already reported in , this has not resulted in a larger outbreak [ ] . the lower level of risk perception in denmark may reflect part of a scandinavian tendency to perceive risks lower than in other countries [ ] . this result is also in line with a lower risk perception of sars among finns compared to dutch [ , ] . one of the explanations for this tendency is that the media in scandinavia appear to report more about risks abroad with less attention to risk inside the country [ ] . however, we need to interpret the differences between countries with care because cognitive constructs such as risk perceptions are not necessarily interpreted in the same way in different cultures [ ] . indeed, the data of our study on comparison of risk perceptions for various diseases show that the relative risk perceptions for these diseases, i.e., the order of levels of risk perceptions, are rather consistent across countries. this may indicate that differences between countries in absolute risk perception levels for specific diseases or conditions may reflect cultural differences in the way survey questions are answered rather than real differences in risk perceptions. voeten et al. [ ] , in their study on risk perception and efficacy beliefs among chinese communities in the uk and the netherlands, have shown that efficacy beliefs of chinese living in the uk and the netherlands were comparable to those of native uk and dutch respondents. this may indicate that country of residence, perhaps because of country-specific public health systems and media coverage, may be more important than ethnicity or country and culture of origin. because country appears to be a relevant correlate of sars-related risk perceptions in the multivariate analyses, further research is needed to explain these country differences. the results on comparative vulnerability indicate that envisioning an outbreak might make a difference; when respondents were asked to compare their personal risk to that of comparable others, the optimistic bias was lower in case of an outbreak. such a situation is characterized by table correlates of perceived threat for sars; regression coefficients (b) and corresponding % confidence intervals ( %ci) derived from linear regression analyses less control, which is associated with less optimism [ , ] . the notion that, for an outbreak, risks were perceived to be more evenly distributed, and thus they seemed to be less prone to an optimistic bias, may offer starting points for public interventions. such interventions should certainly also focus on increasing self-efficacy, especially in the european countries, because low self-efficacy may lead to lack of protection motivation. perceived threat of sars and flu from a new flu virus in case of an outbreak was similar in most countries. however, the level of severity for sars was higher than for flu from a new virus, while vulnerability for flu from a new virus was higher than for sars in all countries. one explanation might be that sars is a more unfamiliar disease for most people compared to flu. it indicates that people do perceive various aspects of risk perceptions differently for different emerging infectious diseases and that risk communication should thus be disease-and perception-specific. perceived threat for emerging infectious diseases such as sars and avian influenza were amongst the highest rated in the present study, especially in case of an outbreak. from a public health perspective, this offers a good starting point for risk communication and precautionary actions. it also asks for realistic risk communications to put the risks for sars and other emerging infectious diseases into the perspective of global health risks to prevent fuelling unnecessary panic [ ] . twenty-first century plague. the story of sars responding to global infectious diseases outbreaks: lessons from sars on the role of risk perception, communication and management world health organization working group on prevention of international and community transmission of sars. public health interventions and sars spread non-pharmaceutical interventions for pandemic influenza, international 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in any medium, provided the original author(s) and source are credited. key: cord- -kb fnbgy authors: nan title: oral presentations date: - - journal: clin microbiol infect doi: . /j. - . . .x sha: doc_id: cord_uid: kb fnbgy nan [ primary immunodeficiency diseases are a heterogeneous group of disorders, caused by inherited defects in the immune system, and characterised by wide spectrum of clinical manifestations, particularly an increased susceptibility to infections and a predisposition to autoimmune diseases and malignancies. recurrent infections or infection with unusual organisms are the most commonly presentation of primary immunodeficiency diseases. although recurrent respiratory tract infections and gastrointestinal manifestations are the most common features of these diseases, especially in predominantly antibody deficiencies and combined immunodeficiencies, other organs can be involved as well. recurrent cutaneous abscesses with unusual organisms or deep abscesses may represent infections with an association with immunodeficiencies, particularly in phagocytes defects. meningococcal infections could have an association with complement deficiencies. meanwhile other bacterial infections, mainly streptococcus pneumoniae and staphylococcus aureus, as well as infections with viruses, fungi and parasites are also common in several primary immunodeficiency diseases. autoimmune diseases such as idiopathic thrombocytopenic purpura, autoimmune haemolytic anaemia, systemic lupus erythematosus, juvenile arthritis, sclerosing cholangitis, and vasculitis are common in primary immunodeficiency diseases. whilst some syndromic immunodeficiencies (e.g., wiskott aldrich syndrome, di george syndrome) have a strong association with autoimmunity, there are a group of disorders (e.g., alps, apeced, ipex) that the autoimmune manifestations are typically the first and most significant findings. malignancies are also common in some primary immunodeficiency diseases (e.g., cvid, alps, xlp, and dna repair defects). other manifestations such as dysmorphic features, associated anomalies, skeletal dysplasia, and oculocutaneous hypopigmentation can be unique characteristics of some cases with primary immunodeficiency diseases. the clinical manifestations of these diseases are often helpful in guiding the appropriate evaluation of the patients. prompt and precise diagnostic laboratory evaluation should be performed in the patients with such features, whereas early diagnosis and successful management of these patients prevent irreparable organ system damage and improve the prognosis. immunodeficiency specialists from all over europe have composed a multistage diagnostic protocol that is based on their expert opinion, in order to increase the awareness of pid among doctors working in different fields. the protocol starts from the clinical presentation of the patient; immunological skills are not needed for its use. a list of relevant symptoms and signs from the history and physical examination that should alert any physician to potential pid is given. these are grouped together to form eight typical clinical presentations of pid: recurrent ent and airway infections; failure to thrive from early infancy; recurrent pyogenic infections; unusual infections or unusually severe course of infections; recurrent infections with the same type of pathogen; autoimmune or chronic inflammatory disease, or lymphoproliferation; characteristic combinations of clinical features in eponymous syndromes; and angioneurotic edema. these presentations lead the user towards different algorithms, which in fact represent the traditional division into antibody, complement, lymphocyte, and phagocyte deficiencies, respectively. the algorithms each are comprised of several steps. this multistage design allows cost-effective screening for pid within the large pool of potential cases in all hospitals in the early phases, while more expensive tests are reserved for definitive classification in collaboration with an immunologist at a later stage. g. schmid°(geneva, ch) in , articles suggesting that male circumcision (mc) decreased the risk of hiv infection appeared. over the next years, studies of two epidemiologic types − ecologic and observational − increasingly supported this contention. ecologic studies showed strong correlations between prevalences of mc and hiv, e.g., tribes with low prevalences of mc had high prevalences of hiv infection. observational cross-sectional studies showed that uncircumcised men had higher rates of hiv than circumcised men. observational cohort studies confirmed these weaker study design findings. a systematic review of observational studies in found a relative risk (rr) of . ( % ci, . − . ), a % protective effect. in and , results from three randomised controlled trials, all from sub-saharan africa, were reported. results were consistent, and the pooled rr of . ( % ci, . − . ) was identical to that of the observational studies. the protective effect in the three trials, found at about − months' follow-up, has been extended in one trial to a protective effect of % at months of follow-up. who and unaids have strongly endorsed mc as an effective hiv prevention strategy in generalised hiv epidemics where mc is uncommon. what about europe? mc is uncommon with an adult male prevalence of < %. hiv incidence is low enough that mc for hiv prevention purposes is unlikely to have much impact. no public health authority recommends routine neonatal circumcision. increasingly, however, data are showing benefits of mc in addition to hiv prevention. lessened risk of urinary tract infection in infants (rr . , % ci . − . ) and lifetime avoidance of phimosis and associated conditions occur when mc is performed neonatally. other benefits occur in males circumcised at any age. mc protects against acquiring sexually transmitted infections characterised by genital ulcers-syphilis, chancroid and herpes-and possibly trichomoniasis. circumcised men may be less likely to acquire hpv and are more likely to clear the infection. through the protective effect against hpv, mc halves risk of penile cancer (rr . , % ci . − . ) and partners of circumcised men are at lessened risk of cervical cancer. other issues must be considered in making public health decisions about mc. cultural objections may occur, but mc in the developing world is readily accepted in non-circumcising societies. studies of sexual pleasure and function have found no relationship to circumcision status. mc may be advised for subgroups, even if not for the entire population. and, surgical risk and cost must be considered. while many sub-saharan african countries are scaling up mc services to prevent hiv infection, public health agencies in many industrialised countries are reconsidering mc policies-the outcomes of both efforts are being followed with interest. acute otitis media (aom) is generally considered a bacterial infection that is treated with antibiotics. however, despite extensive use of broadspectrum antibiotics for this condition, the clinical response to the treatment is often poor. this fact, together with vast clinical experience connecting aom with viral respiratory infections, has prompted research into the role of viruses in aom. to date, ample evidence from studies ranging from animal experiments to large clinical trials supports a crucial role for respiratory viruses in the aetiology and pathogenesis of aom. in most cases, viral infection of the upper respiratory mucosa initiates the whole cascade of events that finally leads to the development of aom as a complication. the pathogenesis of aom involves a complex interplay between viruses, bacteria, and the host's inflammatory response. recent studies indicate that with sensitive techniques viruses can be found in the middle-ear fluid in most children with aom, either alone or together with bacteria. viruses appear to enhance the inflammatory process in the middle ear, and they may profoundly impair the resolution of otitis media. it is important to understand, however, that our increasing knowledge of the importance of viruses in the etiopathogenesis of aom does not diminish the central role of bacteria in aom. therefore, while viruses may explain many of the problems encountered in treating aom, the ultimate decision on whether or not to treat aom with antibiotics cannot be based solely on the degree of viral involvement in aom. the non-judicious use of antibiotics has lead to an epidemic in antimicrobial resistance. acute otitis media (aom) is the most common indication for use of antibiotics in children in the united states (us). despite available evidence that supports a wait and see approach, most us physicians immediately prescribe antibiotics for the treatment of aom. the american academy of pediatrics published a guideline in that addressed the diagnosis and treatment of aom. this guideline recommends the use of observation as a potential strategy for the treatment of aom. the key components of this published guideline will be discussed, as well as the evidence and rationale that supports the use of observation as an initial strategy to treat aom. otitis media (om) is the most common bacterial infection in children aged < years for which antibiotic treatment is prescribed worldwide. although most of the time this entity resolves spontaneously it is associated with morbidity, family dysfunction, antibiotic use and burden on the medical system. efforts to reduce the burden of om by vaccination have not been extremely rewarding, but some progress has been made. the first obvious step would be to reduce viral infections leading secondarily to om. in the modern era, the only viral vaccine with proven effect on aom is the influenza virus vaccine. both the inactivated and the live virus showed some effect, but since influenza virus has only a limited season yearly the effect on the overall om rate is far from being remarkable. haemophilus influenzae (hi) b vaccine did not reduce om since most hi causing om are nontypable (nthi) and not hib. the newly developed pneumococcal conjugate vaccines (pcvs) have all been shown to reduce > % of the om caused by the serotypes included in the vaccines, but some replacement with serotypes not included in the vaccines and non pneumococcal organisms was demonstrated to reduce the overall effect of pneumococcal vaccines. the effect of pcv on the reduction of recurrent om, om with effusion, the need for ventilation tubes and frequent visits for aom has been suggested, and the real impact is still being studied. aiming with pcv at those with established recurrent om has proved disappointing. pcvs can reduce om caused by antibiotic-resistant s. pneumoniae but the continued overuse of antibiotics is responsible for the increase in antibiotic resistance in non-vaccine serotypes. a newly developed pcv with an outer membrane protein for hi (pnpd) is suggested to reduce also om caused by hi, but confirmation studies are needed. the expansion of the serotypes included in the current licensed pcv to or more serotypes may add to the prevention of om in the near future. in the next decade, om will continue to be an important disease in children. however, we can expect it to be modified in terms of bacteriologic aetiologies, antibiotic resistance and hopefully short and long term consequences. v. korten°(istanbul, tr) infectious consequences of an earthquake mainly involve several types of communicable diseases and crush related infections. water-borne and food-borne illnesses often result from the disruption of the public water and sewage systems and contamination of water supply. overcrowding, poor hygiene and sanitation in temporary shelters also may be factors. the type of infectious diseases are associated with the epidemiology of communicable diseases in the area where the earthquake occurred. the most common outbreaks associated with earthquakes are gastroenteritis, infectious hepatitis and pulmonary infections. in unvaccinated populations, there are reports of increased measles. tetanus can be seen in populations where vaccination coverage levels are low. the risk for diarrhoeal disease outbreaks following earthquakes is higher in developing countries than in industrialised countries. an outbreak of acute watery diarrhoea involved > cases occurred in a camp after the earthquake in pakistan. acute respiratory infections, hepatitis e clusters and measles (> clinical cases in the months) also occurred among the displaced victims after the same earthquake. contamination of drinking water led to an outbreak of rotavirus after the earthquake in kashmir, india. an unusual outbreak of coccidiomycosis associated with exposure to increased levels of airborne dust occurred after the southern california earthquake. persons who have been trapped by rubble for several hours or days may develop compartment syndromes requiring fasciotomy or amputation. infectious complications were common in renal victims of the marmara earthquake in turkey and were associated with increased mortality when complicated by sepsis. of renal victims, ( . %) had infectious complications, mainly sepsis and wound infections. most of the infections were nosocomial in origin and caused by gram-negative aerobic bacteria and staphylococcus spp. multivariate analysis of the risk-factors for nosocomial infections revealed a significant association with fasciotomy and length of hospital stay in a back up university hospital. the most frequent pathogens isolated from pus and/or wounds culture in wenchuan earthquake survivors were s. aureus, e. coli, a. baumannii, e. cloacae, and p. aeruginosa. disaster-preparedness plans, focused on trauma and mass casualty management and also on health needs of the surviving affected populations may decrease the health impact of earthquakes. s infections in the disaster setting: famine. experience from darfour, sudan clinic malnutrition is a known risk factor for id worldwide. subsaharan africa and india is at higher risk due to vegetarian habits on absolute absence of animal meat proteins, resulting to depletion of micronutritients (zinc, iron, selenium), responsible for recovery of postmalarial anaemia. in addition, depletion of proteins results to immunoglobulinaemia and to delayed response to many bacterial pathogens causing id in topics (pneumococci, salmonella, etc.) . third problem is absence of vitamins dissolved in oil and fat, resulting to delayed phagocytic activity. therefore proteinocaloric malnutrition results to significant adverse outcome in hiv, tb (diarrhoea, pneumonia), the major killers of children under five. st. elizabeth university tropical programme runs antimalnutrition centres: in sudan, darfour and in kenya amaong upcountry refugees from major conflict areas (sudan − turrana border) and in uganda trying to rehabilitate malnourished children under and helping them to combat disease, responsible for . million deaths in children mean a year − malaria ( . mil), tb ( . mil), hiv ( . mil), pneumonia ( . mil) and diarrhoea ( . mil. children deaths approximately a year). h. giamarellou°(athens, gr) for the last six years greece has faced a large number of infections, mainly in the intensive care units (icu), due to carbapenemsresistant klebsiella pneumoniae. the proportion of imipenem-resistant k. pneumoniae has increased from less than % in , to % in isolates from hospital wards and to % in isolates from icus in . likewise, in , these strains were identified in only three hospitals, whereas now they are isolated in at least of the hospitals participating in the greek surveillance system. until this situation was due to the spread of the blavim- cassette among the rapidly evolving multiresistant plasmids and multiresistant or even panresistant strains of mainly k. pneumoniae and also other enterobacterial species. however, the fact that most strains display mic values below or near the clsi resistance breakpoint create diagnostic and therapeutic problems, and possibly obstruct the assessment of the real incidence of these strains. as of , the emergence of kpc-producing k. pneumoniae has been noted in icus of some greek hospitals and has now spread to most hospitals throughout the country creating a countywide outbreak in . in attikon university hospital we recently described the icu outbreak of kpc-producing k. pneumoniae. twenty-nine patients (admitted from february to december ) were colonised mainly in gi tract. fifteen patients were male ( %) and the median apache ii was . patients had already long hospital stays preceding icu admission with a median of ( − ) days. in twenty-two of these patients ( %) kpc-producing k. pneumoniae colonisation was definitely icuacquired while in ( %) acquisition in other wards or other hospitals was hypothesized. five of these patients are still hospitalised in the icu and, of the remaining , died (icu mortality %). ten of the colonised patients were clinically infected. fifteen infections were documented, mostly bsi ( / ), followed by vap ( / ) and ssi ( / ). only patient died from this infection ( / , . %). an evidence-based consensus on the therapeutic strategy for these infections has been reached by keelpno and the greek ministry of health which proposed the use of high dose meropenem ( − g/day) combined with an active aminoglycoside or colistin for strains with an mic mg/ml whereas for strains with a higher mic the use of carbapenems is contraindicated and active alternatives (monotherapy with tigecycline, colistin, or an aminoglycoside or aztreonam-based combinations) could be used. antibiotic stewardship is of great importance in such a dismal situation but stringent adherence to infection control measures is probably of even greater importance for the effective containment of these pandrugresistant strains. the presentation of clostridium difficile infection (cdi) varies from mild diarrhoea to a potentially fatal pseudomembranous colitis. the recent emergence of types and of c. difficile has been associated with increased virulence. c. difficile takes advantage of disruption of the normal intestinal flora as caused by antibiotic therapy. the antibiotical class and the antimicrobial resistance pattern of c. difficile influence the development of disease. in the netherlands, significantly more patients with cdi due to type used fluoroquinolones (or, . ; % ci, . − . ) compared with those who were infected with other pcr ribotypes. similar as type cdi, patients infected with type also more frequently received fluoroquinolones therapy (or, . ; . the risk to develop cdi due to type was particularly high in persons receiving a combination of cephalosporin and fluoroquinolone (or . , ). this association was also strongly dependent on the duration of therapy. the use of clindamycin was found as a protective factor. however, the recent detection of clindamycin-resistant c. difficile type strains in other european countries is an important and worrying development. since the association of cdi with fluoroquinolones has only been investigated at patient level, a study was performed to investigate the relationship between cdi incidence and the preceding use of different antibiotic classes at hospital level in the netherlands. comparisons were made between hospitals where type caused an epidemic, hospitals where only isolated cases of type were observed and hospitals where no outbreak of cdi or type were encountered. in the pre-epidemic period, the total use antibiotics was comparable between affected and unaffected hospitals. higher use of secondgeneration cephalosporins, macrolides and all other studied antibiotics were independently associated with a small increase in cdi incidence, but the effect was too small to predict which hospitals might be more prone to -associated outbreaks. despite the fact that the netherlands is known by its restrictive and conservative use of antibiotics, outbreaks of cdi due to new emerging types have been recognized. this is probably associated with the use of antibiotics at patient level and hospital department level rather than the use of antibiotics at the level of the healthcare institute. m. peiffer, j. bulitta, h.a. haeberle, m. kinzig-schippers, m. rodamer, v. jakob, b. nohé, f. sörgel, w.a. krueger°(trier, de; albany, us; tubingen, nuremberg, constance, de) piperacillin-tazobactam (pip-tazo) is a broad spectrum antibiotic, used for treatment of severe infections such as ventilator-associated pneumonia (vap). the effectiveness of betalactams is best predicted by the duration of free drug concentrations above the minimal inhibitory concentration (t > mic) of infecting pathogens [ ] . animal experiments suggest that more than % of t > mic should be reached. continuous infusion (ci) of pip-tazo may enhance the therapeutic performance, but there is little data on pharmacokinetic/-dynamic (pk/pd) parameters, when ci is used in critically ill patients. objectives: the aim of our study was to determine concentrations of pip-tazo in plasma and broncho-alveolar epithelial lining fluid (elf) at steady state during ci. based on these results, the penetration ratio (plasma/elf) and pk/pd parameters for pip-tazo are derived. methods: after approval by the ethics committee, mechanically ventilated critically ill patients were enrolled during treatment in intensive care units. each patient received a loading dose of g/ . g of pip-tazo, followed by ci of g/ . g over h. at steady state ( . + . h after loading dose), a total of blood samples were drawn and bronchoalveolar lavage (bal) was simultaneously performed in cases ( sample discarded for technical reasons). samples were stored at − ºc until analysis by liquid chromatography coupled with mass-spectrometry (lc-ms). elf-concentrations were calculated from bal-samples using the relation of ureaplasma:ureabal as dilution factor. results: plasma concentrations of pip and tazo (n = in pts.) amounted to . + . mg/ml, and . + . mg/ml, respectively. elflevels (n = ) were . + . mg/ml, and . + . mg/ml. elf-levels were + %, and + % of corresponding plasma levels (n = ) for pip and tazo, respectively. the ratio pip:tazo was . : in plasma, and . : in elf. conclusions: using advanced analytical techniques, elf concentrations were higher compared to traditional bolus administration [ ] . ci yielded steady state plasma concentrations in excess of mics of susceptible bacteria (< mg/ml, according to eucast) in . % of measurements, respectively, but elf levels exceeded mg/ml in all cases. taken together, our data provide further arguments for ci being the preferred mode of administration for pip-tazo in critically ill patients with suspected vap. [ objectives: staphylococcus aureus is a potential pathogenic microorganism and a causative agent of~ % of infections in intensive care patients. an optimal empiric choice for the treatment of these infections will result in a reduction in morbidity and mortality. therefore, it is essential to provide the clinician with resistance data of the bacterial population to be treated. to optimise the empiric choice and to monitor the emergence of microbial resistance, a national surveillance program of the swab was started in the netherlands in .this study describes the results of the resistance development of s. aureus from icu's of hospitals all over the netherlands over a ten year period. methods: in the first months of each year, the participating hospitals collected clinical isolates from among others blood and respiratory samples. in total isolates were collected: from hospitals in the north, from in the east, from five in the west and from four in the south. the antimicrobial susceptibility was determined as a micro broth dilution method according to the clsi guidelines. results: an increase in resistance to ciprofloxacin was observed from % until to % from in , which dropped again to % in . the resistance to moxifloxacin was rather constant over time, i.e. %, only in % resistance was found. resistance to clarithromycin increased to % in , but decreased in to % the level before . resistance to penicillin, clindamycin and tetracycline fluctuated over time at~ %, − % and − % respectively. during the study period seven methicillin resistant s. aureus were isolated, no resistance to vancomycin, teicoplanin and linezolid was observed. resistance to gentamicin and rifampicin was sporadicly found. regional differences were observed for ciprofloxacin, being the highest in the western and southern part and tetracycline being the lowest in the northern part. conclusion: during the year study period only an increase in resistance to ciprofloxacin was observed. the data presented justify the empiric choice of flucloxacillin, (with rifampicin or gentamicin depending on the indication) in case of an infection in icu patients probably caused by s. aureus. j.j. lu°, p.r. hsueh, s.y. lee (taichung, taipei, tw) objectives: to investigate the prevalence of visa in hospitalised patients with mrsa infections or colonisations at a teaching hospital in taiwan and to evaluate the possible clonal spread of visa in the hospital. methods: from september to august , consecutive mrsa isolates were collected from various clinical specimens of patients hospitalised at a teaching hospital in taiwan. minimum inhibitory concentrations (mics) of vancomycin for all mrsa isolates were determined by the broth microdilution method in accordance with clsi guidelines. molecular characteristics and antimicrobial susceptibilities of visa isolates were investigated and pulsed-field gel electrophoresis was used to evaluate the clonality of the isolates. results: among the mrsa isolates, ( . %) were visa. of the visa isolates, had vancomycin mics of microgram/ml and had vancomycin mics of microgram/ml. all isolates were inhibited by tigecycline at . microgram/ml, linezolid at microgram/ml, and ceftobiprole at microgram/ml. five ( . %) isolates had reduced susceptibility to daptomycin (mics of − microgram/ml). six of the visa isolates had decreased susceptibility to autolysis in . % triton x- . the visa isolates were recovered from patients; of these patients had received glycopeptide treatment prior to the isolation of visa. five ( . %) patients died despite vancomycin therapy. all visa isolates carried sccmec type iii and agr group i but were negative for pvl gene (luks-lukf). none of the enterococcal van genes were detected in the visa isolates. results of pfge analysis revealed that one major clone of visa isolates ( . %, clone a exhibiting sccmec type iii, agr group i, and absence of pvl gene) had disseminated in the hospital. conclusion: this retrospective study demonstrated that clonal dissemination of visa had occurred in the hospital. rapid and correct detection of visa and proper use of antibiotics are the most effective approaches for preventing its emergence and spread. x. zheng°, c. qi, a. o'leary, m. arrieta, s. shulman (chicago, us) objectives: vancomycin remains one of the major options for treating methicillin-resistant s. aureus (mrsa) related infections. some but not all studies have shown an increase in prevalence of mrsa isolates with elevated vancomycin mic values among recent clinical isolates, so called "mic creep". although still within the susceptible range, higher mics may be associated with increased chance of treatment failure. because of the conflicting reports and lack of published data from paediatric patients, we sought to assess possible mic change over time and to compare results generated by using different methodologies including etest, agar dilution, and broth microdilution (microscan) methods. methods: we studied mrsa isolates predominantly community acquired including all blood and normally sterile site isolates collected in our large children's hospital in / , , , and molecular bacteriology o genome sequence of a virulent, methicillin-sensitive staphylococcus aureus clinical isolate that encodes the panton-valentine leukocidin toxin l. faraj, l.a.s. snyder, n.j. loman, d.p. turner, m.j. pallen, d. ala'aldeen, r. james°(nottingham, birmingham, uk) objective: to determine the genome sequence of a virulent meticillinsensitive staphylococcus aureus (mssa) clinical isolate sanot . methods: roche sequencing determined the genome sequence of the clinical isolate at times coverage. newbler sequence assembly (roche) generated scaffolds that were annotated using gendb and compared with other s. aureus genome sequences. results: an -year-old asian girl presented with fever and a -week history of knee pain following a trivial fall. an mr scan revealed a large subperiosteal abscess around the upper tibia secondary to metaphyseal osteomyelitis. a pvl-positive, mssa was isolated from blood cultures and pus. the child deteriorated, required repeated debridement and developed septic shock. further investigation revealed aortic valve endocarditis with an aortic root abscess. whole genome sequencing revealed that sanot is the first sequence of an st s. aureus isolate to be determined. sanot is agr type iii and carries three coding regions that are not found in any other s. aureus genome sequences. amongst the unique genes present in these regions is a dihydrofolate reductase gene (dfrg) which is present in addition to the usual dfrb gene. downstream of the orfx gene, a . kb remnant of sccmec type ivc was found. this sequence has only previously been found in the mrsa genome sequence where it is located between the orfx and sccmec type ii sequences. mrsa is unique in sharing genome regions with s. aureus strain rf , a causative agent of contagious bovine mastitis. all but one of these genome regions are also present in sanot . conclusions: comparison of the genome sequence of sanot and the closely related mrsa ha-mrsa (emrsa- ) isolate reveals new insights in the evolution of both ca-mrsa and ha-mrsa isolates and the link to s. aureus rf . pvl-encoding mssa strains can be significant pathogens but are not currently under mandatory surveillance in uk. as the cost of whole genome sequencing falls further it will become feasible to use this technology to monitor the evolution of both mssa and mrsa in healthcare settings and reveal clinically relevant information that will help to improve patient outcomes. objectives: ca-mrsa often produce panton-valentine leukocidin (pvl), a leukocidin encoded by two co-transcribed genes located on lysogenised phages. five pvl-encoding phages have been described in s. aureus: phipvl, phi pvl, phislt, phisa mw and phisa . single nucleotide polymorphisms (snps) in the pvl genes tend to vary with lineage and may have structural and functional implications. we examined a selection of pvl-positive ca-mrsa reported in our hospital to determine whether sequence variation and the pvl-encoding phage vary with lineage. methods: twenty-two pvl-positive isolates were chosen to reflect mlst clonal complexes identified in our hospital: cc , , , , , and . isolates were characterised by antimicrobial resistance profile, sccmec and spa type, pulsed-field gel electrophoresis (pfge) profile and multilocus sequence typing (mlst); an oligonuleotide array (clondiag arraytube) was used to detect a range of toxin and antimicrobial resistance genes. primers were designed to amplify and sequence the luksf-pv genes. the pvl-encoding phage was characterised using a recently described pcr-based assay (ma et al. j clin microbiol ; : − ) . results: snps were identified at seven positions in the luksf-pv genes and the snp profile varied with lineage. three of the snps were coding mutations, which may have structural and functional implications. cc and cc isolates were both found to carry phisa mw. the pvlencoding phage was not definitively identified in the other lineages, although the cc isolates carried a phisa -like phage and the cc , cc and cc isolates carried elongated head-type phages. one of the cc isolates had an unexpected snp pattern compared with other cc isolates; this isolate also carried a novel or variant phage. conclusion: pvl gene sequence and the pvl-encoding phage vary with lineage in pvl-positive ca-mrsa isolates. this suggests that certain lineages are susceptible to infection or lysogeny with certain phage types. although ca-mrsa commonly carry pvl genes, some strains do not; it is possible that some pvl-negative types are resistant to infection with pvl-encoding phage, perhaps via restriction modification systems. crucially, our findings suggest the pvl genes have co-evolved with their phage and are not freely transmitted between different phages. further work is required to characterise the pvl-encoding phage in other isolates and to investigate whether the pvl sequence variants result in biological differences. objectives: community-associated mrsa (ca-mrsa) of many different mlst clonal complexes (ccs) can harbour lysogenised bacteriophage dna (prophage) encoding panton-valentine leukocidin (pvl). five pvl phages (phipvl, phislt, phisa mw, phi pvl, and phisa ) have been reported to date. we sought to determine the distribution of chromosomally integrated copies of these lysogenised pvl-phages amongst dominant clones of pvl mrsa in england and wales. methods: seventy isolates of previously characterised pvl-mrsa were analysed by pcrs developed by ma et. al, (jcm, ) , to identify and discriminate between the five known pvl phages. to maximise any underlying diversity, representatives of each cc were selected based upon their spa, staphylococcal cassette chromosome mec (sccmec), toxin gene and pulsed-field gel electrophoresis (pfge) profiles. these included isolates of internationally disseminated pvl-mrsa lineages ccs , and which resemble the usa , south west pacific (swp) and european clones, respectively. in addition we analysed pvl-mrsa from ccs , , , , and st . results: all seven cc isolates, which included representatives of the european clone, possessed an elongated-head-type phage and were positive by the pcr specific for the phisa mw phage. one of the cc isolates possessed a phi pvl phage, four swp representatives had elongated head type phages, whilst the remaining four cc isolates harboured an icosahedral-head-type phage. one cc was positive for both head shapes. the cc (including representatives of usa ), eight cc , six cc isolates and the st isolate were all positive for elongated-head-type phage. nine cc isolates were non-typeable for phage head shape and specific phage pcrs. three of four cc isolates, harboured a phisa -like phage of an unknown head type and the other cc isolate was non-typeable. all cc isolates possessed an icosahedral-head-type phage, were positive for the phipvl phage type and one possessed phi pvl type. we have determined the pvl phages present in a diverse panel of distinct pvl-mrsa clones and found considerable inter-lineage variation in the pvl prophage present. there was also evidence of intra lineage variation in some major ccs such as ccs , and . together with variation in mlst cc and sccmec, these data suggest pvl-mrsa have evolved on multiple occasions, sometimes within the same lineage. o transcriptional profiling of klebsiella pneumoniae genes controlled by the transcription factor, rama objectives: rama is an arac/xyls family transcriptional activator where over expression is associated with a multidrug resistance phenotype. in both multidrug resistant klebsiella and salmonella isolates, the rama gene has been associated with increase in expression of the acrab efflux pump. in salmonella it has been shown that a deletion of the rama locus prevents the emergence of multidrug resistant mutants. therefore in order to understand the role of this key regulator in the emergence and development of antibiotic resistance, transcriptomic analyses of its regulon were undertaken in k. pneumoniae. methods: rna was extracted from a combination of isogenic mutants and clinical isolates using the qiagen or ribopure kits. rna integrity was assessed using nanodrop and agilent nanochip systems. the rna was transcribed into double stranded cdna prior to labelling with cy . the cdna was hybridised to the nimblegen expression array platform designed from the k. pneumoniae mgh genome. results: approximately genes were found to be affected by rama expression, of which twenty (involved in metabolism, physiology, transcription, drug efflux, protection responses and the cell envelope) were confirmed by rt-pcr. the rama protein appears to affect drug efflux operons not previously shown to be associated with multidrug resistance and or affected by similar proteins such as mara. comparative transcriptome analyses of different k. pneumoniae clinical isolates overexpressing rama showed that variations exist in the levels of expression of the drug efflux genes. of note genes shown to be directly regulated by rama have a marbox-like sequence within the promoter sequences. conclusion: in this study, the transcriptome of the regulatory protein, rama, was determined in the pathogen k. pneumoniae. drug efflux proteins not previously associated with rama overexpression were found to be directly affected. the rama regulon overlaps with the mara and soxs regulons in e. coli and salmonella but is directly associated with regulating the expression of a subset of genes via a marbox sequence. interestingly, variations in the levels of the expression of the regulon genes were found in the different rama overexpressing strains. m. eshoo°, c. crowder, h. li, h. matthews, s. meng, s. sefers, r. sampath, c. stratton, d. ecker, y.w. tang (carlsbad, nashville, us) objectives: the potential for fatal outcome from tick-borne human infections such as ehrlichiosis emphasizes the need for rapid diagnosis. we developed and validated an ibis t assay (ibis biosciences, inc., carlsbad, ca) that can detect and identify a wide range of tick-borne pathogens from clinical samples. methods: a multi-locus assay was used that employs broadrange pcr primer pairs targeting all known bacterial tick-borne pathogen families. electrospray ionisation mass spectrometry of the pcr amplicons was used to determine their base composition. these base composition signatures were subsequently used to identify the organisms found in the samples. the assay was developed using field collected ticks and a wide range of clinical sample types and has been shown to be sensitive to the stochastic limits of pcr. results: whole blood ( ) , cerebrospinal fluid ( ) and plasma ( ) samples, which were originally submitted for ehrlichia species detection by a colorimetric microtiter plate pcr (pcr-eia), were collected consecutively from january to august , at vanderbilt university hospital. among the total specimens, pcr-eia detected ehrlichia species with a positive rate of . %. the ibis system detected ehrlichia in of the pcr-eia-positive samples and in of the pcr-eia-negative specimens, giving sensitivity and specificity of . % and . %, respectively. the ibis system further characterised the ehrlichia-dual positive specimens to the species level (e. cheffeensis, ; e. ewingii, ) with a % agreement to that identified by pcr-eia using additional species-specific probes. in addition we demonstrated the detection of borrelia burgdorferi from the blood and skin of a patient with lyme disease. conclusions: we demonstrate broad-range detection of tick-borne pathogens in a single assay using skin, whole blood, plasma, skin and csf. in addition to ehrlichia, the ibis system detected rickettsia rickettsii positive specimens, which were confirmed by serology and clinical findings. the ibis t system, which can be completed within five hours from specimen processing to result reporting, provides rapid and accurate detection and identification of a broad range of pathogens causing tick-borne human infections. r. sampath°, l. blyn, r. ranken, c. massire, t. hall, m. eshoo, r. lovari, h. matthews, d. toleno, r. housley, s. hofstadler, d. ecker (carlsbad, us) objective: to investigate the use of a novel platform-based approach for rapid characterisation of hai organisms. pathogens that cause healthcare-associated infections (hais) pose an ongoing and increasing challenge to hospitals, both in the clinical treatment and in the prevention of the cross-transmission of these problematic pathogens. here we describe the utility of a pcr electrospray ionization mass spectrometry (pcr/esi-ms) detection platform as an innovative, rapid approach for detection and complete characterisation of important hai pathogens. methods: we have developed pcr/esi-ms based methods to rapidly identify and characterise mrsa, vre, c. difficile (nap- strain), p. aeruginosa and a. baumannii. each target organism can be analyzed using an independent -well assay that can be run on the same platform and can provide species and strain id, virulence factors, antibiotic resistance and genotyping as appropriate. validation studies were performed using - retrospective, well-characterised clinical isolates for each organism. this was followed by a prospective study for one of the organisms, mrsa, that included screening of clinical specimens (nares swab) from patients who were admitted to a medical unit with a high prevalence of mrsa clinical infections. results: for each of the five hai organisms, pcr/esi-ms species identifications were compared to gold standard testing results from the clinical microbiology laboratory and showed % concordance. for s. aureus, p. aeruginosa and a. baumannii, molecular genotyping by pcr/esi-ms was compared to pulse field gel electrophoresis (pfge) clusters and showed > % concordance. characterisation of virulence and/or drug resistance was performed for mrsa, vre and c. difficile and showed − % correct detection compared to existing testing methods. analysis of clinical specimens for mrsa showed that of the swabs, ( %) contained mrsa, either singly or as a dual infection with cons, ( %) were mssa and ( %) contained meca+ coagulase negative staphylococcus (mr-cons). comparison to gold standard analysis showed % sensitivity for mrsa detection with . % specificity, % ppv and %npv. the pcr/esi-ms technology is a high throughput assay system useful for infection control and for epidemiological studies. it is capable of simultaneous identification of hai organisms while detecting presence of key phenotypic markers and genotypic strain characterisation. m. reijans°, j. ossel, j. keijdener, g. simons (maastricht, nl) objective: molecular diagnostics play an increasingly important role in the detection of infectious agents in cerebrospinal fluids. however, the growing list of targets and the relatively small sample volumes are challenges that demand an improved molecular diagnostic approach. the meningofinder is a multifinder assay allowing the simultaneous detection of viruses and internal control in reaction. until now, the analysis of multifinder assays was based on size-fractionation, identifying each multifinder probe due to its specific length. here we present an alternative approach allowing realtime detection of eight meningofinder probes in a single tube. the realtime detection enables a faster analysis, less handling and lowers the risk of contamination. method: the meningofinder assay is a multifinder assay which detects herpes simplex virus and (hsv − ), human parechovirus (hpev), cytomegalovirus (cmv), epstein-barr virus (ebv), enterovirus (ev) and varicella-zoster virus (vzv) plus an internal control in a single reaction. each meningofinder probe can be distinguished based upon the specific length of each probe by size-fractionation using gel or capillary electrophoresis. we developed an alternative detection method using fluorescently labelled probes which allow specific identification of multifinder probes in a realtime pcr machine. results: a large number of qcmd samples (n = ), several enterovirus types (n = ) and characterised clinical samples (n = ) were analyzed using the meningofinder. all meningofinder reactions were analyzed by capillary electrophoresis and by fluorescently labelled probes in a realtime pcr machine. the results of the meningofinder showed a very good correlation with the expected results (> %). furthermore, the results of both meningofinder analyses showed a high degree of correlation. the realtime detection of the meningofinder probes decreases the analysis time and post pcr handling dramatically. we developed a new assay for the realtime detection of meningofinder probes. the realtime analysis showed a very good correlation with the conventional capillary electrophoresis analysis. in addition, the realtime detection reduced contamination risk and patient results became available more quickly. the combination of multifinder technology combined with realtime detection shows great potential in fast and easy multiparameter screening of clinical samples for infectious pathogens. in-house naats were applied to nucleic acid extracts obtained by own in-house methodology in each centre. results: sensitivities for the detection of the respiratory viruses were % for commercial mx naat, % for in-house mw naat, and % for mono in-house naat. the viral load was low each time false-negative results were obtained. false positive results were obtained by all methods used, resulting in specificities ranging from %- %. for the atypical bacteria, the multiplex naats failed to detect low l. pneumophila positive samples and low m. pneumoniae positive sample resulting in sensitivities of % and % compared to % in the inhouse mono naats. the commercial mx naat also failed to detect strong positive samples. no false positive results were obtained for the atypical bacteria. revisiting phage therapy against problematic pathogens s how the past feeds the future: from d'herelle to modern phagotherapy the increasing antibiotic resistance problem boosts the interest in alternative treatments for infections. a prominent example for this is the so-called phagotherapy. it makes use of bacterial viruses − bacteriophages − as drugs against bacterial agents. these bacteriophages are isolated from nature, characterised and then tested against the bacterial strains that are targeted. in theory, this approach has several advantages. for instance, bacteriophages infect, as a rule, their bacterial prey very specifically. therefore, they do not harm the commensal bacteria of the patient. additionally, if a bacterial strain becomes resistant against a certain bacteriophage strain, evolution will provide for new and active bacteriophage strains. in practice, phagotherapy has been used for a long time. already one of the two discoverers of bacteriophages, félix d'herelle, was an ardent advocate of this method. in fact, he was the first to use bacteriophages against infections − against bacterial diarrhoea (shigella spp.). after that, phagotherapy has been used to quite some extent in europe, the us and other parts of the world until penicillin entered the market in the s. in some parts of the former soviet union and the eastern bloc, the method has been utilised until today. now, several companies and university researchers are developing bacteriophages for therapeutical purposes again. historical documents related to phagotherapy and oral history reveal a fascinating past. bacteriophages have been employed against a wide variety of bacterial diseases in a time in which there were virtually no other anti-infectives. for example, in india, millions of cholera patients were treated with bacteriophages in the s. anti-cholera phages were also poured into drinking wells as prophylactics. bacterial viruses have also been utilised by the german and soviet armies in the second world war. the history of phagotherapy makes for more than an exciting story, however. analysis of the old literature helps identify important factors for success and failure. this is especially relevant for a field which holds promise but which has had limited funds at its disposal in the past few years − and which, therefore, has been making rather slow progress. additionally, examination of the strategy used for phagotherapy in the soviet union and poland also contributes to a better application of this method today. the discovery of bacteriophages, particularly their ability to replicate and lyse pathogenic bacteria may have been among the most important milestones in the history of biomedical sciences. in the pre-antibiotic era of the early th century, phage therapy was becoming a powerful weapon against infectious diseases of bacterial aetiology. unfortunately, phage treatment and research was largely forgotten in the western world as antibiotics became widely available. nowadays, the rapid propagation of multi-drug resistant bacterial strains is leading to renewed interest in phage therapy. in contrast to its decline in the west, phage therapy remained a standard part of the healthcare systems in eastern europe and the ussr during the second half of the th century. phage preparations were used for diagnostic, therapeutic and prophylactic purposes to combat various bacterial infections. the eliava institute of bacteriophages, microbiology and virology (tbilisi, georgia) is perhaps the most famous institution in the world focused on the study of bacteriophages, particularly the isolation and selection of phages active against various bacterial pathogens. phages have been isolated against bacterial strains received from all over the former ussr and socialist east european countries; consequently, a huge collection of phages and pathogenic bacterial strains has been constructed at the institute. thousands of people were treated with individual phages and phage mixtures during the soviet era. the preparations developed in tbilisi have been studied through extensive preclinical and clinical trials. however, little of this information has ever been published and even when details are available, the trial reports do not meet internationally approved regulations and standards. bacteriophages have a number of advantages in comparison to antibiotics. phage therapy as an alternative approach for treatment of infections has become an evident and promising remedy. today, many people from various parts of the world express their willingness to take phage treatment against different infections, including those that are caused by antibiotic-resistant bacterial pathogens. the eliava institute has elaborated new, phage-based products and technological schemes for their production. strong collaboration with the medical community in the design of clinical trials according to international standards is absolutely critical to supporting the broader implementation of phage therapy. an australian male aged years died from an intracerebral haemorrhage ten days after he returned from a trip to rural yugoslavia. his kidneys and liver were donated to three female recipients aged years (kidney), years (kidney), and years (liver). four to five weeks after the organ donation, all three recipients died. all had febrile illnesses with altered mental status. subsequent testing of post-mortem tissues from the recipients identified a novel arenavirus, which was related to lymphocyctic choriomeningitis virus (lcmv). this viral detection process involved the use of high-throughput sequencing techniques to identify novel microbial rna sequences. confirmatory testing was performed using the techniques of reverse transcriptasepolymerase chain reaction, immunohistochemical analysis for arenavirus antigens, and immunofluorescent testing for igg and igm antibodies. the clinical features in these four patients as well as other similar problems with transplant-related illness from classic lcmv will be discussed, as well as details of the laboratory identification of this new virus, and implications for organ transplantation protocols in future. successful management of invasive fungal infections depends on timely and correct treatment. over the last decades a number of new tests have become available which have improved the diagnostic options. in contrast to the scenario for bacterial infections, acquired resistance in fungi is rare and thus species identification is a valuable tool guiding choice of treatment. therefore, microscopy & culture is still a corner stone in diagnosis, but culture and identification are time consuming (app. − and − days, respectively). the sensitivity and speed of microscopy have been improved by the use of fluorescent brighteners such as calcofluor white or blankophor. but only with the recent development of pna probes specific for a number of the candida spp. has species identification become possible directly from a positive blood culture before subculture on agar media. chromogenic agars allow a presumptive identification of several candida spp. and facilitate the recognition of yeast isolates in samples containing several yeasts or yeast and bacteria in combination. the use of such plates has been shown to lead to a better identification of mixed cultures in a recent nordic eqa scheme including more than laboratories. rapid species identification of the most important candida spp. is possible in the routine laboratory using easy commercially available kits. thus, a species identification of c. albicans, c. dubliniensis and c. krusei can be obtained within minutes using latex agglutination kits (bichro-dubli, krusei-color; fumouze diagnostics) and c. glabrata can be rapidly identified due to its high amounts of preformed intracellular trehalase enzyme (glabrata rtt; fumouze diagnostics). finally, pna probes and fluorescence microscopy can also be used for a same day identification of a range of the clinically relevant candida spp. (advandx). susceptibility testing is possible using etest and the results are comparable with those obtained by reference methodologies in head to head comparisons. however, recent data from eqa distributions suggest that detection of isolates with acquired resistance causes many laboratories difficulties. this illustrates that a critical number of isolates should be tested per technician per week and quality control strains should be included on a regular basis. in conclusion, a number of new diagnostic tests have become available over the last decade and the diagnostic laboratories are encouraged to take advantage of these new options. th eccmid, oral presentations since the introduction of newer antifungals with different in vitro spectra, the aetiology of invasive fungal infections (ifi) has become a major diagnostic issue as a prerequisite for a guided antifungal therapy. while molecular methods, such as pcr and sequencing for the diagnosis of ifi have been evaluated from specimens such as blood and bronchoalveolar lavage fluid for some years, they have been less studied for biopsies. characteristics inherent to these molecular methods, e.g. sensitivity, specificity and short turnaround time makes them promising as adjuncts to conventional diagnostic tests, e.g. culture and histopathology from organ biopsies. studies using tissue from animal models of mould infections suggest that pcr might be more sensitive than culture and allows for a better species identification than histopathology. however, most of these studies used assays detecting only a small range of agents or even single organisms. while this may increase the sensitivity of the assays and reduces the likelihood of contaminations it limits the usefulness in the clinical setting, given the broad range of potential fungal pathogens. studies using fresh clinical samples suggest that the detection and identification of a wide range of fungi is possible using broad range assays in combination with sequencing or by combining more specific pcr assays. further studies are needed to optimise dna extraction, define the best molecular targets and the best method for amplicon detection. the prevention of contaminations due to ubiquitous fungi and unspecific amplifications are a major problem, especially when using broad range assays. in contrast, fish probes may potentially be more specific than pcr due to the visualisation of fungal elements in tissue. in contrast to pcr, they appear to work well with formalin fixed specimens. species identification might be more challenging than by pcr and sequencing. direct comparisons between fish and pcr are needed to characterise the pros and cons of each method in determining the aetiology of ifi. molecular tissue diagnosis has the potential to evolve into a useful method to describe the aetiology of ifi even in culture negative samples. results might be obtained fast enough to guide the antifungal therapy in patients with ifi progressive to empiric antifungal therapy. in these patients, the risk associated with invasive tissue sampling might be outweighed by potential benefits of a guided antifungal therapy. the two groups of carbapenemases (serine carbapenemases and metallobeta-lactamases (mbls)) can be encoded by genes that can be carried on plasmids. the serine carbapenemases are distinctly either class a or oxa (class d); the latter being mainly associated with acinetobacter spp. the dominant mbl subgroups, vim and imp have genes that are reportedly carried on plasmids and chromosomes. recent evidence has shown that the majority of blavim- , even those initially reported, are indeed plasmid mediated and probably accounts for their rapid dissemination. blavim- genes have been recently shown to be carried on incn and incw plasmids. the "brazilian" mbl gene, blaspm- , is exclusively chromosomally encoded. the mbls sim- and aim- are both chromosomally encoded whereas gim- is encoded from a plasmid of approx. kb. the recently described blakmh- gene is also carried on a plasmid ( kb). hitherto, only two mbl-positive plasmid sequences are available thus far -those carrying blaimp- and blavim- . the former carries other resistance genes and are approx. kb (inchi ), whereas the latter is a small plasmid ( kb) and shows similarities with incp plasmids. oxa carbapenemase genes have been shown to be both plasmid and chromosomally mediated. thus far, the blaoxa- and blaoxa- / clusters can be both plasmid and chromosomal and have mainly been found in acinetobacter spp. the blaoxa- and blaoxa- clusters have been found in k. pneumoniae and acinetobacter spp., respectively, and both are plasmid mediated. blaoxa- and blaoxa- have been shown to be carried on kb and - kb plasmids, respectively. a blaoxa- plasmid has been recently sequenced and shown to carry two different replicases. the class a carbapenemase genes, blakpc, blaimi- and blages are all carried on plasmids. blakpc is found mainly in k. pneumoniae and carried on plasmids that vary in size − kb and mostly possessing the origin of replication incn. however, kpc- has recently described in a pseudomonas as being chromosomally mediated. blaimi- is exclusive to the usa and carried on a kb plasmid although blaimi- is chromosomal. the blages genes have been found in p. aeruginosa and enterobacteriaceae of which ges- , , and have been shown to be plasmid mediated although little else in known. this lecture will provide a synopsis, discuss the evolution of resistance due to plasmids and briefly predict what we may face in the c with respect to carbapenemase resistance. nosocomial infections caused by multidrug-resistant pathogens, especially gram-negative bacilli, have become a serious clinical concern in every healthcare setting worldwide. as well as carpapenemhydrolysing metallo-b-lactamases, ctx-m-type b-lactamases, and qunolone-resistance genetic determinants such as qnr, aac( )-ib-cr, and qepa, plasmid-mediated novel molecular mechanisms such as rmta, rmtb, rmtc, rmtd, arma, and npma responsible for pan-resistance to aminoglycosides have recently been identified in pseudomonas aeruginosa, acinetobacter spp., serratia marcescens, esherichia coli, klebsiella pneumoniae, proteus mirabilis etc. since , and these enzymes have indeed methylation activity of g or a at the a-site of the bacterial s rrna as found in aminoglycoside-producing actinomycetes. these plasmid-mediated s rrna methylases are speculated to be originated from some nonpathogenic environmental microbes that produce aminoglycosides or some similar compounds, so it is quite natural that several new enzymes would be further identified hereafter in both clinical and livestock farming environments. rmtb and arma have widely spread in asia, europe, america and australia via various pathogenic gram-negative bacilli, we should pay special attention to the further spread of such hazardous microbes. in my talk, i would like to give an outline of newly identified molecular mechanisms that confer pan-resistance to aminoglycosides in pathogenic microbes isolated from both human and veterinary environments. [ acquired resistance to quinolones mainly results from chromosomal mutations responsible for modification(s) of dna gyrase and topoisomerase iv, and for a decrease of drug accumulation into bacteria due to decreased permeability and/or overexpression of efflux systems. plasmid-mediated quinolone resistance (pmqr) was first reported in from the usa, and two other mechanisms have been identified to date. the first pmqr determinants, qnr proteins, belong to the family of pentapeptide repeat proteins. five determinants have been identified: qnra, qnrb, qnrc, qnrd, and qnrs with , , , , and different variants, respectively. they may act by binding directly to both dna gyrase and topoisomerase iv leading to protect them from quinolone inhibition. they confer resistance to nalidixic acid and reduced susceptibility to fluoroquinolones (fqs), but may facilitate recovery of mutants with higher level of resistance. the overall prevalence of qnra, qnrb, and qnrs determinants generally ranges from to %, and they have been identified worldwide mostly in esbl-producing enterobacterial isolates. the origin of the qnra and qnrs genes were identified as shewanella algae and vibrio splendidus, respectively. the second type of pmqr determinant, aac( )-ib-cr, is a variant of the aminoglycoside acetyltransferase aac( )-ib which confers resistance to kanamycin, tobramycin and amikacin. this variant possesses two substitutions (trp arg and asp tyr) that are sufficient to acetylation of ciprofloxacin and norfloxacin with a -to- -fold mic increase. the overall prevalence of aac( )-ib-cr may range from . to up to %, and it has been reported mainly in escherichia coli and klebsiella pneumoniae. the third type of pmqr determinant, qepa, has been identified in two e. coli clinical isolates from japan and belgium. the qepa gene encodes a -transmembrane-segment putative efflux pump belonging to the major facilitator superfamily. this protein confers decreased susceptibility to hydrophilic fqs (e.g. norfloxacin, ciprofloxacin and enrofloxacin) with an -to- -fold mic increase. the two epidemiological surveys for qepa may indicate its low prevalence (< %). the natural reservoir of qepa remains unknown but might be an actinomycetal species. discovering of three main mechanisms of pmqr within the last ten years is peculiar. it may reflect the emergence of novel mechanisms of resistance but also a deeper investigation of resistance mechanisms in clinical isolates. emerging infections: can we cope with them? a. kühn°, c. schulze, h. ranisch, p. kutzer, h. nattermann, r. grunow (berlin, frankfurt-oder, de) objective: little is known about the prevalence of francisella tularensis in humans and animals in germany. interestingly, the pathogen emerged recently when several marmosets (callithrix jacchus) died from tularaemia and a group of hunters became infected in the areas of western germany. to find out more about the distribution of the pathogen also in eastern germany we investigated the seroprevalence of tularaemia under foxes (vulpes vulpes) and raccoon dogs (nyctereutes procyonoides) in the area of brandenburg (around berlin). methods: sera of animals (n = and n = , respectively) from the years and were tested for f. tularensis − lps antibodies in an indirect elisa and suspicious samples were confirmed by western blot for lps ladder recognition using protein g − pod conjugate. furthermore we investigated the serum samples by a competitive elisa using a peroxidase-conjugated anti − lps monoclonal antibody. results: from the serum collection, we tested ( . %) foxes and raccoon dogs ( . %) positive for specific f. tularensis antibodies. the geographical distribution showed hot spots in the area of the investigated region. our results indicate for a higher seroprevalence in wildlife for tularaemia in eastern regions of germany than assumed. since the reported human cases for the last decade seem to be underestimated, the real prevalence of the pathogen is unknown. the high number of tularaemia antibody positive foxes and raccoon dogs indicates that this zoonose is present in wildlife in eastern germany. however, the impact of transmission of zoonotic pathogens from wildlife to domestic animals and humans is not yet well studied. in conclusion, the obtained data will contribute for creating of up-to-date strategy for more efficient control of the two rickettsial zoonoses. objective: helicobacter pylori is established as the primary cause of gastritis and peptic ulceration in humans. in a minority of patients with upper gastrointestinal symptoms long tightly coiled spiral bacteria, clearly distinct from h. pylori, and provisionally named as "h. heilmannii", can be observed in gastric biopsies. our objective was to isolate and identify the spiral organism, resembling "h. heilmannii" from the gastric mucosa of a finnish patient presenting with severe dyspeptic symptoms. methods: we used two different selective media for the isolation of the bacteria from gastric biopsy samples before and after treatment of the patient with a -day course with lansoprazole, tetracycline and metronidazole. the isolates were characterised by testing for urease and catalase activity, light and electron microscopy, and sequencing the partial s rrna and ureab genes. single enzyme aflp was used to analyse the genetic diversity among the isolates. results: growth of long spiral organisms was obtained from out of antrum and all corpus biopsies before and all three antrum biopsies after treatment of the patient. the partial s rrna gene sequence showed high sequence similarities with other gastric helicobacter species. the partial ureab gene showed high sequence similarity with h. bizzozeronii and was clearly distinct from other gastric helicobacter species. aflp indicated that the isolates belonged to the same clone however some minor genetic diversity was observed among the isolates. results: b. pseudomallei was primarily found in close proximity to streams and in grass-rich areas but was also correlated with environmentally disturbed soil such as caused by the presence of animals, farming or irrigation. prediction maps are currently being verified by sampling predicted b. pseudomallei "hot-" and "cold-spots". see in figure a prediction map for rural darwin with red areas indicating high probability for presence of b. pseudomallei. this study contributes to the elucidation of the environmental distribution of b. pseudomallei in endemic tropical australia and to the clarification of environmental factors influencing its occurrence. it also raises concerns that b. pseudomallei are spreading due to changes in land management. o concurrent multi-serotypic dengue infections in various body fluids w. kulwichit°, s. krajiw, d. chansinghakul, g. suwanpimolkul, o. prommalikit, p. suandork, j. pupaibool, k. arunyingmongkol, c. pancharoen, u. thisyakorn (bangkok, th) objectives: dengue virus infection is one of the rapidly-spreading emerging diseases worldwide. the virus is divided into distinct serotypes with limited cross-protective immunity; therefore, one can be reinfected with different serotypes. while each episode is usually caused by a single serotype, an individual can occasionally be infected by concurrent multiple ones. our group has previously detected dengue virus from urine and oral specimens of some patients. in this study, we sought to determine the characteristics of multi-serotype infections when analysing beyond the patients' blood compartments. methods: during during - and adult patients suspected of dengue infections were enrolled. plasma, peripheral blood mononuclear cells (pbmc), urine pellets, buccal brushes, and saliva were collected during and after the febrile episode. only specimens from patients with both positive dengue serology and pan-dengue-specific rt-pcr were included. serotype-specific rt-pcr was then performed on the aforementioned various specimens of each patient. results: patients met the above criteria. serotyping was successful in patients. den- was the most common serotype, accounting for half of the cases. of these ( . %) demonstrated multiserotypic infections when combining data from all specimen types in each individual. serotyping using single, conventional serum/plasma specimens, however, would detect only half of the cases. the phenomenon of concurrent multi-serotypic infections was present in all examined specimen types, including urine pellets, buccal brushes, and saliva. the most frequent combinations were den- + den- and den- + den- ( cases each). two patients were simultaneously infected by serotypes , , and and one by serotypes , , and . there was no demonstrable significant difference in clinical severity between single-and multi-serotypic infections. conclusion: in a dengue-hyperendemic country with simultaneous circulation of all four serotypes, the phenomenon of concurrent multiserotypic infections are more common than previously demonstrated by traditional serotyping on single serum/plasma specimens. this may be explained by the sensitivity limitation of the detection method or by biological behaviour of the virus. our findings have an implication for potentially more accurate epidemiologic studies in the future, and for further exploratory investigations regarding dengue virus in various secretions and excretions. o emerging concepts about the evolutionary history of hantaviruses h.j. kang, s.n. bennett, l. sumibcay, s. arai, a.g. hope, j.a. cook, j.w. song, r. yanagihara°(honolulu, albuquerque, us; tokyo, jp; seoul, kr) objective: recent discovery of genetically distinct hantaviruses in shrews (family soricidae), captured in widely separated geographic regions, challenges the conventional view that rodents are the principal and progenitor reservoir hosts of hantaviruses, and raises the possibility that other soricomorphs, notably moles (family talpidae), harbour hantaviruses. methods: using oligonucleotide primers based on conserved genomic regions of rodent-and soricid-borne hantaviruses, rna extracts from tissues of the japanese shrew mole (urotrichus talpoides), american shrew mole (neurotrichus gibbsii) and european common mole (talpa europaea) were analyzed for hantavirus sequences by rt-pcr. newfound s-, m-and l-segment sequences were aligned using clustal w and were analyzed phylogenetically by the maximum-likelihood and markov chain monte carlo tree-sampling methods, with the gtr+i+g model of evolution. results: novel hantavirus genomes, designated asama virus (asav), oxbow virus (oxbv) and nova virus (nvav), were detected in tissues of urotrichus talpoides, neurotrichus gibbsii and talpa europaea, respectively. sequence and phylogenetic analyses indicated that asav and oxbv were related to hantaviruses harboured by soricine shrews in eurasia and north america, respectively. by contrast, phylogenetic analyses of full-length s-and l-segment sequences showed that nvav formed a unique clade, clearly distinct and evolutionarily distant from all other hantaviruses. despite the high degree of sequence divergence at the nucleotide and amino acid levels, the secondary structures of the nucleocapsid proteins, as well as the l-segment motifs, of the moleassociated hantaviruses were well conserved. conclusions: while cross-species transmission has influenced the course of hantavirus evolution, such host-switching events alone do not satisfactorily explain the co-existence and distribution of genetically distinct hantaviruses among species in two taxonomic orders of small mammals spanning four continents. when viewed within the context of molecular phylogeny and zoogeography, the close association between distinct hantavirus clades and specific subfamilies of rodents, shrews and moles is likely the result of alternating and variable periodic codivergence at certain taxonomic levels through evolutionary time. thus, the primeval hantavirus might have arisen from an insect-borne virus, with ancestral soricomorphs, rather than rodents, serving as the original mammalian hosts. from south-eastern france m. kaba, b. davoust, j.l. marié, m. barthet, m. henry, c. tamalet, j.m. rolain, d. raoult, p. colson°(marseille, toulon, fr) objectives: autochthonous hepatitis e is currently considered as an emerging disease in industrialised countries and several studies suggest that hepatitis e is a zoonosis, especially in pigs, boars and deer. we aimed to study whether hepatitis e virus (hev) is commonly present in domestic pigs in southern france, and to determine the relationship between hev sequences detected from pigs and those described in human hepatitis e cases. methods: serum and stools samples were collected from three or six-month-old pigs from different regions of southern france. sixmonth-old pigs were from a slaughterhouse, and three-month-old pigs were from a pig farm. swine igg anti-hev antibodies testing was performed using a commercial elisa kit for clinical diagnosis with minor modifications. swine hev rna detection was conducted by realtime pcr and amplification/sequencing assays using in house protocols targeting the orf region of the hev genome. results: % of pigs were seropositive, and % of three-monthold pigs were hev rna-positive, whereas none of the six-monthold pigs were hev rna-positive. hev rna was significantly more frequently detected from stools than from serum ( % versus %; p < . ). phylogenetic analysis showed that swine hev sequences belong to genotype f or e and formed two clusters within which sequences showed high nucleotide homology (> %). these clusters were correlated with the geographical origin of pigs as well as with their repartition into pens and buildings in the pig farm where samples were collected. swine hev sequences from the present study were genetically close to hev sequences found from humans or swine in europe, although no strong phylogenetic link could be observed neither with these latter sequences nor with those from human hepatitis e cases diagnosed in the laboratory. conclusion: our data indicate that three-month-old farm pigs from southern france might represent a potential source of contamination to humans, and they underscore the great potential of hev to cause epizootic infections in populations of farm pigs. o clostridium difficile: changing epidemiology trends, - objectives: clostridium difficile infection (cdi) has become a growing concern world-wide with an increased reported incidence and an increase in the associated financial burden. our aim therefore was to review trends in cdi occurring from - inclusive. methods: all patients admitted to lothian university hospitals division (luhd) tested for c. difficile toxins a+b by eia were included. retrospective analysis of prospectively collected data was performed. the number of occupied bed days was provided by nhs-lothian statistics department. the most recent published costs associated with cdi were used to estimate potential costs to lothian nhs trust. results: , faecal samples were tested for c. difficile toxins from - inclusive; of these samples were positive. overall cdi was identified in . cases/ patient days and . cases/ inpatient hospital admissions. the incidence of identified cdi rose from . cases/ patient days in to . cases/ patient days in . incidence also increased with age from . cases/ patient days in the − years age group to . cases/ patient days in the − years age group. renal medicine and intensive care had the highest incidences of identified cdi with greater than cases/ patient days each followed by infectious diseases and gastrointestinal medicine whose rates were . and . cases/ patient days respectively. medicine of the elderly in comparison had an incidence of . cases/ patient days. of note % of all patients were transferred through a minimum of two specialties during the period in which they remained positive for c. difficile toxins. estimated costs over the study period for toxin testing alone were in the region of £ , and the minimal potential hospitalisation costs of patients with cdi was in the region of £ , , . conclusion: the incidence of patients identified with cdi has risen markedly and not surprisingly the incidence has also been noted to increase with age. medicine of the elderly however had a much lower incidence than several other specialties and therefore risk assessment of cdi development and containment should now also be targeted within other specialties. with % of identified cdi patients transferred through different specialties and the significant financial burden cdi imposes on healthcare institutions judicious application of infection control measures remains an important factor to prevent cdi spread. isolates of this strain were pvl negative, but positive for enterotoxin a (sea) and, in most cases, also for seb, sek and seq. a fifth strain was the "taiwan clone", st / -mrsa-v (wa mrsa- and - ) which also comprised two closely related sequence types. this strain carried a sccmec element of type v(t) or vii as well as pvl and, usually, seb, sek and seq. it was the most common cc strain in wa. the sixth strain differed from the "taiwan clone" in the presence of a sccmec type v element and in the absence of pvl. the differentiation of this clonal complex into various different strains indicates a rapid evolution and spread of sccmec elements, and the diagnostic microarray technology allows one to distinguish beyond mlst level and hence to accurately trace outbreaks and spread of these strains. a sample taker has daily contact with poultry and is excluded from analysis. b sample taker reported no contact with livestock elsewhere than in this study at that moment (spa-types of sample taker and farm are not corresponding). c sample taker tested mrsa-negative in following tests. d sample taker was not tested again. complete data sets (samples taken before, directly after and hours after a visit) were collected on visits by sample takers visiting farms. on farms mrsa was collected from pigs or stabledust ( %). these farms were visited times by different sample takers. one sample taker (# ) was positive for mrsa before visiting a farm, he was removed from the following analysis. fifteen of the ( %) visits to mrsa-positive farms resulted in acquisition of mrsa and / ( %) sample takers acquired mrsa at least once after visiting a positive farm. of these positive sample takers acquired mrsa twice and sample taker acquired mrsa three times after separate visits. of the acquisitions of mrsa, were negative after hours. the spa-types of mrsa isolates found on the farms and sample takers were grossly comparable. on the negative farms, none of the visits resulted in mrsa acquisition. for further information see the table. discussion: mrsa-cc was acquired by % of the sample takers after occupational exposure in this study. however, in of the cases the strain was not recovered the next day, therefore acquisition was of short duration, posing a limited treat to human health. some persons seemed to be more vulnerable to acquire mrsa during their work. the sample size of this study was too small to draw final conclusions concerning this inter-personal variation. this requires a more extensive study. [ objectives: community-associated mrsa is an increasing problem and an association with food animal contact has been made in some regions. this has led to concerns about the potential role of food in mrsa transmission. the objective of this study was to evaluate the prevalence of mrsa colonisation of retail pork in canada. methods: pork chops, ground pork and pork shoulders were purchased at retail outlets in four canadian provinces in conjunction with the canadian integrated program for antimicrobial resistance surveillance. both direct inoculation of meat into enrichment broth and rinsing of meat in broth were performed for pork chops and shoulders, followed by inoculation onto chromogenic agar. ground pork was tested only using the direct method. mrsa isolates were typed by pfge and spa typing. real time pcr was used to detect panton-valentine leukocidin genes. results: mrsa was isolated from / ( . %, % ci . − . %) of samples. there was a significant difference between provinces (p < . ) but no difference between different products, with mrsa isolated from / ( . %) pork chops, / ( . %) ground pork and / ( . %) pork shoulders (p = . ). / ( . %) samples were positive using direct culture while mrsa was isolated from / ( . %) of samples testing using the rinse method. nine samples were positive on direct culture but negative using the rinse method, while others were positive only with the rinse method and only were positive with both methods. seven samples (ground pork) that were positive on direct culture were not tested using the rinse method. main clones were present. the most common ( % of isolates) was a group of related spa types (t , t and new related type) were classified as canadian epidemic mrsa- by pfge, an st human epidemic clone that has been associated with horses. pfge-non-typable spa t were not surprisingly common, accounting for % of isolates. the rd main group was related spa types (t , t and new type) that were cmrsa- (usa ), an st clone that is common in humans in canada, that also accounted for % of isolates. the clinical relevance of mrsa contamination of pork is currently unclear. it is possible that contact with contaminated food could be a mode of mrsa transmission in the community, although further study of the prevalence of contamination, amount of mrsa in contaminated samples, sources of contamination and implications on human health are required. o prevalence of the novel trimethoprim resistance gene dfrk among german staphylococcal isolates of the bft-germvet monitoring study k. kadlec°, s. schwarz (neustadt-mariensee, de) objectives: very recently a novel trimethoprim resistance gene, dfrk, was identified on a tet(l)-harbouring plasmid in a porcine mrsa isolate from the bft-germvet monitoring study. this study included in total independent coagulase-positive and coagulase-variable staphylococci collected between and all over germany: isolates from infections of the urinary-genital tract of pigs, isolates from skin infections of pigs, isolates from respiratory tract infections of dogs/cats, and isolates from infections of skin/ear/mouth of dogs/cats. in this study, we investigated the prevalence and the plasmid location of the dfrk gene among these isolates. methods: pcr primers were designed and a pcr with subsequent restriction analysis of the pcr product was established to detect dfrk. isolates with positive results were tested for a plasmid location of dfrk by transfer experiments and dfrk-carrying plasmids were further analysed. the trimethoprim resistance gene dfrk was detected in another isolates. all isolates were from pigs: from skin infections and the remaining from a urinary-genital tract infection. six staphylococcus hyicus subsp. hyicus isolates, s. aureus isolates ( mrsa and mssa) and s. pseudintermedius. all these isolates harboured plasmids. in isolates ( s. hyicus, mrsa and the single s. pseudintermedius), the plasmid location of dfrk was confirmed by protoplast transformation with subsequent susceptibility testing and pcr analysis of the transformants. in all cases, the plasmids harbouring dfrk also carried a tet(l) tetracycline resistance gene. the results of a combined pcr assay with primers from tet(l) and dfrk confirmed that the dfrk gene was always located immediately downstream of the tet(l) gene. further analysis of these dfrk-and tet(l)-harbouring plasmids showed that they varied in size between and kb and that similar sized plasmids differed in their ecorv and hindiii restriction patterns. the novel trimethoprim resistance gene dfrk occurred in ( . %) of the porcine staphylococcal isolates from the bft-germvet study. in ( . %) of the isolates, it was located on structurally diverse plasmids, however, always in close proximity to a tet(l) gene. the linkage of the dfrk and tet(l) genes allows the maintenance and coselection of such plasmids under selective pressure by either tetracyclines or trimethoprim, both of which are widely used in veterinary medicine. (table) . the isolates were resistant to ciprofloxacin, clindamycin, erythromycin, gentamicin but susceptible to vancomycin. only one se was methicillin-susceptible and two isolates were quinupristin/dalfopristin non-susceptible. all strains were clonally related and clustered into three subtypes (a, a and a ). cfr gene was detected in a linezolid non-susceptible strain (mic, mg/l), which was recovered from a y/o male who underwent liver transplantation. plasmid analysis identified six plasmid bands ranging from c.a. . -to -kb in the cfrcarrying strain. hybridisation signals were observed from the -kb plasmid band as well as from a chromosomal band after i-ceui digestion. mutations at the s rrna, l or l were not detected. the cfr increased the linezolid mic value between -and -fold. this report highlights the ability of se to acquire linezolid resistances. the potential mobility of cfr combined with the clonal tendency for dissemination among staphylococcus spp., represent a serious threat to several potent gram-positive-active agents, including oxazolidinones. active surveillance combined with effective infection control and molecular studies seem prudent to minimise the spread of these resistance mechanisms. the objective is to get a glimpse of the potential impact of infectious diseases on music, as regards to the composer's or performing musician's own disease, living conditions or other relevant elements which might have affected the end result, the music we enjoy today. as music is an art of senses, full of drama, despair, realities of life − or just the opposite, blissful ignorance of those realities, full of romance, beauty, and delicacy − various forms of music was researched paying special attention to infections which potentially have played a significant role in the birth of that particular piece or performance. the entire research process was subjective, biased, and emotional, but done wholeheartedly. it aimed at to taking into account, not only the personal life of a composer or performing musician, but also the historical context in which the music was born. musical examples, served to the audience along with the essential background data, will show the extent to which infections have impacted music. regarding the aetiology of those infections, bacterial, viral and parasitic agents are well represented. in addition, many epochs in history have played their role. sometimes, the connections are surprising, even dramatic. if listened to with a tender ear, music quite often turns out to be affected also by infectious diseases. as physicians we should realise the strength with which some people are driven by this demonic, divine − but altogether beautiful force: music. the prevalence of antibiotic resistance has been increasing in asian countries in recent years. this problem has most likely arisen due to a combination of inadequate infection control practices particularly in hospital settings and the widespread misuse of antibiotics in hospital and community settings. factors that lead to antibiotic misuse include inappropriate antibiotic prescription due to a lack of clinical, microbiological and/or imaging data in many clinical settings in the asian region. a lack of separation of prescribing and dispensing by medical practitioners as practised in many countries in asia as well as the easy availability of over the counter medications also contribute to antibiotic misuse. optimal control of antibiotic use can only be achieved through a multipronged approach that includes better education of the public and medical practitioners on rational use of antibiotic, a review of the health system structure, as well as better control of over the counter sales of antibiotics. upgrading of microbiology and other laboratories and radiological facilities that will enhance the accuracy of clinical diagnosis is also urgently needed in most developing countries to keep pace with the complexities of managing patients in this new era to minimise the widespread practise of inappropriate antibiotic use. examination of the csf for microorganisms, wbc and differential counts, and concentrations of glucose and protein is the primary investigation to diagnose meningitis. however, this csf examination may not always be conclusive, and it can be difficult to distinguish bacterial from viral meningitis. therefore, improvement in diagnostic sensitivity and specificity of bacterial meningitis and development of rapid test for a bacterial aetiology are still needed. this presentation gives a review of the strength and weakness of several analyses and methods to reveal the microbiological agent (i.e. csf microscopy and culture, antigen or antibody detection, molecular methods to detect dna or rna) and the use of several mediators of the host immune response for diagnostic and prognostic purposes. bacterial meningitis is a medical emergency that requires a multidisciplinary approach. a diagnosis of bacterial meningitis is often considered, but the disease can be difficult to recognize. recommendations for antimicrobial therapy are changing as a result of the emergence of antimicrobial resistance. in this lecture, current concepts of the initial approach to the treatment of adults with bacterial meningitis will be summarised. the management of the critically ill patient with bacterial meningitis poses important dilemmas. controversial areas (i.e., prehospital admission antibiotics) will be reviewed and relevant literature will be discussed in the framework of current treatment guidelines, highlighting new developments in adjunctive dexamethasone therapy. acute bacterial meningitis (abm), especifically when caused by infection with streptococcus pneumoniae, still has an unacceptably poor prognosis with a mortality of − %. bacterial infection of the meninges causes one of the most powerful inflammatory reactions known in medicine. yet years ago, this inflammatory reaction was suggested to contribute substantially to brain damage. this concept underlies the use of anti-inflammatory agents as adjunctive therapy in abm. of all adjunctive treatments in abm, only corticosteroids have been properly evaluated in clinical trials. these trials recommend corticosteroids in patients with haemophilus influenzae type b and pneumococcal meningitis (pm). however, adjunctive corticosteroid therapy has several weaknesses such as a narrow treatment window and borderline effects on neurologic sequelae. thus, there is still the need for additional or alternate adjuvants in the therapy of abm. experimental studies using animal models (predominantly of pm) have provided insight into the pathogenic mechanisms underlying brain injury in abm. it is now clear that the autodestructive inflammatory reaction is initiated by the interaction of bacterial components with host pattern recognition receptors (prr) like toll-like receptors (tlr). prr signaling results in the activation of transcription factors like nf-kb which up-regulate the production of proinflammatory cytokines. cytokines like il- b are also potent triggers of nf-kb activation and therefore can exaggerate the inflammatory reaction (via positive feedback loops). as a consequence, great numbers of neutrophils are recruited to the meninges. activated neutrophils release many potentially cytotoxic agents including oxidants and matrix metalloproteinases that can cause collateral damage to brain tissue. additionally to the inflammatory response, direct bacterial cytotoxicty has been identified as a contributor to tissue damage in abm. thus, experimental studies point at four different targets of adjunctive therapy, namely interference with (i) the induction of inflammation (e.g., tlr blockade), (ii) the exaggeration of inflammation (e.g., il- antagonism), and (iii+iv) the generation of cytotoxic factors (either of host or bacterial origin, e.g., scavenging of oxidants). this presentation will give an overview of the pathophysiology of abm (with special emphasis on pm) and highlight promising targets for adjunctive therapy in abm, as deduced from experimental studies. a clinician's approach to managing difficult infections s acute post-surgical prosthetic joint infection optimal management of prosthetic joint infections (pji) remains undefined. important issues such us when the implant can be retained (conservative strategy), optimal duration of antimicrobial therapy (at) or the role of rifampin are yet matter of controversy. in spite of a number of reports, literature appears confusing. among the limitations of the literature we must emphasize: ) different criteria to classify pji; ) different criteria to select for conservative strategy (cs); ) no description of the initial population from which patients were selected for cs; ) very different at (from weeks to chronic suppressive therapy); ) low numbers of patients or short follow-up; ) absence of clinical trials. it is not so surprising that the rates of cs success have varied from to almost %. the most useful classification to approach pji was proposed by tsukayama ( ) . in his series out of patients with early pji managed by a cs (debridement, exchange of polyethylen and implant retention) were cured after weeks of at. the spanish group for the study of pji was constituted in within the spanish network for the study of infectious pathology (reipi), a public funded initiative. data from consecutive cases of early pji attended in hospitals were recorded in an online database. cases managed with cs could be analysed (mean followup of years). sixty-seven patients ( . %) were cured after a mean of days of at. in ( . %) the infection was not controlled (or relapsed) after a mean of days of at, and the implant had to be removed. in other patients ( . %) the implant was not removed, but suppressive at was given because of suspected ongoing infection. results were significantly worse in one hospital. no other factors resulted statistically significant, but there was a trend of worse results for mrsa produced infections (p = . ). time from the symptoms appearance to debridement was shorter in successfully treated cases (median, days) than in failures (median, days); p = . . good functional results were obtained in patients with successfully cs. in summary, a substantial proportion of early pji can be managed with cs strategy and a definite (non suppressive) at. it is difficult to identify patients at higher risk for failure, although mrsa aetiology and longer time until debridement seem to predict failures. different outcomes in some centres suggest that surgical technique could be an important factor for failure. more than million cardiac pacing systems are implanted worldwide and the estimated rate of infections after implantation of permanent endocardial leads is % to %, but varies between . to %. pacemaker infections correspond to different clinical situations including localised infection in the device pocket, pacemaker leads to systemic infection associated with bacteraemia and lead-associated endocarditis. this latter represents to % of all cases of pacemaker infections. the severity of pacemaker related infective endocarditis is sustained by a mortality range between to %. risk factors related to infections of implanted pacemakers are correlated with fever before h before implantation, temporary pacing before implantation and early re-interventions (haematoma, lead dislodgment). in contrast, an inverse correlation is observed between development of infection and antibiotic prophylaxis and implantation of a new system. data to guide therapy in patients with pacemaker infection are limited and the most appropriate management remains to be determined. according to different series, staphylococci accounted for to > % of the responsible organisms. coagulase-negative staphylococci (cns) are reported as predominant pathogens following by staphylocococcus aureus. the biofilm production, responsible for bacterial survival, and the emergence of methicillin-resistant in s. aureus and cns have complicated the management of pacemaker infections. this implies that empiric treatment of suspected pacemaker infection should coverage for staphylococci including methicillin-resistant strains. streptococci, corynebacterium spp, propionibacterium acnes, gram-negative bacilli and candida spp can cause occasional infections. the optimal therapy combines complete device extraction (percutaneous ablation or surgical removal during extracorporeal circulation) and prolonged course of antibiotics, in particular in case of multiresistant bacteria. leaving the device intact is associated with increased mortality and risk of relapsing or persistent infections. in absence of prospective studies, the duration of antibiotic treatment remains to be determined but month has been shown not to be associated with an increased incidence of relapse. shortest course of treatment ( weeks) has been proposed in case of vegetations strictly localised to leads without affecting cardiac valves. antibiotic therapy working alone should be reserved for highly selected patients. infection remains the most critical complication of ventriculoperitoneal shunt placement with an incidence of . − %. factors as the age of patient, aetiology of hydrocephalus, the type of shunt implanted, and the surgeon's experience are determined to be associated with increased risk of infection. children are more likely than adults to acquire shunt infection. the possible reasons are longer hospital stay, higher skin bacterial concentrations, immature immune systems, or more adherent strains of bacteria. staphylococci, as skin commensals, are the main causative organisms. nevertheless, in recent years a change in the epidemiology of microorganisms was observed with an increase of gram-negative bacteria. appropriate systemic antibiotics according to the antimicrobial susceptibility testing and surgical removal of the shunt with temporary external cerebrospinal fluid drainage and shunt replacement following the eradication of the infection are the cornerstone of the treatment of cerebrospinal fluid shunt infections. good compliance with infection control practices, inserion of the catheter under aseptic techniques and short-term perioperative antimicrobial prophylaxis in order to prevent the emergence of drug-resistant subpopulations are important steps in the prevention of shunt infections. o influenza in adults admitted to canadian hospitals: data from two seasons a. mcgeer, d. gravel, g. taylor°, c. weir, c. frenette, j. vayalumkal, a. wong, d. moore, s. michaud, b. amihod (toronto, ottawa, edmonton, montreal, saskatoon, sherbrooke, ca) objective: seasonal influenza (flu) remains a cause of substantial morbidity and mortality. antiviral treatment should be considered for all hospitalised patients with influenza. to better understand the epidemiology and burden of illness within the hospital sector in canada and the current use of antiviral therapy, we carried out a multihospital survey of virologically confirmed flu in hospitalised adults. methods: cnisp is a network of largely teaching hospitals across canada that collaborates to collect data on infections in hospitalised patients. during two consecutive years ( / and / ) hospitals within cnisp identified inpatients > years who had virologically confirmed flu. case patient charts were reviewed to capture demographic and clinical data and to determine whether flu was community (ca) or hospital acquired (ha). cases were reviewed at days to determine outcomes. deaths at days were reviewed to determine whether flu was a main or contributing cause. results: fifteen ( / ) and ( / ) hospitals were recruited from the cnisp network. virologically confirmed cases of flu were found, in / ( % flu a) and in / ( % flu a). mean patient age was years, % were male. there was documentation of patient vaccination that season in %. incidence of ca flu was / , admissions in / (range by hospital − ) and in / ( − ). admitting diagnoses in ca cases were: pneumonia or influenza %, exacerbation of copd %, sepsis or fever not otherwise specified %, cardiac diagnoses %, other diagnoses %. % of cases were ha, range by hospital . − . / , patient days. % of patients were managed with droplet and contact isolation practices, an n- mask was used in %. % of ca cases but % of ha cases received antiviral therapy p < . , almost entirely oseltamivir. % of cases were admitted to an icu; -day mortality was % with . % attributed to influenza. conclusion: there is considerable season-season and hospital-hospital variation in flu in patients in canadian hospitals. hospitalised patients ca flu present with a wide spectrum of clinical diagnoses; nearly a quarter of all cases were ha. few ca cases but most ha cases were treated with antiviral drugs. attributable day mortality was . %. v. papastamopoulos, e. kakalou°, t. panagiotopoulos, j. baraboutis, m. samarkos, a. skoutelis (athens, gr) objectives: our study sought to describe influenza vaccination coverage among adults in greece for the season / . methods: we conducted a random-sampling, telephone based household survey among adult individuals in greece. for this purpose a sample of adults representative of the basic demographic, social and geographical characteristics of the overall greek population according to the latest national survey, was used. two target groups were determined for analysis: persons > years of age and persons with chronic conditions such as respiratory and heart conditions (other than hypertension), diabetes mellitus and other conditions. results: the influenza vaccination rate for the season / among the adult population in greece was: % for the overall adult population ( . % for men, . % for women), . % for people > years of age, % for persons with chronic illness ( . % for persons with respiratory illness, . for persons with heart conditions, % for persons with diabetes mellitus). a high rate of % of the overall population reaching % among persons with chronic conditions report having had any type of contact with the national health system or a private physician within the last three years. among them only . % had been recommended to get vaccinated. among the ones recommended any vaccination, . % of persons with respiratory illness, % of persons with diabetes mellitus and . % of persons with heart conditions had been recommended to get the influenza vaccine. conclusions: available data show unacceptably low levels of influenza vaccination coverage among vulnerable groups such as the population over years of age and people living with chronic illness. influenza vaccination is the only preventive measure reducing influenza morbidity and mortality and its use has proven cost-effective among high risk groups. it is also the main vaccine recommended by physicians. however the overall rate of physicians recommendation of vaccination is very low. dynamic efforts are thus needed to design and implement strategies and policies that have demonstrated their rigorous effectiveness in enhancing influenza vaccination coverage rates. conclusions: nasopharyngeal sampling with flocked swabs is well tolerated and suitable to be used in an outpatient setting. implementation of real-time mono and multiplex naats results in a significant improvement of the rate in diagnosing lrti. hrv account for the majority of viral lrti in primary care followed by influenza and coronaviruses but also rsv and hmpv are prevalent in an adult population. in this study, polyomaviruses were detected of which were involved in a double infection. methods: observational analysis of a prospective cohort of nonseverely immunosuppressed adults with pp requiring hospitalisation ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) . of them, were diagnosed by urinary antigen and/or were diagnosed by culture. overall, % of pneumococcal strains were available for serotyping (quellung) and % for pfge (smal) and or mlst. the diagnosis of septic shock was based on a systolic blood pressure < mmhg and peripheral hypoperfusion with clinical or bacteriologic evidence of uncontrolled infection. results: a total of ( %) patients with pp had septic shock at presentation. patients with shock were younger ( vs yrs; p = . ), were more frequently current smokers ( % vs %; p = . ), had received more commonly corticosteroid therapy ( % vs %; p = . ), and were more frequently classified into high-risk psi classes ( % vs %; p < . ) than those who did not have this complication. they were also less likely to have received prior influenza vaccine ( % vs %; p = . ) and had more frequently bacteraemia ( % vs %; p = . ). no significant differences were found in rates of penicillin-( % vs %) and erythromycin-resistance ( % vs %). serotype was more commonly associated with shock ( % vs %; p = . ), whereas serotype was rarely associated with this complication ( % vs %; p = . ). no significant differences were found regarding genotypes: st ( % vs %), netherlands-ser -st ( % vs %), netherlands-ser -st ( % vs %), spain-ser v-st ( % vs %). patients with shock required more frequently mechanical ventilation ( % vs %; p < . ), and had longer los ( vs days; p < . ). early ( % vs %; p < . ) and overall case-fatality rates ( % vs %; p < . ) were higher in patients with shock. conclusions: pp presenting with septic shock is still associated with a poor outcome. it occurs mainly in current smokers, patients receiving corticosteroids, and in those infections caused by serotype . prior influenza vaccination and pp caused by serotype are associated with a lower risk of shock. o high long-term mortality rate after initial recovery from severe community-acquired pneumonia background: despite the presence of antibiotics and vaccination strategies against pneumocci, community-acquired pneumonia (cap) is still a major cause for mortality in developed countries. however, it is unclear how an episode of cap influences long-term survival after initial recovery. therefore, we determined mortality up to years after discharge in patients hospitalised because of an episode of severe cap in a non-intensive care setting. methods: in hospitals in the netherlands, patients (pts) with severe cap (psi class iv and v without need for treatment in icu) were prospectively followed for days and mortality up to years after discharge was determined using the dutch municipal public records database. we used cox regression analysis to examine predictors for mortality. results: compared to strategy , strategy resulted in slightly higher costs (chf , vs. , ) but fewer infections (. vs. . ) during patients' mean length-of-stay, producing an incremental costeffectiveness ratio (icer) of chf , per mrsa infection avoided. strategy was dominated by strategies and (both more costly and less effective). sensitivity analyses suggest that prevalence of colonisation on admission is a stronger predictor of cost-effectiveness than the costs of infection or rapid screening, the probability of cross-transmission, or the incremental costs of isolation and contact precautions. increasing the relatively low on-admission prevalence at our centre by % lowers the icer to chf , per infection avoided. in contrast, increasing the cost of each infection, the cost of rapid screening, or the risk of cross-transmission by % only marginally affects the icer. conclusion: this analysis suggests that compared to risk factor identification and pre-emptive isolation, universal rapid screening upon surgical admission is not strongly cost-effective at our centre. however, local epidemiology plays an important role. in particular, settings with higher prevalence of colonisation on admission may find universal rapid screening more cost-effective. of note, no screening is undesirable, as costs and infections would be higher. results: admission and weekly screening coupled with patient isolation was found to dramatically reduce the number of mrsa acquisitions. the largest reductions were obtained with pcr technology, followed by chromogenic agar. the differences, however, were surprisingly small, and all screening technologies achieved reductions in mrsa acquisition of close to % compared with the no-intervention scenario. nonetheless, chromogenic and pcr-based systems were able to decrease the number of unisolated mrsa-bed-days by approximately and % respectively. conclusions: the small differences in the ability of the screening technologies to reduce mrsa acquisition reflect both a relatively low estimated isolation efficacy and the observed highly skewed distribution of icu-stays, and may provide some important insights into the reasons for recent disappointing trial results. in particular, the skewed length of stay distribution means that most mrsa-bed days are accounted for by relatively long-stay patients for whom rapid detection will make the least difference. key sources of uncertainty were found to be isolation effectiveness and attributable mortality due to mrsa infections, both of which are difficult to accurately estimate with currently available data. the model results allow us to quantify the expected value of reducing these key uncertainties, and help to provide a rational basis for setting future research priorities. objectives: we have shown that there is substantial colonisation of mrsa among nursing home residents and staff with our recently conducted point prevalence study in nursing homes which revealed an overall prevalence rate of % in residents and . % in staff. the aim of this study was, therefore, to test the effectiveness of an intervention in nursing homes which sought to improve standards of infection control as a means of reducing mrsa prevalence. methods: a cluster randomised controlled trial (crct) involving nursing homes, with each home representing the unit of analysis, was performed. the study ran for months with data collected at baseline, , and months. nasal swabs were taken at baseline from consenting residents and staff in all homes prior to randomisation with an audit of infection control procedures also undertaken. following collection of these baseline data, nursing homes were allocated to the intervention or control arm ( : ). intervention home staff were trained in infection control, specifically hand hygiene, catheter care, barrier approaches such as use of gloves, aprons and masks, and decontamination of equipment and the environment with usual practice continuing in control homes. after each data collection timepoint, feedback was given to the intervention homes in terms of their performance and further education and training provided as required. the primary outcome was the prevalence of mrsa in intervention homes compared to control sites. results: preliminary analysis of the data has revealed no significant change in the prevalence of mrsa in the intervention and control homes, taking account of the clustering, over the one-year intervention period [risk ratio . ; % confidence intervals (ci) . − . ]. however, there was an improvement in infection control audit scores in the intervention homes, with a mean score in control homes at months of . % compared with . % in the intervention sites; these scores were significantly different (paired t-test, p < . ). the results suggest that infection control education and training as implemented in this study was not sufficient to affect mrsa prevalence. therefore, a more detailed education and training package either alone or in combination with mrsa decolonisation of staff and residents, may be required to reduce mrsa prevalence within this unique environment. [ objectives: in a response to the rapid global increase in the nosocomial prevalence of multi-resistant micro-organisms, infection control measures, such as patient isolation, are increasingly used. it is unknown how these measures influence the quality of life (qol) of patients during short-term isolation, and this was determined in a prospective matched cohort study. methods: all adult patients needing isolation in a single-patient room between / and / in the umc utrecht were eligible and included − hours after start of isolation (after giving informed consent and being able to fulfil study requirements). for each index patient we identified two control patients, admitted to the same wards at the same time, yet not subjected to any isolation measure. anxiety and depression and qol were assessed using the hospital anxiety and depression scale (hads) and visual analogue scale (eq- d-vas) in all patients. opinions on and experiences with isolation were measured in isolated patients by means of a self-developed 'isolation evaluation questionnaire'. results: isolated patients and controls were included, with comparable baseline characteristics (age, sex, nationality, level of education, length of hospital stay and severity of underlying disease and co-morbidity (using the cumulative illness rating scale)). reasons for isolation were clostridium difficile-associated disease (n = , %), high risk for mrsa carriage (n = , %), or resistant gram-negative bacteria (n = , %). mean scores of questionnaires are presented in table . isin univariate analysis only duration of isolation of hours (compared to hours) was associated with a reduced quality of life (vas . compared to . , p . ). on a visual analogue score of opposite terms isolation measures were rated with means of . , . and . for safety, usefulness and quietness, respectively. conclusion: short-term isolation (up to hours) is not associated with anxiousness or depression, but with positive feelings about safety, usefulness and quietness. index patients (n = ), mean (sd) . ( . ) . ( . ) . ( . ) . ( . ) control patients (n = ), mean (sd) . ( . ) . ( . ) . ( . objectives: there is a lack of data about the impact of healthcare associated infection (hai) on the experience of individual patients. this information is essential to empower health organisations to understand, prioritise, develop and implement solutions that will minimise risks to patients. this study explored comparable narratives from patients who had experienced a staphylococcus aureus blood stream infection with patients who had not. we conducted qualitative semi-structured interviews with eighteen adults who had previously been an in-patient in an acute teaching hospital in scotland. nine patients had had a laboratory diagnosed staphylococcus aureus blood stream infection and nine had no blood stream infection. all patients were interviewed for − minutes. the interviewer asked patients about their thoughts around hai, what concerns they had or still do, what measures they took to safeguard themselves from hai and how their experience impacted on their confidence of the nhs. probing questions were then asked depending on the responses given to the initial questions. all interviews were recorded, transcribed and analysed thematically. results: analysis of transcribed interviews is ongoing. preliminary analysis showed that all patients had positive and negative comments about infection prevention and control practice in the hospital. specific concerns included poor communication, poor cleanliness, awareness of patient boarding, lack of facilities, staff shortages and multi-tasking. some patients who had experienced bacteraemia said they had not been informed about the infection. those who had been informed were not given clear information about treatment or subsequent results. most patients were not specifically told what they or their family should do to safeguard them from infection and little or no written information about hai was provided. most patients are worried about hai on future admissions. the concerns of patients were not fundamentally different if they did or did not experience blood stream infection. the patient's reported experiences show that they have a broad awareness of systems issues that may increase risk of infection. consequently we need to involve patients in the design and evaluation of systems change and information that will improve patient experience. improving the safety and reliability of the system will have direct benefits for all patients in the hospital, not just the ones at risk of hai. analysis of surgical specialties separately revealed a significant reduction of mortality in cardiothoracic surgery who had been treated with mup-chx ( . % ( / ) vs. . % ( / ), p = . , figure) . in other surgical specialties no significant difference was found. conclusion: peri-operative application of mup-chx in nasal carriers of s. aureus undergoing cardiothoracic surgery results in a threefold reduction of mortality after one year. o a lot done, more to do − a survey of teaching about healthcare-associated infections in uk and irish medical schools h. humphreys°, d. o'brien, j. richards, k. walton, g. phillips (dublin, ie; norwich, newcastle-upon-tyne, dundee, uk) objectives: patient safety and the prevention of healthcare-associated infections (hcai) are increasingly important health issues. medical doctors have traditionally been poor in complying with preventative measures to minimise hcai such as hand hygiene compliance. we surveyed medical schools in the uk and ireland to assess what is being taught and assessed in this area. methods: a questionnaire was drafted, piloted and then subsequently forwarded to the heads of medical schools as well as to known contact professionals with an interest in hcai in medical schools. the questionnaire surveyed topics covered in the curricula, the modalities used to assess knowledge and practice, the usefulness of various teaching methods and materials, e.g. lectures, and what education resources were available. results: replies were received from ( %) medical schools; two supplied data on their undergraduate and postgraduate courses. only ( %) covered hcai as a quality and safety issue but over % covered prevalence, recognised risk factors, transmission, and preventative measures. ( %) medical schools assessed competence in undertaking aseptic techniques and the disposal of sharps and mcqs were the most common ( %) means of assessment. case scenarios, resource materials and clinical skills stations were used in educating students in ( %), ( %) and ( %) medicals schools respectively. ( %) medical schools would be willing to share educational resources on hcai with other medical schools. conclusions: medical schools in the uk and ireland include hcai in their curricula but its importance as a safety and quality issue needs to be further emphasized. there is potential for agreeing a core curriculum on hcai and for sharing teaching resources such as videos and e-learning material. objectives: noroviruses are most common cause of outbreaks of gastroenteritis in uk national health service hospitals, leading to ward closure costing as much as £ million per annum. using a detailed data set on norovirus outbreaks from three hospital systems in the south west of england, we estimated ( ) the relative importance of introduction of norovirus from the community and within the hospital and ( ) the cost effectiveness of ward closure at different time points during an outbreak. methods: using regression models we examined the association between number of new outbreaks in a hospital and community levels of activity and number of outbreaks currently occurring in other wards within the hospital. we examined the effect of different ward types (admission, general and long stay units) and whether the ward was open or closed to new admissions on a given day. we then undertook as analysis of cost (-effectiveness) of unit closure by developing a dynamic transmission model taking into account that ward closure may reduce norovirus transmission within and between wards. the stochastic simulation model was based on the actual characteristics of an acute hospital and the norovirus transmission parameters quantified in the statistical analysis. we measured the costs and benefits of closing affected wards at , and days after the onset of symptoms in the first case. results: community level of norovirus infection had a significant effect on the occurrence of new outbreaks as did outbreaks in admission and general medical units. the cost of closing wards to new admissions varied between £ . million to £ . million depending on the assumed effectiveness of closure in curtailing transmission. cost of bed day loss − compared with staff illness -accounted for around % of the total cost of closure. although the total number of cases tends to fall with rapid ward closure (by around % compared with no closure), the actual cost of control is similar regardless of when the closure is performed. we have developed a modelling framework to assess the effectiveness and cost-effectiveness of strategies to control norovirus outbreaks in hospital settings. ward closure is effective at preventing cases but since closure itself is an expensive intervention, it may not always be cost-effective. . other prevalent ribotypes were ( %) and ( %). % of the isolates originated from hospitals located in healthboard areas. the remaining isolates of ribotype originated from hospitals across scotland. in vitro % of isolates were resistant to clindamycin with a mic range of − mg/l, mic of mg/l and mic of mg/l. furthermore % of the isolates were highly resistant to erythromycin (mic mg/l, mic mg/l), and to levofloxacin and moxifloxacin (mic mg/l, mic mg/l for both), while % of these isolates were resistant to cefotaxime (mic = mg/l, mic = mg/l). all isolates were susceptible to metronidazole, vancomycin, meropenem and piperacillin-tazobactam. high frequencies of clindamycin, erythromycin, levofloxacin, moxifloxacin and cefotaxime resistance were also found among isolates of ribotype ( − %) and ( - %). conclusion: until c. difficile ribotype was only reported infrequently in scotland. in , reports of ribotype became more frequent and clusters were detected in hospitals. the majority ( %) of ribotype isolates were resistant to clindamycin. three other european countries have previously reported clindamycin resistance in pcr ribotype , albeit with a higher mic of > mg/l. objectives: to analyze trends in mortality due to clostridium difficile enterocolitis and to describe the most affected groups in order to better understand current clostridium difficile changing epidemiology. methods: we reviewed mortality data from the flanders and brussels regions in belgium (about million inhabitants). we selected those records in which icd- code a . (enterocolitis due to clostridium difficile) appeared as underlying cause of death within the death certificate. age-and sex-specific mortality rates were calculated for the period - . direct standardisation was performed using the european standard population and % confidence intervals were calculated. stata ® and excel ® were used as statistical software. objectives: toxigenic clostridium difficile is an enteric pathogen typical in the hospital environment but also community-acquired cases have been reported. however, relatively few attempts have been made to clarify the role of soil or water as a source of c. difficile infection. in november-december , the drinking water distribution system in the town of nokia, finland was massively contaminated with treated sewage effluent resulting in a large gastroenteritis outbreak. the aim of the present study was to evaluate if contaminated water in this outbreak was also a potential source of c. difficile infection. a sample from the contaminated tap water and a treated sewage effluent sample were collected as soon as possible after the massive faecal contamination of the drinking water distribution system had occurred. c. difficile was isolated from heat-treated water samples by filtrating of ml, ml and ml volumes of water and placing the membranes on selective ccey agar plates, which were anaerobically incubated for d. stool samples from the patients fallen ill during the epidemic were examined for enteric pathogens, including c. difficile. all potential c. difficile colonies were subcultured on ccfa agar plates and toxin-positive isolates were identified by pcr. pcr ribotyping was performed according to the protocol of the anaerobe reference unit in cardiff, uk, using the cardiff-ecdc culture collection as a set of reference strains. after gel electrophoresis, the band patterns were analyzed using the bionumerics software. results: altogether c. difficile isolates were found in water samples. twelve isolates were toxin-positive; isolates were from contaminated tap water and isolates from treated sewage effluent, the latter being the contamination source. among the tap water and sewage effluent isolates, and distinct pcr ribotype profiles were identified, respectively. the human faecal c. difficile isolates detected were divided into distinct pcr ribotype profiles. none of the profiles were identical with that of the hypervirulent pcr ribotype . two isolates, one from tap water and another from a patient, had an indistinguishable pcr ribotype profile. conclusion: our observation implies that c. difficile contamination of a tap water distribution system had occurred. waterborne transmission of toxigenic c. difficile and subsequent c. difficile infection seems possible. objectives: an accurate and rapid method is needed for typing of toxigenic clostridium difficile. a commercial automated repetitive pcr system (rep-pcr; diversilab ® , biomérieux inc., st louis, usa) utilises amplification and subsequent automated electrophoretic separation of the repetitive extragenic palindromic sequences of c. difficile. our aim was to evaluate the performance of this rep-pcr method for genotyping of c. difficile isolates and to compare it to pcr ribotyping. in addition, the correlation between the rep-pcr and the virulence gene profiles of c. difficile strains was studied. methods: a total of toxin-positive c. difficile isolates were studied. we included consecutive isolates from two laboratories in finland, containing also strains of the hypervirulent c. difficile ribotype . in addition, selected c. difficile strains with > bp deletions in their tcdc genes were analyzed. the dna was extracted and the rep-pcr performed according to the manufacturer's instructions. the amplification products of rep-pcr were detected and analyzed using the diversilab system. further analysis was performed with the web-based software accompanying the system. the usefulness of the library construction option of the diverslab system for isolate comparison was tested. the virulence genes (tcda, tcdb, cdta, cdtb and tcdc) were analyzed by conventional pcr and the whole gene sequencing of tcdc was performed from isolates with deletions > bp. pcr ribotyping was performed using the protocol of the anaerobe reference unit in cardiff, uk. the correlation between the rep-pcr profile and the ribotype was excellent. all major ribotype groups were clustered in their own rep-pcr groups. interestingly, subgroups could be found with rep-pcr within two most prevalent ribotypes and . the automated rep-pcr proved to be reproducible; the results from separate dna isolations and pcr-runs/microfluid electrophoresis as well as the results performed by different individuals of laboratory personnel were comparable. the rep-pcr profiles and pcr ribotypes correlated also with the virulence gene profiles. conclusion: this automated rep-pcr represents an effective and reproducible method for the genetic characterisation of c. difficile strains in clinical laboratories with molecular biology facilities. the constructed c. difficile library allows comparing the relatedness of c. difficile strains and their fingerprints over time. objectives: clostridium difficile infection (cdi) is a serious diarrhoeal illness associated with high morbidity and mortality. currently available treatments (oral vancomycin or metronidazole) usually produce good resolution of diarrhoea but are associated with a % to % incidence of recurrence. opt- , the first in a new class of macrocyclic antibiotics, is bactericidal via unique inhibition of rna polymerase. this phase , non-inferiority clinical trial was conducted in more than sites in north america and compared the efficacy and safety of opt- and vancomycin in treating cdi. methods: eligible patients were adults with acute cdi symptoms and a positive stool toxin test. patients received oral opt- ( mg twice daily) or oral vancomycin ( mg times daily) for days. primary end point was clinical cure (resolution of symptoms and no further need for cdi therapy days after stopping study drug). secondary end point was cdi recurrence (diarrhoea and positive stool toxin test within weeks after treatment). global cure was defined as a clinical cure with no recurrence. results: patients were enrolled and % were evaluable. in the per protocol (pp) population (n = ), mean age was . ± . years and . % of patients were male. equivalent rates of clinical cure were observed with opt- ( %) and vancomycin ( %) in the pp analysis; similar outcomes were observed in a modified intent-to-treat (mitt) analysis. significantly fewer patients treated with opt- ( %) than vancomycin ( %) experienced recurrence in the pp analysis (p = . ) and in the mitt analysis ( % vs %; p = . ). significantly more opt- -treated patients achieved global cure ( %) than vancomycintreated patients in the pp analysis ( %; p = . ) and in the mitt analysis ( % vs %; p = . ). opt- was well tolerated with an adverse event profile similar to that of vancomycin. in this study -the largest comparative trial of a new antimicrobial agent versus vancomycin for the treatment of cdi -clinical cure rates after treatment with opt- or vancomycin were equivalent. however, opt- was associated with a significantly lower recurrence rate and a higher global cure rate than vancomycin. opt- is an oral, non-absorbed agent that has a convenient (twice daily) dosing schedule and low risk of adverse events. opt- represents a potential new treatment option for cdi that is associated with a lower recurrence rate than currently available treatments. results: sequence analysis (sa) revealed that locus a is absent in type and that some mismatches are present in the primer annealing sites for loci b, c and g. lowering the annealing temperature and increasing the magnesium chloride concentration for loci b, c and g resolved the low yield of pcr products. applying the mlva on type strains revealed that ( %) strains, encompassing isolates from human (n = ) and porcine (n = ) origin, are genetically related with a summed tandem repeat differences (strd) ). three clonal complexes (cc, defined by strd ) were recognized; one cc contained both human (n = ) and porcine (n = ) strains. the optimised mlva identified genetically related clusters and cc among the isolates from e and ni. ccs contain isolates from more than one hospital and indeed for several clusters isolates from both e and ni. isolates obtained from ni years earlier were part of one large cc. the optimised mlva can distinguish and/or group type strains from distinct settings. type strains from human and animal origin are genetically related. the clustering of some isolates from distinct settings is consistent with community sources for type . the last observations suggest zoonotic transmission. objectives: this paper updates our assessment of the contribution that community-associated clostridium difficile infection (cdi), as reported to the english mandatory surveillance scheme since , makes to both the acute and community sectors of the national health service (nhs) in england. methods: nhs acute trusts (hospital groups) in england are required to report all c. difficile toxin positive diarrhoeal specimens processed by their laboratories whether the patients were in hospital or the community at the time of onset of the illness or when the specimen was taken via a web enabled reporting system. positive specimens from the same patient within days are not reported. reported cases in patients under years of age were omitted from this analysis. enhanced surveillance data (including information on date of admission, patient location prior to testing, sex, age and patient category) on cdi have been collected through a web-enabled reporting system since april . risk factor information is completed on a voluntary basis. results: more than , cases of cdi in patients aged > years were reported, % of these cases were taken in non-acute settings of which % were taken by a general practitioner. a further % of specimens were taken on presentation or < days of admission into an acute trust. approximately % of all cases had at least one risk factor field completed, > , cases reported risk factor information on episode category; % of these cases were community associated and % were hospital acquired. the information reported suggests that only % of the community associated cases were from patients with continued infection or relapsed episodes of cdi, this is compared to % of the hospital acquired cases who had continued infection or relapsed episodes of cdi. conclusions: % of the c. difficile specimens reported by acute trusts were diagnosed in a community setting. published studies suggest that − % of these might be expected to have been acquired during a hospital stay within the previous month (i.e. were community onset hospital acquired cases). future work is required to investigate whether there are differences in the epidemiology, risk factors e.g. antibiotic exposure and outcome of patients with community onset disease. o clostridium difficile-associated disease: a newly notifiable disease in ireland m. skally, f. roche, d. o'flanagan, p. mckeown, f. fitzpatrick°( dublin, ie) new cases of clostridium difficile-associated disease (cdad) became notifiable in ireland on th may . the main objective of this new notification process was to provide a national overview of the epidemiology and burden of cdad. this paper review the first six months of preliminary data notified. methods: the interim case definitions for new and recurrent cdad cases proposed by the european society for clinical microbiology and infectious diseases (escmid) study group for c. difficile were employed. this report reviews the weekly events of cdad extracted from the computerised infectious disease reporting (cidr) system in january . census of population figures were used as denominator data in the calculation of incidence rates. results presented represent weeks of data submitted. results: there were new cdad cases notified on cidr between the th may and th december , representing a crude incidence rate (cir) of . cases/ population (estimated annual cir is . cases/ , ). all cases were laboratory confirmed. there was a higher occurrence of cases in females. the male:female ratio for the period was : . . in . % of cases the sex was unknown. . % of cases were in the greater than years age category. the preliminary data submitted on cidr indicate that . % of cases were hospital inpatients and . % of cases were either gp patients or outpatients. the origin of . % of samples is unknown. there was large variation between the public health regions (table ) . the incidence of cdad in ireland is prominent in older age groups and in healthcare settings. what is more remarkable is the regional variation of cases reported. this varies from . per , in the north east to . per , in the west. the seasonal trend is indistinguishable at present due to late and batch notifications from institutions. o clostridium difficile-associated diarrhoea in immunosuppressed patients with cancer objective: to assess the epidemiology, clinical features and outcome of clostridium difficile (cd) associated diarrhoea in immunosuppressed patients with cancer. methods: review of all episodes of cd associated diarrhoea documented in adults with cancer and haematopoietic stem cell recipients ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) . microbiologic diagnosis included cd isolation from stool samples, direct detection of cd toxin, and testing for cytotoxin production by the isolated strain. we documented a significant increase of cd associated diarrhoea, from . / admissions in to . / admissions in (p < . ). there were episodes in patients. thirty-one patients were male ( %) with a mean age of years (± ). forty three ( %) patients had an haematological underlying disease and had solid tumour; ( %) had received previous chemotherapy, ( %) were stem cell transplant recipients ( presenting with gvhd) and ( %) were neutropenic (< ). in the previous month patients ( %) had received one or more antibiotics (cephalosporins . %, glycopeptides %, carbapenems . %, betalactam + betalactam inhibitors %, quinolones %). fever > ºc ( %) and abdominal pain ( %) were the most frequent manifestations, and the diarrhoea was hemorrhagic in % of the cases. most patients ( %) were treated with metronidazole (median days), and the antibiotic therapy was discontinued in %. in patients who had recovered from neutropenia, the diarrhoea resolved just by discontinuing the antibiotic therapy. no patient developed toxic megacolon or needed surgery. three patients ( . %) had relapses. overall mortality (< days) was % ( patients). the incidence of cd associated diarrhoea in cancer patients has increased significantly in recent years. it is related with important morbidity and mortality. better strategies to improve its prevention and treatment are needed. s linking research to the clinic: how laboratory findings relate to management of invasive candida infections the role of the research laboratory in the management of invasive candida infections goes beyond routinely available tests for identification of candida species and susceptibility testing of antifungal agents. cutting-edge molecular epidemiology technologies have been used to type isolates of candida species based on their dna sequences. multilocus sequence typing schemes have been designed for c. albicans, c. dubliniensis, c. glabrata, c. krusei and c. tropicalis. multi-locus sequence typing can be used to investigate possible hospital outbreaks of infection (finding widely different strain types within a unit indicates no outbreak, although the converse is not true). for c. albicans, typing multiple isolates from the same patient has shown that people tend to harbour as commensals a mixture of closely related but different strain types, which may provide for selection of the most appropriate type for invasion of a particular tissue or in response to antifungal treatment. strains in c. albicans clade , the largest group of related strain types, have a higher proportion of isolates resistant to flucytosine than other clades, and they all share a common resistance mechanism. research on mechanisms of resistance of candida species to many types of antifungal has progressed to the point that some investigators are looking to design dna chips that could be used both for identification and for susceptibility testing of a candida isolate. much research effort goes into detailed study of host-fungus crosstalk in experimental candida infections. animal models of infection have been greatly refined and the latest research shows how early release of chemokines that attract neutrophils into infected tissues contributes to the immunopathology of candida infection. this rapid, innate immune response also emphasizes the need for antifungal intervention at the earliest possible stage to provide the best chance for successful treatment of a disseminated candida infection − a finding now supported by clinical data as well as experimental models. translation of the latest research advances into practical diagnostic tests and new therapeutic approaches for candida infections always takes a long time − typically years − and not all research results find clinical applications. however, the level of effort invested in basic candida research ensures support for steady progress in diagnosis and management. the echinocandins are semi-synthetic lipopeptides that are increasingly used for the prevention and treatment of invasive fungal infections. understanding the pharmacokinetic and pharmacodynamic (pk/pd) characteristics of these compounds is critical for their optimal clinical use. the echinocandins have potent in vitro activity against candida spp., although c. parapsilosis is less susceptible than other candida species. the molecular mechanisms of resistance in candida species, which relate to amino acid substitutions in 'hot spots' within the fks gene, are becoming well characterised. susceptibility breakpoints for all three clinically available compounds have been determined recently by the clinical laboratory standards institute, with a 'susceptible-only' breakpoint of > mg/l suggested. the pk/pd of the echinocandins have been determined in experimental models of disseminated candidiasis, and of both disseminated and pulmonary invasive aspergillosis. these studies suggest that the echinocandins: ( ) display concentration-dependent antifungal killing (or effect); ( ) are extensively distributed into peripheral tissues, where they exhibit prolonged mean residence times at the site of infection; ( ) are fungicidal against candida spp. and induce dose-dependent morphological changes in aspergillus spp.; and ( ) result in a diminished propensity for angioinvasion by aspergillus spp. recent evidence also suggests that the echinocandins have important immunomodulatory properties, which may contribute significantly to their observed antifungal effect. pk/pd modelling and laboratory animal-to-human bridging techniques have been used to identify safe and effective dosages for the echinocandins for relatively uncommon clinical syndromes such as neonatal haematogenous candida meningoencephalitis. these techniques are an efficient method of identifying effective regimens for humans that can be expedited for study in clinical trials. pk/pd modelling techniques can and should be used to address outstanding clinical queries in relation to these compounds, including optimal dosages, decision-support analysis for the setting of in vitro antifungal susceptibility breakpoints and the clinical relevance of inherent or acquired reduced antifungal susceptibility. s invasive candidiasis: which antifungal treatment for which patient? management of patients with invasive candidiasis represents a complex issue owing to the heterogeneity of patients in whom these infections occur. established risk factors for invasive candidiasis, which include total parenteral nutrition, multiple organ failure and candida colonisation, are common to many types of patients that are treated within the critical care setting. furthermore, the severity of the underlying condition in these patients necessitates swift antifungal treatment to ensure optimal outcomes. an additional factor for consideration when treating candida infections is the changing epidemiology of candida species; potentially fluconazole-resistant species such as c. glabrata and c. krusei are becoming more common, particularly in patients with prior fluconazole exposure. a range of antifungal agents is available with in vitro activity against candida species. however, not all of these agents are suitable options for the clinical management of invasive candidiasis because of the overall complexity of both infection and underlying condition. for example, the position of the polyenes, particularly amphotericin b deoxycholate, is becoming less tenable as the risk of renal complications is increasingly regarded as unacceptable in patients that are likely to have or be at risk of multiple organ failure. furthermore, because of the increasing prevalence of fluconazole-resistant species, recent guidelines no longer recommend the use of azoles as first-line treatment for invasive candidiasis except in special cases, focusing instead on the echinocandin agents. there is now a wealth of clinical data available for the echinocandins. micafungin, for example, has been assessed in invasive candidiasis in clinical trials that included a wide variety of underlying conditions and patterns of infection, including neutropenic patients and those with deep infections such as peritonitis. furthermore, micafungin is the most extensively evaluated of the echinocandins in paediatric patients, having been tested both in children up to the age of years and in premature infants and neonates. optimal management of patients with invasive candidiasis depends on a strategy that takes into account the complex nature of the disease. judicious selection of antifungal treatment should be accompanied by consideration of non-drug-related factors that improve survival, such as careful assessment of intravenous catheters and their potential involvement in candida infections. patients with invasive candidiasis often have underlying conditions that are severe illnesses in themselves. these range from neutropenia during cancer chemotherapy to the multi-organ failure of intensive care unit patients. against this background of severe underlying illness, it can be difficult to appreciate the success or otherwise of treatment strategies for candida infections. in the last decade, major advances have been made in antifungal therapy with the introduction of . echinocandins; . extended-spectrum azoles; and . lipid formulations of amphotericin b. robust clinical studies for their successful use in candidaemia have been published. however, it is important to translate these studies into practical strategies for the care of individual patients. in this presentation, individual cases will be used to provide insights into the successes and failures of these antifungal classes for the management of invasive candidiasis. specific interest will be focused on the use of fluconazole versus the echinocandins. these micafungin-based cases will be supported by insights from the evidence-based literature combined with practical experiences at the bedside. the factors to be considered are: . spectrum of activity; . drug toxicity; . drug interactions; . drug resistance; . pharmacology; . diagnosis; . site of infection; . use of biomarkers/cultures in treatment strategies; and . costs. it is important to realise that large clinical trials exclude many patients with invasive candidiasis. therefore, with the use of individual cases, it is possible to provide further insights into the clinical use of these outstanding antifungal agents. patient management: the era of rapid diagnostic results (symposium organised by cepheid) s will community mrsa and clostridium difficile change infection control in hospitals? infections caused by methicillin-resistant staphylococcus aureus (mrsa), vancomycin-resistant enterococci, and clostridium difficile are inter-related in healthcare institutions. the emergence of epidemic mrsa and c. difficile strains has placed a greater burden on infection control systems in healthcare facilities, which often must increase surveillance and change disinfection strategies to halt the transmission of these pathogens in hospitals. ironically, the usa mrsa strain arose in the community but now is being transmitted frequently in healthcare settings, while the epidemic nap /bi/ c. difficile strain was originally a healthcare-associated pathogen, which now is causing considerable morbidity in community settings. to successfully slow the spread of these pathogens, infection control must work closely with both the laboratory and pharmacy services to ensure that these organisms are detected rapidly and that the selective pressure to maintain the organisms in the institution are reduced. clearly, bundles of interventions, rather than single approaches, are necessary to contain the spread of these organisms in hospitals. the continued influx of patients with communityacquired mrsa and c. difficile infections into healthcare institutions is a challenge for infection control practitioners that will clearly increase in the future. the food borne pathogen l. monocytogenes discovered by murray in is responsible for a severe infection with various clinical features (gastroenteritis, meningitis, meningoencephalitis and materno foetal infections) and a high mortality rate ( %). the disease is due to the ability of listeria to cross three host barriers during infection: the intestinal barrier, the placental barrier and the blood brain barrier. it is also due to listeria capacity to survive in macrophages and to enter into non phagocytic cells, such epithelial cells. recovery from infection and protection against reinfection are due to a t-cell response, explaining why listeria has since many years has become a model in immunology. nearly three decades of molecular biology and cell biology approaches coupled to genetic and post-genomic studies have promoted listeria among the best models in infection biology. in depth studies of the mechanism of entry into cells has help unraveling how listeria crosses the intestinal and placental barrier. unsuspected concepts in cell biology were discovered. post-genomic studies have recently allowed to unveil the listeria transcriptional landscape during switch from saprophytism to virulence. the talk will give an overview highlighting recent results in the frame work of well established data. the last several decades of research in medical mycology have offered great insights into fungal cell biology, epidemiology, phylogenetics and the cells and molecules involved in the pathogenesis of fungal disease. a legitimate question is to ask to what extent our extensive advances in comprehension of the biology of fungal pathogens have contributed to improvements in diagnosis and treatment. to what extent do patients benefit from translation of basic research into tools for clinical management? and the equally valid question: to what extent does biological science benefit from study of fungi that are opportunistic pathogens? the speaker will examine some of these questions from the perspective of long experience in the field and the curmudgeonly attitude that develops with age. objectives: the incidence of invasive meningococcal disease (imd) has been reported in the czech republic since . in response to the emergence of a new hypervirulent clonal complex, cc , nationwide enhanced surveillance of invasive meningococcal disease was implemented by the national reference laboratory for meningococcal infections (nrl) in . the case definition is consistent with the ecdc guidelines. culture and pcr are used for confirmation of cases. notification is compulsory and is performed by local epidemiologists. strains of neisseria meningitidis isolated from imd cases are referred by the field laboratories to the nrl to be characterised by serogrouping, pora and feta sequencing (http://neisseria.org/nm/typing/) and multilocus sequence typing (mlst) (http://pubmlst.org/neisseria/). in the nrl, the epidemiological database is matched against that of strains to avoid duplicate reporting in the final enhanced surveillance database. results: despite the stable trend in imd incidence ( . / ) since , the case fatality rate was high ( . %) in . the disease was caused mainly by serogroup b meningococci ( . %) in , followed by serogroups c ( . %) and y ( . %). the most frequent clonal complexes were cc , cc / and cc (typical for serogroup b) and cc (typical for serogroup c). the highest age-specific morbidity rates were observed in the lowest age groups, i.e. − months and − years ( . / and . / , respectively), and were associated with high prevalence of serogroup b. the case fatality rate was the highest in infants under year of age ( . %). the incidence of imd caused by serogroup c is currently low and there is no indication for mass vaccination with menc conjugate vaccine. menb vaccine is needed for infants, but the sero/subtype coverage by the currently developed porin-based vaccines is low for czech meningococcal isolates (maximum . % for nine-valent meningococcal pora vaccine). methods:the vaccination programme incorporates dedicated vaccine clinic with a multi-disciplinary team including a nurse, data manager, a pharmacist specifically appointed to the unit. additional interventions to improve vaccine uptake and outcome have included use of sms texting to announce availability of influenza annually and improve adherence to completion of hepatitis b vaccination, educational programmes changes in guidelines e.g. varicella vaccination and creation of a vaccine passport. we reviewed vaccination clinic activity in the cohort of , hiv positive patients since introduction of a dedicated vaccine service. results:there has been a large increase in the uptake of vaccinations since introduction of this service. the varicella vaccination uptake increased from ( ) to ( ) due to targeted vaccine programme.(see graphic, legend reads left to right) conclusion: strategies implemented increased the uptake of recommended vaccinations in our hiv population. these included appointment of a dedicated health professional team, use of it supports, education of staff and patients and development of a vaccine passport. we developed the vaccine passport to help with patient education and awareness and it will serve as a record of vaccine administration for physicians off site. in the latter year, post guideline change, we have targeted our varicella non immune population. the next intervention planned is to assess all late entrants to our healthcare system to determine need for catch up vaccines, including mmr. results: column purified recombinant protein sspb was found to be a good antigen for both groups of animals used for immunisation. antibodies against the recombinant sspb tested by opsonophagocytosis were found to enhance phagocytosis of gbs strains belonging to different serotypes at the average . times relatively to control. affect against gas strains was less pronounced ( . times) but still statistically significant. antibodies were also capable to interfere with adherence of gbs strains carrying sspb relatively to the strain without the protein. adherence of the strain with sspb towards different cell lines was dramatically higher which proves the function of the protein as adhesin. in passive protection test carried out with mice challenged with virulent gbs or gas strains introduced intranasaly were eliminated from the lungs of the animals times faster in case of the usage of anti sspb serum relatively the control. in the experiments with active protection sspb immunised animals were found be significantly better protected against gbs and gas infection. (table ) . similar results were obtained in the analysis of factors associated with -day mortality. conclusion: these data suggest that outcomes of both community-onset and nosocomial bloodstream infections due to s. aureus may be improved by an expert consultation service. the factors most critical for better outcomes and modifiable in time by id specialist consultation remain to be determined and may be explored as process of care quality indicators. objective: worldwide, the present tuberculosis epidemic is characterised by an alarming emergence in drug resistance. given the limited therapeutic options in mdr (and especially xdr) tuberculosis, there is a need to define the resistance levels and mechanisms present in clinical isolates categorised as drug resistant on the basis of critical concentration testing, so as to facilitate rapid therapeutic decisions. methods: we determined quantitative resistance levels of drug resistant isolates of mycobacterium tuberculosis sampled in switzerland over the past years. resistance-conferring genetic alterations were identified by probe assays and pcr-mediated gene sequencing. results: rifampicin resistant isolates unanimously showed a high-level resistant phenotype (> mg/l) associated with mutations in rpob. in contrast, a significant fraction of clinical tb isolates categorised as isoniazid resistant on the basis of critical concentration testing showed a low-level resistant phenotype (mostly mutations in inha); heterogeneous phenotypic resistance levels were associated with mutations in katg. one third of streptomycin resistant clinical isolates had a low-level resistance phenotype (< mg/l). ethambutol resistance occurred mostly in mdr strains and was linked to alterations in embb, but resistance never exceeded mg/l. our data indicate that some first line agents may be considered as therapeutic treatment option despite in vitro resistance at the critical concentration. diagnostic mycobacteriology would benefit from standardised measures of quantitative drug susceptibility testing in particular for those drugs were significant variations in phenotypic resistance levels are found in clinical isolates, e.g. isoniazid, ethambutol and streptomycin. introduction recent advances in the diagnostics of varicella zoster virus (vzv) infections have changed the perception of this virus as a cns pathogen. a real-time pcr method amplifying a nt segment of the vzv gb region gave . log improved sensitivity over conventional pcr and was employed for routine diagnosis of vzv dna in samples of cerebrospinal fluid (csf). in addition, a new elisa method for detection of antibodies in the csf to glycoprotein e was developed, using a mammalian cell expression system for optimal glycosylation of the antigen. these methods were utilised for studies of vzv-induced cns infections. in a retrospective study, almost all patients had a reactivated vzv infection, but only % showed skin lesions. the following diagnoses were made: acute aseptic meningitis (aam), n = ; encephalitis, n= ; meningoencephalitis, n = ; cranial nerve affections, n = ; encephalopathy, n = ; and cerebrovascular disease, n = . in patients in whom vzv dna levels were determined, significantly higher viral loads were found in those with aam and encephalitis compared to patients with cranial nerve affection (including ramsay hunt syndrome). of the % (n = ) who had a follow-up, % (n = ) had neurological complications after months. sixty-two percent had a ct/mri scan of the brain performed and % of these had pathological findings. vzv encephalitis showed a more broad disease spectrum as compared with herpes simplex encephalitis (hse), as will be presented. detection of intrathecal synthesis of vzv ge antibodies was positive in the vzv encephalitis patients, as well as in some of the hse patients, arguing for a previous suggested role for vzv as a co-pathogen at least in some cases of the latter disease. vzv vasculitis was a more common finding ( % of all cases) than expected from the literature of case reports. mr findings showed that middle and posterior cerebral arteries were targeted. surprisingly, despite substantial vzv dna loads in the csf of these patients, investigated serum samples were pcr negative. thus, vzv might be suggested to be neuronally transported to the arterial walls rather than haematogenously spread. conclusions: vzv is a serious and underestimated cause of cns infection. a substantial number of the patients presented with serious neurological symptoms and sequela, and pathological findings on ct/mri of the brain were abundant, especially in patients with encephalitis and vasculitis. pk/pd controversies for the clinician s pk/pd and azoles the triazoles have revolutionised the treatment of invasive and allergic fungal diseases. fluconazole, itraconazole, voriconazole and posaconazole are available for clinical use. isavuconazole and ravuconazole are in development. the triazoles have broad spectrum antifungal activity. the pharmacokinetics and pharmacodynamics (pk-pd) of the triazoles have been extensively investigated in murine models of disseminated candidiasis. the pd parameter that optimally links drug exposure with the observed antifungal effect is the ratio of the area under the concentration-time curve (auc) to mic (auc:mic). there is increasing information on the magnitude of the auc:mic that is required for optimal antifungal effect. pk-pd principles have been used to define in vitro susceptibility breakpoints. the triazoles are fungistatic against candida spp. their mode of action against aspergillus spp. is less well defined, although they clearly exhibit dose-dependant decrement in fungal burden in laboratory animal models of invasive pulmonary aspergillosis. the triazoles accumulate in tissues and this is important for an understanding of their antifungal effect. in humans, the triazoles are characterised by complicated pharmacokinetic properties. both itraconazole and voriconazole exhibit nonlinear pharmacokinetics. the triazoles all exhibit clinically relevant exposureresponse relationships. recent work from our laboratory suggests that itraconazole exhibits clinically relevant concentration-toxicity relationships. higher concentrations of voriconazole are associated with a progressively higher probability of hepatotoxicity, photopsia and central nervous system toxicity. because of the significant pharmacokinetic variability and clinically relevant drug exposure-response relationships, therapeutic drug monitoring (tdm) is frequently used. a strong argument can be made for the routine monitoring of itraconazole and voriconazole. there may also be grounds to consider monitoring posaconazole levels. tdm should be considered for all patients receiving triazoles who have refractory disease. furthermore, tdm should be considered when compliance, drug interactions and variable pharmacokinetics result in uncertainty about resultant drug exposures. an understanding of the pk-pd relationships of the triazoles has been instrumental in optimising their clinical efficacy. innate immunity s the inflammasomes: danger sensing complexes triggering innate immunity the nod-like receptors (nlr) are a family of intracellular sensors of microbial motifs and 'danger signals' that have emerged as being crucial components of the innate immune responses and inflammation. several nlrs (nalps and ipaf) form a caspase- -activating multiprotein complex, termed inflammasome, that processes proinflammatory cytokines including il- beta. amongst the various inflammasomes, the nalp inflammasome is particularly qualified to sense a plethora of diverse molecules, ranging from bacterial muramyldipeptide to monosodium urate crystals. the important role of the nalp inflammasome is emphasized by the identification of mutations in the nalp gene that are associated with a susceptibility to inflammatory disorders. these and other issues related to the inflammasome will be presented. it is now years since charles janeway hypothesized the existence of clonally derived pattern recognition receptors and pointed to the importance of these in initial responses to bacterial and viral infections. janeway's hypothesis has been validated by the discovery of three groups of prrs. first, are the toll-like receptors which detect microbial lipids and non-self nucleic acids at the cell surface an in intracellular compartments. in addition cytoplasmic sensors of bacteria (nods) and of viral nucleic acids (rigs) have also been characterised. as well as being critical for responses to infections, these prrs also underlie a large burden of autoimmune and inflammatory disease in the human population and are thus important targets for therapy. in my talk i will describe the molecular mechanisms by which these conserved pathogen associated moecules are recognized by the tlrs with particular reference to lipo polysaccharide and single stranded viral rnas. i will also present new results which show how receptor activation is coupled to downstream signal transduction and in particular the role played by oligomeric signaling platforms assembled form adaptors and other signaling molecules involved in the pathway. i will discuss the potential for structural analysis to be used in the rational design of new drugs. this session proposes a critical review of the most salient recently published papers in the field with a special focus on control of multi drug-resistant organisms, prevention of infections in the intensive care unit, surgery etc. and highlights the need for validity/scope assessment. it emphasizes also the importance to prioritise information published in the abundant literature available so as to be able to summarise and understand the potential changes in clinical practice, and identify unresolved issues and areas of possible future clinical research. tourism is europe's face to the world. it is also a major source of revenue, employment and productivity. each year over million arrivals are recorded into the continent, and of those, approximately million are from latin america. returning travelers are even more numerous and more often associated with disease transmission into europe. within countries of the european continent, imported cases of environmental and zoonotic illnesses such as cholera, dengue, malaria, viral haemorrhagic fevers and west nile virus infections are a rare but established fact. diseases imported from latin america with the potential for autochthonous transmission (chikungunya, malaria, yellow fever) and or high infectivity (viral haemorrhagic fevers) will be described in detail and the possibility of european outbreaks from latin american countries will be discussed. cutaneous leishmaniasis (cl) is a worldwide disease, endemic in countries, that has shown an increasing incidence over the last two decades. so far, pentavalent antimony compounds have been considered the treatment of choice, with rates of curing close to %. however, the high efficacy of these drugs is counteracted by their adverse events. recently, in vitro and in vivo studies have shown that no plays a key role in the eradication of the leishmania parasite objective: to determine whether a no donor patch (developed by electrospinning technique) is as effective as meglumine antimoniate in the treatment of cl while causing less adverse events methods: a double-blind, randomised, placebo-controlled clinical trial was conducted with patients diagnosed with cl in santander, colombia, south-america. the patients were randomly assigned to two groups. during days group received simultaneously meglumine antimoniate and placebo of nitric oxide patches while group received active nitric oxide patches and placebo of meglumine antimoniate. biochemical determinations (aspartate aminotransferase, alanine aminotransferase, creatinine and pancreatic amilase) were measured at he beginning and at the end of the treatment. a follow up was realised , and days after the beginning of the treatment results: the study included ( . %) women and ( . %) men. the average age in group was . ± . years; while in group it was . ± . years. clinical and demographic data were similar in the two groups. after the follow up period, the complete clinical healing of group was . % versus . % for group (p= . ). treatment with no patches generated both, a lower frequency of non-serious adverse events (fever, anorexia, myalgia, arthralgia, headache), and a reduced variation in biochemistry determinations (asat the treatment with no patches resulted in a lower percentage of complete clinical response compared with meglumine antimoniate. despite its inferior effectiveness, the safety, the lower frequency of adverse events, the facility of administration (topical) and the low cost of the patches justifies its evaluation in further poblational studies, especially in populations as the colombian ones, where the serious adverse events due to glucantime have increased dramatically. objectives: trichinellosis is a zoonotic disease which has never been reported in taiwan and is rarely linked to consumption of reptiles. we investigated the first documented outbreak of trichinellosis in taiwan consisting of patients who became acutely ill after eating at the same restaurant in may . we conducted a retrospective cohort study by interviewing the patients and persons who ate together with them. a case was defined as illness in an attendee who had fever (> . ºc) or myalgia weeks after the festivals and was seropositive to trichinella antigen using an enzymelinked immunoassay and immunohistochemical staining. environmental study of the soft-shelled turtle farm was performed. results: of the attendees, persons met the case definition (attack rate = %). the most common presenting symptoms were myalgia ( %), fever ( %), and periorbital swelling ( %). all patients sought medical care; five were hospitalised. of the patients who underwent blood test, all had moderate eosinophilia. all patients' serum samples were strongly reactive to trichinella excretory-secretory antigen. the only food item significantly associated with illness was the raw softshelled turtle meat (relative risk undefined; p = . ). traced back to the farm, histological examination of soft-shelled turtles was negative for trichinella species. the most likely cause of this outbreak was consumption of raw soft-shelled turtle served in the festivals. this investigation indicates taiwan is not free of trichinellosis. prevention and control programs of trichinellosis should be established. the public should be aware of the risk of acquiring trichinellosis from consumption of raw soft-shelled turtle. objective: to develop and evaluate a modified, rapid giemsa staining procedure for detection of malaria parasites in blood smears. disadvantage of the rapid commercially available staining methods is that they require highly experienced technicians for interpretation of results because the interpretation can be difficult. for this reason, many laboratories use the giemsa stain. shorter giemsa staining times have been reported previously, however, to our knowledge, the effect of and minute staining in different giemsa dilutions have not been evaluated. the stock solution of giemsa stain (merck, darmstadt, germany) was used in different dilutions ( : and : ) and incubated for different lengths of time ( min and min). the staining effect was compared to our standard giemsa stain ( : , min). sensitivity was determined by examining smears of p. falciparum from fresh and edta blood. the level of parasitaemia was followed in two patients admitted to our hospital with p. falciparum parasitaemia's of . % and . % (see table; patient a and b) by examination of blood smears taken at different time points after initiation of therapy. these samples were used to evaluate the different giemsa dilutions and staining times. smears were read by three independent observers (a clinical microbiologist, a laboratory technician specialised in parasitology, and a resident in clinical microbiology). in the table results of the three staining methods on blood from two patients from ghana with high parasitaemia's on admission and during follow-up are shown. all smears were equally easy to read and yielded parasite counts within internationally accepted ranges of variation (see united kingdom national external quality assessment service). conclusion: staining blood smears for detection of plasmodium falciparum parasites with a : dilution of giemsa stain for five minutes provides easy to read slides and results comparable to those obtained with the standard giemsa staining. advantage of the rapid method is the shorter turnaround time, disadvantage is the larger amount of stain used. objectives: diarrhoeal diseases are common in developed and developing countries and are major causes of morbidity and mortality worldwide. the need to differentially diagnose protozoan parasites versus other gastrointestinal (gi) aetiologies is well recognized. the most common gi protozoan parasites infecting humans worldwide are considered to be entamoeba histolytica, giardia lamblia, blastocystis hominis, dientamoeba fragilis and cryptosporidium spp. laboratory detection of these parasites is relying on microscopic analysis of stool samples and water concentrates, as well as enzyme immunoassay (eia) tests. utilising the microscopic examination usually results in underdetection of gi parasites, while usage of eia is often not cost-effective. methods: savyon diagnostics is currently engaged with developing an approach aiming to address the unmet needs and the current limitations in this field. this approach includes major aspects: ( ) the ability to detect a panel of all the above organisms in one test kit, ( ) the possibility to perform the diagnosis in two steps − first, simultaneous detection of these organisms without distinguishing between the different species for screening of large number of specimens, and second, distinctive detection of the specific aetiology in the positively-found specimens, and ( ) the ability to apply eia diagnosis in formalin-preserved specimens for all the mentioned parasites. results: polyclonal antibodies were produced in-house based on native antigen extracts, recombinant antigens and synthetic peptides. the resulted inventory of antibodies enabled finding the optimal combination that provided the desired performance parameters for separate detection of each of the parasites in fresh, frozen or formalin preserved faeces specimens. the analytical limit of detection and the performance in characterised clinical specimens were comparable to microscopy or to reference eia, when available. the results show unique detection of e. histolytica in formalin-preserved specimens, which is comparable to detection in fresh specimens. furthermore, we demonstrate simultaneous detection of the parasites without compromising performance characteristics in fresh or preserved specimens. the presented work is a paradigm of an innovative approach, expected to advance the diagnosis of protozoan parasites in gi patients, thus, enabling appropriate and cost-effective diagnosis and treatment. objectives: systemic administration of certain facultative anaerob bacteria to mice bearing solid tumours leads to accumulation in tumours compared to normal target organs, like spleen and liver, and to retardation of tumour growth. salmonella enterica serovar typhimurium (s. typhimurium) as well as escherichia coli nissle (ecn) are such bacteria. preliminary experiments showed that such bacteria that exhibit the ability to form biofilms in vitro might also do so in tumours. in the present study this was systematically investigated. methods: biofilm formation of bacteria were detected on low-salt biofilm plates. additionally, salmonella-or e. coli-infected ct tumours of balb/c mice that were left untreated or were treated with anti-gr to deplete neutrophilic granulocytes were removed two days post infection, fixed and prepared for electron microscope analysis. the expression of different genes which are probably involved in the biofilm formation were tested via real-time pcr. results: when examined after colonising tumours s. typhimurium sl and sl as well as ecn are almost exclusively found extracellular although they are able to invade the ct cells in vitro. interestingly, like in vitro all three bacteria form biofilms to various extend when residing in the tumours. this was followed in more detail for s. typhimurium sl . biofilms were not formed by sl when neutrophils had been removed by antibodies. in addition, when arda a central switch for biofilm formation in the salmonellla had been deleted no biofilms could be found. importantly, now bacteria could be found intracellularly most likely in neutrophilic granulocytes. conclusion: the formation of biofilms by facultative anaerobic bacteria when residing in solid tumours is a novel and surprising finding. when neutrophils were removed, no biofilms are formed, while uptake into neutrophils is allowed when the ability of the bacteria to form biofilms was blocked. hence, it appears that the bacteria use biofilm formation as a defence system against the immune system of the host. objectives: rama is an arac/xyls family transcriptional activator found in klebsiella pneumoniae, salmonella spp. and enterobacter spp., the overexpression of which is associated with an mdr phenotype. recently a tetr-like gene that lies upstream of rama, known as ramr, has been identified as a repressor of rama. k. pneumoniae kp is a diazotrophic endophyte strain which has been reported to exhibit notable resistance to antibiotics. despite its mdr phenotype kp has been shown to exhibit attenuated pathogenicity in mouse models in comparison to clinical k. pneumoniae strains. the aims of this study were to: determine the levels of rama expression and establish its role in kp 's mdr phenotype; determine the effect of ramr complementation on rama expression and antibiotic susceptibility. methods: genome and sequence analysis performed in k. pneumoniae strain kp demonstrated a bp deletion within the ramr gene. cloning and complementation with full size wild type ramr was performed in kp (hereby known as kp /ramr). rt-pcr was used to assess levels of gene expression which were subsequently quantified using bio-rad quantity one software. mic testing was performed against chloramphenicol (cm), norfloxacin (nor) and tetracycline (tet) according to bsac guidelines. biofilm formation was measured using a modified protocol of o'toole and kolter. results: kp containing the mutated ramr gene ( bp deletion) was shown to overexpress rama and the putative outer membrane protein roma. complementation of the ramr gene resulted in the repression of both rama and roma transcription by − fold. interestingly, the ramr complemented strain demonstrated increased biofilm formation (up to -fold increase) over a hour period in both lb and m medium after static growth at ºc. mics of the tested antibiotics were reduced up to -fold in kp /ramr compared to the ramr mutated kp . conclusions: this result demonstrates that ramr acts as a repressor of both rama and putative outer membrane protein roma thereby increasing its susceptibility to antibiotics. however the restoration of a functional ramr in kp also increases biofilm formation significantly, suggesting that ramr plays a role in the regulation of biofilm formation genes and possibly bacterial virulence. rifampicin showed the highest activity on biofilm matrix and bacteria in sa and pa biofilms. results also indicated that biofilm viable mass was more susceptible to treatment than the biofilm matrix, which is mainly responsible for biofilm persistence. further research should specifically focus on compounds destroying matrix and which can be used as an adjunct to antibiotic therapy. [ objectives: staphylococcus epidermidis is a common cause of foreignbody infections (fbi) because of its ability to form biofilms. biofilms are very resistant to antibiotics. active and passive immunisation against biofilm-associated bacterial antigens may be an alternative. we studied the effect of immunisation against the lpxtg protein sesc in s. epidermidis biofilms in vitro and in vivo. we previously reported that sesc is present in all s. epidermidis strains tested. sesc is mainly expressed during the early and late fbi and at a higher level in sessile cells than in planktonic cells. methods: we used rabbit polyclonal anti-sesc-iggs ( mg/ml) to study biofilm inhibition in vitro and in vivo in our rat model ( mg igg per rat) on -day old biofilms. we also vaccinated rats twice with sesc according to standard protocols. serum samples taken at day and weeks after the st and nd immunisation were tested by elisa and showed an increase in anti-sesc antibody levels. s. epidermidis strains b and are biofilm forming strains and have been described before. for in vitro experiments, s. epidermidis b or were mixed with anti-sesc-iggs and incubated for hours at ºc. subsequently cells were added to each well. after h at ºc biofilms were washed and stained with crystal violet and od was measured. for in vivo experiments, catheter fragments were pre-incubated with s. epidermidis b and implanted subcutaneously in each rat. after explantation, the average number of cfu was determined after hrs. results: our data show that rabbit anti-sesc-iggs inhibit in vitro biofilm formation by s. epidermidis strains b and by % and %, respectively (n = ). in the in vivo rat model, rabbit anti-sesc-iggs reduced the bacteria in a -day old biofilm -fold (n = ). active immunisation with recombinant sesc led to a -fold reduction of cfu compared to control rats in day-old biofilms (n = ). after days, the reduction in biofilm-associated bacteria in the immunised rats was -fold (n = ) (fig .) . conclusion: sesc represents a promising target for prevention of s. epidermidis biofilm formation. the higher effect of passive immunisation compared with active immunisation is probably due to the subcutaneous injection of anti-sesc-iggs at the place of catheter insertion. objectives: staphylococcus epidermidis has emerged as a pathogen associated with infections of implanted medical devices impeding their long-term use. characteristics of s. epidermidis that allow persistence of infection are the ability of bacteria to adhere to surfaces in multilayered cell clusters, followed by the production of a mucoid substance more commonly known as slime, encoded by the ica operon. the adherent bacteria and slime are collectively known as biofilm. the coupled effects of specific chemical terminal surface groups and flow conditions on slime production and biofilm formation by s. epidermidis were investigated in correlation to the expression of two genes of the ica operon. methods: reference control strains (atcc , slime-positive and atcc , slime-negative), and two clinical strains isolated from different hospitalised patients, (one ica-positive/slime-positive and one ica-positive/slime-negative) were tested. bacteria grown in bhi medium were suspended in physiological saline at a concentration of~ × cells/ml. hydroxyl (oh)-terminated (hydrophilic) and methyl (ch )terminated (hydrophobic) glass surfaces were used as substrates in a parallel plate flow chamber. bacterial adhesion was examined under two flow rates: ml/min and ml/min for two and four hours. total rna from both planktonic (p) and adherent (a) bacteria, after detachment with trypsin, was isolated by the trizol method. reverse transcription followed by relative real-time pcr (rrt-pcr) towards a bp part of s rrna gene, allowed the detection of expression levels of icaa and icad. adherent bacteria were investigated with scanning electron and confocal laser microscopes. results: higher expression levels of both icaa and icad genes onto glass and especially methyl-terminated glass surfaces were calculated by rrt-pcr, under higher flow rate in two hours by the reference and the clinical slime-positive strains. these results correlate well with adherent bacterial cell counts and images taken by both microscopes. the icapositive slime-negative clinical strain showed lower expression levels of ica genes, less adherent ability and pia production on glass surfaces, as observed by microscopes. higher flow rate enhances the expression level of both ica genes, with a peak in two hours. hydrophobic biomaterial surfaces seem to play a crucial role to initial adherence, increasing ica gene expression and pia synthesis. consenting men and women with dfi (predefined by clinical signs and symptoms) caused by mrsa were potentially eligible including those associated with bacteraemia. patients with initial osteomyelitis were excluded. patients could receive l mg bid either iv or po. primary end point were cure or improvement rates (c+i) and microbiologic eradication (me) at days after the beginning of l. secondary end points were c+i on days and after the beginning of treatment and hospital discharge day, need of amputation, duration of therapy and mortality rates. all the adverse events were collected. results: patients were enrolled. relation men:women was . .the age of patients was . ± years and the average period from the diagnosis of diabetes was . ± . years. associated bacteraemia was present in . % of patients included. primary end points: c+i days after the beginning of l was achieved in . % of patients and me was obtained in . % of patients. secondary end points: c+i on day , hospital discharge day and day after the beginning of treatment and were; %; . % and . % respectively. only patients needed a minor amputation. the primary and secondary end points in the subgroup of bacteraemic episodes were not statistically different of those previously described. the mean duration of therapy was . ± . days. global mortality was . %. only one episode of polineuropathy was reported. neither thrombocytopenia nor lactic acidosis was found. conclusions: l achieved excellent c+i even at first evaluation visit in documented dfi caused by mrsa. l also showed high me rates. although patients received prolonged periods of treatment, l was a safe drug. objectives: azithromycin microspheres formulation (azm) was developed to enable a higher dosage of g to be administered as a single oral dose without decreasing the safety profile. this study compared azm with moxifloxacin (mox) aimed at confirming the efficacy and safety of azm in acute exacerbations of chronic bronchitis (aecb). methods: this prospective, multicentre, randomised, double-blind, double dummy study compared azm g single dose with mox mg once daily for days, enrolled aecb patients years old and above, with anthonisen type exacerbations, and with at least exacerbations of aecb in the past months. subjects were to have a history of smoking of at least pack-years and documented forced expiratory volume in second (fev ) less than % of predicted. they were followed up for up to months. results: a total of patients were treated ( in each of the treatment groups) the distribution of the age, and mean fev were similar for the treatment groups. pathogens were isolated from . % of the patients ( . % of patients on azm and . % of patients on mox). the clinical success (signs and symptoms related to the acute infection had returned to the subject's normal baseline level, or clinical improvement was such that no additional antibiotics were deemed necessary) rate for the per protocol population at test of cure (toc) at day − was . % for azm and . % for mox group ( % ci − . , . ). bacterial eradication rate (bacteriologic pre protocol population) at toc was . % for azm group and . % for mox group ( % ci − . , . ). although the study population had history of at least exacerbation in the past months, less than half of the subjects experienced a recurrence during the follow-up, and there was no statistically significant treatment difference in time taken to first occurrence of aecb. both treatments were well tolerated. the incidence of treatment related adverse events was low, being reported by % of subjects receiving azm and % of subjects receiving mox. most aes were mild or moderate in severity. the most common aes were gastrointestinal disorders, being reported by % of subjects receiving azm and % of subjects receiving mox. conclusions: a single oral dose of azm was as effective as a -day course of mox in the treatment of aecb and was well tolerated. objectives: optimal duration of gentamicin containing regimen for therapy of human brucellosis is not clearly determined. methods: this randomised clinical study was conducted to compare the efficacy of gentamicin mg/day for days plus doxycycline mg twice daily for eight weeks (gd group) versus streptomycin gr im for weeks plus the same dose of doxycycline for days (sd group). all cases were followed for one year after cessation of therapy. efficacy of both regimens (failure of therapy or relapse) were compared. results: seventy-nine patients with the mean age of ± . years and cases with the mean age of . ± . years were treated with regimen of gd or sd, respectively. the clinical manifestations in these two treated groups were similar. failure of therapy was seen in one patient in gd group and in cases in sd group ( objectives: to study the efficacy of telavancin (tlv), an investigational bactericidal lipoglycopeptide, for the treatment of complicated skin and soft tissue infections (cssti) caused by presumed or confirmed grampositive organisms. methods: atlas and atlas were methodologically identical, double-blind, randomised, multinational, phase studies. adult men and women presenting with cssti including major abscess were randomised : to tlv mg/kg intravenous (iv) q h or vancomycin (van) g iv q h for to days. test-of-cure (toc) visit was conducted to days after end of study treatment. the all-treated population (at) included patients with confirmed diagnosis of cssti who received dose of study medication. this analysis examined the baseline characteristics and cure rates at toc for patients with major abscess in the combined atlas at population. results: in the pooled at population of atlas, patients presented with major abscess. more than % of these patients required hospitalisation. the baseline lesion surface area exceeded cm in % of the cases, while % of the patients presented with lesions exceeding cm (table ) . elevated white blood cell counts were found in more than % of the cases (table ) . nearly all patients required surgical drainage, with approximately / performed prior to the first dose of study medication. very few patients required a surgical procedure more than days after the start of study medication. clinical cure rates at toc are presented in table . overall, adverse events in the at population were similar between the treatment groups with regard to type and severity. conclusion: telavancin administered once daily was non-inferior to vancomycin for the treatment of major abscess. objectives: b. fragilis and related species, members of the normal bowel flora, are the most widely isolated anaerobic bacteria from different infections. to follow the development and spread of the resistance among these strains is difficult, as antibiotic susceptibility testing of clinically relevant anaerobes in different routine laboratories in europe is less and less frequently carried out due to the fact, that clinicians treat many presumed anaerobic infections empirically. to follow the changes in the antibiotic resistance of bacteroides strains three europe-wide studies were organised during the past twenty years. the evaluation of the results of these studies may show changes in the resistance to different antianaerobic drugs. only clinical isolates and no normal flora members of bacteroides strains belonging to different species were collected from different countries throughout europe during these studies. agar dilution method was used for the antibiotic susceptibility determination. actual breakpoints accepted by nccls (clsi) and eucast were used. molecular genetic investigations were carried out to detect resistance mechanisms. since the first study the chromosomally mediated beta-lactamase production and tetracyclin resistance is the most prevalent among bacteroides strains in europe. clindamycin resistance in bacteroides is mediated by a macrolide-lincomycin-streptogramin (mls) mechanism and its frequency differs in different countries in europe. resistance to beta-lactam-beta-lactamase inhibitor combinations was studied using amoxicillin-clavulanic acid and/or piperacillintazobactam. increase in resistance was observed to both combinations throughout the years. the same is true for cefoxitine and in the third study several hetero-resistant isolates were found. the occurrence and spread of resistance to imipenem and metronidazole among bacteroides strains merit special clinical importance. the presence of the cfia gene is much more prevalent than the expression of the imipenem resistance; however the spread of the cfia gene among species other than b. fragilis is still very rare. the molecular genetic methods looking for the resistance genes among strains with elevated mics against these antibiotics prove that resistance breakpoints should be reconsidered. the resistance to moxifloxacin shows great differences in different countries. the lowest resistance rate was observed in the case of tigecyclin. many factors may affect the response to treatment such as site of infection, surgical procedures, severity of the illness, patient status, presence of other pathogens (mixed infection), pk/pd parameters of the antibacterial drugs. thus, correlation between treatment failure and antibiotic resistance among anaerobes remains difficult to assess. the main discrepancies came from intra-abdominal infections and a worrisome disjunction between surgeon and microbiologist opinions emerged in the 's. but, patients in whom primary therapy failed had more resistant strains compared with patients in whom therapy succeeded. in contrast many failures may be due to the lack of isolation of anaerobes from clinical samples! during anaerobic bacteraemia, salonen et al. demonstrated that mortality increased dramatically from % for initially effective treatment to % when an ineffective treatment was started. facing new mechanisms of resistance and global increase resistance to many antibiotics among anaerobes may lead nowadays to a different answer. clindamycin vs. penicillin studies for the treatment of lung infections pointed out the failure due to b-lactamase production among gram-negative anaerobes. we found many reports of failure after clindamycin treatment in osteomyelitis, septic arthritis, brain abscess in presence of clindamycin-resistant anaerobes (bacteroides fragilis group and prevotella), probably because when resistance occurs, clindamycin mic's are high. similarly, the lack of coverage of an undetected resistant anaerobe allows the selection of an anaerobic strain resistant to the treatment chosen against the associated aerobes such as imipenemresistant eghertella lenta or metronidazole-resistant strains of prevotella or bacteroides fragilis. the later failures may give opportunity to set up a new metronidazole breakpoint for resistance (mic > mg/l). the main problem is related to the difficulty to detect some heterogeneous resistant strains, that needs prolonged incubation period on agar medium. this kind of situation is probably the most suitable to correlate the bacterial antibiotic resistance with the failure of the antibiotic treatment. methicillin-resistant s. aureus isolates causing community-acquired infections (ca-mrsa) in children is a major problem in several areas around the world. ca-mrsa are associated with both skin and soft tissue infections and invasive infections. recurrent soft tissue infections and infections within the family caused by ca-mrsa isolates are common. ca-mrsa s. aureus isolates containing gene coding for pvl have been associated with serious staphylococcal pneumonia as well as osteomyelitis complicated by subperiosteal abscesses or venous thromboses. in addition to vancomycin, ca-mrsa generally are susceptible to clindamycin and trimethoprimsulfamethoxazole. treatment of superficial skin and soft tissue infections involves surgical drainage of abscesses followed by an oral agent such as tmp-smx or clindamycin. minocycline or doxycycline is a consideration for children > years old. empiric vancomycin is typically administered for more serious and invasive infections such as osteomyelitis, septic arthritis, serious head and neck infections or suspected staphylococcal pneumonia. clindamycin is efficacious in treating invasive ca-mrsa infections caused by susceptible organisms. linezolid or daptomycin is another option in selected circumstances. mri is the optimal imaging modality for assessing children with ca-mrsa osteomyelitis. aggressive surgical drainage of subperiosteal abscesses or sites of pyomyositis is recommended. venous thombosis is increasingly recognized as a complication of ca-mrsa osteomyelitis. anti-coagulation until the thrombus has resolved is recommended. the optimal approach to prevention of recurrent ca-mrsa infections is unclear but a strategy that includes emphasizing personal hygiene, plus/minus antimicrobial soaps, mupirocin to the nose or "bleach baths" is frequently suggested. s understanding the pathogenesis of group a streptococcal disease: the bedside-to-bench approach invasive group a streptococcal (gas) infection presents itself in a range of guises, most notoriously necrotising fasciitis and the streptococcal toxic shock syndrome. as a human pathogen, gas pathogenesis research should ideally be shaped by clinical questions arising from either epidemiological or case-based investigation of human disease. in the mid s, large epidemiological studies pointed to a central role for specific t cell-stimulating superantigens in the aetiology of streptococcal toxic shock. this sparked a series of clinical and laboratory investigations that demonstrated production of superantigens during infection which were indeed capable of triggering massive t cell activation in patients but were unlikely, alone, to account for all the features observed in toxic shock. genomic, clinical and laboratory-based investigations have identified novel and highly potent superantigens that appear to directly contribute to sepsis pathogenesis and, together, may constitute targets for adjunctive treatments in invasive disease. epidemiological, clinical, and laboratory studies have highlighted a role for blunt trauma in the aetiology of at least a quarter of cases of gas necrotising fasciitis. one of the most striking findings on examination of tissues from patients suffering with necrotising fasciitis is the failure of neutrophils to migrate to the focus of infection. investigation of patients with invasive gas infection led to the discovery that gas produces an enzyme that can cleave and inactivate human chemokines and study of patients with bacteraemia has highlighted a likely role for the causal enzyme spycep in disease pathogenesis; this bacterial surface enzyme has also shown promise as a potential vaccine antigen. notwithstanding a potential role for individual virulence factors in disease causation, clinical studies have demonstrated that gas bacteria may persist at the site of infection despite high concentrations of bactericidal antibiotics, and this has been borne out by experimental studies; the reasons behind such persistence are unclear but may include internalisation of gas by immune cells, formation of biofilm, and antibiotic penetration of necrotic tissues. the persistence of viable bacteria in such cases is not widely recognized and deserves focused consideration in the research laboratory. genome-wide analysis of microbial pathogens and molecular pathogenesis processes has become an area of considerable activity in the last years. these studies have been made possible by several advances, including completion of the human genome sequence, publication of genome sequences for many human pathogens, development of microarray technology and high-throughput proteomics, and maturation of bioinformatics. despite these advances, relatively little effort has been expended in the bacterial pathogenesis arena to develop and use integrated research platforms in a systems biology approach to enhance our understanding of disease processes. we have exploited an integrated genome-wide research platform to gain new knowledge about how the human bacterial pathogen group a streptococcus causes disease. results of these studies have provided many new avenues for basic pathogenesis research and translational research focused on development of an efficacious human vaccine and novel therapeutics. new data stemming from use of a systems biology approach to provide new data about group a streptococcus pathogenesis will be presented. streptococcal toxic shock syndrome and necrotising fasciitis caused by group a streptococcus are rapidly progressive invasive diseases that are associated with significant morbidity and mortality, ranging from − % despite prompt antibiotic therapy and surgical debridement. s. pyogenes is known to primarily cause disease by activating and modulating host immune responses. the exotoxins with superantigenic activities have been demonstrated to be crucial triggers of excessive inflammatory responses and consequently systemic toxicity, organ dysfunction, tissue necrosis and shock. another important virulence determinant is the m-protein, which is classically known for its antiphagocytic properties, and lately, was shown to trigger pro-inflammatory responses as well as induction of vascular leakage and shock. this likely represents important mechanisms contributing to the rapid development of shock and systemic toxicity in patients with severe invasive group a streptococcal infections. the understanding of these infections as hyperinflammatory diseases highlighted the potential of immunotherapy to improve outcome. one such strategy includes the administration of intravenous polyspecific immunoglobulin (ivig) as adjunctive therapy. the mechanistic actions of ivig in this setting are believed to include opsonisation of the bacteria, neutralisation of the superantigens and suppression of the pro-inflammatory responses. there is growing evidence to support the use of ivig in patients with streptococcal toxic shock syndrome. these studies include one observational cohort study based on canadian patients identified through active surveillance of invasive group a streptococcal infections, and one european multicentre placebo-controlled trial. however, the question remains whether ivig is efficacious also for the severe streptococcal deep tissue infections. an observational study of seven patients with severe streptococcal deep tissue infections suggested that the use of high-dose ivig in patients with severe gas soft tissue infections may allow an initial non-operative or minimally invasive approach, which can limit the need to perform immediate wide debridements and amputations in unstable patients. the fact that seven patients with severe group a streptococcal infections survived with this approach definitely warrants further studies to be conducted on the use of ivig in these severe infections. hepatitis o prevalence and outcome of pregnancy in chronic hepatitis c virus infection i. julkunen°, a. sariola, m. sillanpää, k. melen, p. koskela, p. finne, a.l. järvenpää, s. riikonen, h.m. surcel (helsinki, oulu, fi) objectives: in the western countries the incidence of hepatitis c virus (hcv) infection has steadily been increasing especially among young adults. it is thus likely that an increasing prevalence of hcv infection is also found in pregnant women. methods: to assess the frequency of hcv infection in the metropolitan area of helsinki selected anti-hcv antibody testing was carried out for pregnant women during the years - . in addition, hcv prevalence was analysed in serum specimens collected from pregnant maters during the years of - . results: altogether mothers were identified among mothers. the frequency of anti-hcv positivity rose from . % in to . − . in - . in early 's only % of mothers knew about their seropositivity, whereas by the end of the follow-up period almost % of mothers knew about their hcv infection already before the pregnancy. intravenous drug abuse was the major risk factor ( % of cases) for contracting the disease. in % of the mothers chronic hcv infection was well under control and in this population the mean serum alanine aminotransferase (alt) values decreased towards the end of the pregnancy. however, % of anti-hcv ab positive mothers developed intrahepatic cholestasis (odds ratio . ) as characterised by itching and elevated serum bile acid levels. the correspondig value in the control pregnancies was only . %. anti-hcv ab positive mothers were younger, delivered earlier and gave birth to babies with smaller birth weight as compared to control deliveries. to have a more comprehensive view of the problem of hcv infection during pregnancy randomly selected serum specimens from the finnish maternity cohort were tested. - serum specimens were tested in selected cohorts ( , , , and ) . in the nationwide prevalence was . % and it steadily role to . % in . in the metropolitan area of helsinki the prevalence was higher being . % and . in and , respectively. conclusion: our study indicates that there is an increasing problem of hcv infection in pregnant women in finland. although most women cope well with their disease during pregnancy there is a subpopulation of mothers who develop cholestasis and their liver status should thus be followed-up carefully. testing of all mothers for serum anti-hcv antibodies is recommended. objectives: the viral genome of hepatitis c virus constitutes a . kb single-stranded positive-sense rna which encodes altogether viral proteins. in order to study the humoral immune responses against different hcv proteins in patients suffering from chronic hcv infection, we produced three structural (c, e and e ) and six nonstructural proteins (ns , ns , ns a, ns b, ns a and ns b) in sf insect cells by using the baculovirus expression system. the recombinant hcv proteins were purified and used in western blot analysis to determine antibody responses against individual hcv protein in hcv rna and antibody positive human sera that were obtained from patients suffering from genotype , , or infection. results: these sera were also analysed with inno-lia score test for hcv antibodies against core, ns , ns ab and ns a, and the results were similar to our western blot method. based on our western blot analyses we found that the major viral antigens were the core, ns b, ns and ns a proteins and they were recognized in %, %, % and % of patient sera, respectively. there were no major genotype specific differences in antibody responses to individual hcv proteins. a common feature within the studied sera was that all except two sera recognized the core protein in high titers, whereas none of the sera recognized ns protein and only three sera (from genotype ) recognised ns b. the data shows significant variation in the specificity in humoral immunity in chronic hcv patients. anti-hcv antibody pattern also remains very stable within one individual. alt and ast levels were tested in all subjects. the presence of hbv-dna was determined quantitatively in plasma samples of hd patients with anti-hbc alone (hbsag negative, anti-hbs negative and anti-hbc positive) by real-time pcr using the artus hbv rg pcr kit on the rotor-gene real-time thermal cycler. results: of patients enrolled in this study, subjects ( . %, % ci, . %- . %) had anti-hbc alone. hbv-dna was detectable in of hd patients ( %, % ci, %- %) with anti-hbc alone. plasma hbv-dna load was less than iu/ml in all of these patients. our study showed that detection of anti-hbc alone could reflect unrecognized occult hbv infection in hd patients. the majority of these infections are associated with low viral loads. were included in the study. all the subjects had never been exposed to antiretroviral therapy. genotypic resistance testing was performed at the time of diagnosis with a sequence-based assay (trugene hiv- genotyping test) targeted at the protease region (codons to ) and rt region (codon to ) of the hiv-l genome. results: of patients ( . %) harboured a virus with at least one mutation associated with phenotypic resistance; / with mutations associated with resistance to nucleoside reverse-transcriptase inhibitors (nrtis), / to non-nucleoside reverse-transcriptase inhibitors (nnrtis) and / to protease inhibitors (pi). resistance to nrtis was associated with the key mutation m v, while resistance to nnrtis was associated with y c and k n mutations. among mutations to pi, major resistance mutations l m and d n were found in three patients, whereas there was a high prevalence of accessory pi resistance mutations at positions , , and . conclusion: our data estimate the prevalence of primary resistance and mutations patterns among naive hiv patients, underlining the importance of genotypic resistance testing in hiv patients before starting treatment, especially when nnrtis would be included in the initial antiretroviral therapy. objectives: few data are available on the genetic mechanisms of protease inhibitor (pi) resistance in non-b hiv- , and pi resistanceassociated mutations (rams) are commonly observed in pi-naive patients with subtype a/e infection. this study aimed to compare pi-rams between pi-naive and -experienced patients. methods: genotypic resistance testing was conducted among a cohort of hiv- infected patients who had virologic failure. patients were categorised into groups: pi-naive and pi-experienced. we focused on pi-rams previously described by ias-usa . results: we studied patients (mean age, . years; % male). median cd cell count and hiv- rna at virologic failure were cells/cu.mm. and copies/ml, respectively. % of patients were infected with subtype a/e; the others had subtype b ( %), ab ( %), and c ( %). there were patients in pi-naive group and patients in pi-experienced group. the clinical characteristics between groups were similar (p > . ) except for the duration of antiretroviral therapy which was shorter in pi-naive group ( . vs. . months, p = . ). percentage of patients who had primary pi-rams was % in pinaive and % in pi-experienced groups (p = . ). the most common primary pi-rams in the latter group were v a ( %) and i v ( %). percentage of patients with secondary pi-rams in the corresponding groups was % and %, respectively (p = . ). median number of secondary pi-rams was also similar between groups (p = . ). the most common secondary pi-rams in both groups were m i ( %), h k ( %), l m ( %), i v ( %), l p ( %), l i we also defined a "silent score" (ss) and a "resistance score" (rs) as the number of synonymous mutations and of resistance mutations (in the second sequence in comparison with the first one) divided by number of days between the two tests, respectively. ( ); pts with drms in non-b-st (%) were ( . ), ( ), ( ) and ( . ). a significant increase of non-b-st (p = . ) and a significant decrease in drms (p < . ) were observed. crf _ag was the prevalent non-b st ( %). . % of non-b st pts were italians. among b-st, drms predicted a reduced susceptibility to one drug class in , , and cases in the different periods; to two drug classes in , , and ; to three classes in , , and . in non-b-st, a reduced susceptibility to one drug class was found in , , and cases; to two drug classes in , , and ; to three drug classes in , , and , respectively. among pts with one or two classes of resistance, a decrease of percentage of protease inhibitors related drms, and a persistence of non nucleoside rt inhibitors involving drms, mainly n and a, were observed. methods: from hiv+ persons with a history of, or an acute episode of opc, oral fungal burden was evaluated bi-weekly and buccal mucosa tissue was collected bimonthly for a period of one year. tissue was evaluated for the presence of cd + t cells and e-cadherin by immunohistochemistry or flow cytometry. objectives: to define the secular trends in the epidemiology of candidaemia in queensland, australia (population, . million) over a -year period. methods: all episodes of candidaemia within queensland public hospitals from - were identified from laboratory information systems. data on species identification, antifungal susceptibility, demographics, and hospital ward of diagnosis, and denominator data (hospital admissions, accrued patient-days (pt-days) and fluconazole usage) were collected. results: over the -year period, unique episodes ( % case ascertainment) were identified from healthcare facilities ( tertiary, paediatric, secondary and smaller hospitals). the median patient age was . years. the overall incidence-density was . / ptdays, highest in paediatric ( . / pt-days) and tertiary hospitals ( . / pt-days). over the years, the incidence-density increased . -fold in tertiary hospitals and . -fold in secondary hospitals (both p < . for trend), but not in paediatric or smaller hospitals. the incidence-density in icus ( . / pt-days) was -fold higher than in non-icu wards, but did not significantly increase over the study period. the relative proportion of episodes occurring in adult general medical/surgical (ie non-oncology/non-icu) wards significantly increased (p < . ), accounting for % of episodes at the end of the -year period, whereas that occurring in paediatric and adult oncology wards decreased (p < . and p = . respectively). overall, c. albicans accounted for %, c. parapsilosis % and c. glabrata %. although the incidence-density of all species increased over the study period, the relative proportion caused by c. albicans decreased (p = . ) and c. parapsilosis increased (p = . ). despite significantly increased fluconazole usage (from . to . ddd/ pt-days, p < . ), the relative proportion caused by c. glabrata/c. krusei did not change (p = . ). the overall incidence of candidaemia has increased almost % in queensland public hospitals over the last years. the relative proportion of episodes occurring among general medical/surgical patients and caused by c. parapsilosis has increased. candidaemia is an increasing problem the epidemiology of which continues to evolve. it is increasingly affecting patients outside traditional risk groups. conclusions: this surveillance study and pharmaco-economic modelling has proved immensely beneficial in setting up inhouse processing, improved tat, reduced costs of outsourcing and subsequent use of expensive antifungals. reduction in mortality has been noted but is not statistically significant. c. albicans was the commonest isolate; fluconazole resistance is minimal and associated mortality is lower than reported from europe. many pts received systemic prophylaxis ( %); itraconazole and fluconazole were used in and pts respectively. no differences emerged between empirical vs pre-emptive therapy and none of the drugs resulted to significantly influence outcome. in % of pts initial empirical/pre-emptive drug remained unchanged after ia diagnosis, while in % clinicians shifted to a combined treatment. conclusion: this study allows as to analyzed multiple factors as potentially influencing outcome. we confirmed that aml phase and neutropenia influence ia outcome. present data confirm the perception that during last years the application of a correct and timely diagnostic work-up and the availability of more efficacious and less toxic drugs (i.e. voriconazole, liposomal amphotericin b, caspofungin) have modified the course of ia. however none of the new drugs emerged as the most efficacious in our series. even combined treatment did not confer any advantage in survival analysis. (< % each). the first line therapy was monotherapy with voriconazole ( %), caspofungin ( %), lipid formulations of amb ( %) or used antifungal drugs combination ( %). the mortality rate at day was % when first line therapy included voriconazole compared to % when it did not (p < . ). conclusion: comprehensive collections of cases based on systematic reporting and description of cases using a dedicated network of hospitals in selected regions and stringent definition criteria applied by trained clinicians and microbiologists are useful to describe ia, to assess its burden and secular trends, and to identify potential changes in diagnostic and therapeutic procedures. this network will expand to other regions in the near future, and data will help assessing the impact of new management strategies such as prophylaxis with posaconazole, the impact of modification of new diagnostic criteria as recently proposed (clin infect dis, ), and identifying new populations at risk for ia. nosocomial aspergillosis represents a serious threat for severely immunocompromised patients and outbreaks have been attributed to airborne sources. the role of hospital-independent fungal spread sources e.g. the private homes or business suites are not known. we investigated the relationship between fungal exposure prior hospitalisation and the ensuing onset of invasive mould infections (imi) in patients at risk. patients admitted to the department of haematology and oncology or to the department of transplant surgery of the innsbruck medical university received a structured questionnaire regarding their fungal exposure prior hospitalisation. questions inquired heavy fungal exposures up to five days prior hospitalisation. patients were enrolled in this study and % were smokers, % suffered from an airborne allergy, % lived in old buildings, % were ruralists, % and % were exposed to any outdoor or indoor fungus sources. poor housing conditions and other fungus exposures were associated with the onset of community-acquired imi only in patients with acute myelogenous leukaemia (p < . ). aml patients being more at risk for imi when smoking cigarettes (p < . ), living on the country site (p < . ), having two or more fungus exposures (p < . ) and suffering from allergy to dust, pollen and/or moulds (p < . ). a similar trend was for lung transplant recipients receiving extensive immunosuppressive agents to treat allograft rejection. overall, % of imi were community-acquired cases. hospital-independent fungal sources highlight risk-factors for imi in severe immunocompromised patients and the rate of communityacquired imi does increase. an analysis of an individual patient's risk factors for fungal infection and the type of fungus to which they are most susceptible, indicates the preventative strategies that are likely to be successful. to the icu-mhs with aspergillus spp detected in significant amounts in clinical samples. the underlying conditions of the patients were heart transplantation (n = ), major heart surgery (n = ), and other (n = ). eight ( . %) patients developed proven/probable ia ( with lung infection, with mediastinitis, with disseminated ia, and with prostate involvement). the mortality of patients with ia was . %. the icu-mhs is divided into areas, one of which is equipped with hepa filters. only case of ia occurred in the protected area. we measured the fungal conidia levels in the air of each of the areas ( samples analyzed) monthly. a total of strains of a. fumigatus ( clinical strains from patients and environmental strains) were genotyped using microsatellites (de valk et al, jcm ) . the mean airborne conidia levels ( months) before and after the outbreak were, respectively, . ( − ) cfu/m and . ( − ) cfu/m . no cases of ia occurred during these periods. however, all cases of ia were linked to peaks of abnormally high airborne conidia levels ( , , and cfu/m ). a. fumigatus was involved in cases of ia; patient was infected by non-fumigatus aspergillus (not further genotyped). in patients ( mediastinitis, pulmonary ia and colonisation), we demonstrated similar genotypes in the air and in clinical samples. patient was located in the protected area and had a unique genotype. patient had two different clusters of genotypes: one cluster was similar to that of patient and the other was also found in patient and in the air. the genotype present in patients and was also detected in the air during a -month period. conclusions: epidemiologic and molecular typing suggests that there is a causal relationship between aspergillus causing ia and those present in the air. our finding also supports the need for hepa filtration in icu-mhs. j. guinea is contracted by fis (cm / ). sensitivity, specificity, positive predictive value (ppv) and negative predictive value (npv) were calculated in reference to proven and probable cases of ia. reasons for performing bronchoscopy on patients were also recorded. the protocol received approval by the local ethic committee. results: from the samples studied, ( . %) were classified as proven, ( . %) as probable, and ( . %) as possible cases of aspergillosis. twelve samples ( . %) represented colonisation, and bal samples were obtained during routine surveillance. pulmonary aspergillosis was the main clinical presentation of ia ( . %). using roc analysis, the best cut-off for galactomannan testing in bal was defined as . (sensitivity . %, specificity . %, ppv % and npv . %). median bal gm index for the group of patients with proven/probable aspergillosis and for 'negative cases' were . and . , respectively (p < . ). overall mortality was % (n = ). the odds for death for patients diagnosed with ia were . , in comparison to patients who did not have this infection ( % ci . − . ). conclusion: gm testing in the bal added to the diagnosis of ia in lung transplant recipients. in order to avoid false-positive results, a higher test cut-off should be applied to bal samples, in comparison to sera. increasing the cut-off to . resulted in a very high npv, with an associated sensitivity of > %. objectives: ) determine the performance characteristics of the galactomannan (gm) assay in broncho-alveolar lavage (bal) in haematology-oncology patients; ) evaluate the prognostic value of the gm assay in this particular population. methods: the platelia gm eia assay (bio-rad) was performed on all bal specimens obtained from haematology-oncology patients at our institution between march and april , in addition to routine laboratory stains and cultures. all results were reported to physicians. we conducted chart reviews to classify cases as proven, probable, possible or without invasive pulmonary aspergillosis (ipa) according to the revised definitions of invasive fungal disease from the eortc/msg consensus group. for performance characteristics, proven and probable cases were considered as ipa; possible cases were considered as without ipa. the result of bal gm was not considered as a criterium to classify cases in order to avoid incorporation bias. in patients with > positive (gm index > . ) specimen, only the first one was considered for the analysis. mortality was calculated at days following the first bal procurement. data were analyzed with stata . . results: there were bal samples from patients, including haematopoietic stem cell transplant (hsct) recipients. we found proven, probable and possible cases of ipa (total of ipa cases; . %). gm on bal was positive in ( . %) specimens. the sensitivity and specificity of the gm assay in bal were % and . % respectively. positive predictive and negative predictive values were . % and %, respectively. false-positive results were found in patients without ipa and in with possible ipa. an index value . was significantly associated with a -day mortality risk ( / patients with a positive gm died within days after bal compared to / with a negative gm (or = . , %ci . − . ; p = . ). this association was even stronger when restricted to hsc recipients (or = . , %ci . − . ; p = . ). the clinical utility of gm assay in bal mainly lies in its negative predictive value, identifying patients at low risk of ipa. this test also carries a prognostic value in predicting patients at higher risk of mortality. (see table below) . not significant differences have been found among pneumocystis colonisation and copd status evaluated by fev- %. as well as no significant differences respect to age, sex or lymphocytes and leucocytes blood count were found. background: infliximab, a monoclonal antibody targeting tumour necrosis factor alpha (tnf-a), is indicated for the treatment of rheumatoid arthritis (ra) and other autoimmune diseases. however, its use has been associated with opportunistic infections, including pneumocystis jirovecii pneumonia (pcp). moreover, p. jirovecii has been observed colonising to humans with several disorders. objectives: to obtain information about p. jirovecii colonisation among patients with rheumatologic disease treated with infliximab. this information could be useful for assessing new strategies in the prevention of pcp in patients at risk. methods: consecutive patients treated with infliximab for rheumatic disorders were included in the study. oropharyngeal washes (ow) samples were collected for p. jirovecii detection. clinical and demographic data were collected (sex, age, rheumatologic diagnosis, duration of infliximab use, concomitant use of other drugs for rheumatologic treatment, use of any other anti-tnf-a agent, use of anti-pc drugs in the last six months, smoking, and diagnosis of chronic pulmonary respiratory disease). p. jirovecii colonisation was identify in ow samples by pcr at mtlsu-rrna gene, with primers paz -x and paz -y. we adapted a method previously described to a real-time pcr setting, using a lightcycler . (roche, germany). individuals in whom the presence of p. jirovecii was detected at two independent assay in the absence of respiratory symptoms or radiological findings suggestive of pcp were considered to be colonised. results: clinical and demographic data for patients treated with infliximab are presented in table objectives: most research with human bocavirus, a recently found respiratory pathogen, has been done by molecular biology (polymerase chain reaction, pcr). the results have been ambiguous because the virus has often been found in co-infection with other viruses, and also in clinically healthy subjects. it has been proposed that, for bocavirus, antigen detection could better indicate the aetiology than qualitative nucleic acid detection. we have developed a rapid antigen detection test for the virus. the one-step test for bocavirus vp antigen is based on a separation-free two-photon excitation fluorometry (arcdia tpx assay technique). the assay protocol is simple; the swab sample is dissolved in sample buffer, and the solution is dispensed ( ml) onto a -well microtitre plate (containing the reagents in dry form) for incubation and automated quantitative measurement. the immunoassay applies microspheres as solid-phase carriers of purified bocavirus-specific polyclonal antibodies. the virus antigens concentrate onto the solid-phase which is probed in real-time with fluorescently labelled antibody reagents. strong positive samples are reportable in minutes, while low positive and negative samples are reported in hours. the performance of the method was studied with recombinant human bocavirus-like particles (vp ), and purified respiratory pathogens (group a streptococci, streptococcus pneumoniae, and influenza a and b, respiratory syncytial, metapneumo, adeno, and parainfluenza − viruses). results: analytical detection sensitivity of the method (lowest limit of detection, -control + sds) was ng/ml, dynamic concentration range was three orders of magnitude, and intra-assay imprecision was − %. cross-reactions with the other respiratory pathogens were not found. the new method enables rapid detection of bocavirus antigens. the new test is very easy to perform in comparison to standard elisas. the analytical sensitivity of the method is expected to allow analysis of clinical samples. the sensitivity of the antigen detection test could be significantly increased by the use of monoclonal antibodies ( - fold). our future objectives include increasing the detection sensitivity, and analysis of clinical samples in order to study the correlation of antigen detection and the clinical aetiology. life-year for patients who survived. all analyses were performed using treeage software ( ). results: the overall mortality rates for empiric vancomycin (v) and semi-synthetic-penicillin (ssp) was % and %, respectively, as apposed to % for those receiving the rapid mrsa pcr testing. these mortality rates were similar in both the eu and us subsets. furthermore, the number needed to test in order to save one life was and for empiric v and ssp, respectively. using sensitivity analysis the prevalence of mrsa was varied from % to % and yielded an absolute mortality difference favouring the pcr testing group of % and %, respectively as compared to empiric v and % and % compared to empiric ssp. in eu the c/e for empiric v and ssp treated patients was € and € , respectively as compared to € for rapid pcr testing. in the us the c/e for empiric v was $ , as compared to $ for rapid pcr testing. using sensitivity analysis the prevalence of mrsa was varied from % to % and yielded favourable c/e in both the eu and us for rapid pcr testing regardless of the empiric treatment regimen. conclusion: rapid mrsa pcr testing using the xpert mrsa/sa blood culture pcr assay appears to improve mortality rates and is cost effective in the eu and us across a wide range of mrsa prevalence rates. background: rapid detection of gastro-intestinal carriage of glycopeptide-resistant enterococci (gre) from screening cultures is crucial for an efficient control of their spread. we assessed media − chromogenic, chromid, (biomérieux), and chromagar (chromagar microbiology), and selective, vre selective (oxoid) and eccv (bd) − for their ability to detect gre using well-characterised isolates and stool samples from hospitalised patients at high risk of gre colonisation. methods: twenty-five isolates consisting of gre. faecalis/faecium carrying various van genes and non-vre at concentrations of - cfu/ml and cfu/ml, respectively, and stool samples were randomised and spiral plated on all media and scored by blinded investigators for characteristic colonies after hrs incubation. standard confirmatory tests were done on putative gre colony or on characteristically coloured colony each for e. faecalis/faecium from the selective and chromogenic media, respectively. detection of van genes, and ddl or soda based speciation was done on pcr-sequencing. mean sensitivity (sen) and specificity (spec), and confidence intervals (cis) were estimated for each medium by a logistic regression model using a penalised likelihood approach based on the reader response for the stool samples and isolates, and additionally on confirmation test results for the stool samples, both at the aggregated (gre detected) and penalised level (correct species-colony colour correlation). results: chromagar showed the highest sen based on reader response at the aggregated and penalised level for both stool samples and isolates (table) . using confirmation test results at the aggregated level, sen for eccv was highest while the two chromogenic media showed a decrease in sen by at least % in comparison to the values obtained based on reader response. sens for the chromogenic media were even lower (< %) based on confirmation test results at the penalised level. eccv and chromid showed the highest specs with both reader response (stool samples) and confirmation test results at the aggregated level, and chromid also at the penalised level, with narrow cis indicating a high precision of this parameter estimate. for isolates, specs were highest for chromagar at both levels. conclusions: chromagar showed the best overall performance considering both sen and spec estimates. eccv performed well as a selective medium for gre detection from stool samples. objectives: metallo-beta-lactamases (mbls) expressed from pseudomonas are able to confer resistance to all beta-lactams with the exception of aztreonam. however, enterobacteriaceae possessing mbls exhibit moderate cephalosporin and low carbapenem mics and thus are often underestimated. herein, we describe data from new etest prototypes specifically designed to detect this problematic resistance mechanism. methods: mbl-positive (vim or imp derivatives) enterobacteriaceae clinical isolates from countries and randomly selected enterobacteriaceae negative controls (including the atcc type strains) were tested against the different etest mbl prototypes. beta-lactam substrates used were imipenem (ip), meropenem (mp), ceftazidime (tz) and cefotaxime (ct) with or without the inhibitors dipicolinic acid (dpa) and edta. the etest standard procedure for gram negative aerobes was used and a reduction of beta-lactam mic by equal to or greater than dilutions by edta or dpa was interpreted as positive for mbl. presence of esbls was tested using the etest ct/ctl, tz/tzl and cefepime (pm)/pml strips. ampc production was detected using the etest cefoxitin (fx)/fxi and cefotetan (cn)/cni strips. of the select specimens that were negative for gbs, grew turquoise-blue colonies, but the majority that required further work to rule out gbs grew after hours. two strains of gbs that were missed grew as white colonies on select, and even at h, did not exhibit the characteristic turquoise-blue colour. conclusion: ssb enrichment followed by select subculture was extremely sensitive ( . %) and superior to cna/ssb for detection of gbs from genital specimens. however, non-gbs organisms can produce turquoise-blue colonies on select and further work must be performed to rule out the presence of gbs. objectives: screening for chlamydia trachomatis (ct) specific antibodies is valuable in investigating recurrent cause of miscarriage, pelvic inflammatory disease and tubal damage following repeated episodes of pelvic inflammatory disease. immunofluorescence (if) is considered the gold standard for detection of ct antibodies. the present study aims to compare the performance of other commercial tests for the detection of serum igg antibodies specific for ct: two ct igg pelisa both using major outer membrane protein (momp; ["momp-medac", ct-igg-pelisa; medac, wedel, germany and "momp-ruwag", ct pelisa; ruwag, bettlach, switzerland), one ct hsp- igg pelisa ("hsp -medac", chsp -igg-pelisa; medac, wedel, germany), and a new automated epifluorescence immunoassay ("inodiag", "must chlamydiae; inodiag, signes, france). methods: a total of patients with (n = ) and without (n = ) miscarriages were tested by all serological tests described above. sensitivity and specificity were calculated using if as gold standard. a second standard, defining true positive or negative samples as sera respectively positive and negative in all others tests, was also used (see table) . objectives: participation in diagnostic microbiology internal and external quality control (qc) processes is good laboratory practice, an essential component of a quality management system and compulsory in some european countries. currently, there is no qc scheme for diagnostic oral microbiology. the aim of this study was to collate information on current qc needs, and processes undertaken in diagnostic oral microbiology laboratories. method: an on-line questionnaire was devised to ascertain interest in participating in an oral microbiology qc scheme and sent to oral microbiology diagnostic laboratories. the laboratories were identified from participants attending the european oral microbiology workshop in helsinki, . following this, a pilot round of qc samples was distributed to all interested laboratories. results: we identified individuals that worked in diagnostic oral microbiology laboratories and received ( %) positive responses. of these laboratories (representing european countries) % did not participate in either internal or external qc. each laboratory processed on average a total of samples annually. % of participants were in favour of a european-wide oral microbiology qc scheme. the preferred frequency for receiving external qc specimen was once in − months. the most preferred specimen types were periodontal pocket and oral pus specimens (both %), followed by oral mucosal swabs and caries activity tests. all participating laboratories were willing to share and harmonise their specimen processing and interpretation standard operating procedures. the pilot round specimen was a periodontal pocket sample. six laboratories reported their findings in the specified time. the predominant pathogens (aggregatibacter actinomycetemcomitans, porphyromonas gingivalis) were identified by of laboratories. in addition to conventional culture, one laboratory used pcr. laboratories performed antibacterial sensitivity testing primarily by disc diffusion. conclusions: this is the first attempt to a standardised europeanwide approach to diagnostic oral microbiology. the findings from this feasibility study have indicated that a qc scheme for oral microbiology is of interest and have raised a number a pointers for subsequent rounds of specimens. further work to improve the quality, to standardise the methodology and the interpretation of diagnostic oral microbiology at the european level is on-going. objectives: since severe sepsis with acute organ dysfunction can be fatal within hours, it is customary to start empirical broad-spectrum antimicrobial therapy in all patients hospitalised for a suspicion of systemic inflammatory response syndrome. however, increased use of broad-spectrum antimicrobials over the years has contributed to the emergence of drug resistant strains of bacteria. especially, drug resistance among gram-positive bacteria, the leading cause of sepsis, is now a serious problem. the objective of this preliminary study was to develop a method for distinguishing between gram− and gram+ bacterial infection. methods: in this prospective study, leukocyte and neutrophil counts, crp, esr, and quantitative flow cytometric analysis of neutrophil complement receptors (cr /cd ) and (cr /cd b), were obtained from hospitalised febrile patients, of which had bacterial and viral infection. the patient data were compared to healthy controls. results: it was noticed that in gram− infection (n = ) the average amount of cd b on neutrophils was significantly higher than in gram+ infection (n = ). on the contrary, serum crp level was significantly higher in gram+ than in gram− infection. other measured parameters did not differ significantly between gram+ and gram− infections. we derived a crp/cd b ratio dividing the serum crp value by amount of cd b on neutrophils. in thirteen ( %) out of patients with gram+ sepsis had crp/cd b ratio cutoff value of . (figure ). of these patients, ( %) were diagnosed with streptococcus pneumoniae, with staphylococcus aureus, with enterococcus faecalis, and with both streptococcus intermedius and streptococcus oralis. corresponding percentages in patients with local gram+ infection, gram− infection, clinical pneumonia, other clinical infection, and viral infection were %, %, %, %, and %, respectively. conclusion: the detection of gram+ sepsis is possible after combination of neutrophil cd b data and serum crp level. crp/cd b ratio viral infections of the central nervous system s displayed % sensitivity and % specificity for detection of gram+ sepsis. the proposed crp/cd b ratio test could, for its part, assist physicians to decide appropriate antibiotic treatment in patients with severe bacterial infection. a bacterial biofilm is a structured consortium of bacteria cells surrounded by a self-produced polymer matrix. biofilms may be monospecies or polyspecies biofilms. biofilm growing bacteria give rise to chronic infections, which persist in spite of therapy and in spite of the host's immune-and inflammatory responses. biofilm infections are characterised by persisting pathology and immune response (in contrast to colonisation). bacterial biofilms use both biofilm specific (b) and conventional (planktonic) resistance mechanisms (p) when they are exposed to antibiotics. the following resistance mechanisms have been described in bacterial biofilms: . stationary phase physiology (b), low oxygen tension (b) and slow growth (b) especially inside biofilms whereas the surface of biofilms is more similar to planktonic growth. . penetration barriers (b), binding to the polymer matrix (b). . mutations, hypermutators (b, p). . chromosomal betalactamase is upregulated (b, p). . antibiotic tolerance/adaptive resistance (b). . efflux pumps (b, p). . alginate production (b). . high cell density and quorum sensing (b, p). . pbp − sos response ? (b). the knowledge of these resistance mechanisms can, however, be used to design new therapeutica approaches especially as regards quorum sensing inhibitors. we consider two factors that contribute to treatment failure in the absence of inherited resistance, the density of the population being treated and the physiological state of the bacteria. we also explore how these factors might contribute to the evolution of inherited resistance during the course of treatment. we conclude with a computer-and chemostat-assisted consideration of the potential clinical implication of these density and physiology effects and make suggestions for treatment protocols to deal with them. using in vitro cultures of staphylococcus aureus atcc or the clinical isolate ps and antibiotics of six different classes we determined the functional relationship between the inoculum density and the efficacy of the antibiotics. as measured by the rates and extent of kill and/or the minimum inhibitory concentration (mic), the efficacy of all of these antibiotics declined with increases in the density of bacteria, albeit to different extents. for daptomycin and vancomycin, much of this density effect can be attributed to bacteria-associated declines in the effective concentration of the antibiotic in the medium. for gentamicin, vancomycin, ciprofloxacin and oxacillin, our bioassays failed to reveal significant reductions in their effective concentration in the medium. the effects of the physiological state of s. aureus on the efficacy of these antibiotics were examined for bacteria from cultures in "stationary phase" for different times and from chemostats run at different generation times. these experiments are currently under way but by the time of the symposium we will have the full (and true) story. it is, however, clear that the efficacy of all of these antibiotics declines with the time in stationary phase (its "age"). and, even slowly dividing cultures from chemostats are more susceptible to antibiotic-mediated killing that early stationary phase batch cultures. the efficacy in killing non-growing bacteria varies among the bactericidal antibiotics examined. to ascertain the potential clinical implications of these density and physiological effects, we use both computer and in vitro simulations of antibiotic treatment. the results of these simulations provide compelling support for the proposition that antibiotic treatment regimes, including those designed to prevent the ascent of resistance, should take into account the anticipated density and physiological state of the target population of susceptible bacteria. there have been an increasing number of neurotrophic viral infections playing an important role in the world over the last decade. the list includes west nile virus, nipah and hendra virus (both paramyxoviruses), as well as chikungunya virus which suddenly emerged. furthermore, the relation between jc virus in progressive multifocal leukoencephalopathy (pml) in patients with multiple sclerosis treated with a new immunosuppressive drug, has triggered our attention. the development and implementation of molecular based amplification method has assisted us to detect these viruses more efficiently. these technologies have been used now routinely in a large number of laboratories to enable the detection of more commonly known neurotrophic viruses, like hsv, vzv and the neurotrophic picornaviruses like enterovirus and parechovirus. the pitfalls of these molecular methods have been generally solved by implementing regular quality control testing schemes, like organised by qcmd (quality control of molecular diagnostics) and the introduction of internal controls during the whole diagnostic process. finally, with the ability to quantify the amount of nucleic acid present in csf, more information on the pathogenesis of these viral infections, as well as significant tool to monitor the antiviral effect of treatment options for these viruses, has become available. to as a rare disease in europe restricted to some endemic foci. however, current data suggest that the incidence of ae has significantly increased, and the disease is spreading to the north, west, and east. ae has become an emerging disease in the baltic countries. thus, human infections with e. multilocularis have arrived in the "centre" of europe. ae is a lifethreatening disease, and is characterised by a tumour-like lesion in the liver. the larva can infiltrate the surrounding tissues and metastasize to distant organs. in an attempt to classify the large variety of anatomical findings in ae, the pnm-classification system was developed and serves as a benchmark for standardised evaluation of diagnostic and therapeutic measures. modern imaging techniques, such as ultrasound, ct or mri and pet/ct contributed not only to a much better description of the lesions, but also to a judgment upon the activity of the metacestode. the differential diagnosis of ae varies from haemangioma-like lesion of the liver or cancer. the diagnostic skills are limited, and are the reason for frequent misdiagnosis in geographic areas where ae is rather unknown. continuous treatment with benzimidazoles is the backbone of a lifelong management of ae. however, radical resection is the procedure of choice and should always be strived for. ae is still a rare disease in europe, but where it occurs, it is often diagnosed too late. patients are misdiagnosed for months and years, before receiving the correct treatment. at that late stage the disease has progressed, and radical cure of the liver lesion(s) is not anymore possible. recent reports provided hints for an accelerated larval growth of echinococcus spp. in the immunodeficient host. a careful monitoring of patients receiving immune-modifying drugs is warranted. the modern clinical management and long-term parasitostatic treatment with benzimidazoles are highly effective. thus, a higher alertness for the "tumours from the centre" would increase the prognosis of this hepatic disease resembling liver cancer. the percutaneous treatment of liver hydatid cysts were considered to be contraindicated due to two main potential risks: anaphylactic shock and abdominal dissemination of the disease. since the first case percutaneously treated was published, several series of successful percutaneous treatment of the liver and the other abdominal organs, peritoneum, thorax, soft tissue and orbital cavity hydatid cysts have appeared in the literature. percutaneous treatment of hydatid liver disease is an effective and safe procedure with its unique advantages (e.g., shorter hospital stay, low complication rate). today, the percutaneous approach has an important role in treatment of hydatid cysts not only in the liver but also in the other organs and tissue. therefore it must be first treatment option whenever it is indicated. in europe, dirofilaria immitis and dirofilaria repens are responsible of autochthonous filariases in dogs. adults of d. immitis kills the dogs with an heart location and d. repens is often found in subcutaneous nodules in dogs and cats. the microfilariae are present in the blood of these animals. dirofilariasis is due to the transmission of microfilariae by some mosquito bites (aedes, culex, anopheles, mansonia, psorophora and taeniorhynchus). usually non pathogenic to humans, these parasites are particularly present around the mediterranean basin. d. immitis is very rare in humans in europe, sometimes found in a pulmonary nodule and the heart location is not described. d. repens is more frequent and emerging in humans. usually, only one larva develops, producing an immature adult worm inside a subcutaneous nodule. ultrasound examination may suggest the parasitic origin of the lesion before an extraction and a parasitological diagnosis of the worm. more often, a fortuitous diagnosis is made on histological examination. very rarely, an adult worm may mature and produce systemic diffusion of microfilariae. dirofilariasis due to d. repens can present problems in diagnosis and treatment. an ocular and subconjunctival location of the worm and a subcutaneous nodule enclosing an immature adult are the commonest clinical forms. exceptional pulmonary locations are described. the subcutaneous locations described are: skull, cheek, breast, inguinal area, buttocks, arms and legs. cases of testicular location with painful symptoms have been observed. blood hypereosinophilia was exceptionally observed in human. it is treated surgically, by excision, without chemotherapy. while the majority of esbls, isolated in clinically-relevant gram negative bacteria (gnb) (mostly enterobacteriaceae, p. aeruginosa, a. baumannii) are tem-, shv-or ctx-m-types, a few others have been reported (sfo, bes, bel, tla, ges, bel, per, veb-types, and some oxa-esbls). laboratory detection of esbl-producers is important to avoid clinical failure due to inappropriate antimicrobial therapy and to prevent nosocomial outbreaks. selective culture media (macconkey and drigalski agar supplemented with cefotaxime and/or ceftazidime) have been proposed for detection of gnb resistant to expanded-spectrum cephalosporins (esc). media using chromogenic based substrates and selective antibiotics have been developed recently for the detection and presumptive identification of esbl-producing enterobacteriaceae directly from clinical specimens. detection of esbls based only on susceptibility testing is not easy due to the variety of b-lactamases and their variable expression of blactam resistance. commercially available esbl detection methods yield at most % accurate esbl identification, since some esbl-producers may appear susceptible to some escs. therefore, any organism showing reduced susceptibility to esc should be investigated using esbl confirmatory tests. these tests should be able to discriminate between esbl-producers and those with other mechanisms conferring esc resistance. these phenotypic tests (double-disk synergy test, esbl etest, and the combination disk method) are based on clavulanate inhibition and esc susceptibility testing. they often need slight changes by either reducing the distance between the disks of esc and clavulanate, the use of cefepime (not hydrolysed by ampcs), the use of cloxacillincontaining plates (that inhibits ampc), or by double inhibition by edta and clavulanate (masking metallo-enzymes). enzymatic tests have also been proposed for identification of esbl-producers. several pcr-based techniques (end-point or real time) have been developed on clinical samples or on colonies. several esbl genes have been detected using pcr coupled to either pyrosequencing, inverse hybridisation, to dhplc, or to fluorescent probes. these techniques even though more specific require technical knowledge, special equipment, are costly and detect only known genes, regardless of their expression. detection of esbl-producer remains a challenge for the microbiology laboratory and one shall be aware that esbl screening media are now available. resistance to antimicrobial agents has become common in many bacterial species, particularly those that cause human infections. the rapid detection of resistant organisms directly in clinical samples by real-time pcr coupled with molecular beacons, or of potentially resistant bacteria and yeast in blood culture bottles by peptide nucleic acid-fluorescence in situ hybridisation (pna-fish) is already having a positive impact on antimicrobial therapy. the direct detection of mycobacterium tuberculosis in sputum in approximately hours with concomitant detection of mutations in rpob indicating rifampin resistance (as a surrogate for multidrug resistance) in the near future will likely improve the outcomes for tuberculosis patients in many developing and developed countries. several molecular technologies, including microarrays, bacterial tag encoded flx amplicon pyrosequencing (btefap), and ultra deep sequencing, have not yet transitioned to clinical laboratories but will likely provide even greater information about antimicrobial resistance not in just a single species, but in a whole community of microorganisms. complex wounds, like diabetic foot ulcers, containing multiple resistance genotypes are amenable to analysis by btefap. the implementation of these technologies in the clinical laboratory will be expensive but the potential to dramatically improve therapeutic outcomes especially for life-threatening diseases is unprecedented. objective: to determine the appropriateness of antimicrobial therapy (amt) in dutch hospitals. method: data were obtained from a prevalence survey performed within the dutch surveillance network for nosocomial infections (prezies). amt administrated on the day of the survey was registered. antiviral and antifungal drugs, tuberculostatics, cements containing amt and prophylaxis administrated in the operation-theatre were excluded. the appropriateness of amt was assessed according to a standardised algorithm based on the local antimicrobial prescription guidelines. per patient a classification in appropriate use, inappropriate use and insufficient information was made. figure: relative risk of ia use of amt against largest hospital (hospital c). results: a total of , patients were included of which , ( %, range per centre (rpc): − %) received amt. in the latter group, amt was considered appropriate in % (rpc: − %), inappropriate in % (rpc: − %) and was not judged because of insufficient information in % (rpc: − %). there was considerable variation in inappropriate use among the participating centres (figure). in univariate analysis older age, the use of quinolones, being on the urology ward and presence of a suprapubical catheter were associated significantly with inappropriate use. admission on the icu and presence of an intravascular catheter were associated significantly with appropriate use. in a multivariate analyses the presence of suprapubical catheter, being on the urology ward and the use of quinolones were determinants for inappropriate use. this study showed large differences in overall use and appropriateness of use of amt between hospitals. based on these results it is possible to define targets for intervention to improve the prudent use of amt. the high fraction of patients with insufficient information in several centres may have influenced the analyses and should be addressed in future studies. m. struelens°, s. metz-gercek, r. mechtler, f. buyle, a. lechner, h. mittermayer, f. allerberger, w. kern objectives: the eu-project antibiotic strategy international (abs) qi team developed process qis for auditing the performance of key treatment and prophylactic practices. an international network of pilot hospitals tested these tools for feasibility, reliability and sensitivity to improvement. methods: qis included: . surgical prophylaxis (indication, drug choice, timing and duration of administration); . management of community-acquired pneumonia (cap) (blood culture and legionella antigen tests and drug choice for empirical treatment); . management of s. aureus bacteraemia (echocardiography, iv catheter removal and duration of therapy); and . iv-po switch for bio-available antibiotics. a minimum of consecutive cases per centre and qi were retrospectively reviewed from clinical, laboratory and administrative records and assessed for data availability, inter-observer reliability, data collection workload and performance score. results: a total of patients were evaluated in acute care hospitals from countries, with a range of to cases and to centres per indicator. seven centres had already implemented antibiotic quality improvement and audit programmes. availability of data was > % of cases and ranged between % (catheter removal in s. aureus bacteraemia) and % (diagnostic tests for cap). / indicators were found to be reliable with kappa . (good to excellent agreement). the workload per case ranged from a median time of (cap) to min (iv-po switch). the intention to treat qi scores showed high levels of adherence to the surgical prophylaxis qi bundle, with median values of to % for hip prosthesis and to % for colo-rectal surgery. for cap management, diagnostic testing appeared sub-optimal (< % compliance with idsa guidelines). for s. aureus bacteraemia management, indicator results ranged from to %. for use of bio available antibiotics, a median of % iv administrations were avoidable. there were marked differences of scores between centres for all qis. conclusions: the abs qis are reliable and broadly applicable tools for auditing antibiotic treatment and prophylactic practices. inter-hospital variation in adherence to recommended practice indicates substantial potential for improvement with different local priorities. these qis can be recommended for assessing the effect of quality of care interventions at either local or multi-centre level. d.j. noimark°, e. charani, s. smith, b. cooper, i. balakrishnan, s.p. stone (london, uk) introduction: reduction of clostridium difficile infection (cdi), which often follows use of third generation cephalosporins, is a national priority. over a three year period, antibiotic policies were reviewed and changed in an elderly medicine department according to local sensitivities of common pathogens and levels of cdi. a laminated pocket-sized card describing antibiotic policies was given to all doctors in the department on induction with instructions not to depart from these without microbiologists' approval. this prospective controlled interrupted time series examines whether this intervention increased compliance with antibiotic policy and decreased cdi incidence. methods: the department's "narrow-spectrum, no cephalosporin" antibiotic policy was changed on st august to replace trimethoprim with cephradine ( st generation cephalopsporin) as empiric treatment for urinary tract infection, reflecting local escheriscia coli sensitivities. in october , all cephalosporins and quinolones were removed from the policy as cdi levels had increased. notional day antibiotic usage was calculated from prospective pharmacy generated data with aspirin, calcium, bisphosphonate & laxative prescription use as a non-antibiotic control, and analysed by segmented regression with a robust variance estimator. cdi rates were prospectively collected separately & analysed by a poisson regression model. results: an immediate response to change in antibiotic guidelines was observed (figure) . from august -sep there was a highly significant increase in cephalosporins ( - % of which was cephradine alone) (p < . ), a significant fall in trimethoprim (p < . ) and a significant increasing trend in cdi ( no tools existed to assess the readiness of public hospitals to receive this technology, and therefore guide resource allocation to facilitate implementation. aim: to assess the readiness of victorian public hospitals to introduce electronic antimicrobial stewardship. method: literature on readiness for change, organisational culture and information technology acceptance were reviewed. group interviews with project teams at site initiation meetings, one on one interviews with project officers at subsequent meetings, and observation where appropriate were all used to determine potential barriers and enablers. this information was recorded using a 'readiness assessment tool' and analysed to identify a number of key domains. to triangulate the data, questionnaires were distributed to project officers asking them to assess their sites' readiness to implement the system. results: a novel 'readiness assessment tool' was developed. it covered the domains of technical readiness, skills readiness, process readiness, administrative support readiness, resource readiness and hospital organisational characteristics. assessments at several hospitals highlighted a variety of issues at different sites and allowed early efforts to address these. a formative readiness assessment can be used to identify systematic problems that might facilitate or hinder uptake of electronic antimicrobial stewardship and to inform the adopters of potential resources required. [ ] buising, k, thursky, k, robertson, m, black, j, street, a, richards, m & brown, g ( ) . electronic antibiotic stewardship-reduced consumption of broad-spectrum antibiotics using a computerised antimicrobial approval system in a hospital setting. j antimicrob chemother. w.v. kern°, m. steib-bauert, a. pritzkow, g. peyerl-hoffmann, h. von baum, u. frank, m. dettenkofer, c. schneider, k. de with, h. bertz (freiburg, ulm, de) objectives: fluoroquinolone prophylaxis (fqpx) may reduce morbidity and mortality in cancer patients (pts) with neutropenia, but the development of fluoroquinolone resistance (fqr) in escherichia coli and other target organisms limits its usefulness. we evaluated changes in the incidence density of gram-negative bloodstream infection (gnb) and in the in vitro fqr rates after the introduction of fqpx (with levofloxacin) as a standard of care for pts with high risk neutropenia in a university hospital. methods: we collected individual data for pts admitted during baseline and during the first months following the intervention to assess clinical outcomes. individual pt data were compared with aggregate data ( -month periods). aggregate data analysis (unit-wide antibiotic consumption, gnb and numbers of in vitro fqr bloodstream isolates) was continued for a total of eight -month periods for both the haematology-oncology service and for general internal medicine. the new policy was introduced in the second half of the year when unit-wide baseline fqr of e. coli and of coagulase-negative staphylococcal (cons) bloodstream isolates had been % and % in the haematology-oncology unit, and % and % in general internal medicine, respectively. the individual pt data analysis revealed that pts not given fqpx had a much higher incidence of gnb than those given fqpx ( - ) . the monthly use of iv and oral quin was calculated based on data from the pharmacy department. statistical analyses were performed using segmented linear regression analysis. bayesian model averaging was used to account for model uncertainty. results: before the interventions the use of quin (both iv and total) was stable. the best fitting models indicated that the first intervention was associated with a stepwise reduction in iv use of prescribed daily doses (pdd) ( % ci: , (p < . )). there was also an indication of smaller reduction in iv use associated with intervention , but only the intervention effect was robust to model uncertainty. the overall use of quin was also significantly reduced (figure) with a large stepwise reduction of pdd ( % ci: , ) associated with intervention . this study showed that the hospital-wide use of quin can be significantly improved (and decreased) by an active policy consisting of multiple interventions. marwick°, j. broomhall, c. mccowan, s. gonzalez-mcquire, k. akhras, s. merchant, p. davey (dundee, high wycombe, uk; raritan, us) aim and objectives: to describe the antibiotic treatment and outcomes stratified by severity in a representative sample of adult patients aged or older who were treated in hospital for skin and soft tissue infections. inadequate. we also judged that % of patients received unnecessarily broad spectrum therapy. conclusions: ssti is common and is associated with significant mortality. however, choice of empirical therapy is not evidence based, with significant under treatment of high risk patients. ab were mostly ( / ) prescribed by gps and delivered by public (n = ) or hospital pharmacies (n = ). surveillance of ab use in nhs was organised in only ms. in countries a nh specific pharmaceutical formulary was available. prescription profiles by prescriber were available in countries. other quality improvement initiatives in nhs such as regular training of prescribers, promoting microbiological sampling, collection of antimicrobial resistance profiles or pharmacist advice on ab prescription were scarce. guidelines for ab treatment of most frequent infections were available in many countries but were focussing on ambulatory care and did not consider the specific nh situation. only in country the presence of an infection control practitioner was compulsory and partnership with hospital infection control teams was legally imposed in ms. conclusion: important structural, functional and regulatory nh differences exist between eu countries. specific tools to improve infection prevention and ab therapy in nhs should take into account these differences. a european nh network was created in the framework of the esac nh subproject, which will organise point prevalence surveys on ab use in . c. escherichia coli in south-western finland j. jalava°, o. meurman, h. marttila, a. hakanen, m. lindgren, k. rantakokko-jalava (turku, fi) objectives: extended-spectrum betalactamases (esbls), especially enzymes of the ctx-m group, are spreading rapidly in europe. enterobacteriaceae with reduced susceptibility to third generation cephalosporins and a positive esbl confirmatory test are also increasing in southwest finland. the purpose of this work was to study the resistance genetics of these esbl-positive enterobacteriaceae. methods: the study comprises a total of clinical enterobacteriaceae strains isolated from both inpatient and outpatient specimens. all enterobacteriaceae strains that were esbl confirmatory test positive between january and december were included in this study ( escherichia coli, klebsiella pneumoniae, one isolate per patient). of these strains, ( %) were urine isolates. resistance determinations were done using disk diffusion method (clsi) or vitek and esbl confirmations by the double disk method using cefotaxime and ceftatzidime with and without clavulanate. thus far, strains (those collected by end of june ) have been analysed for the presence of the most important esbl genes (tem, shv and ctx-m) using pcr and pyrosequencing as described before (haanpera et al. aac, : ; ) . results: in only esbl-positive strains were found. all of them harboured a ctx-m type esbl gene. since then, the number esblproducing enterobacteriaceae strains has increased significantly being tenfold in compared to year (figure) . a high majority, ( %) of the strains analysed thus far had a ctx-m-type esbl gene. most of those ( %) belonged to the ctx-m- group according to the pyrosequencing results. ctx-m- group was the next common, with % of the ctx-m genes belonging to this group. only two strains with ctx-m group enzyme were found. conclusions: enterobacteriaceae strains which produce esbl are increasing rapidly in southwest finland. this is especially true with e. coli strains isolated from urine. towards the end of the study period, the esbl enzymes were almost exclusively ctx-m, ctx-m- group being the most common. further research is needed to characterise genetic elements that carry these esbl genes. esbl strains and the proportion of ctx-m genes in - . ( ) ( ) ( ) ( ) ( ) ( ) ( ) in france (n = ), spain (n = ), portugal (n = ), uk (n = ), kuwait (n = ), canada (n = ) and china (n = ), including hong kong (n = ) were studied. clonality was established by pfge and phylogenetic groups of ec and kp were determined as reported. susceptibility testing (clsi), blactx-m- transferability and location (i-ceu-i/s nuclease) were investigated. plasmid analysis included determination of inc group (pcr-replicon typing, hybridisation, sequencing) and comparison of rflp patterns. association of blactx-m- with isecp , isecp -is or iscr was established by pcr and sequencing. we identified pfge types among isolates: / ec, / kp and / cf. distribution among phylogroups were as follows: i) ec: a (n = ), b (n = ), b (n = ) and d (n = ), and ii) kp: kpi (n = ) and kpii (n = ). resistance to tetracycline ( %), nalidixic ( %), streptomycin ( %), sulfonamides ( %), ciprofloxacin ( %) and trimetroprim ( %) was common. were spreading horizontally in our hospitals and, here, we characterised the plasmids responsible in the major k. pneumoniae strains identified during the survey. methods: plasmids from representative k. pneumoniae strains with ctx-m- enzyme were extracted by alkaline lysis and compared by apai, psti and ecori restriction analysis. they were transferred into e. coli dh a by electroporation. transformants were selected on cefotaxime-containing agar and were screened by pcr for beta-lactamase genes, the aminoglycoside resistance genes aac( )-ib and aac -iib, and the plasmid-mediated quinolone resistance genes qnra/b/s. results: twelve isolates were characterised, representing major strains (a-d, and f) found in the most-affected hospitals. restriction analysis divided their plasmids into several groups. representatives of strain a (n = ) had essentially the same plasmid (group ), as did the two representatives of strain d (group a). one strain f isolate had a plasmid (group b) very similar to plasmid a from strain d, indicating possible horizontal transfer. plasmids of group were retrieved from representatives of strains b and c, again indicating probable transfer. plasmids from three other strains differed substantially from each other and from plasmids , a, b and . nevertheless, on all plasmids, blactx-m genes were linked to an upstream isecp element, known to be involved in their mobilisation. all encoded multi-resistance: all but one group and one ungrouped plasmid carried aac( )-ib; blaoxa- and aac( )-iia were detected on all except group plasmids; blatem was found on group , b, one group and two ungrouped plasmids. blashv and qnra/b/s genes were not detected. the considerable diversity of plasmids encoding ctx-m- enzyme in major slovenian k. pneumoniae strains suggested only limited transfer, even when multiple strains were present in the same hospital. evidence of plasmid transfer was between strains b and c, and possibly between strains d and f, although these plasmids were not strictly identical. analysis of resistance genes encoded by the plasmids revealed diversity, with groupings coinciding largely with those based on restriction profiles. a. ingold, g. borthagaray, a.k. merkier, d. centrón, h. bello, c.m. márquez°(montevideo, uy; buenos aires, ar; concepción, cl) objectives: to examine the genetic context of class integron harbouring blactx-m- in fifteen nosocomial k. pneumoniae isolates from south america in order to enhance the understanding of the antibiotic resistance spread among the region. methods: dna was extracted with the use of axypreptm bacterial genomic dna miniprep kit. the analysis of the cassette array was carried out with the use of primers hs /hs targeting adjacent conserved regions. the examination of the surroundings were performed using two pcr primer pairs, hs /hs and hs /hs , to amplify the initial(iri) and the terminal(irt), inverted repeat boundary, respectively. the primer pair hs /hs was used whenever a negative result was obtained with hs /hs . all pcr products were purified and sequenced and the data was analyzed with ncbi blast tool. the sequence obtained with primers hs /hs revealed the presence of three different transposons backbones at the iri end. the tn -like module and the tn -like module were present in isolates, the tn -like module was present in isolates. no amplicons were obtained with the use of primers hs /hs that amplify a tn -like insertion. two uruguayan isolates with a tn boundary at the iri end were tested with hs /hs that target a tn -like backbone and one generated a product consistent with a tn -like mer region. uruguayan isolates carried a single aada cassette ( / ) and the other one contained a dfra -aada array, while the four argentinian isolates carried the combination aaca -aada -orfd. chilean isolates arrays are in process. conclusions: among the extended-spectrum beta-lactamases, the cefotaximases constitute a rapidly growing cluster of enzymes that have disseminated geographically. there is a high frequency of isolation of ctx-m- producing k. pneumoniae associated with a class integron in the region. despite being common the presence of iscr linked to blactx-m- in k. pneumoniae isolates, this study provides new and relevant information in the sequence context at the iri. here we report about the cassette array diversity and the diversity of elements in which the class integron are embedded. different integron/transposons carrying the blactx-m- gene seem to be circulating and different regional patterns could be emerging, this study highlights the ability of different genetic elements to act cooperatively to spread and rearrange antibiotic resistance. l. vinué, a. garcía-fernández, d. fortini, p. poeta, m.a. moreno, c. torres, a. carattoli°(logroño, es; rome, it; vila real, pt; madrid, es) objectives: ctx-m enzymes are frequently detected in europe. in particular, ctx-m- and ctx-m- -producing strains have been recovered from both humans and farm animals in spain, italy, greece, and portugal, suggesting the existence of community reservoirs for these enzymes. the aim of this study was to compare escherichia coli strains and plasmids harbouring blactx-m- and blactx-m- genes isolated from human and animals. methods: four e. coli ctx-m- and eight ctx-m- epidemiologically unrelated producers from sick or healthy animals (pig, dog, cow and chickens) and from humans (urine, blood and faecal samples) were analysed by xbai-pfge, plasmid transferability, pcr-based replicon typing, plasmid restriction analysis and southern blot hybridisation. all isolates were from spain but the dog isolate was from portugal. the genetic context of the blactx-m genes was previously investigated for all the strains. results: three ctx-m- strains (one from healthy chicken and two from hospitalised patients) showed the same pfge pattern. a chromosomal localisation of the blactx-m- gene was suspected in these strains. the five remaining ctx-m- producers showed the blactx-m- gene on plasmids belonging to the incn ( strains) or untypable groups ( strain). two incn plasmids showed identical pvuiirestriction patterns: one was identified in a strain from a healthy chicken and one was from a hospitalised human patient; these two strains were isolated in and , respectively and showed different pfge patterns. ctx-m- producers (three from animal strains and one a healthy human) did not show clonality by pfge and the blactx-m- gene was always located on plasmids, three belonging to the incn and one to the inci groups. two of the incn plasmids carrying the blactx-m- gene showed highly related restriction patterns: one was from a healthy dog and one from a healthy human. conclusion: this study demonstrated the presence of clonal e. coli ctx-m- producers in animal and human sources and also detected epidemic incn plasmids disseminating among unrelated isolates from humans and animals, clearly suggesting a potential animal reservoir for the blactx-m- / genes. o characterisation of bladim- , a novel integron-located metallo-beta-lactamase gene from a pseudomonas stutzeri clinical isolate in the netherlands l. poirel°, j. rodriguez-martinez, n. al naiemi, y. debets-ossenkopp, p. nordmann (k.-bicetre, fr; amsterdam, nl) objectives: characterisation of the mechanism involved in the uncommon resistance to carbapenems observed from a pseudomonas stutzeri isolate recovered from a patient hospitalised in the netherlands with a chronic tibia osteomyelitis. that strain was resistant to ticarcillin, piperacillin-tazobactam, imipenem and meropenem, of intermediate susceptibility to ceftazidime and cefepime, and susceptible to aztreonam. methods: screening for metallo-beta-lactamase (mbl) production was performed using the e-test method with a strip combining imipenem and edta. shotgun cloning was performed with xbai-digested dna of p. stutzeri and pbk-cmv cloning vector. selection was performed on amoxicillin and kanamycin-containing plates. results: e. coli top (pdim- ) recombinant strains were obtained, displaying resistance to penicillins and ceftazidime, reduced susceptibility to cefepime, imipenem and meropenem, and full susceptibility to aztreonam. sequence analysis identified a novel ambler class b betalactamase dim- for "dutch imipenemase" (pi . ) weakly related to all other mbls. dim- shared % amino acid identity with the most closely related mbl gim- , and and % identity with the imp and vim subgroups, respectively. dim- hydrolyzes very efficiently imipenem and meropenem, expanded-spectrum cephalosporins, but spares aztreonam. the bladim- gene was as a form of a gene cassette located at the first position in a class integron, but the be of that gene cassette was truncated giving rise to a fusion with an aadb gene cassette encoding an aminoglycoside adenylyltransferase. the third and last gene cassette corresponded to the qach cassette encoding resistance to disinfectants. conclusion: a novel mbl gene was identified in p. stutzeri further underlining (i) the diversity of acquired mbl genes, especially among non-fermenters, (ii) that pseudomonas sp. may be a reservoir of these genes and (iii) the possibility of spread of important resistance determinants in northern part of europe. isolates in greece p. giakkoupi, o. pappa, m. polemis, a. bakosi, a. vatopoulos°( athens, gr) objectives: metallo-beta-lactamases of the vim family are the main mechanism of carbapenem resistance in p. aeruginosa in greece. in this preliminary report we attempted to survey the subtypes of vim betalactamase currently prevailing in p. aeruginosa clinical isolates in greek hospitals, the genetic relatedness of the respective isolates, as well as the genetic environment of the blavim gene. methods: fifteen mbl producing and epidemiologically unrelated p. aeruginosa clinical isolates were collected in september from fifteen different hospitals around greece. mbl production was initially identified by an edta synergy test. identification of blavim gene, as well as mapping of the blavim cassette carrying integrons were performed by pcr and sequencing of the products. the o serotypes of the isolates were determined by a slide agglutination test using p. aeruginosa antisera (biorad). molecular typing was performed by pulse-field gel electrophoresis of spei-restricted genomic dna. results: blavim- gene was detected in nine isolates, blavim- in five and blavim- in only one isolate. the blavim- cassette of all nine isolates was located on the bp variable region of a class i integron, preceded by aaca gene cassette. blavim- cassette of all five isolates was the first cassette of the bp variable region of a class i integron, followed by the aaca and blapse- gene cassettes. blavim- was the unique cassette of a class i integron. vim- producers belonged to o , o and o serotypes, whereas four isolates were non-typeable. vim- producers belonged to the same three serotypes, whereas only one was non-typeable. the vim- producer belonged to o serotype. the nine vim- producing p. aeruginosa isolates revealed a great degree of variability in pfge molecular typing, belonging to seven types. contrary, the five vim- producing p. aeruginosa isolates displayed higher genetic similarity and fell into one major type with % homology, which also included the vim- producing isolate. there was no correlation between the results of serotyping and molecular typing. conclusions: mbl production in p. aeruginosa in greece seems to be mainly due to specific class i integrons harbouring either blavim- or blavim- genes. genetic variability was higher among bacteria carrying vim- beta-lactamase, a fact indicating wider intraclonar spread of the respective integron. j.m. rodriguez-martinez, l. poirel°, p. nordmann (k.-bicetre, fr) objectives: extended-spectrum beta-lactamases of ampc-type (esacs) contributing to reduced susceptibility to imipenem have been recently reported from enterobacteriaceae. the aim of the study was to evaluate the putative role of natural ampc-type beta-lactamases of p. aeruginosa in a similar resistance profile. methods: thirty-two non-repetitive p. aeruginosa clinical isolates recovered in our hospital in were included. they were selected on the basis of criteria of intermediate susceptibility or resistance to ceftazidime and intermediate susceptibility or resistance to imipenem. mics were determined by agar dilution and e-test techniques. the level of expression of the ampc beta-lactamases was evaluated by measuring specific activities. pcr, sequencing, and cloning allowed to characterise the different bla(ampc) genes. identified esacs were purified and their km and kcat values for beta-lactams determined by spectrophotometry. results: using cloxacillin-containing (an ampc beta-lactamase inhibitor) plates, the susceptibility to ceftazidime was restored for out of isolates, suggesting overproduction of the ampc. in addition, in presence of cloxacillin, reduced mic values were also observed with ceftazidime, cefepime and imipenem for out of those isolates. cloning and sequencing identified distinct ampc b-lactamase variants among the isolates. recombinant plasmids expressing the ampcs were transformed into reference p. aeruginosa strain and reduced susceptibility to cefepime and imipenem was observed only with recombinant p. aeruginosa strains expressing ampc beta-lactamases that had an arginine residue at position . the catalytic efficiencies (kcat/km) of the ampc variants possessing this arginine residue were increased against oxyiminocephalosporins and imipenem. in addition, in-vitro assays demonstrated that those ampc variants constituted a favourable background for selection of additional degree of carbapenem resistance. conclusions: some ampcs of p. aeruginosa possessing extended activity torward carbapenems may contribute to carbapenem resistance. background: most oxa-type esbls are oxa- , oxa- or oxa- derivatives. they display a very low homology, the percentage of which is between % and %. oxa-type esbls are divided into five groups according to the different homology by frederic bert, etc. group includes oxa- , oxa- , oxa- and its derivants;group includes oxa- , oxa- , oxa- and oxa- ;group includes oxa- , oxa- , oxa- and oxa- ; group is named after oxa- ; group only includes a single enzyme called lcr- . oxa-type esbls has been reported widespread in the world since the first report in , such as turkey, france, england and so on. but there is few report about it in china. objective: to investigate the prevalence and genotype distribution of oxa-type extended-spectrum beta-lactamases (esbls) in clinical pseudomonas aeruginosa strains isolated from xiangya hospital of central south university in changsha city, hunan province, china. methods: ninety-seven non-repetitive clinical isolates of p. aeruginosa were collected between october and january from the hospital. they were screened for oxa-type esbls production by polymerase chain reaction pcr with five pairs of primes specific for blaoxa genes, respectively. then amplification of oxa-type esbls production was performed by pcr with specific primers. the purified and amplified products were sequenced to confirm the genotype of the oxa-type esbls. results: the sequences of the three oxa-type esbls pcr products were then compared in genbank database and there were no the completely same ribonucleotide and amino acid sequence with them. they were two novel oxa-type esbls, named as blaoxa- and blaoxa- , which have been registered in genbank database under accession numbers eu and eu , respectively. conclusions: there have occurred infections caused by p. aeruginosa producing oxa-type esbls in xiangya hospital of central south university. two novel oxa-type esbls in p. aeruginosa strains have been discovered in our study, which are named blaoxa- and blaoxa- , respectively. pneumonia is one of the most common nosocomial infections and is associated with high mortality. in the last years, gram-positive bacterial pathogens have risen in prevalence as a cause of hospitalacquired pneumonia (hap), including that occurring during mechanical ventilation (ventilator-associated pneumonia; vap). in particular, staphylococcus aureus is a major cause of hap, including vap. the rise of multidrug-resistant infections is a source of concern, with methicillinresistant s. aureus (mrsa) accounting for > % of s. aureus isolates in some european hospitals. this symposium will take the format of a question-and-answer roundtable session in which experts will answer questions and initiate discussion surrounding emerging concerns and appropriate therapeutic strategies in nosocomial pneumonia, including that caused by multidrug-resistant gram-positive pathogens. recently, shifts in the susceptibility of s. aureus to established therapeutic agents for nosocomial pneumonia have added to the challenge of selecting appropriate empiric therapy. in patients with suspected multidrug-resistant infections or those who are mechanically ventilated, prompt initiation of therapy, often before the pathogen has been confirmed, is critical. vancomycin is the gold-standard treatment for multidrug-resistant infections and resistance has been remarkably slow to emerge. however, clinical reports in europe of 'mic creep' and the emergence of vancomycin-intermediate s. aureus (visa), hvisa and linezolid-resistant mrsa have presented new clinical dilemmas. elevated vancomycin mics are linked to treatment failure and increased mortality. hence, while vancomycin remains a useful therapeutic tool, treatment decisions present an increasing challenge, especially in groups of patients in whom rapid eradication of infection with appropriate agents is critical. telavancin is a novel lipoglycopeptide under investigation for treatment of nosocomial pneumonia. a number of key features suggest telavancin as a potentially attractive option for nosocomial pneumonia. telavancin has a unique dual mechanism of action that disrupts both bacterial cell wall biosynthesis and cell membrane integrity. the agent is rapidly bactericidal against a broad range of clinically relevant grampositive bacteria, including mrsa. two pivotal phase iii studies have demonstrated telavancin efficacy equivalent to vancomycin in hap, including vap, including in seriously ill patient subgroups and in that caused by mrsa. hantaviruses are enveloped rna viruses, each carried primarily by rodents or insectivores of specific host species. they have coevolved with the hosts in which they cause almost asymptomatic and persistent infections. in humans some hantaviruses cause disease: haemorrhagic fever with renal syndrome (hfrs) in eurasia. in europe puumala (puuv) from bank voles and saaremaa (saav) from field mice cause mild hfrs and dobrava (dobv) from yellow-necked mice severe hfrs. in asia hfrs is caused mainly by hantaan and seoul viruses. in americas some viruses cause hantavirus cardiopulmonary syndrome: sin nombre, andes and other viruses carried by sigmodontine rodents, not found in eurasia. in addition, in europe the common vole carries tula and rats seoul virus. however, they have not been definitely associated with disease in europe, although both can infect humans. we discuss the epidemiology, molecular genetics, detection of infection in carrier hosts and humans (including rt-pcr and -min serological tests), functions of hantaviral proteins, risk factors for humans to catch hantavirus infection (including smoking) and disease (including risk and protective hla haplotypes), role and mapping of epitopes of cytotoxic t-cells, mechanisms of hantavirus-induced apoptosis, newly discovered clinical features (including hypophyseal haemorrhages in puuv infection), and long-term consequences and pathogenesis of hfrs (endothelial permeability, thrombocytopenia, tnf-alpha and il- ). puuv occurs widely in europe except in the far north and mediterranean regions, saav in northern, eastern and central europe and dobv mainly in the balkans. the epidemiological patterns differ: in western and central europe hfrs epidemics follow mast years with increased oak and beech seed production promoting rodent breeding. in the north, hantavirus infections and hfrs epidemics occur in − year cycles, driven by prey-predator interactions. the infections and hfrs are on the increase in europe, partly because of better diagnostics and partly perhaps due to environmental changes. in several european countries hantavirus infections are notifiable and in some countries (e.g. belgium, finland, france, germany, scandinavian countries, slovenia) their epidemiology is relatively well studied. in large areas of europe, however, hantavirus infections and hfrs have not been studied systematically and they are still heavily under-diagnosed. mrsa screening − will we ever agree? s mrsa: universal screening! the successful control of any outbreak or epidemic relies on detection of those harbouring the pathogen (infected and colonised persons) combined with eliminating spread to new individuals. the approach to containment and reduction of the global mrsa pandemic is now being discussed. a challenge for this infection is that most persons harbouring mrsa do not exhibit signs of disease and thus in order to detect all potential spreaders of this organism some surveillance must be done. the required level of detection (surveillance through screening) is not known and likely varies with the prevalence of colonisation and disease. for a given mrsa prevalence, the factor that seems most crucial in reducing spread is the percentage of potential isolation days captured. the operational processes that highly influence this are ) the sensitivity of screening detection (including sites tested and laboratory methods used), ) the speed at which results of newly detected positive patients are reported from the laboratory (assuming pre-emptive isolation is not employed), and ) the selection of patient populations who are to undergo screening. laboratory testing has a major impact on detecting mrsa colonised patients with real-time pcr having a sensitivity of % and a possible hour reporting time compared to direct chromogenic agar cultures with a sensitivity of % and > hour reporting and enriched chromogenic agar testing with a sensitivity of % and > hour reporting (am j clin pathol, ); both reduced sensitivity and prolonged reporting time negatively impacting the success of mrsa timely isolation. we have shown that capturing % of mrsa isolation days in a modest mrsa prevalence setting ( infections/ , patient days) with a high sensitivity test having a > hour result reporting time did not reduce hospital-wide mrsa disease (ann int med : , ) . others have demonstrated that surveillance in an icu with similar mrsa prevalence, again with a high sensitivity test having day result reporting, did not reduce icu disease until preemptive isolation was initiated (crit care : r , ) . finally, we demonstrated that universal admission surveillance and decolonisation capturing % of possible mrsa isolation days had a dramatic impact by reducing % of all in-hospital infections from mrsa. future research in this area should focus on better defining those patients that benefit from mrsa screening and the role of decolonisation in these programs. clostridium difficile infection (cdi) is a toxin-mediated intestinal disease and extraintestinal manifestations are exceptional. clinical outcomes can range from asymptomatic colonisation to mild diarrhoea and more severe disease characterised by inflammatory lesions and pseudomembranes in the colon, toxic megacolon or bowel perforation, sepsis, shock, and death. the main clinical symptoms, secretory diarrhoea and inflammation of colonic mucosa, can be in great part explained by the actions of two large protein toxins, toxin a (tcda) and toxin b (tcdb). both toxins are cytotoxic, destroy the intestinal epithelium and decrease colonic barrier function by disruption of the actin cytoskeleton and tight junctions resulting in a decreased transepithelial resistance allowing fluid accumulation. in addition, c. difficile toxins also cause release of various inflammatory mediators which affect enteric nerves, sensory neurons and promote inflammatory cells, adding to the fluid secretion, inflammation and transmigration of neutrophils. some experimental evidence points also to possible extraintestinal action of c. difficile toxin b. in zebrafish embryos tcdb caused damage and edema in cardiac tissue and in hamsters the same toxin caused lung damage. only recently efficient systems have been developed to genetically manipulate c. difficile. comparison of knock-out mutants producing only one of both toxins have shown that tcdb-positive-only mutants retain the ability to kill hamsters, whereas tcda-positive-only mutants were not virulent for hamsters. these results are in concordance with epidemiological findings that naturally occurring a-b+ strains still cause the entire spectrum of cdi, but are not in concordance with effects observed after intragastric challenge of hamsters with purified toxins tcda and tcdb. the role of the third toxin produced by c. difficile, binary toxin cdt in the development of human disease is not well understood. cdt was shown to have enterotoxic effect in rabbit ileal loop assay, but natural strains producing cdt but neither tcda nor tcdb colonised animals but were not lethal in hamsters. comparative genomic analysis will most likely reveal additional factors involved in pathogenesis and in increased virulence (including cell surface layer proteins, sporulation characteristics and antibiotic resistance). additionally, the role of the host immune response in cdi has just started to be better understood. since , there has been an escalation in rates of clostridium difficile infection (cdi) with epidemic c. difficile (pcr ribotype /north american pulsed-field type [nap ]) responsible for outbreaks of severe infection in north america and europe. while fluoroqinolone resistance and over-use are thought to be driving the epidemic, the ageing population and improved case ascertainment are contributing to the dramatic increase in cases. other factors may also be important, such as the increase in prescription of proton pump inhibitors. in the netherlands, since , there has been an increase in prevalence of human cdi with ribotype strains usually found in animals. these infections were in a younger population and more frequently community acquired. there was alarm when it was reported that % of retail beef samples in canada contained c. difficile. the figure is higher in the usa where more than % of packaged meats (beef, pork and turkey) from arizona stores contained c. difficile. most animal isolates of c. difficile produce binary toxin, and both pigs and cattle harbour pcr ribotype a strain that, like ribotype , also produces more toxins a and b, and binary toxin. in the eastern part of the netherlands where > % of pig farms are located, > % of human isolates are now ribotype , and human and pig strains of c. difficile are highly genetically related. it has been suggested that the overlap between the location of pig farms in the netherlands and the occurrence of human ribotype infections involves a common source. that source is likely to be the environment. the upsurge in cdi has prompted diagnostic companies to try to either improve current tests or develop new ones. laboratory diagnostic methods can be divided into groups; traditional faecal cytotoxin detection (with or without culture), enzyme immunoassays (eias) and molecular methods. faecal cytotoxin detection is specific but lacks sensitivity, culture is sensitive but lacks specificity. new eias should find a niche in medium sized laboratories. current in-house pcr methods have the potential for great sensitivity and specificity but have been available only in larger laboratories. new commerciallyavailable platforms will make this methodology more accessible to smaller laboratories. whatever method is chosen, it is necessary for the laboratory to have as fast a turn-around-time as possible, particularly in an outbreak situation. d. lévy-bruhl°(saint-maurice, fr) in , the advisory board on immunisation (abi) has been asked to make recommendations to the ministry of health regarding the inclusion or not in the french immunisation schedule of the soon to be licensed first hpv vaccine. the main elements considered in the establishment of the benefit-risk balance of routine hpv vaccination were: on the benefit side: -the very significant potentially preventable burden of diseases; -the very high efficacy of the vaccine against persistent hpv / infections in naive subjects; -the expected additional impact on other hpv / related lesions and cancers; -the fact that vaccination, by preventing the pre-cancerous lesions, has the advantage over screening to reduce the cost and anxiety related to their detection and management; -the available data in favour of a satisfactory safety profile; -the benefit of vaccination for the women not covered by the opportunistic screening program. on the "risk" side: -the high cost of vaccination; -the unknown duration of protection; -the need for continuation of screening, even for vaccinated women; -the fact that the majority of residual cervical cancers could be prevented by the organisation of the screening program; -the risk of a decrease in compliance to screening for vaccinated women; -the low benefit if vaccinated and screened women were the same. a cost effectiveness analysis, carried out on a multi cohort markov model, showed that, over a years period, the impact of vaccinating % of years old girls or of organising the screening were comparable (reduction of cancer deaths close to %). however, the cost-effectiveness ratio of the vaccination was higher than that of the screening organisation, resp. , and , € per life year saved (at a % discount rate). on the basis of the economical analysis, the screening organisation was therefore the first priority. however, if both interventions were implemented, the overall reduction in cervical cancer deaths was estimated at %. the cost-effectiveness of the addition of vaccination on the top of the organisation of the screening appeared acceptable ( , € per life year saved). based on those results, the abi issued in march a recommendation to include the hpv vaccination in the immunisation schedule for years old girls, together with a catch up for to years old women not having started their sexual life more than one year ago. the vaccine cost has been reimbursed since july . clinical microbiology − is outsourcing the way to go? s the (r)evolution of clinical microbiology in europe − is it good or bad? laboratory medicine in general and clinical microbiology in particular is presently subject to rapid (r)evolution. are we aware? are we in command? do we know where we are going? should we oppose or cooperate? do we have a choice? do we recognise a driving force other than money? is it good, bad or just plain necessary? and are we gaining or losing? it is not one evolutionary process -it is several parallel processes with varying emphasis in different areas. there are at least four distinctive major trends over the last years; the gradual formation of bigger and bigger units (concentration), the amalgamation of many different laboratory services into one (laboratory medicine), accreditation and an explosion of professional proficiencies and backgrounds of staff in microbiological laboratories. personally i have withstood the first two, with pleasure succumbed to the latter. a recent th trend, outsourcing microbiology services to large private consortiums, is splitting clinical microbiology into a purely analytical high-throughput money-saving activity, often leaving the consultative, clinical part of microbiology and health care infection control adrift. what is driving the evolution? not only cost-saving but also our inability to recruit medically trained microbiologists, the need to broaden the knowledge base of microbiology laboratories, automation, the development of new techniques and apparatus common to many laboratory disciplines, computerised medicine, political trendiness, power struggles, and much more. there is much to be gained by both concentration and amalgamation but much to be lost as well and many consider the heart and soul of clinical microbiology at risk. over a period of years, rational high-throughput production has won over consultation and personalised microbiology. that may be fine for the production of negative hiv-antibody/antigen analysis as for the screening of blood-donors but certainly not for the bacteriological cultures taken in conjunction with a hip replacement. or when it comes to understand and advise on the intricacies of antimicrobial resistance development. in other cases "outsourcing" and/or "amalgamation" mean that blood cultures are sent to x-town, cmv-antibodies to y-town and everything else to z-ville. when that happens clinical microbiology is lost. there are several instances where concentration, amalgamation and/or outsourcing of clinical microbiological services, alone or with other services, have meant that the tie between clinical microbiology and infection control has been severed and that many, both small and large hospitals have lost the personalised service so necessary to control outbreaks of multi-resistant bacteria and other health care related infections. a good service requires a strong knowledgeable and enthusiastic champion. a service which encompasses too many branches of laboratory medicine cannot be expected to champion each and every one with equal strength and fervour. and when outsourced to "big companies", there is no "clinical", only "microbiology". in "medical microbiology" broke out from "laboratory medicine" in uems. we are now striving towards a strong "medical microbiology" service in europe. it will have many facets, much strength, some weakness, great opportunities, but many threats. escmid certainly intends to help shape microbiology in europe. the optimal organisation of microbiology laboratories in european metropolis is an evolutionary task, driven by the evolution in laboratory tasks, laboratory technologies, communication technologies, regulations and financial issues. in the past five-ten years, medical and societal query for a more rapid and refined detection and identification of pathogens and antimicrobial resistance determinants coincided with the expansion of internet-based and remote tools for communication, an unprecedented revolution in laboratory technologies and new financial constraints. the concentration of laboratory workforces into one unique laboratory is one way to address these apparently contradictory issues. the tertiary medical school hospital system in marseille, a -million metropolitan area in france, comprises four hospitals for a total of , beds. the system had once four microbiology laboratories which have been progressively embedded into a unique, , acts per year, laboratory which deals with bacteriology, virology and environmental microbiology and hygiene. the medical staff comprises of , the ingenior staff of , technical staff of and support staff of persons for a total of persons. this organisation allowed reducing labour time for routine microbiology, to develop prospective and sophisticated time-consuming diagnostic methods and to develop advanced diagnostic methods such as molecular methods (real-time pcr-based tests, sequencing, and mass spectrometry identification) and new generation serology. new, sophisticated technologies such as automated serology and mass spectrometry were corner-stones on which to base the constant diminution of routine labour time and the development of time-consuming tasks such as fastidious organisms' isolation. these evolutions paralleled the exponential increase in the ratio of ingeniors in the laboratory. this paradigm allowed for the constitution of large collections of biological specimens for retrospective analyses, the specialisation of every medical senior in one particular field of internationally recognized expertise and the increase in knowledge output in terms of peer-reviewed papers, patents and grants. implantation of point-of-care in the emergency department, in permanent internetbased connection with the central laboratory, was the last, but not least, evolution of this system. when tuberculosis epidemiology is seen in a global perspective, and the millennium development goals are considered, it is clear that two regions of the world, africa and europe, are severely behind in the control of the disease. in africa, especially sub-saharan africa, the tb problem is closely related to the endemic hiv/aids situation. in europe, especially the eastern part and in parts of the former soviet union, the main obstacle to an effective tb control is related to drug resistant forms of m. tuberculosis. the prevalence of the most severe forms of resistance, mdr-and xdr-tb, is so high that it makes control efforts both extremely complicated and very expensive. unfortunately, increasing levels of drug resistant tb are today also seen in many african countries, and hiv infection is spreading in eastern europe. during the last ten-year period new tools, based on molecular fingerprinting of m. tuberculosis strains, have been increasingly adapted to study tb transmission. with such molecular methods to characterise clinical isolates of m. tuberculosis it is now possible to study the spread of individual strains of the bacteria in detail. the laboratory tools used, rflp, miru/vntr, spoligotyping and others, will be presented and their use exemplified. how molecular epidemiology contributed to the detection and characterisation of a major outbreak of drug resistant tb in the stockholm area will be discussed. molecular characterisation of clinical isolates from different parts of the world has led to an increased recognition of the differences between different families of m. tuberculosis strains. to further describe and understand the role of these differences in the clinical field as well as for tb epidemiology is an ongoing and interesting field of research. an increased understanding of how tb is transmitted will hopefully help in the efforts to control this global health threat both on the local level and in a global perspective. living in the era of increasing tuberculosis drug resistance, the importance of making an early and accurate diagnosis with drug sensitivities has never been greater. the epidemiology of tuberculosis defines the extent of latent disease and the proportion which becomes active. accurate diagnosis is vital if patients are to be treated in a timely manner and to reduce the amount of time infectious individuals go untreated in the community disseminating disease. in many areas of the world, dots programmes are at the forefront of tuberculosis control. however, as a diagnostic this currently relies on sputum smear microscopy which is known to miss % of cases of tuberculosis and provides no data on drug sensitivity. the second major issue around tb is the lack of worldwide diagnostic facilities. there is a need for a simple, low cost, easily implemented diagnostic test. this talk will briefly consider the issues around the diagnosis of latent and active disease which are quite distinct. the focus will be on the diagnosis of active infection. in particular, the use of mods (microscopic observation drug-susceptibility) assay in diagnosis of tuberculosis will be discussed. the potential for using this in resource poor countries will be reviewed as well as the way sophisticated technology maybe harnessed to improve reporting and allow translation to all parts of the world. the important issue of how to distinguish patients with latent and active disease will also be considered. key issues and principles in diagnosis both now and in the future will be reviewed. in terms of treatment, there are main issues. the first is that even short-course therapy is prolonged being a minimum of months leading to issue of compliance. this may result in drug resistance. the massive rise of multi-drug resistant tuberculosis to approximately , cases world-wide with around countries reporting extensively drug-resistant disease means that the need for new approaches to therapy are urgent. the second part of this talk will review different approaches to using current anti-mycobacterial drugs, the emergence of a small number of new drugs such as the diarylquinolones and entirely novel approaches to control and treat tuberculosis. there has been great success and also many threats in the field of infectious diseases during the previous year. the antimicrobial resistance, especially increasing carbapenem resistance among aerobic gram-negative rods and xdr mycobacterial tuberculosis strains are already big threats in some countries and they will probably spread to many other areas all over the world in the future and we will need new drugs for these indications but unfortunately very few new promising drugs seem to be in the pipeline at the moment for these purposes. the virulent clostridium difficile strain spreads rapidly to many new countries and e.g. in finland it killed many times more people compared with mrsa and esbl strains in . however, it is possible to stop its spreading but it needs new thinking in antibiotic use policy and infection control policy in hospitals. clostridium difficile infection has a high relapse rate after metronidazole or vancomycin therapy, but an experimental "stool exchange treatment" is a promising therapy although controlled studies are needed to prove this assumption. an interesting research area during the last years has been the role of infections in the etiopathogenesis of chronic diseases like cancer, atherosclerosis, cardiovascular diseases and many autoimmune diseases. we can fight against many cancers like liver cancer and cervix cancer with virus vaccines and gastric cancer with antimicrobial drugs. also the high incidence of malignant tumours seems to decrease during haart treatment in hiv patients. the role of infections in the etiopathogenesis of cardiovascular diseases and atherosclerosis is complex. it is obvious that infections play a role in the etiopathogenesis of atherosclerosis, stroke and myocardial infarction but the undirected routine antimicrobial treatment is not recommended for these patients but there seems to be subgroups in patients with various cardiovascular diseases which may benefit from antimicrobial treatment. recent studies seem to suggest that there are hla types which protect or make people susceptible for coronary heart disease. the hla type hla-b* seems to be a risk factor for coronary heart disease but it is also a risk factor for chronic chlamydia pneumoniae infection. the feared pandemia due to h n influenza a did not appear during the recent year and the world is now much more prepared to meet the next pandemia which, however, hopefully does not come during the next year. Ø. samuelsen°, c. giske, u. naseer, s. tofteland, d.h. skutlaberg, a. onken, r. hjetland, a. sundsfjord (tromsø, no; stockholm, se; kristiansand, bergen, oslo, førde, no) objectives: the worldwide dissemination of kpc-producing multidrugresistant enterobacteriaceae is worrisome. the first kpc-producing klebsiella pneumoniae in norway was isolated late from a patient after hospitalisation in greece. throughout the following year seven additional kpc-producing k. pneumoniae isolates have been detected in clinical samples from six new patients. the aim of this study was to perform molecular characterisation of the strains and examine their epidemiological relatedness. materials and methods: antimicrobial susceptibility was examined by etest. molecular characterisation was performed by mlst, pfge and sequencing of the blakpc genetic structure. plasmid analysis was carried out by pfge of s nuclease-digested total dna and southern blot hybridisation using a blakpc probe. relevant epidemiological data were collected retrospectively. results: eight kpc-producing clinical isolates of k. pneumoniae have been identified from seven patients in two different regions of norway from the following specimens: blood culture (n = ), urine (n = ), expectorate (n = ), perineal swab (n = ) and wound secretion (n = ). two blood culture isolates with clonally related but different pfgeprofiles were observed in one patient. the detection of kpc-producing k. pneumoniae isolates in norwegian patients was associated with import in four cases after hospitalisation in greece. two patients had been hospitalised at the same hospital in greece. isolation of a kpc-producing isolate in a fifth patient was epidemiologically linked to one of these imported cases and was a case of nosocomial transmission in norway. for the latter two cases no risk factors were identified with respect to recent hospitalisation or travel abroad. molecular analysis of six isolates has shown genetically related pfge-patterns and a common sequence type (st ). st has been associated with dissemination of ctx-m- in hungary. the blakpc gene was localised in tn on a~ kb plasmid. the two most recent isolates are currently undergoing similar analysis. conclusion: the first seven cases of kpc-producing k. pneumoniae in norway are associated with hospitalisation abroad, nosocomial transmission in norway, or urinary tract infections in outpatients without obvious risk factors. the clonal relationship between isolates underlines the existence a biological fit genetic lineage of kpcproducing k. pneumoniae with an epidemic potential. objectives: two recent publications have reported the isolation of kpc producing k. pneumoniae from infections in two patients, one in france and one in sweden, who originally had been hospitalised in greece. since this resistant mechanism had not been identified before in this country, the purpose of this report was to confirm the presence of blakpc producing k. pneumoniae in greece, to assess the extent of its spread and to study the genetic relatedness of the respective bacterial strains and the transferability of the blakpc harbouring plasmids. methods: for a three month period (february to april ) hospitals participating in the greek system for surveillance of antibiotic resistance (www.mednet.gr/whonet) were asked to seek for possible kpc producers among k pneumoniae isolates displaying reduced susceptibility to imipenem (equal or higher than mg/l), a positive hodge test for the presence of carbapenemase and a negative edta synergy test for the presence of metalloenzymes. the presence of blakpc gene in these strains was confirmed by pcr and sequencing. mics to carbapenems were determined by etest. conjugation experiments were carried out both in broth and on agar. the possible absence of ompk porin was detected by pcr. molecular typing was performed by pulse-field gel electrophoresis of xbai-restricted genomic dna. results: ninety two k. pneumoniae clinical isolates (one per patient) from hospitals all over greece were found to harbour blakpc- gene. although colonies present in the inhibition zone made the exact determination of imipenem mic difficult, the absence of ompk porin was always associated with mic of imipenem higher than mg/l. all isolates exhibited resistance to all other drug classes except colistin, tetracycline and tigecycline. pfge analysis revealed that isolates from hospitals displayed more than % similarity and were classified into one pulsotype, whereas the remaining seven isolates belonged into four different pulsotypes. blakpc- gene could not be transferred by conjugation from strains belonging to the main pulsotype. however, it was transferred from strains belonging to three out of the four remaining pulsotypes. conclusion: production of kpc- betalactamase seems to be a new emerging resistance mechanism in klebsiella pneumoniae in greece. blakpc- gene's possible clonal spread imposes the urgent need of implication of infection control practices in the affected hospitals. i. galani, m. souli, e. papadomichelakis, f. panayea, n. mitchell, a. antoniadou, g. poulakou, f. kontopidou, h. giamarellou°(athens, gr) background: until now, carbapenem resistance among klebsiella pneumoniae (kp) clinical isolates in greek hospitals has been attributed to the dissemination of vim- metallo-beta-lactamase. we describe the first outbreak of kpc-producing kp in greece; the first to occur outside the usa or israel. setting: -bed icu of attikon university hospital, athens. methods: kp isolates with an imipenem mic > mg/l and a negative edta-imipenem disk synergy test were submitted to boronic acid disk test, to pcr for a kpc gene with specific primers and sequencing. records from patients colonised or infected with a kpc-producing kp were retrospectively reviewed for clinical and epidemiological data. environmental cultures for kpc-producers were performed. clinical isolates were submitted to molecular typing using pfge. results: from february to november , kp were isolated from patients, ( . %) of which were boronic acid positive and produced kpc- . most of them ( / , . %) were isolated since august. a total of patients were identified as colonised or infected by a kpc producer which in of them belonged to the same genetic clone. the source was faeces ( ), bronchial secretions ( ), blood ( ), cvc tip ( ), urine ( ), pus ( ) and throat ( ). among patients whose medical records were available, median age was , apache ii score; , length of preceding hospital stay; days, total length of stay; days, immunosuppresion was identified in one and crude mortality was %. the kpc-producing kp was more frequently icu acquired whereas in a minority of patients it was already present on icu admission. seventy percent of the patients had previously received a carbapenem for a median of days. environmental colonisation was not identified. ten ( . %) of the kpcproducers from ( . %) patients were identified as the cause of an infection: bacteraemia ( ), ventilator-associated pneumonia ( ) and surgical site infection ( ) and exhibited mic (mg/l) for imipenem, > ; meropenem, > ; gentamicin, ; ciprofloxacin, > ; fosfomycin, > ; colistin, . and tigecycline, . most patients were successfully treated with a colistin-containing combination mostly with a beta-lactam. there was no attributed mortality. isolates from the same bacterial species were typed by pfge or automated ribotyping. kpc-encoding gene was fully sequenced. plasmid preparations and i-ceu digestion of total dna were resolved in agarose gels, blotted and hybridised with a blakpc probe. the blakpc-carrying element (tn ) was amplified with various primer pairs, digested with eag i and sequenced. results: strains each carried kpc- and kpc- . one e. cloacae carried kpc- . k. oxytoca were kpc- -producers and s. marcescens harboured blakpc- , all from usa. great genetic diversity was observed among the isolates ( different types). one clone of e. cloacae was detected in new york state ( ) ( ) . small clusters of and strains were detected among e. coli, e. cloacae, k. oxytoca. plasmids were present in all but isolates. persistence of clones throughout the years was not observed. in isolates the kpc-encoding gene was located in high molecular weight plasmids (> kb). blakpc was located in the chromosome of strains (e. cloacae, e. coli and k. oxytoca) and the location of this gene could not be determined in strains. small plasmids were present in several strains, but did not harbour blakpc. tn carried blakpc in isolates, and the transposon element was conserved. this structure was not detected in strains. conclusions: kpc-encoding genes were most often located in tn among several enterobacteriaceae species collected in usa and israel. this blakpc-carrying element was located in plasmids and on the chromosome. this study highlights the importance of tn in the dissemination of blakpc genes in several genetically diverse bacterial species. blakpc was not associated with tn in only of strains. these strains are under further investigation. objective: to evaluate the carbapenem resistance mechanism in a raoultella planticola bacteraemia isolate recovered from a patient hospitalised in ohio, usa. methods: species identification was performed by vitek and confirmed by s rrna sequencing. susceptibility testing used clsi broth microdilution method. blakpc was amplified and sequenced. the blakpc genetic element (tn ) was amplified and sequenced. plasmid extractions and conjugation experiments were carried out and the isolate was screened for esbl-encoding genes, qnr and qepa. a year old female patient was admitted to a hospital located in akron with a diagnosis of cap in may/ . sputum, paracentesis and blood cultures were negative. urine culture grew e. coli and patient received courses of moxifloxacin, ceftriaxone, azithromycin and meropenem. the patient was discharged and returned after three weeks with respiratory problems. tracheal aspirate grew a multidrug resistant a. baumannii and the blood culture grew the enteric-like gramnegative bacillus. the isolate was identified as r. planticola by the vitek , which was confirmed by s sequencing. r. planticola strain demonstrated resistance against most b-lactams, including carbapenems. screening for kpc-encoding genes was positive and this strain carried blakpc- . fluoroquinolone and aminoglycoside mic values were elevated. kpc- -encoding gene was located in tn , but conjugation experiments failed. esbl and qnr/qepa genes were not detected. conclusions: kpc serine-carbapenemases have been detected in several gram-negative species commonly isolated from clinical specimens. kpc genes are embedded in transposon-like structure usually harboured in conjugative plasmids carrying multiple antimicrobial resistance mechanisms. this is the first report of kpc-producing r. planticola that is an environmental organism related to klebsiella spp. the similarity between these organisms could facilitate the transfer of genetic material. kpc-producing isolates appear to be prevalent among different enterobacteriaceae species in usa hospitals and was detected in an isolates of apparent environmental origin. objectives: it is long known that not all individuals with a specific disease present with the same clinical manifestations, nor do they have identical prognoses or responses to treatments. it has become clear that variations in the human genome are likely to have an impact on these aspects. tank-binding kinase (tbk ) is a central molecule in the induction of a.o. the type i interferon response to pathogens. our goals for this study were ) to investigate the frequency of single nucleotide polymorphisms (snps) in the promoter and coding region of tbk in a dutch caucasian population and ) to search for potential associations between these snps and bloodstream infections. methods: whole blood samples or samples of positive blood cultures were collected and after genomic dna was isolated, pcr and sequencing were performed for snp identification. functional studies included promoter activity measurements using a luciferase assay as well as electrophoretic mobility shift assays (emsa) to study binding of the transcription factor usf to the wt and mutant promoter. snp incidences were studied in a case control study. results: in samples from dutch caucasian healthy volunteers, snps were found with allele frequencies higher than % whereas other known snps had frequencies lower than % in our cohort. two snps (rs and rs ) located in the promoter region were studied in a larger cohort of anonymised patients from the maastricht university medical center with either gram-positive or gram-negative blood cultures. we found that the prevalence of rs was significantly increased in patients with positive blood cultures in comparison with those with negative blood cultures or healthy volunteers. further investigation of this snp showed that it is located just outside a usf -binding site. measuring the promoter activity using luciferase assays, the mutant promoter exhibited a decreased activity of < %. this observation was confirmed by emsa which showed that recombinant usf protein had a reduced binding affinity to the mutant promoter. conclusions: snp rs in the promoter region of tbk has a significant association with gram-positive infections. our results demonstrate that this is likely due to a decreased expression of tbk due to reduced binding of the transcription factor usf to the mutant promoter. our results support recent findings that tbk plays also an important role in the host response to gram-positive infections. objective: lymphocyte apoptosis has been recognized as an important factor contributing to both the onset of sepsis post infection and to the progression into septic shock. animal data suggest that prevention of lymphocyte apoptosis by caspase inhibition stabilises the immune system, improves bacterial clearance and decreases mortality in experimental sepsis. the present study evaluated the potential of vx- , a novel broad caspase inhibitor, as a therapy for sepsis. methods and results: initial characterisation of vx- in a number of enzymatic and cellular assays clearly demonstrated that the compound is a broad caspase inhibitor with potent anti-apoptotic activity in vitro. in vivo, vx- was tested in a murine model of endotoxic shock and a clinically relevant model of peritonitis. in the endotoxic shock model, male cd- mice (n = per group) were administered lps ( mg/kg iv) and survival was monitored for h. vx- administered by repeat iv bolus ( , , and h post-lps) significantly improved survival in a dose-dependent fashion (p < . ). in the rat peritonitis model, adult male sprague-dawley rats (n = per group) underwent caecal ligation and puncture (clp) and survival was monitored over d. continuous administration of vx- by mini-osmotic pump ( . mg/kg/h) immediately following surgery significantly improved survival (p < . ) from % in the control group to % in the compound-treated group. mode of action studies in the rat clp model confirmed that vx- reduced thymic atrophy and lymphocyte apoptosis (p < . ), supporting the anti-apoptotic activity of the compound in vivo. in addition, vx- reduced plasma endotoxin levels (p < . ), strongly suggesting an improved clearance of bacteria from the bloodstream. most importantly, we demonstrated that vx- fully retained its efficacy when dosed hours after insult (p < . ) by improving survival to % versus % in control animals, further highlighting the potential of anti-apoptotic therapy in sepsis. overall these data demonstrate that vx- inhibits lymphocyte apoptosis, improves the clearance of bacterial endotoxin and improves survival in experimental sepsis. importantly vx- improves survival in the clp model when dosed post insult, and therefore represents significant progress in the development of therapeutically viable broad caspase inhibitors for the treatment of this disease. v. vankerckhoven°, s. van voorden, n. hens, h. goossens, g. molenberghs, e. wiertz (wilrijk, be; leiden, nl; hasselt, be) objectives: toll-like receptors function as key regulators of both innate and adaptive immunity. lactobacilli modulate the immune system in different ways. the aim of this study was to examine toll-like receptor (tlr , tlr / and tlr ) signalling induced by clinical and probiotic lactobacillus strains. methods: a total of lactobacillus strains ( l. paracasei and l. rhamnosus) of different origin ( probiotic, faecal, and clinical) were tested for tlr , tlr in combination with tlr , and tlr . tlr signalling was measured as relative il- promotor activation in transfected human embryonic kidney (hek) cells. il- concentrations were measured using an enzyme-linked immunosorbent assay. heat-killed listeria monocytogenes (hklm) was used as positive control in all assays, whereas pam , pam , and lps were used as positive controls for, respectively, tlr , tlr / , and tlr . all assays were performed at least in duplicate. linear mixed model analyses and stepwise model selection were used to identify the statistically significant effects. random effects were used to account for heterogeneity across and homogeneity within isolates. p < . was considered statistically significant. results: hek-tlr and hek-tlr / , but not hek-tlr , cells released il- upon stimulation with uv-inactivated lactobacilli, which was enhanced by co-transfection with cd- . interestingly, the production of il- was shown to be variable for the different lactobacillus isolates. although similar results were seen for all isolates for tlr and tlr / , il- production was significantly higher for tlr ( . log pg/ml) compared to tlr / ( . log pg/ml) (p < . ). no significant differences in il- production were seen between clinical and probiotic isolates. however, l. rhamnosus isolates induced a significantly higher il- production compared to l. paracasei isolates in both cell lines, . and . log pg/ml, respectively (p = . ). intra-isolate correlation was found significant (p < . ). conclusions: our study shows that lactobacilli activate both tlr and tlr in combination with tlr . our results also indicate that heterodimerisation of tlr with tlr does not lead to an improved recognition of lactobacilli. furthermore, taking intra-isolate correlation into consideration proved to be important. finally, our results suggest that differences in immunomodulation by lactobacilli may be related to differential signalling through tlrs, including tlr and tlr / . m.c. gagliardi, v. sargentini, r. teloni, m.e. remoli, g. federico, m. videtta, g. de libero, e. coccia, r. nisini°(rome, it; basel, ch) objective: to gain insights into the mechanisms used by mycobacterium tuberculosis and bacillus calmette guérin to cause human monocytes differentiation into cd negative dendritic cells (my-modc), unable to present lipid antigens to specific t cells. methods: human monocytes infected or not with mycobacteria were induced to differentiate into dc with gm-csf and il- in the presence or absence of p or erk specific inhibitors. kinases activation was detected by western blot using antibodies specific for phosphorylated and non phosphorylated isoforms. differentiation of monocytes into dc and the cd a, cd b and cd c expression was evaluated by flow cytometry and by real time pcr at different time points from infection. functional expression of cd molecules was assessed by recognition of lipid antigens by cd restricted t cell clones. results: we show that mycobacteria trigger phosphorylation of erk and p mitogen-activated protein kinase in human monocytes as well as of activating transcription factor (atf)- . mycobacteria-infected monocytes treated with a specific p inhibitor, but not with a specific erk inhibitor become insensitive to mycobacterial subversion and differentiate into cd positive my-modc, which are fully capable of presenting lipid antigens. data indicate that phosphorylation of p is directly involved in cd inhibition. conclusions: we propose p signaling as a pathway exploited by mycobacteria to affect cd expression, thus representing a novel target of possible pharmacological intervention in the treatment of mycobacterial infections. s. ebert°, s. ribes, r. nau, u. michel (gottingen, de) objective: activin a (act a) is a multifunctional cytokine with roles in the immune system and the inflammatory response. act a levels are elevated in the cerebrospinal fluid of patients with meningitis. microglial cells, the major constituents of innate immunity within the brain, express toll-like receptors (tlrs) recognising exogenous and endogenous ligands. upon stimulation with tlr agonists, primary mouse microglial cells become activated and release nitric oxide (no), cytokines, and also act a, suggesting that they are a source of elevated conclusions: pre-treatment with act a enhances no release from microglial cells activated by agonists of the principal tlrs involved in the recognition of bacteria. these findings provide further evidence for a role of act a in the innate immune response and suggest that act a acts as an pro-inflammatory modulator during infection and inflammatory processes in the cns. insertion sequences (is) are genetic tools that can mediate expression of previously silent genes or be responsible for the overexpression of certain genes (in each case by providing promoter sequences). in addition to be involved in gene transcription levels, is elements also play a very important role for gene acquisition/mobilisation. an is is usually made of of two inverted-repeat sequences (irs) bracketing a gene encoding the transposase which activity enables this entity to replicate and target another sequence. the is-related mechanisms at the origin of antibiotic resistance gene acquisition are diverse, including composite-transposition, rolling-circle transposition, one-ended transposition. is elements may be also involved in gene acquisition by mediating co-integration processes, or recombination events as hypothetized for is in relation with blashv extendedspectrum b-lactamase (esbl) genes originating from the chromosome of klebsiella pneumoniae. the blactx-m esbl genes known to be extremely widespread worldwide are encoded on plasmids, and have been found in association with isecp (acting by one-ended transposition) or iscr (acting by rolling-circle transposition). in that case, iss have played a role in the mobilisation from the chromosome of kluyvera spp. being the blactx-m progenitors and then in their expression. also, genes encoding acquired ampc b-lactamases, being of the blaacc, bladha, and blacmy-types, are mostly found in association with iscr or isecp . sometimes antibiotic resistance genes are mobilised by composite transposons which are made of two copies of a given is bracketing the mobilised fragment. in acinetobacter baumannii, the worldwide disseminated blaoxa- carbapenemase gene is part of a composite transposon structure made of two copies of isaba , forming transposon tn which had mobilised a chromosomal fragment from acinetobacter radioresistens that actually corresponds to the progenitor of blaoxa- . another possibility can be the forming of composite transposon structure bracketed by two different is (sharing similar irs) as observed with the blaper- esbl gene in pseudomonas aeruginosa. this diversity of iss elements at the origin of mobilisation/acquisition of antibiotic resistance genes is therefore responsible for the very efficient dissemination of many of them. s resistance islands − their role in the accumulation and spread of antimicrobial resistance genes historically, multi-antibiotic resistance in many bacterial species was largely attributed to the acquisition of resistance (r)-plasmids encoding one or more resistance determinants. however, over the last decade the r-plasmid paradigm has begun to be challenged. 'resistance islands' comprising large, chromosomally-integrated spans of alien dna harbouring multiple antibiotic resistance genes have been identified in the major hospital pathogens methicillin-resistant staphylococcus aureus (mrsa) and multi-resistant acinetobacter baumannii, and the foodand water-borne diarrhoeal pathogens shigella, salmonella and vibrio cholerae. in addition, comparative genomics analysis of the archetypal haemophilus influenzae conjugative resistance element that had spread worldwide revealed that it belonged to a large syntenic family of integrative islands, members of which could be found in at least other b-and g-proteobacteria. with the exception of the a. baumannii island, these elements can be described as classic self-excising, -circularising and -integrative elements. all three functions are mediated by short island-flanking direct repeats and cognate integrase proteins encoded by the islands. in fournier et al. described an kb a. baumannii island (abar ) which harboured resistance genes packaged within a highly mosaic, integron-rich element that had almost certainly evolved via recombination, transposition and integron-mediated cassette capture from an 'empty' ancestral prototype. abar probably represents a new class of resistance island as it exhibits several features reminiscent of complex nested transposons, suggesting a distinct functional natute. however, despite the widespread distribution of resistance and genomic islands only a minority are known to code for part or all of the conjugative machinery necessary for their dissemination; others have been mobilised by helper plasmids or bacteriophages. regardless, data on the mechanisms of mobilisation of the vast majority of similar nonresistance islands remain sparse. importantly, resistance islands may not consists merely of packages of resistance genes. on the contrary, these diverse and frequently hybrid entities could potentially confer upon their hosts other advantageous traits relating to host-pathogen interaction, virulence, survival in the environment and/or transmissibility, truly justifying the label 'selfish islands' and further explaining their evolutionary success. due to the availability of new techniques, genome sequencing of bacteria has become fast and inexpensive. furthermore, recent methods using paired-end reads located several kb apart in the genome eases the assembling process, even though no reference sequence is available. in a reasonably close future, it should be possible to obtain the fully assembled sequence of a bacterial isolate overnight. the new sequencing techniques generate enormous amounts of genomic data and, thereby, a need for new tools. these should able to quickly analyze genomes and point to zones of interest, prompting further analysis on a reduced number of regions or genes, such as genomic islands. pathogenicity islands, a subset of genomic islands, carry genes such as toxins or resistance genes and have the particularity to be mobile, i.e. they may transfer to other species or strains. thereby, they confer their new hosts a more resistant or infectious phenotype, making this phenomenon particularly important to study. nucleotide composition of genomes is fairly homogeneous inside bacterial genomes. in general, horizontally transferred regions can be spotted due to their particular nucleotide content, because they tend to retain the composition of their original host and don't share the one of their new hosts. to do an analogy with languages, genomes speak dialects, and as one would easily spot a paragraph in finnish in an english text while not knowing finnish, one can spot genomic and pathogenicity islands transfers in a given genome. several techniques relying on various compositional aspects and on different algorithmic methods have been recently developed to detect pathogenicity islands in bacterial genomes. even very simple measures of the genome composition, such as the variation in t vs. a bias (ta skew) can lead to the identification of all known prophages in streptococcus pyogenes. it can even trigger the discovery of a putative ancient genomic island carrying a large number of genes related to pathogenicity in all strains of that species. in conclusion, with the rise of fast and inexpensive genome sequencing, new quick and simple methods are being developed. they take the advantage of the homogeneous nucleotide composition of bacterial genomes to uncover mobile genetic elements carrying genes involved in pathogenicity. in the past years, significant progress has been achieved in the management of chronic hepatitis b with the successive development of six potent antiviral medications (lamivudine, adefovir dipivoxil, pegylated interferon alpha, entecavir, telbivudine and tenofovir). however, the clinical results of antiviral therapy have been limited by the emergence of antiviral drug resistance especially with the first generation of nucleoside analogs (lamivudine, adefovir and telbivudine). furthermore, the unique mechanism of viral genome replication and persistence within infected cells is responsible for viral persistence even after prolonged therapy with the newer antivirals (entecavir and tenofovir). this is the major reason why life-long treatment is envisaged in the majority of patients, which may expose them to long-term risk of developing resistance. the use of in vitro phenotypic assays has been crucial for the characterisation of newly identified resistant mutants and determine their cross-resistance profile. results allowed to understand the different mechanism of viral resistance to lamivudine and adefovir, the mechanism of primary failure to adefovir therapy, the unique mechanism of entecavir resistance, and to characterise the emergence of multi-drug-resistant strains in patients receiving sequential antiviral therapy. the crossresistance profile for the main resistant mutants was determined which allowed to provide recommendation to clinicians for treatment adaptation based on molecular virology data. the understanding of the development of hbv drug resistance has allowed to significantly improve the management of antiviral resistance and to design better treatment strategies to prevent resistance. the current standard of care relies on treatment initiation with antivirals combining a strong antiviral potency and a high barrier to resistance. a precise virologic monitoring is required to measure antiviral efficacy, and to diagnose partial response or viral breathrough at an early stage. this allows to adapt antiviral treatment preferrably using an add-on strategy with a drug having a complementary cross-resistance profile. this strategy has been shown to be efficient in controling viral replication and preventing liver disease progression in the majority of patients. treatment of chronic hepatitis b virus (hbv) infection is aimed at suppressing viral replication to the lowest possible level. in many prospective clinical trials it has been shown that a sustained hbv dna response was correlated with serologic, histologic, or biochemical responses. despite the recent progress in hepatitis b antiviral treatment, it is shown that antiviral drug resistance is inevitable against many of the nucleoside analogs. the emergence of antiviral-resistant strains of hbv leads to viral and subsequently biochemical breakthrough and may lead to disease progression and increased death. most of the data on the clinical impact of antiviral resistant hbv came from the data derived from studies of lamivudine therapy. there is limited data on other hbv antiviral drugs like adefovir. it is shown in several studies that treatment of hbeag-negative chronic hepatitis b with lamivudine effectively suppresses hbv replication and results in biochemical remission and histologic improvement in more than two thirds of patients. however, relapse has occurred in the majority of hbeag-negative patients after the cessation of therapy. there are several studies to support the occurrence of severe hepatic flares, and liver failure after the emergence of lamivudine resistance. several studies, where liver biopsies were taken, demonstrated that histological improvement was reduced in those patients experiencing lamivudine resistance. the clinical outcome for patients with antiviral resistance is related to their age, the severity of the underlying liver disease and the severity of the hepatic flares. on the other hand in a different study it was found that long-term lamuvidine treatment was associated with a reduced chance of developing cirrhosis and hcc in patients without advanced disease but, although resistant mutants reduced the benefits from lamivudine therapy, the outcome of these patients was still better than untreated patients. results of several clinical trials have shown that the addition or substitution of newer antiviral agents can restore suppression of viral replication, normalisation of liver function and reverse histological progression in patients with antiviral resistance. consequently, well-tolerated, potent therapies that offer a strong genetic barrier against the development of resistance are desirable, since antiviral resistance and poor adherence are key risk factors for treatment failure and subsequent reversal of clinical improvement. resistance of enteric fever-causing and non-typhoid salmonella serovars to agents traditionally used to treat these infections in the past shows extensive geographical variation. decreased susceptibility to ciprofloxacin is rapidly increasing all over the world with target alteration and increased efflux being the most important mechanisms behind. infections with such strains often result in extended hospitalisation or even in therapeutic failures. furthermore, it is likely that moderately increased mic values facilitate the development of strains with higher level of resistance, i.e. a pattern described at various locations. screening methods based on quinolone sensitivity testing may fail to indentify decreased fluoroquinolone susceptibility both in typhoid, as well as in non-typhoid salmonella. plasmid mediated quinolone resistance genes are detected increasingly all around the world although neither the frequency nor the variety of genes identified has approached that seen in some other members of enterobacteriaceae. treatment with gatifloxacin or azithromycin are alternative options for invasive and systemic infections caused by strains with decreased susceptibility to ciprofloxacin. at some parts of the world resistance to extended spectrum cephalosporins reached such incidence that may have therapeutic implications particularly when initial, empiric treatment of invasive infections is concerned. resistance is due to plasmid coded ampc type beta lactamases (particularly to cmy- ), and most often to esbls of which usually some of ctx-m types are the frequently encountered ones. carbapenem resistance is still rare, albeit does occur, among salmonella isolates. the recent description of a non-typhoid salmonella strain with the blaimp- gene co-located on a class- integron with several other resistance determinants on a conjugative plasmid is of particular concern. campylobacters exhibit natural resistance to a variety of antimicrobials. the drugs of choice used to be fluoroqunolones or macrolides. however, the current incidence of ciprofloxacin resistance made the former drugs already obsolete or seriously limited their use at several parts of the world. with the exception of few locations the incidence of macrolide resistance is still relatively low and is seen more frequently in c. coli than in c. jejuni. however, strains exhibiting resistance against both groups of drugs have been emerging, particularly in south-east asia. neisseria meningitidis, the meningococcus, is a major cause of meningitis and septicaemia worldwide while neisseria gonorrhoeae, the gonococcus, is responsible for one of the most widespread sexually trasmitted disease. the behaviour of these two species towards antibiotics is very different: resistance in n. gonorrhoeae is now widespread occuring as both chromosomally and plasmid mediated to a variety of drugs, whereas, besides resistance to sulphonamides, n. meningitidis remains largely susceptible to antibiotics used both for therapy and prophylaxis. however, as in the gonococcus, the resistance to antibiotics of n. meningitidis is also evolving, as documented by the ever higher frequency of strains with intermediate resistance to penicillin in many countries. transformation has apparently provided both species with a mechanism by which they can increase resistance to penicillin by replacing part of their pena gene, which encodes pbp , with part of the pena gene of related species that fortuitously produces forms of pbp less susceptible to the antibiotic. n. meningitidis is still at this step, whereas n. gonorrhoeae has acquired also mutation in the pona gene that encodes pbp , mutation in porin ib, increased expression of efflux pump and the tem- b-lactamase plasmid. the emergence and the spread of gonococci fully resistant to penicillin since the second half of the s years led to the recommended use of fluoroquinolones as primary therapy. however, this class of antibiotics became rapidly unefficacious, mainly in asia, due to the emergence of mutations in gyra and parc which are able to block the activity of the quinolones on gyrase and topoisomerase iv. since , cdc no longer recommends their use for treatment of gonococcal diseases. fortunately, the occurrence of quinolone resistant meningococci, due to mutations in gyra, is still rare but even if cases are still few they are of great concern for the epidemic potential of this pathogen and the required prophylaxis of contacts. also for the other antibiotic, frequently used to this aim, rifampicin, some meningococci have showed to be resistant, again for the presence of mutations, in this case in the rpob gene coding for the b-subunit of the meningococcal rna polymerase. the molecular epidemiological identification of clonal clusters for both neisseria species with distinct resistance profiles is required to monitor ongoing trends that may pose problems both in therapy and prophylaxis. l. brookes-howell°, c. butler, k. hood, l. cooper, h. goossens (cardiff, uk; antwerp, be) introduction: grace is a european network of excellence established to focus on antibiotic use for community-acquired lower respiratory tract infection (lrti) and antimicrobial resistance across europe. grace- , the second study to begin within grace, is a large qualitative study that explores the attitudes of clinicians and patients to antibiotic use for lrti and antibiotic resistance. aims: this presentation will focus on clinicians' accounts of the factors that contribute to variation in management of lrti and patient views on when antibiotics are necessary. methods: semi-structured interviews with clinicians and patients were conducted in primary care networks in nine european countries. interviews were audio-recorded, transcribed and, where necessary, translated into english for analysis. themes were identified, organised and compared using a framework approach. results: analysis of clinician interviews shows that, beside clinical findings, factors which influence the management decision for patients can be divided into two main areas. firstly, within each european network there is a group of country specific factors imposed by the system in which consultations take place. these factors include: near patient test usage, self-medication, patients' finances and lack of consistent, local prescribing guidelines. secondly, there is a group of factors, similar across all networks, that relate to personal characteristics of certain groups of clinicians. these include clinicians' professional ethos, self-belief in decision making and attitude towards the doctorpatient relationship. analysis of patient interviews shows that beliefs about antibiotic use tend to draw on clinical factors, namely the severity of specific symptoms (fever and/or coughing). many patients also implied a period of waiting or alternative action required before antibiotics are used − to identify whether the immune system would fight the infection or whether nonantibiotic management was effective before turning to antibiotics. discussion and conclusion: with a greater understanding of the factors that contribute to the decision to prescribe, we discuss ideas to enhance appropriate prescribing. this analysis highlights the need for interventions to be sensitive to factors relating to the systems in which different european networks operate, to target the individual characteristics of specific groups of clinicians and to build on the clinical beliefs already held by patients. o pre-treatment with low-dose endotoxin prolongs survival from experimental lethal endotoxic shock k. kopanakis, i. tzepi, e.j. giamarellos-bourboulis°, a. macheras (athens, gr) objective: clinical trials of immunointervention with anti-endotoxin antibodies in patients with severe sepsis have failed to disclose survival benefit. these failures led us to the assumption that the opposite approach with a low endotoxin stimulus may result to low level immunoaralysis and subsequent survival benefit. this approach was tested in an experimental setting. methods: a total of male c b mice were studied divided into two groups: group a stimulated with the ip injection of sodium saline followed after one day by the ip injection of mg/kg of lipopolysaccharide (lps) of escherichia coli o :h ; and group b stimulated with the ip injection of mg/kg of lps of the same isolate followed after one day by the ip injection of mg/kg lps. lps was diluted in sodium saline and the volume of each injection was . ml. survival was recorded at six hour time intervals. results: survival of group b was considerable prolonged compared with group a (log-rank: . , p: . ) as shown in figure . thirteen mice of group a died ( . %) compared with seven mice of group b ( . %, p: . between group). conclusions: administration of low doses of lps prolongs survival after lethal endotoxic shock. this approach opens a promising novel pathway for immunointervention in sepsis. fragilis isolates with an mxf mic of mg/ml (n = ), mg/ml (n = ) and mg/ml (n = ), which were virulent in the mgp model, were used to determine the efficacy of mxf. for the mgp model, pouches were created by injecting ml of air and . ml of . % croton oil in olive oil under the skin of the back. on day , the air was withdrawn and replaced by ml soft agar. on day , a bacterial suspension was injected into the pouch. infected mice (n = mice/group) were treated with mxf mg/kg iv, b.i.d. for days. this dose simulates the auc of the human mg once-daily mxf iv dosage. efficacy was assessed by the reduction in colony forming units (cfus) in pouch exudates hours post-infection compared with the untreated infection control. results: in the mgp model, mxf, mg/kg b.i.d., displayed good efficacy in term of cfu reduction against all used strains in this study. there were no non-responders in terms of cfu reductions. conclusion: the loss of atle had no impact on the mics of cloxacillin and vancomycin. conversely, the mutant atle(−) strain was less susceptible to bactericidal activity of both antibiotics, supporting the implication of atle in the tolerance of s. epidermidis to cell wall active antibiotics. the loss of atle did not alter the virulence of s. epidermidis in the mouse peritonitis model, whereas it decreased virulence in previously published experiments using an intravenous catheter infection model. therefore, the mouse peritonitis model was suited to compare antibiotics efficacy against atle(+) and atle(−) strains. our results showed that the loss of atle did not alter significantly the activity of cloxacillin and vancomycin in the mouse peritonitis model. this study shows that the loss of atle results in decreased susceptibility to bactericidal activity of cell wall active antibiotics, with no apparent impact on the activity of these antibiotics in the mouse peritonitis model. in infant rat pneumococcal meningitis, ceftriaxone plus daptomycin versus ceftriaxone attenuates brain damage and hearing loss while ceftriaxone plus rifampicin versus ceftriaxone does not d. grandgirard, m. burri, k. oberson, a. bühlmann, f. simon, s.l. leib°(berne, ch) objectives: lytic antibiotics for therapy of bacterial meningitis (bm) increase the release of pro-inflammatory bacterial compounds which, in turns, induce inflammation. exacerbation of the inflammatory response in cerebrospinal fluid (csf) contributes to the development of neurological sequelae in survivors of bm. daptomycin, a nonlytic antibiotic acting on gram-positive bacteria has been shown to decrease inflammation and brain injury vs. ceftriaxone in experimental pneumococcal meningitis. with a view on the clinical application for empiric therapy of paediatric bacterial meningitis we investigated, whether therapies combining daptomycin or rifampicin with ceftriaxone are beneficial when compared to ceftriaxone monotherapy in infant rat pneumococcal meningitis. methods: eleven day old wistar rats were infected by intracisternal injection of s. pneumoniae and animals were treated with daptomycin ( mg/kg, s.c., daily) plus ceftriaxone ( mg/kg, s.c., bid), rifampicin ( mg/kg, i.p., bid) plus ceftriaxone or ceftriaxone alone. csf was sampled at h and h after the initiation of therapy and assessed for concentrations of chemo-and cytokines (mcp- , mip- a, il- b, il- , il- ; il- and tnf-a). a subset of animals was sacrificed h post infection (h pi) and brain damage quantified by histomorphometry. the remaining animals were treated for d and were tested for hearing loss, by assessing the auditory brainstem response (abr) at weeks after infection. results: compared to ceftriaxone alone, daptomycin plus ceftriaxone significantly (p < . ) lowered csf concentrations of mcp- , mip- alpha and il- at h and mip- a and il- b at h after initiation of therapy, led to significantly (p < . ) less apoptosis assessed at h pi, and significantly (p < . ) improved hearing capacity. while rifampicin plus ceftriaxone also led to lower csf inflammation (p < . for il- at h), apoptosis and hearing loss were not significantly different from the ceftriaxone group. conclusion: compared to ceftriaxone monotherapy, daptomycin plus ceftriaxone lowers the level of pro-inflammatory mediators in the csf and reduces hippocampal apoptosis and hearing loss in infant rat pneumococcal meningitis. d. croisier-bertin°, l. piroth, p.e. charles, d. biek, y. ge, p. chavanet (dijon, fr; alameda, us) objectives: ceftaroline (cpt) is a novel, parenteral, broad-spectrum cephalosporin exhibiting bactericidal activity against gram-positive organisms, including methicillin-resistant s. aureus (mrsa) and multidrug-resistant s. pneumoniae, as well as common gram-negative pathogens. the efficacy of simulated human dosing with cpt or ceftriaxone (cro) was evaluated in a rabbit model of penicillin-resistant pneumococcal pneumonia. methods: s. pneumoniae strains were used to induce pneumonia in rabbits: pssp, pisp, and prsp. mics (mg/l) were . / . , / . , and / . for cro and cpt, respectively. the animals were randomised to no treatment (controls), intravenous (iv) cpt human equivalent (he) dosage ( mg/ h), iv cro he dosage ( g/ h), or intramuscular (im) cpt ( or mg/kg) for prsp-infected rabbits. serum levels were measured by microbiological assay and pk data were obtained. evaluation of efficacy was based on bacterial counts in lungs and spleen (per gram tissue). results: − animals/group were tested. for iv cpt/iv cro, mean auc − was / mg.h/l, cmax was / mg/l and cmin was . / mg/l, respectively. bacterial counts in target tissues are listed in the iv cpt and iv cro were highly efficacious against pssp and pisp. iv and im cpt were superior to iv cro against prsp with a quasi sterilisation of lungs and spleen. combined results from the iv and im studies indicated that %t > mic for cpt of % and % were associated with % and % bacterial count reductions, respectively. in this rabbit model of penicillin-resistant pneumococcal pneumonia, cpt administered iv (with he dosing) or by im administration was more effective against prsp than iv cro. r. endermann°, d. hoepker, k. merfort, m. glenschek-sieberth (wuppertal, de) objective: moxifloxacin (mxf) is approved in the usa and other countries for the treatment of complicated intra-abdominal infections (ciais). we compared the efficacy of mxf with piperacillin/tazobactam (pip/taz), a commonly used treatment for ciais, in three different models: ( . c. clp model: survival over days was significantly higher in the mxf group than in the pip/taz group (p < . ). conclusions: using humanised dosages, mxf had greater antimicrobial activity and provided higher survival rates that pip/taz in three different models for ciai. m. nairz, i. theurl, a. schroll, m. theurl, s. mair, t. sonnweber, g. fritsche, r. bellmann-weiler, g. weiss°(innsbruck, at) mutations in hfe predispose to hereditary haemochromatosis type i, a frequent genetic disorder characterised by progressive parenchymal iron deposition and eventual organ failure. since hfe mutations are associated with reduced iron levels within mononuclear phagocytes, we hypothesized that hfe deficiency may be beneficial in infections with intramacrophage pathogens. using hfe+/+, hfe+/− and hfe−/− mice in a model of typhoid fever, we found that animals lacking one or both hfe alleles are protected from systemic infection with salmonella typhimurium, displaying prolonged survival and improved bacterial control. this increased resistance can be referred to an enhanced production of the siderophore-binding peptide lipocalin and the reduced availability of iron for salmonella engulfed by hfe deficient macrophages. this effect is mediated via stimulation of lipocalin -dependent iron export from infected cells since hfe−/− macrophages concurrently knocked out for lipocalin are unable to efficiently control the infection or to withhold iron from intracellular salmonella. correspondingly, infection of hfe+/+ and hfe−/− mice with siderophore deficient salmonella abolishes the protection conferred by the hfe defect. thus, by inducing the formation of the iron-capturing peptide lipocalin , the hfe mutation harbours a genetically determined immunological advantage towards infections with intracellular pathogens such as salmonella. i. koutelidakis, a. kotsaki, p.d. carrer, k. louis, a. savva, e.j. giamarellos-bourboulis°(thessaloniki, athens, gr) objective: the majority of clinical trials of immunointervention in severe sepsis have failed to disclose survival benefit. a likely explanation may be administration of therapy when immunoparalysis of the septic host supervenes. in an attempt to reverse immunoparalysis, injection of mononuclear cells was attempted in experimental sepsis by multidrugresistant pseudomonas aeruginosa (mdrpa). methods: peripheral blood mononuclear cells (pbmcs) diluted in rpmi were isolated from five healthy human volunteers after gradient centrifugation over ficoll. × /kg of one mdrpa live or heat-killed isolate from one patient with severe sepsis was injected intraperitoneally for bacterial challenge. a total of male c b mice were studied divided into four groups: group a (n = ) pre-treated with rpmi and challenged after one hour with live isolate; group b (n = ) pretreated with × pbmcs/kg and challenged after one hour with live isolate; group c (n = ) pre-treated with rpmi and challenged after one hour with heat-killed isolate; group d (n = ) pre-treated with × pbmcs/kg and challenged after one hour with heat-killed isolate. survival was recorded for mice of groups a and b and for all mice of groups c and d. six mice of groups a and b were sacrificed six hours after challenge. blood was collected from the lower vena cava and tnfalpha and il- were estimated in serum by an enzyme immunoassay. bacterial growth of liver and lung at the same time was assessed. results: median survival of group a was hours and of group b hours (log-rank: . , p: . ). nineteen animals of group a died ( %) compared with eight animals of group b ( %, p: . ). four animals of group c died ( %) compared with nil animals of group d ( %, log-rank: . , p: . ). median serum tnf-a of groups a and b at sacrifice was and pg/ml respectively (p: . ). respective values for il- were and pg/ml (pns); for liver bacterial cells . and . log cfu/g (pns); and for lung bacterial cells . and . log cfu/g (pns). conclusions: allogeneic transplantation with pbmcs prolonged survival in experimental sepsis by mdrpa. its mechanism of action was related with a) blockade of cell wall structures as shown by survival experiments with heat killed isolate; and b) reversal of immunoparalysis as evidenced by increase of serum tnf-a. this approach creates a promising novel perspective for immunointervention in sepsis. a. marangoni°, c. nanni, m. donati, r. aldini, d. di pierro, s. trespidi, s. accardo, s. fanti, r. cevenini (bologna, it) objectives: chlamydia trachomatis is one of the world's major causes of sexually transmitted diseases of the cervix and urethra and it is a major agent of pelvic inflammatory disease. genital tract infection of female mice with chlamydia muridarum closely mimics acute genital tract infection in women. aim of this study was to assess the predictivity of ga-chloride small animal positron emission tomography ( o inadequate statistical power of published comparative cohort studies on ventilator-associated pneumonia to detect mortality differences between the compared groups m. falagas°, v. kouranos, a. michalopoulos, s. rodopoulou, a. athanasoulia, d. karageorgopoulos (athens, gr) objective: comparative cohort studies are often conducted to identify novel therapeutic strategies or prognostic factors for ventilator-associated pneumonia (vap). we aimed to evaluate the statistical power of such studies to provide statistically and clinically significant conclusions. methods: we searched in pubmed and scopus for comparative cohort studies evaluating the mortality of patients with vap. we calculated for each of the included studies the statistical power to detect the observed difference in mortality between the compared groups (observed power), as well as expected, clinically relevant, effect sizes (expected power). we identified ( prospective) comparative cohort studies on vap as eligible for inclusion in this analysis. the median observed power of these studies was . % [interquartile range (iqr), . − . %]. the median expected power was . % (iqr, . − . %) for a risk ratio for mortality of . between the compared groups; . % (iqr, . − . %) for a risk ratio of . ; and . % (iqr, . − . %) for a reduction in mortality from % to %. all expected power measures were significantly lower than the observed power. the statistical power of most cohort studies to detect the observed difference in mortality between compared groups of patients with vap is low. the power is even lower when expected, clinically relevant, differences in mortality are considered. for a wiser utilisation of resources allocated to research, we favour the conduction of cohort studies with larger sample size so that potential differences between the compared groups are more likely to be shown. objective: to clarify issues regarding the frequency, prevention, outcome, and treatment of patients with ventilator-associated tracheobronchitis (vat), which is a lower respiratory tract infection involving the tracheobronchial tree, while sparing the lung parenchyma. methods: we performed a systematic review and meta-analysis of relevant available data, gathered though searches of pubmed, scopus, and reference lists, without time restrictions. a conservative random effects model was used to calculate pooled odds ratios (or) and % confidence intervals (ci). results: out of the initially retrieved articles, papers were included. frequency of vat was . %. selective digestive decontamination was proved an effective preventive strategy against vat. presence, as opposed to the absence, of vat was not associated with higher mortality (or: . , % ci . − . ). administration of systemic antimicrobials (with or without inhaled ones), as opposed to placebo or no treatment, in patients with vat was not associated with lower mortality (or: . , % ci . − . ). most of the studies providing relevant data noted that administration of antimicrobial agents, as opposed to placebo or no treatment, in patients with vat was associated with more ventilator-free days and lower frequency of subsequent pneumonia, but without shorter length of intensive care unit stay or shorter duration of mechanical ventilation. conclusions: approximately one tenth of mechanically ventilated patients suffer from vat; an infection potentially prevented by the implementation of selective digestive decontamination. antimicrobial treatment of patients with vat may protect against the development of subsequent ventilator-associated pneumonia. degranulation. subsequently, allergen specific ige to chlorhexidine was demonstrated and skin prick/intradermal testing was positive to chlorhexidine, confirming the diagnosis of chlorhexidine-precipitated anaphylaxis in each patient. a detailed review of the case-notes revealed that each patient had manifest evidence of minor cutaneous reactions to pre-operative chlorhexidine use that had not been ascribed to chlorhexidine at the time. discussion: fda issued a public health notice [ ] following st description of anaphylaxis to chlorhexidine coated central venous catheter. a recent case cluster has also been reported from another cardiac centre in the uk [ -cases over a -month period]. references to be presented. it is interesting that these reports of chlorhexidine anaphylaxis have all occurred in patients undergoing cardiac surgery. these patients receive multiple exposures to chlorhexidine during their pre-operative investigations and preparation. this has increased recently as a result of the drive to reduce the incidence of hospital-acquired infections. we wish to postulate that these patients have been sensitised by repeated topical exposure to chlorhexidine and have exhibited anaphylaxis when this allergen was presented to the patient in the form of the chlorhexidine coated central venous catheter. type i strains of helicobacter pylori possess the cag pathogenicity island to deliver virulence factors. cag is a specialised type iv secretion machinery that is activated during infection and comprises genes originated from a distant event of horizontal transfer. after translocation the effector protein caga is phosphorylated on tyrosine residues restricted to a previously identified repeated sequence called d . this sequence is located in the c-terminal half of the protein and contains the five amino acid motif epiya, which is amplified by duplications in a large fraction of clinical isolates. tyrosine-phosphorylation of caga is essential for the activation process that leads to dramatic changes in the morphology of cells growing in culture. in addition, we observed that two members of the src kinases family, c-src and lyn, account for most of the caga-specific kinase activity in ags cell lysates. translocated caga interacts with the zo- and jam host-cell proteins causing disruption of the apical junctional complex. transfection of the caga gene into polarised epithelial cells induces disruption of cell-to-cell contacts and altered morphology. strikingly caga-expressing cells become migratory and invasive penetrating into collagen gel. the study of different portions of the molecule revealed the presence of two distinct functional domains and both are necessary to induce abnormal cell differentiation through interactions with host cell morphogens. cell polarity and invasion have been suggested to contribute to both early and late stages of cancer formation. these results suggest a mechanism by which caga may acts at the early stage of tumorigenic progression causing loss of cell polarity, increased cell motility and invasiveness of epithelial cells. after a period of years of silence, a disease with an unpronouncable name, "chikungunya" (chik), has recently become a medical reality and reached the public throughout the world. conclusion: low mhla-dr expression after septic shock independently predicts ni. this promising biomarker may be of major interest in identifying patients at increased ni risk who could benefit from targeted and tailored therapy aimed at restoring immune functions. pneumonia, the leading infectious cause of death in the us, kills more people annually than aids, tuberculosis, meningitis and endocarditis combined. from a wide range of observational studies of communityacquired pneumonia (cap), only half of the cases had an aetiologic agent identified. streptococcus pneumoniae was consistently the predominant bacterial aetiology. this lecture will primarily focus on the innate immune response to pneumococcal pneumonia. toll-like receptors (tlrs) are key molecules that recognize pathogen associated molecular patterns (pamps) and induce an inflammatory response. pneumolysin, an intracellular toxin found in all s. pneumoniae clinical isolates, is an important virulence factor of the pneumococcus that is recognized by tlr . although tlr is considered the most important receptor for gram-positive bacteria, tlr does not play a decisive role in host defence against s. pneumoniae pneumonia; likely, pneumolysin-induced tlr signalling can compensate for tlr deficiency during respiratory tract infection with s. pneumoniae. besides tlr and tlr , tlr contributes to an effective host defence against s. pneumoniae in the airways. the importance of tlr signaling for host defence against pneumococcal pneumonia is illustrated by the fact that mice lacking the common tlr adaptor protein myd are highly susceptible to this infection. activation of tlrs results in the production of proinflammatory cytokines. there is ample evidence that underlines the importance of tumour necrosis factor (tnf) and interleukin (il)- in host defence in bacterial pneumonia: in a murine s. pneumoniae pneumonia model, treatment with a neutralising anti-tnf mab strongly impaired antibacterial defence. in addition, il- a receptor type i deficient mice infected with s. pneumoniae displayed an increased bacterial outgrowth. of considerable interest, treating il- receptor deficient mice with a neutralising anti-tnf antibody made them extremely susceptible to pneumococcal pneumonia. infection of the lower airways by s. pneumoniae is associated with complex interaction between the pathogen (e.g. cell wall components, pneumolysin) and the host (e.g. tlrs, cytokines). these interactions play a crucial role in the outcome of this clinically important infection. severe bacterial pneumonia remains uncommon unless specific conditions exist that tip the balance between the host and pathogen in favour of the microorganism. such conditions include: persons at the extremes of age; exposure to especially virulent organisms; patients with concomitant illness impairing pulmonary clearance mechanisms; and immunocompromised hosts. pathogens overcome an array of innate and acquired host defences to successfully invade the host. the known virulence traits of three common respiratory pathogens (streptococcus pneumoniae, staphylococcus aureus, and pseudomonas aeruginosa) will be briefly reviewed. the capsular polysaccharide of pneumococci is the major anti-phagocytic virulence trait but many other factors contribute to disease pathogenesis including the critically important exotoxin known as pneumolysin, bacteriocins, adherence factors, choline binding proteins, lipoteichoic acid, iron, manganese and magnesium transporters, pili, competence and biofilm capacity, and virulence genes that promote invasion and impair clearance once the organism has entered the blood stream. s. aureus is notorious for the numerous a/b type toxins, cytotoxins, and superantigens it generates during the course of invasion. staphylococci deploy a complex series of quorum sensing signals that coordinate adhesin and invasion genes within biofilms or between planktonic organisms and likely contribute to the success of this pathogen. p. aeruginosa produces an array of extracellular exotoxins and cytotoxins delivered by type iii secretion systems. these include elastase, phospholipases c, a series of apoptotic and anti-phagocytic exotoxins, along with an alginate capsule and an unusual and variable lps structure that participate in microbial invasion. the pathogen expresses at least three interacting, quorum sensing systems to coordinate virulence and biofilm formation. a detailed understanding of these virulence factors is now providing therapeutic options to control these respiratory pathogens. surface expressed and extracellular toxins of pneumococci have been selected as new vaccine targets. inhibitory peptides and small molecule inhibitors of quorum sensing and biofilm formation are under investigation for staphylococcal and p. aeruginosa infections. these innovative and non-antibiotic treatment strategies are gaining greater importance as progressive antibiotic resistance threatens the management of these severe bacterial infections in the future. brucellosis, possibly the commonest zoonotic infection worldwide, has troubled humans since antiquity. recent years have seen the expansion of the animal reservoir of the disease to a wide spectrum of wildlife species, extending to marine mammals, and the recognition of novel brucella species. furthermore, animal and human disease has re-emerged in numerous countries which were brucellosis-free, and currently the most important endemic foci include near east and central asia. complex socioeconomic and political factors may be incriminated for these alterations in endemicity. the complex mechanisms by which brucella evades immune response and survives intracellularly are progressively clarified. novel diagnostic techniques as real time pcr may shed light in the life cycle of brucella inside the human host; preliminary studies have indicated that the pathogen may persist in latent form for years after apparent clinical cure, in asymptomatic individuals. treatment principles have not evolved significantly. the expert guidelines issued recently under the name of "ioannina recommendations" support the need for a six-week combined treatment that includes traditional antibacterials and is modified accordingly in serious complications as spondylitis and central nervous system involvement. the road to the development of a vaccine for humans seems long though. anthrax is ancient diseases and relatively a forgotten disease in western world until when spores were mailed in usa causing five deaths. currently, human anthrax is seen most commonly in agricultural regions of the world where anthrax in animals is prevalent, in which countries of middle east, in africa, central asia and south america. it is also an endemic disease in turkey. human cases may occur in an agricultural or an industrial environment. the infection is an occupational hazard of workers who process hides, hair, bone and bone products, and wool and of veterinarians and agricultural workers who handle infected animals. the main route of transmission is contact with or ingestion of contaminated meal with or inhalation of bacillus anthracis spores. leptospirosis is a very old disease that has been known for more than a hundred years and possibly even longer since the time of hippocrates. it remains a major cause of illness in many tropical and subtropical countries and thus in travellers. it has also been identified as a zoonosis in europe and north america. it is a disease that can surprise us because the clinical presentations are not always typical. in recent years, pulmonary and other atypical presentations have been more widely recognised. there is no effective vaccine but chemoprophylaxis is effective in selected populations. prompt recognition and early institution of appropriate treatment as with most other infectious diseases appear to be critical in ensuring a good outcome for our patients. there are interesting new developments in diagnostics and molecular epidemiology but clearly there are many challenges remaining in this field. objectives: the spread of carbapenemase genes within gram negative bacteria is of great cause for concern. in , the first report of a blaoxa- gene outwith acinetobacter baumannii was reported in acinetobacter genospecies . we had also identified a genospecies isolate encoding a blaoxa- -like gene, and the aim of this study was to examine the genetic environment of the gene to investigate the mobilisation between species. methods: restriction analysis of rrna was used to confirm identity to the species level. susceptibility to imipenem and meropenem was determined through the plate doubling dilution method. screening by pcr for blaoxa- -like, blaoxa- -like, blaoxa- -like and blaoxa- -like genes was carried out. analysis of the genetic environment surrounding the blaoxa- -like gene was conducted by sequencing inverse pcr products and gene-walking fragments. the structure of the surrounding sequence was confirmed using internal primers, which were also used to screen other blaoxa- -like positive isolates in our collection. results: restriction analysis confirmed the isolate belonged to acinetobacter genospecies . the isolate showed reduced susceptibility to imipenem and meropenem with mics of mg/l for both antibiotics. the isolate was negative for a blaoxa- -like, blaoxa- -like or blaoxa- -like gene, but positive for a blaoxa- -like gene. analysis of the genetic environment of the blaoxa- -like gene revealed the gene was within a novel genetic structure. upstream of the blaoxa- -like gene was the left-hand end of an isaba element, interrupted by an isaba element. the elements contained putative promoter sequences. downstream was an arac and a lyse gene, followed by a sequence similar to the re element described previously. following this was a complex region containing the right-hand end of an isaba tnpa gene, interrupted by an incomplete tnpa gene with % similarity to isaba , itself interrupted by an isaba sequence. this region was followed by a second blaoxa- -like gene. all other blaoxa- -like positive isolates in our collection were negative for isaba upstream of blaoxa- . this study is the first to report multiple copies of a blaoxa- -like gene in an acinetobacter genospecies isolate, and has identified a novel structure containing two blaoxa- -like genes and two isaba sequences. the isaba elements may be responsible for the duplication of the blaoxa- -like gene. objective: acinetobacter baumannii is an important nosocomial pathogen with wide intrinsic resistance. however, due to the dissemination of the acquired resistance mechanisms; such as extended-spectrum beta-lactamase (esbl) and metallo betalactamase (mbl) production, multidrug resistant strains have been isolated more often. per- was first detected in turkey and was found to be widespread among acinetobacter spp. and p. aeruginosa. since then, per- has been discovered in other countries, and most recently found in northern italy and in korea. in this study, the presence of per- type esbl was investigated in caftazidime resistant a. baumannii strains isolated from bloodstream infections by pcr and also the clonal relatedness of the isolates were investigated by random amplified polymorphic dna (rapd) and pulsed field gel electrophoresis (pfge) in all per- producing a. baumannii strains. methods: a. baumannii strains isolated from bloodstream infections was included in this study. the isolates were identified as a. baumannii by conventional methods and phoenix bd automated system system (becton dickinson diagnostic systems, sparks). ceftazidime resistance was determined by e-test. per- genes were screened by these clusters encode: (i) resistance genes and transporters plausibly involved in drug efflux ( transporters of the mfs, dmt, abc, rnd, mop and acr families were unique of drug resistant strains and absent in the susceptible sdf strain); (ii) pili and fimbriae systems related to biofilm formation and motility; (iii) haemolysin-and haemagglutininrelated proteins differently distributed among the four genomes, (iv) iron uptake and other metabolic genes. conclusion: genome comparison identified unique features of a. baumannii epidemic clones and provided novel insights into the genetic basis of multidrug resistance and pathogenesis in this species. this study may contribute to understand the concept of infection, invasiveness and colonisation in the emergent pathogen a. baumannii. hard to swallow − emerging and re-emerging issues in food-borne infection (symposium arranged with efwisg) s mrsa in food products: cause for concern or case for complacency? in first, a switch from intravenous-to oral medication ( - ); second, education programs for interns/residents and physicians and the release of a new antimicrobial formulary ( - ); third, a restriction note was printed on all laboratory rapports ( - ) and fourth, active monitoring and giving feedback on prescriptions ( - ). susceptibility patterns for e. coli including ciprofloxacin, cefuroxim, ceftazidim, co-trimoxazole and tobramycin from hospitalised patients were analyzed starting in . statistical analyses were performed using segmented poisson regression models to look at effect of interventions on resistance (both sudden stepwise changes and changes in trends). bayesian model averaging was used to account for model uncertainty. results: before the start of the interventions the resistance rate was increasing by an average of . % per year. the interventions resulted in a significant reduction of quin use from on average prescribed daily doses to pdd per month. in the best fitting poisson model for the resistance data, a significant stepwise decrease was found to be associated with interventions and . however, there was substantial uncertainty in the model choice, and after accounting for this there was no conclusive evidence in support of any particular intervention, although there was evidence that at least one of the interventions was associated with the observed reduction in resistance. there were no stepwise decreases or decreasing trends in resistance rates to other antimicrobials during the study period. conclusion: many mds prescribe antibiotics often and believe their practice may have an effect on antibiotic resistance. results indicate that mds value information, interventions and surveillance in order to support responsible use of antibiotics. there is an ongoing effort in germany to address these findings at the national level e.g. by establishing a surveillance system for antibiotic resistance and antibiotic usage. table) . . ir for pn, er and tt were always higher in children (ch) than in adults (ad). significant differences were found for pn ( ), er ( er ( , er ( , er ( , er ( , , tt ( tt ( , . generally, cp-ir was higher in ad than in ch. ir was lower in the north (n) than in the south (s). significant differences: pn ( pn ( , , er ( er ( , er ( , , tt ( ) . both n and s knew a deceasing ir tendency: pn= n ( . − . ), s ( . − . ); cp= n ( . − . ), s ( . − . ); tt= n ( . − . ), s ( . − . ). er increased in the n ( . − . ). total outpatient antibiotic use (did) decreased from . ( ) to . ( ) and increased to . ( ) . did for pn and fq increased, mls stabilised and tt decreased. conclusions: since - an ir decrease was noted for pn, cp and tt. er-ir increased further over the years. the decrease paralleled the start of public campaigns on antibiotic use. ir rates remain higher in ch than in ad. the n/s difference became less marked. objectives: parachlamydia acanthamoebae is a new recognized member of the order chlamydiales. growing evidences suggest that this bacteria may have a pathogenic role in humans causing respiratory diseases. it has also been recently identified as an agent of bovine abortion and may be a cause of miscarriage in women. in contrast, little is known about the pathogenic role of rhabdochlamydia crassificans, another related chlamydiales. molecular diagnostic tools are useful to detect these obligate intracellular bacteria because of their inability to grow on conventional culture media. the aim of this work was (i) to develop a real-time pcr for the diagnosis of rhabdochlamydia infection and (ii) to study respiratory secretions of newborns for the presence of parachlamydia and rhabdochlamydia dna. methods: a new quantitative real-time taqman pcr (q-pcr) to be used on abi prism was developed. the q-pcr was then blindly applied to consecutive respiratory samples (endotracheal or nasopharyngeal secretions) taken from critically-ill newborns admitted in the neonatology ward of our university hospital. these samples were also tested using a previously developed parachlamydiaspecific pcr. results: most newborns ( / ) were premature (median gestational age: . weeks; range: . − . ). initial respiratory distress syndrome was present in % of them. positive pcr results were obtained in / ( %) patients ( parachlamydia, rhabdochlamydia, both species) at a median of . days (range: - ) after birth. when compared to the control group ( patients with negative pcr), these newborns had a significantly worse primary adaptation and a higher incidence of resuscitation maneuvers at birth (table) . duration of noninvasive mechanical ventilation and stay in neonatology ward were also significantly longer. a fatal issue was observed in infected cases, as compared to no death in controls (p = . ). gestational age at birth as well as the incidence of pulmonary or systemic infections did not differ between cases and controls. conclusion: a high prevalence of parachlamydia and rhabdochlamydia dna was observed in respiratory secretions of premature critically-ill newborns. the presence of dna of these microorganisms was associated with a worse primary adaptation, a more severe respiratory distress syndrome and a trend towards a higher mortality. their pathogenic role should be further investigated. the genus kingella consists of species, k. kingae, k. oralis and k. denitrificans. all are gram negative, sometimes difficult to stain, rod shaped bacteria that are normal respiratory and genitourinary flora. they are slow-growing and fastidious. although improved recovery was shown when using fan or peds-f blood culture bottles, the majority of these infections remain undetected, especially in pre-treated patients. we report the use of real time polymerase chain reaction (rt-pcr) assays for detection of k. kingae and s. aureus in paediatric osteoarticular infections. methods: synovial fluid samples from patients, month and years of age, were collected over months ( / to / ). the samples were from knees, hips, ankles, elbows, shoulders, wrists and femur abscesses. after automated dna/rna extraction, specimens were subjected to hour pathogen-specific rt-pcr. samples were inoculated onto sheep blood and chocolate agar as well as a peds-f bottle. final species identification and antimicrobial susceptibilities were determined by phoenix (tm). results: patients ( specimens) had positive culture and/or rt-pcr, resulting in an overall positivity rate of %. s. aureus was the predominant pathogen accounting for specimens of patients ( mrsa, mssa) and. % of positive specimens ( patients) were due to k. kingae (n = ). among children − years (n = ), k. kingae was the predominant pathogen accounting for positive patients ( %), followed by mssa in patients ( %). the positivity rate for this age group was %. only children > years ( and years) were positive for k. kingae. mrsa was the predominant pathogen in − year olds, and mssa was evenly distributed among children − years old. culture detected only of specimens positive for k. kingae and of s. aureus. other pathogens were detected by culture only. the use of these molecular assays enhances detection of organisms, especially for k. kingae ( % vs. % for culture). additionally, faster identification (tat hrs) allows for rapid targeted therapy. this improvement in tat could lead to shorter hospital stays in about % of cases. results: genotyping revealed a high degree of diversity, indicative of a panmictic bacterial population. further, there was no association between genotype and colonisation frequency, or year of isolation. pcr screening for virulence genes revealed an incidence of % for uspa , % for hag, % for uspa and % for uspa h. no significant difference was observed in the prevalence of virulence-associated genes between isolates originating from children who were colonised only once or children colonised on all occasions (p = ). pcr-rflp analysis of uspa , hag and uspa showed many gene variants, with no association between pcr-rflp patterns and colonisation frequency, or year of isolation. conclusion: even in relatively localised geographical settings, the genotypic diversity of m. catarrhalis isolates colonising children is large, with no yearly pattern of genotype predominance. children serially colonised with m. catarrhalis isolates appear to clear a particular genotype only to become subsequently colonised with a different genotype. the incidence of virulence genes in this relatively localised study group is remarkably similar to that reported in global m. catarrhalis isolates, possibly indicating that similar selection pressure exists for m. catarrhalis at both the local and global level. virulence gene variation appears to be high, even in this relatively restricted geographical group. these results could have consequences for vaccines designed against virulence genes. a. naessens°, i. foulon, a. casteels, w. foulon (brussels, be) objectives: to evaluate the epidemiology of cytomegalovirus in pregnancy and to evaluate the risk for delivering a child with congenital cmv (ccmv). methods: between - , unselected mother-infant pairs were included. in the mother a serological screening was performed consisting in the detection of cmv igg and igm antibodies at the first prenatal visit and at birth. in the neonate cmv urine culture was performed to diagnose congenital infection. when a pregnant woman was found to have a second trimester spontaneous abortion or a death in utero, an investigation for possible congenital cmv infection was carried out. results: serological screening at the first prenatal visit showed no immunity in women, evidence of past infection (igg positive igm negative) in women ( . %) and in women ( . %) both igg and igm antibodies were detected. after investigation of stored and follow up samples from these patients, could be classified as having a primary cmv infection during pregnancy, patients had previous immunity before the current pregnancy and from patients the type of the maternal cmv infection could not be determined. follow-up serology of the women without immunity revealed a seroconversion in of them ( . %). a total of ( . %) congenital infections (ccmv) were diagnosed. the incidence of the ccmv among the different groups of women are summarised in the table. conclusion: ccmv infection occurs in . % of our population of pregnant women. ccmv was considered to be due to a primary maternal cmv infection in % of the infants; % due to a recurrent maternal cmv infection and in % the type of maternal infection could not be determined. the risk for a seronegative pregnant woman of acquiring cmv during pregnancy is . %. the transmission risk after a maternal primary infection is %. women with prior immunity have a very low risk ( . %) for ccmv, this risk increases to % when igm are find in women with know prior immunity. the risk for women with undetermined infectious status in early pregnancy to give birth to a congenitally infected neonate is . %. this report provides the first data on rotavirus epidemiology and disease burden in norway. further studies are needed to assess the economic impact of rotavirus disease and the cost-effectiveness of vaccination to inform decisions on introduction of rotavirus vaccines into the national program of childhood immunisation. pseudomonas aeruginosa may colonise the lungs of cystic fibrosis patients over years but may also cause acute infections in mechanically ventilated patients and immuno-compromised hosts within a matter of days. despite aggressive antibiotic treatments the organism is rarely eradicated. instead p. aeruginosa adapts to its host environment by developing resistance mechanisms and changing its lifestyle and virulence properties. focusing on mechanically ventilated patients, we will detail the dynamics of resistance emergence and persistence of p. aeruginosa lung populations during antibiotic therapy. we further discuss how p. aeruginosa populations evolve naturally in the absence of any antimicrobial treatment within the lungs of intubated patients by changing their virulence properties. the relevance of these findings both with respect to concepts of social evolution and the development of novel anti-infective strategies will be highlighted. the genome of p. aeruginosa encodes many potential efflux systems. however, only a few of them appear to play a significant role in antibiotic resistance. in this respect, the mex (for multiple efflux) systems are of particular interest because of their ability to extrude a wide range of antimicrobials. these polyspecific machineries result from the assembly of (i) a drug/proton antiporter, (ii) a periplasmic adaptor protein, and (iii) an outer membrane gated channel. it is now well established that the constitutive expression of the tripartite pump mexab-oprm provides p. aeruginosa with a relatively high intrinsic resistance to quinolones, blactams (except imipenem), tetracyclines, macrolides, chloramphenicol, trimethoprim, and novobiocin. this protective mechanism is potentiated by the poor permeability of the outer membrane and activity of another pump, mexxy/oprm, whose expression is induced by substrates targeting the ribosome (e.g., tetracyclines, macrolides, aminoglycosides). accumulating reports indicate that multidrug resistant mutants upregulating one or both of these systems are quite common in the clinical setting. such mutants, which are readily selected by sub-optimal treatments with fluoroquinolones, b-lactams or aminoglycosides, tend to accumulate various resistance mechanisms without loosing the wildtype pathogenicity of p. aeruginosa. whether the low resistance levels (mic x -to -fold) conferred by efflux may promote second-step mutants with altered drug targets (gyra, gyrb, parc) or derepressed ampc b-lactamase has not been confirmed in vitro. in the specific context of cystic fibrosis (cf), a recent study from our laboratory showed that the mexxy/oprm pump can be responsible for much higher resistance levels to aminoglycosides ( -to -fold). this increased efficacy of the system partially results from adaptive mutations in the mexy gene. in contrast, subpopulations deficient in mexab-oprm tend to emerge during long-term colonisation of cf airways. while easily selected in vitro on selective media, mutants overexpressing other mex systems (mexcd-oprj, mexef-oprn, mexghi-opmd, mexjk/oprm, mexvw/oprm) have been rarely described in cf and non-cf patients. some data support the notion that up-regulation of mexcd-oprj or mexef-oprn might be detrimental to the virulence of p. aeruginosa. in conclusion, therapeutic strategies based on efflux inhibitors should target the mexab-oprm and the mexxy/oprm systems in priority. european aspects of malaria s rapid diagnostic tests for malaria: twenty years to convince . . . prompt diagnosis and treatment of malaria are critical factors in reducing morbidity and mortality. microscopy has long been the gold standard for malaria diagnosis, but the newer rapid diagnostic tests (rdts) now offer considerable advantages, especially so in endemic countries. after close to twenty years of development and operational research, the diagnostic performance of rdts is now established in all settings. meta-analyses have clearly demonstrated equivalence of rdts over expert microscopy to detect parasites, and clear superiority over routine microscopy. actually, one of the major reasons that have delayed successful implementation of rdt in endemic areas was the use of poor quality microscopy that has impeded reliable measurement of sensitivity and specificity and undermined confidence of health workers in rdts. other factors were poor product performance, inadequate methods to determine the quality of products and a lack of emphasis and capacity to deal with these issues. for the potential of rdts to be realised, it is crucial that high-quality products that perform reliably and accurately under field conditions are made available and that quality insurance is performed on all steps of the procedure. in achieving this goal, the shift from symptom-based diagnosis to parasite-based management of malaria can bring significant improvement for the management of fever in endemic areas. for travelers returning in temperate climates with fever, rdts have also the potential to improve diagnostic procedures, especially so in hospitals where reliable microscopy is not available out of hours. in patients with no danger sign or significant thrombopenia, a negative rdt is sufficient to exclude malaria and allows waiting − hours for performing or reading the microscopy slide. rdts should be repeated every − hours for three consecutive days if fever persists and in the absence of alternative diagnosis. rdts represent a revolution in the fight against malaria and will tremendously help to manage appropriately patients with fever, especially so when malaria is declining and hence other causes of fever increasing. the ambitious deployment that is foreseen in the coming years in africa through large grants from the global fund should contribute to achieving the millennium goals. fever is the key symptom of malaria among returning travellers ( %). headache, chills, myalgia, sweating and lack of a focus are frequently recorded, but non-specific. nausea and vomiting are often seen in children. the differential diagnosis of other infections, mainly of viral origin, is further difficult because (dry) cough and (mild) diarrhoea are often present. laboratory findings (thrombocytopenia, low or normal leucocyte count) can be helpful in the assessment of mild to moderate malaria. clinical signs and symptoms, e.g. fever, may be mitigated in semiimmune patients (visiting friends and relatives, foreign visitors) seen in non-endemic countries who represent the majority of cases diagnosed in industrialised countries. caution is warranted in assessing such patients as many of them may no longer be exposed to malaria in their countries of origin, thus no longer partially protected and also at risk of suffering from severe complications. up to % of all imported malaria cases may be severe, presenting with jaundice, impaired consciousness to coma, acute renal failure, and, in the course of events, acute respiratory failure. delay in diagnosis and start of treatment is partly responsible for fatality rates of % and more in some countries. if you don't look for them, you won't find them: anaerobes revisited s anaerobic microbiota of the mouth − friend or foe? anaerobes form a major part of the commensal microbiota in the digestive tract where they constitute an integral component of the function on mucosal surfaces. in the mouth, teeth create a unique, non-shedding environment for bacteria to attach and to form biofilms. there is an age-related succession order of species in bacterial colonisation of the mouth, and once established, individual anaerobic species tend to remain as members of the oral microbiota. the agerelated pattern of the colonisation of anaerobic bacteria is partly connected with the development (or loss) of the dentition. interactions between different bacteria residing in the same microenvironment influence the composition of the microbiota − or the development of pathologic conditions. although commensal bacteria are regarded beneficial to the host, some anaerobic members of the oral microbiota contain characteristics potentially detrimental for the health status of an individual. molecular means of characterisation have resulted in increased knowledge about the "normal" microbiota of the mouth and in detection of new species and genera as well as phylotypes, which can be associated with infectious situations in the mouth. oral infections are multifactorial and polymicrobial in nature, and their aetiologic organisms originate mainly from the oral resident microbiota. the involvement of anaerobes is most obvious in infections of root canals, periodontal tissues, and tissues surrounding erupting wisdom teeth where typical anaerobic findings are gram-negative rods. in addition, gram-positive anaerobic cocci and non-spore-forming gram-positive anaerobic rods are common in odontogenic infections. on some occasions, anaerobes of localised dentoalveolar infections can spread to adjacent tissues and even to the bloodstream, resulting in severe complications in extraoral sites. interestingly, a relatively limited number of anaerobic species are involved in clinically severe infections, however, microbial findings seem to vary depending on geography. concomitant with the increase in the number of immunosuppressed patients, the number of opportunistic infections caused by commensal anaerobes may increase. identification to the species level will help to establish associations between individual anaerobic species and specific disease states. studies on the bacteriology of diabetic foot infections (dfi) have yielded varied and often contradictory results. the role of anaerobes is particularly unclear, often because the type and severity of the infection is poorly defined, recent antibiotic therapy is unknown, and specimen collection and culture techniques are inadequate. when optimal collection, transport, and culture techniques are used, multiple organisms including aerobes and anaerobes are usually recovered from severe dfi. interactions within these polymicrobial soups lead to production of virulence factors, such as haemolysins, proteases, collagenases, and short chain fatty acids, which promote inflammation, impede healing and contribute to the chronicity of the infection. to better define the bacteriology of diabetic foot infections, we analyzed our data from a large prospective u.s. multicentre trial of patients with moderate to severe infection that required initial parenteral antibiotic therapy and used optimal post-debridement sample collection, transport and culture procedures. of the culture-positive specimens (of total), only . % were pure cultures while . % yielded or more organisms. a total of anaerobes (range − , average . , per specimen) were recovered from % of patients, with gram-positive cocci (gpc) accounting for . % of all anaerobic strains. s is culture still the gold standard, really? tremendous technological advances are made in culture-independent methods of detection and identification of human bacterial pathogens, such as pcr or hybridisation of their genomic dna. yet, time honoured pastorian bacterial culture in liquid and solid nutritive media still remains the gold standard for the laboratory diagnosis of a majority of bacterial infections. this unusual robustness of a th century technology stems from its unmatched operational characteristics: . broad range of detected agents, depending on adequate combination of media/incubation conditions; . unlimited source of clonal population for individual isolate, allowing versatile characterisation of antibiotic susceptibility and/or pathogenic factor production and/or epidemiological subtyping; . possibility of storage/bio-banking of cells for complementary clinical testing, research and diseases surveillance collections; . proof of pathogenic role of agent at the time of viable cell isolation from the site of infection, in contrast to false-positive results with molecular tests (tissue translocation or persistence of bacterial dna, soluble antigen,. . . ). major drawbacks of bacteriological culture include long turn-around time, cost and labour/skill intensity. these are partly alleviated by new technologies, including automated processing, physical/chemical growth detection and rapid molecular fingerprinting (maldi-tof, raman spectrometry, s rdna snp detection). it is likely that the next decade will see a complete redefinition of the place of direct detection methods and culture-based confirmation methods in clinical bacteriology, enabling a rejuvenation rather than elimination of culture as a daily diagnostic tool. the advent of real-time pcr revealed instrumental to the successful implementation of molecular methods in routine clinical microbiology laboratories. automated nucleic extraction platforms can now be coupled to robotic handling for large-scale detection and quantification purposes, mostly in virology. i will review here the attempts of implementing home-brew and commercial nucleic-acid based detection methods directly from blood samples and highlight hopes and pitfalls. i will then expand on two promising nucleic acid amplification methods: lamp (loop mediated isothermal amplification) and a protein-free method called dnazyme. these isothermal amplification methods share several strengths: robustness across highly diversified physico-chemical conditions, versatility in assay development and minimal requirements (if any) for sample preparation. they will definitely compete against current real-time pcr assays and might become a novel standard, due to lower costs and improved performances. the ribosomal rna (rrna) approach to microbial evolution and ecology has become an integral part of microbiology. rapidly growing databases exist that encompass besides the s rrna sequences of almost all validly described bacteria and archaea also numerous s rrna sequences of so far uncultivated microbes, directly retrieved from the environment by pcr or metagenomics. based on the patchy evolutionary conservation of rrna genes oligonucleotide probes can be designed in a directed way with specificities ranging from species up to large evolutionary entities like phyla or even domains. when such probes are labeled with fluorescent dyes or the enzyme horseradish peroxidase they can be used to identify single microbial cells by fluorescence in situ hybridisation (fish) directly in complex environmental samples. an update on recent applications and methodological improvements will be given which includes the identification of small bacterial cells by catalyzed reporter deposition (card)-fish. with optimised methods and proper controls fish yields exact cell numbers and spatial distributions for defined bacterial populations also in highly complex mixed microbial communities. r. amann & b.m. fuchs ( ) nature reviews microbiology : - . quick and reliable species identification of microorganisms is of great importance in medical microbiology. several bacterial and fungal species can be identified only using laborious and time-consuming methods. furthermore, in many cases misidentification occurs due to e.g. limited biochemical reactivity, different morphotypes or limited information in reference panels. in this talk, matrix-assisted laser desorption/ionisation time-of-flight (maldi-tof) mass spectrometry will be presented as a method for species identification. this technology applies protein pattern matching based on mass spectrometry. during the identification process, a mass pattern is generated for each organism. the subsequent comparison of this pattern with a database comprising reference patterns derived from well-characterised reference strains leads to species identification. as examples, the identification of various nonfermenting bacterial strains isolated from clinical specimens in comparison to partial s rdna sequencing will be shown. moreover, speed, accuracy in comparison to other methods, and inter-and intra-laboratory reproducibility of maldi-tof ms-based species identification will be discussed. o trends in invasive streptococcus pneumoniae serogroup sequence types in belgium t. goegebuer, k. van pelt, j. verhaegen, j. van eldere°(leuven, be) objectives: s. pneumoniae serogroup (sg ) isolates frequently cause invasive pneumococcal disease, particularly in children. from onwards a marked increase in sg isolates was observed; overall prevalence increased from . % ( - ) to . % ( ) ( ) ( ) ( ) . we determined the sequence types (st) in sg isolates in order to better understand trends in sg resistance and spread. methods: as national reference centre, we receive all invasive isolates from more than of laboratories in belgium. randomly chosen sg isolates from all ages from to were analysed via multi-locus sequence typing (mlst) as described by enright & spratt (microbiol. ; : − ) . we also included data on strain characteristics and patient characteristics. results: different sequence types (st) were identified: st (n = ), st (n = ), st (n = ), st (n = ), st (n = ), st (n = ), st (n = ), st (n = ), and st (n = mutations usually increase the mic slightly, but enhance the probability of further mutations. efflux pumps like pmra reduce antibiotic concentrations in the bacterial cell, enabling longer survival. we hypothesised that efflux positive bacteria are more likely to develop resistance than efflux negative bacteria. the following questions were addressed: . do the efflux pump inhibitors reserpine and verapamil reduce the mutation frequency? . do fluoroquinolone-susceptible efflux positive pneumococci exhibit higher parc or gyra qrdr mutation frequencies than efflux negative isolates? . does efflux phenotype impose a fitness cost? methods: matched efflux positive and negative pneumococcal isolates with identical or similar genotype according to multi-locus sequence typing collected by the german community acquired pneumonia network capnetz were analysed (n = ). strains tigr and r were included as efflux negative controls. ciprofloxacin (cip) mics and efflux phenotype were measured by agar dilution method, for efflux detection reserpine ( mg/l) was added and a fourfold decrease in mic was considered as efflux positive. mutation frequencies were determined by plating bacterial suspensions onto agar with and without cip. after incubation colonies were counted and the ratio of cfu/ml yielded the mutation frequency. equally, the mutation frequency was determined adding different concentrations of verapamil ( , , , , mg/l) or reserpine ( . , . , , , mg/l). biological fitness was calculated as the maximum slope of growth curves recorded in a microtitre plate reader. results: ) even at low concentrations, reserpine clearly reduced the mutation frequency of efflux positive and, to a lesser extent, efflux negative pneumococci when exposed to cip (figure ); verapamil exhibited this effect merely at high concentrations. ) efflux positive isolates produced more frequently mutants ( / ) than efflux negative isolates ( / ) (p = . , fisher's exact test). ) efflux phenotype had no measurable impact on the biological fitness. conclusion: a positive efflux phenotype increases the qrdr mutation frequencies in the presence of fluoroquinolones and this effect can be inhibited by very low concentrations of reserpine. as a matter of concern, efflux is not associated with decreased biological fitness. background: use of fluoroquinolone (fq) has been associated with increasing fq resistance in s. pneumoniae. because respiratory fqs (levofloxacin (levo) and moxifloxacin (moxi)) are first line therapy for serious respiratory infections, increasing fq resistance (fqr) in sp is a concern. levo targets parc, and moxi targets gyra, which may permit differentiation of degree of selective pressure. we examined fq use, and changes in the prevalence of fqr and qrdr mutations in canadian isolates of sp. methods: cbsn is a canadian collaborative network of microbiology laboratories that has performed surveillance for antibiotic resistance in sp since . antimicrobial resistance is performed in a central lab to clsi standards. we sequenced qrdr regions of all fqr isolates and a stratified sample of fq susceptible isolates. population fq use was obtained from ims canada. results: from to , fq use increased from to rx/ pop/yr; levo use from to rx/ pop/yr, and moxi use from to rx/ pop/yr. isolates were available for testing. levo r rates increased from in to . % in then remained stable until ( . % in ). moxi r rates increased to . % in , then stabilised ( . % in ). the prevalence of parc only mutations has not increased significantly in the last decade (see table) . the prevalence of isolates with both parc and gyra mutations increased until , but has decreased in . the first gyra only mutant was detected in ; the prevalence of gyra only mutants since then has increased, but remains very low ( / , . % in ) . conclusion: despite increasing use of respiratory fqs, fqr in pneumococci is very low and not increasing in canada. the prevalence of isolates with parc mutations is decreasing. isolates with mutations in gyra alone remain extremely rare, suggesting that moxi exerts minimal selective pressure for resistance. in streptococci, two well characterised macrolide resistance have been described: target modification and active drug efflux. target site modification is mediated by the erm genes -erm(b), erm(a), erm(c)which confers the mlsb phenotype. target modification by mutations in s rrna as well as mutation in l and l ribosomal proteins have also been reported. expression of mef(a) genes activate an efflux mechanism responsible for m-type resistance we characterised a clinical isolate of s. agalactiae mb gbs exhibiting the mlsb phenotype and tetracycline resistance. in this study, we determined the resistance genes, their association, and their localisation and mobility by conjugation. methods: the macrolide and tetracycline resistance genes were confirmed by pcr. the association between macrolide and tetracycline genes was investigated by long-pcr and sequencing. conjugation experiments were performed by filter matings. the genetic localisation of resistance genes was determined by endonuclease i ceui -followed by pfge and southern blot. the hybridisation study was performed using three specific probes for the s and s rrna genes, for erm(b) and tet(o) genes. results: s. agalactiae mb gbs carried erm(b) and tet(o) genes on the same amplicon of kb in size. the nucleotide sequence analysis of the entire product was identical to the peoc of kb from pediococcus acidilactici that contains four orfs, of which orf and orf encode a putative resolvase and topoisomerase type i, respectively. the endonuclease i ceui method, that easily distinguishes between plasmid and chromosomal localisations as i-ceui only cuts chromosomal dna, revealed the localisation of resistance genes on the plasmid. all attempts to transfer erm(b)-tet(o) structure by conjugation from s. agalactiae mb gbs to og ss e. faecalis as recipient failed. conclusion: our results show the first case of the association between erm(b) and tet(o) genes on the unique mosaic structure in s. agalactiae, probably on the plasmid, as demonstrated by the i ceui-assay. further studies are on going to characterise the entire genetic element carrying resistance genes. o improving influenza pre-analytic collection systems: alternative collection systems to inactivate, preserve, or extract influenza for rapid testing s. castriciano°, k. luinstra, m. ackerman, a. petrich, m. smieja (brescia, it; hamilton, ca) objectives: in this study, alternative influenza sample collection systems were evaluated for potential use in a pandemic situation. the objectives were to develop: ) a non-temperature dependent swab collection and transport system, that inactivates influenza virus infectivity but preserves cell morphology and nucleic acid (na) for the detection of suspected influenza infections and/or ) a system compatible with direct na testing without the need for purification prior to detection by a rapid real-time rt-pcr. methods: flocked nasopharyngeal swabs (nps) collected in utm (u) were compared to nps collected in a cymol (c), m-swab (m) or dry (d) flocked swab collection system (copan, italia). cymol is an alcoholbased medium that preserves cells for dfa testing. the m-swab contains ul of medium and ul of glass beads, and requires no na purification step. shell vial culture was used to assess influenza virus inactivation after minutes exposure to the collection media. a mockinfected influenza a virus sample was absorbed to duplicate swabs then placed into the collection systems. the infected collection media were held at rt for minutes and then inoculated in duplicate into shell vial culture and stained after hours. influenza a stability and na recovery after mock infection of each collection system was assessed after , , and days (d) at ºc, − ºc, room temperature (rt) and ºc. aliquots of infected collection media were extracted by easymag and ul of purified na tested by a quantitative influenza a rt-pcr on the roche lightcycler. m-swab collected samples were also tested directly or after boiling, without na purification. results: shell vial culture found that influenza a virus was inactivated after minutes exposure to the c medium but not when exposed to the u and m media. influenza a was detected by dfa from the u and c cell smears. quantitation of influenza a rna was constant after , and d in u, c, m and d collection systems at − , ºc and rt. the quantity of rna recovered declined significantly after d at ºc in all collection systems. m with boiling yielded data comparable to the easymag extraction. the copan cymol medium inactivates influenza infectivity, preserves cells and stabilises rna up to days at − , ºc and rt. cymol medium is a potential alternative for safe sample collection during a pandemic influenza situation. the m-swab presents a rapid testing alternative. luminex respiratory viral panel in respiratory specimens from children r. selvarangan°, s. selvaraju, d. baker, k. estes, l. hays, d. abel, s. hiraki (kansas city, us) objective: luminex respiratory viral panel (rvp) is a multiplex pcr capable of detecting and differentiating twelve different respiratory viruses and their subtypes; influenza a (flu a) (subtypes h and h ), influenza b (flu b), respiratory syncytial virus (rsv) (subtypes a and b), adenovirus (adv), parainfluenza (piv ), parainfluenza (piv ), parainfluenza (piv ), human metapneumovirus (hmpv) and rhinovirus (rhv). the aim of this study was to evaluate the analytical performance characteristics of rvp assay and to evaluate its ability to detect respiratory viruses from nasopharyngeal aspirates obtained from children. method: analytical sensitivity, specificity, accuracy and precision of the luminex rvp assay were determined using control viral stocks and respiratory specimens previously tested by rmix shell vial culture. result: luminex rvp assay reliably detected atcc viral stocks of flu a, flu b, rsvb, rhv and piv in the range of e- to e- tcid /ml. no cross reactivity was noted with cmv, hsv, hhv , ebv, vzv, piv , cornoavirus e and oc . among respiratory specimens previously characterised by culture specimens were accurately detected with overall accuracy of %. the median coefficient of variation in mean fluorescent index values of signals from replicate analyses of influenza a, b and rsv was % ( % to %). the clinical specimens tested by rvp assay included culture positive and culture negative specimens. respiratory viruses isolated from the culture positive specimens include the following; adv, flu a, flu b, rsv, piv , piv , piv , hmpv and rhv. rvp assay detected all of the respiratory viruses except one each of rsv, piv and piv virus with overall sensitivity ranging from % to % for the different respiratory viral groups. among the culture negative specimens respiratory viruses were detected by rvp of which were subsequently confirmed by repeat analyses. conclusion: luminex rvp assay is a highly sensitive and specific test useful in the detection of commonly encountered respiratory viruses in respiratory specimens. the addition of rvp assay to the viral testing algorithm of respiratory infections in children provides rapid results, improves diagnostic yield and may result in decreased antibiotic usage, reduced diagnostic testing and reduced hospital stay. m. savvala, i. daniil, i. berberidou, a. koutsibiri, a. stambolidi, m. papachristodoulou, n. spanakis, d. petropoulou°, a. tsakris (athens, gr) objective: in developed countries, viruses, particularly noroviruses, are recognized as the leading cause of acute gastroenteritis. we determined the aetiology, prevalence and seasonal distribution of viral gastrointestinal infections in hospitalised patients with acute diarrhoea. methods: during one-year period (november -november ), a total of faecal specimens were collected from children, premature neonates and adults who were hospitalised with symptoms and signs of acute gastroenteritis. stool samples were tested for the presence of rotavirus, adenovirus, astrovirus and norovirus. rotavirus, adenovirus and astrovirus antigen detection was performed by chromatographic immunoassays (rotavirus and adenovirus, vikia ® -biomerieux, france; h&r astrovirus-vegal farmaceutica, spain). noroviruses were detected by an enzyme immunoassay (ridascreen ® rbiopharm, germany) and confirmed by reverse transcription-pcr. data were analyzed for seasonality of infection and possible transmission mode. the overall incidence of viral identification in acute diarrhoeal stool was % ( of patients). fifty one viral antigens were detected one patient with positive antigen detection is suffering from a disease of unclear aetiology. so, an association of replication of cihhv- with the disease might be considered. in contrast, the other patient did not show any symptoms at the time of antigen detection. this patient shows a special mode of acquisition of cihhv- (by bmt) possibly resulting in differences in the immunological priming and response. in addition, in the latter patient cihhv- is restricted to blood cells. two other patients did not show antigen expression. so, it is unclear how the transcription and translation of viral genes is influenced? furthermore, is there a pathophysiological impact of viral replication in individuals with cihhv- ? objectives: several case studies have reported on meningo-encephalitis caused by a primary epstein-barr virus (ebv) infection. we aimed to investigate the viral loads, and the inflammatory characteristics of this thus far poorly defined disease entity. we evaluated all cases from - , in which an ebv polymerase chain reaction test (pcr) was requested on a cerebro spinal fluid (csf) sample. primary infection was defined as a clinical presentation with sore throat/pharyngitis/malaise in combination with lymphocytosis, and detectable heterophile antibodies or positive ebv igm antibodies. patients with proven neuroborreliosis served as control group. leukocyte response and ebv viral loads in csf, and serum were compared between primary ebv and neuroborreliosis cases. results: we identified six cases with a primary ebv infection (median age: , male: ) with neurological symptoms ranging from meningeal signs to encephalitis. these were compared to patients with neuroborreliosis (median age: , male: ). in four out of six patients with a primary ebv infection with neurological symptoms ebv dna was detected in csf and in serum, whereas all neuroborreliosis cases were ebv pcr negative in both compartments. viral loads were lower in csf as compared to serum. in blood, leukocytes, lymphocyte, and monocyte counts were significantly increased as compared to the neuroborreliosis cases (see table ). specific for vp and vp genes, using pools of g and p type specific primers. all strains (niv/brv/ , niv/brv/ , and niv/brv/ ) were not typeable for the vp and vp genes. after purification by "qiaquick gel extraction kit" (qiagen, germany), the vp , vp , vp , and nsp first amplicons of the borv-a strains were subjected to sequence analysis with automated sequencer abi xl dna analyzer (applied biosystems, usa). phylogenetic analysis was performed using mega version . . objectives: dengue is a flavivirus and is among the most widely-spread viral diseases. our previous report demonstrates existence of live dengue virus in blood and urine even in the convalescent postfebrile period. in some cases, excretion in the patient's urine can be detected as late as days after the onset of illness. this goes along with the model of west nile virus, another type of flavivirus, which can be excreted in the urine for months after acute infection in both animal studies and human case report. here we report a pilot study to address a magnitude of such findings. methods: between april and october , paediatric and adult febrile patients suspected of dengue infection were enrolled. diagnosis of dengue was based on standard specific serology on paired sera. patients with negative serology served as controls. blood and urine specimens were collected at several time points. whole blood was separated into plasma and peripheral blood mononuclear cells (pbmc). these have been aliquoted and used for earlier studies and some stored in freezers. available plasma, pbmc, and urine were processed and inoculated into aedes aegypti. surviving mosquitoes at days after inoculation were employed for viral detection by dengue-specific rt-pcr. indirect fluorescence antibody (ifa) staining of mosquito heads was performed on all positive rt-pcr specimens, except for the one from pbmc (awaiting ifa result). results: and cases of primary and secondary infections, respectively, and negative controls were included. these translated into and early and late dengue specimens, and and early and late negative-control counterparts, respectively. dengue virus were isolated in some blood and urine specimens as late as days after the onset of illness. no virus was isolated from control specimens. all but positive rt-pcr specimens also demonstrated positive ifa. out of negatives were from early-phase specimens. conclusion: our study demonstrates prolonged survival of dengue virus after clinical recovery. this finding has pathologic and epidemiologic significance, adding a potential role of urine in the transmission of the disease. spread of the virus to humans might occur through infectious urine with help from arthropod vectors. this research could provide new insights into our understanding of the pathogenesis of denv infection. isolation of dengue virus from blood and urine specimens during early (days − after onset of illness) and late (days − ) phases of infection (specimens with dengue isolated/total specimens for mosquito inoculation) early phase late phase plasma / ( %) / ( %) pbmc not performed / ( %) urine / ( %) / ( %) all specimens / ( %) / ( %) dna copies) (< - ) † ; n =