key: cord- -uqsayb d authors: sirtori, carlo title: australia antigen, coronavirus, and reverse transcriptase in viral hepatitis date: - - journal: lancet doi: . /s - ( ) - sha: doc_id: cord_uid: uqsayb d nan two hospitals from which our series was assembled. these derive from a random sample of unaffected births over the -year period. as shown in the table, this sample shows no evidence of a downward shift in the maternal-age distribution of births in the hospital. indeed, the slight changes in these means parallel quite closely the changes in the observed values for the affected individuals. these data effectively rule out as an explanation of this epidemic any phenomenon that would be expected to follow a cohort pattern. the lack of a cohort pattern is consistent with explanations in terms of changes in factors operative in early pregnancy-such as would seem more consonant with existing knowledge of the causes of congenital malformations-although the specific change associated with this particular episode is still unknown. sir,-the discovery of a reverse transcriptase in australia antigen by hirschman and his colleagues strongly suggests that the antigen is associated with an r.n.a. virus ; and this idea is corroborated by the finding of small amounts of r.n.a. in the same antigen. all this is in keeping with our previous studies of the acute-hepatitis liver with the electron microscope, > revealing the simultaneous presence of australia antigen and coronaviruses, and showing how the particles of australia antigen, present in the cytoplasm, fell together to form coronavirus membranes. from this we deduced - that the australia antigen might contain an r.n.a.-polymerase capable of forming the adult virus (coronavirus). also zuckerman et al., holmes et al.,' and wright et al. found both the australia antigen and coronaviruses in the blood of patients with acute or chronic hepatitis. we have tried to cultivate bits of hepatitis liver containing both the australia antigen and the coronavirus on kb cells, and we have seen that the kb cells developed clusters of particles in their cytoplasm, suggesting the early stages of australia-antigen formation; on the other hand, perhaps the coronavirus, or adult form of the virus, occurs only exceptionally or is very short-lived. sir,&mdash;i i would like to report another case of aplastic anaemia associated with infectious hepatitis. a woman aged was attending queen victoria memorial hospital and was at weeks gestation in her first pregnancy in june, , when she had mild infectious hepatitis. at that time her haemoglobin was - g. per ml. and a blood-film showed well hasmoglobinised red blood-cells with some variation in size and some polychromasia. leucocytes and platelets appeared normal. for weeks she was admitted to fairfield hospital for communicable diseases. recovery was apparently complete, and a healthy live female baby was delivered normally at weeks gestation. membranes had ruptured week before delivery, and because of this she had received penicillin megaunit every hours and sulphadimidine g. every hours for days. during the pregnancy she received ferrous sulphate and for weeks in the first trimester had taken meclozine mg. twice daily for morning sickness. in november, , she was readmitted to fairfield hospital with a -week history of malaise, anorexia, fever, pale stools, and increasing jaundice. her liver was enlarged fingers breadth and tender. serum bilirubin was - mg. per ml.; glutamic-oxaloacetic transaminase (g.o.t.) sigma-frankel (s.f.) units per ml., and alkaline phosphatase king-armstrong (k.a.) units per ml. prothrombin activity was % of normal. hxmoglobin was g. per ml., red blood-cells were mildly hypochromic with some anistocytosis and some target cells. leucocyte-count was per c.mm. she was treated with prednisolone mg. daily reducing to mg. daily over weeks. discharged at this stage, she felt well, her liver was no longer tender or palpable; serum bilirubin was - mg. per ml. and g.o.t. s.f. units per ml. days later she had an exceptionally heavy menstrual period, but otherwise remained well for the next weeks. then she noticed bruising on her legs which gradually became generalised. five days later she developed painful blue nodules on her hands, lips, and mouth, had a severe epistaxis, and was again admitted to queen victoria memorial hospital. at this time she was pale, febrile, and had numerous purpuric areas in her skin and a number of mixed infective-purpuric lesions on hands, lips, and mouth. liver and spleen were impalpable. initial blood findings were: haemoglobin - g. per ml.; white blood-cells per c.mm. (neutrophils %, eosinophils %, lymphocytes %); platelets , per c.mm.; reticulocytes less than % ; blood-film showed marked anisocytosis. the bone-marrow was markedly hypocellular and consistent with marrow aplasia. serum bilirubin - mg. per ml., g.o.t. s.f. units per ml., alkaline phosphatase k.a. units per ml. culture of the lesions on her hands and mouth grew staphylococcus aureus. over the next months she was treated with fresh blood and platelet transfusions, corticosteroids, antibiotics, and oxymetholone. in spite of this she eventually died of a gram-negative septicxmia and associated hxmorrhagic state. at necropsy the liver was enlarged ( g.) with a brownish-grey, slightly granular cut surface. histological examination showed patchy liver-cell necrosis with replacement by fibrous tissue and increased connective tissue and cellular infiltration of portal tracts, and was consistent , iv, . we have not seen any evidence of coronavirus in these cells key: cord- - ronfq authors: nicholson, karlg; prestage, howard; cole, peterj; turner, georges; bauer, sallyp title: multisite intradermal antirabies vaccination: immune responses in man and protection of rabbits against death from street virus by postexposure administration of human diploid-cell-strain rabies vaccine date: - - journal: lancet doi: . /s - ( ) - sha: doc_id: cord_uid: ronfq lymphocyte transformation, production of neutralising antibody, and the development of antirabies igg antibody were studied in ten healthy volunteers in response to · ml of human diploid-cell strain (hdcs) rabies vaccine administered on one occasion in divided doses in intradermal (i.d.) sites. all ten volunteers rapidly developed substantial titres of rabies antibody, and eight of the ten had t lymphocytes that were immunologically stimulated by hdcs rabies-virus antigen. postexposure treatment with · ml of hdcs vaccine given at i.d. sites completely protected fourteen rabbits from death by street virus. the results suggest that in developing countries patients could be protected with small volumes of potent tissue-culture vaccine administered intradermally shortly after exposure. lymphocyte transformation, production of neutralising antibody, and the development of antirabies igg antibody were studied in ten healthy volunteers in response to &middot; ml of human diploid-cell strain (hdcs) rabies vaccine administered on one occasion in divided doses in intradermal (i.d.) sites. all ten volunteers rapidly developed substantial titres of rabies antibody, and eight of the ten had t lymphocytes that were immunologically stimulated by hdcs rabies-virus antigen. postexposure treatment with &middot; ml of hdcs vaccine given at i.d. sites completely protected fourteen rabbits from death by street virus. the results suggest that in developing countries patients could be protected with small volumes of potent tissue-culture vaccine administered intradermally shortly after exposure. introduction in , forty-five people severely bitten by rabid dogs and wolves in iran were treated after exposure with a new rabies vaccine produced in cultures of human diploid cells. all except one also received one injection of rabies immune serum. this treatment, in contrast to past experience with other vaccines, resulted in protection of all individuals against rabies. this resounding success has been repeated in trials in germany and the u.s.a. using or doses of human diploid-cell strain (hdcs) rabies vaccine and human rabies immune globulin.', thus, almost a century after the post exposure treatment of man began, effective antirabies prophylaxis appears to have been achieved. with few exceptions, rabies is a problem of impoverished areas of the world, where the annual per-caput expenditure on health care is often far less than the cost of a single ml dose of hdcs vaccine. as a consequence, potent tissueculture vaccine is seldom used in the third world. the need for an effective but less expensive method of treatment prompted us to investigate the possibility of administering potent vaccine more economically and efficiently than at present. our previous studies have shown that substantial titres of antibody can be achieved with small quantities of hdcs vaccine administered by the intradermal (i.d.) route and that the cost of vaccination can be reduced considerably. - in this paper we report the antibody and cellmediated immune response of man to multisite i.d. vaccination and application of the method to postexposure protection of rabbits. it appears possible that the i.d. route could be applied successfully to the post exposure treatment of man. approval for the volunteer study was given by northwick park hospital ethical committee. hdcs vaccine ( - ml) was given i.d., on single occasion, to ten volunteers at sites on the medial and lateral aspects of the upper arms and thighs. blood samples for tests of lymphocyte transformation and antibody determination were taken before vaccination and , , , and days later. a further blood sample for antibody titration was taken on day . four subjects were vaccinated with a dermojet injector;* the six remaining volunteers were given vaccine with a -gauge needle and tuberculin syringe. no volunteer had received antirabies vaccine previously. the nuchal muscles of forty-two new zealand white rabbits were inoculated with rabbit ld ofa first mouse-brain-passage arcticfox rabies virus isolate in two separate sites ( - ml each side). h later fourteen rabbits were given - ml of hdcs vaccine intramuscularly (i.m.) into the left forelimb, and fourteen others received i.d. injections of - ml of vaccine into each limb. the remaining fourteen were used as controls and received no prophylaxis. each animal was then observed for months for signs of rabies. none of the rabbits had been exposed to rabies previously or had been immunised against the disease. in both studies whole-virion hdcs rabies vaccine (i'institut merieux; lot r ; antigenic value - ) inactivated with -propiolactone was used. all blood samples were titrated for rabies neutralising antibody with the mouse neutralisation test; titres in iu/ml were calculated by reference to the international standard antiserum to rabies virus (statens seruminstitut, copenhagen, denmark). in addition, the sera were assayed for igg rabies antibody by enzyme immunoassay (elisa) using a modification of the method used for the detection of coronavirus antibodiesl&deg; (k. g. nicholson, h. prestage, unpublished). absorbance values were read at nm on a flow laboratories titertek multiskan spectrophotometer , , , and min after addition of the substrate. rabies antibody was considered present when the optical-density reading of the test sample was greater than the mean + standard deviations of comparable dilutions of negative control sera. an enriched t-lymphocyte population was obtained by passing a thrice-washed mononuclear-cell suspension taken from the top of a ficoll-triosil gradient (pharmacia fine chemicals, uppsala, sweden) twice through a nylon-fibre column." the cell suspension obtained contained less than % b lymphocytes as judged by staining with polyvalent fluorescein-labelled antihuman immunoglobulin reagent. an enriched b-lymphocyte population was obtained by sedimenting rosettes formed between t lymphocytes and sheep red blood cells." lymphocytes from human cord blood and a non-vaccinated subject were used as controls. hdcs rabies-virus vaccine (l'institut merieux; lot r ) was exhaustively dialysed against phosphate-buffered saline (pbs) and adjusted to the original volume with pbs for use as antigen. phytohaemagglutinin (pha; purified grade, wellcome laboratories, beckenham) was used as control at a concentration of - mitogenic units/ml. cultures containing of antigen or mitogen and of cell suspension containing x lymphocytes were established in microtitre plates then pulsed with tritiated thymidine and harvested as described previously.' because of the ph indicator in the vaccine, needle inoculation immediately resulted in magenta-coloured skin blebs at each injection site. vaccination with the dermojet injector was generally quicker, but bleb formation was less satisfactory and in some areas where the skin was especially soft it appeared that all the vaccine had entered the subcutaneous tissue. this method of inoculation was also associated with lower titres of antibody than occurred after needle inoculation (figs. six subjects who were inoculated with a needle and syringe. by days, neutralising antibody ranged between and iu/ml (geometric mean titre [gmt] iu/ml) and antirabies igg ranged between / and / (gmt / ). peak titres of virus neutralising antibody were found on day (gmt ' iu/ml), but substantial titres were still present days after vaccination. the increments (cpm) in lymphocyte transformation are expressed as a ratio to the cpm values of non-stimulated control cultures (table). the results show that t lymphocytes from eight of ten vaccinees were significantly stimulated in vitro to days after vaccination. this blast transformation occurred with cells from three of four people given vaccine by the dermojet injector and from five ofthe six people inoculated with a needle and syringe. there was no significant difference between the transformation increments of the two groups, and no correlation was found between the transformation increment and the titre of antirabies igg or nine of fourteen rabbits developed paralysis and died after infection with rabbit ldso of street-rabies virus. in these animals, forelimb paralysis developed within to days of infection and progressed to complete paralysis and death to days later. postexposure treatment with a single dose of hdcs vaccine reduced the mortality significantly; the administration of i - ml of vaccine i.m. gave significant (p= ' , fisher's exact test) but incomplete protection, two of fourteen animals developing paralysis and dying after incubation periods of and days. none of fourteen rabbits died after receiving i.d. inoculations of . ml of the vaccine in each limb (p = ' ). britain, [ ] [ ] [ ] [ ] , france, and germanyls, that the administration of hdcs vaccine by the intradermal route is followed by substantial titres of virus-neutralising antibody with occasional mild local and systemic reactions. it has also been shown that or doses of ml given in separate sites on a single occasion rapidly induce high titres of antibody. i , the present report confirms these observations and shows in addition that the early production of virus-neutralising antibody is accompanied by high titres of antirabies igg. this early igg response may be most important, for it is now well established that neutralising antibody of the igg class, unlike igm neutralising antibody, confers protection on animals challenged with rabies and may be the key to successful postexposure treatment of man. the possible role of cell-mediated immunity in rabies infection is poorly understood, but it too may be an important component of the host's immune response. we have reported that transformation of lymphocytes occurred with cells taken from eight of ten vaccinees after the first x ml doses of an established postexposure regimen for hdcs vaccine.' in the present study we separated the lymphocyte subpopulations and have shown that the blast transformation is a t-cell response. furthermore, it occurred in the same proportion of vaccinees (eight often) as was found in the previous study, but with only a quarter of the volume of vaccine. clearly, if high titres of neutralising antibody and a cell-mediated response are both important for protection, the present study suggests that they can be obtained equally well with much smaller quantities of vaccine than are used at present. we further showed that rabbits could be completely protected by injecting x - ml doses of hdcs vaccine intradermally h after intranuchal infection with street-rabies virus. by contrast, nine of the fourteen controls ( %) died from rabies with incubation periods of to days (mean days). opponents to the administration of rabies vaccine by the i.d. route claim that it is technically difficult, especially in the elderly and the very young. nevertheless, many vaccines are routinely administered by the i.d. route with apparent success and considerable financial savings. there seems to be ample experimental evidence to justify a postexposure study of hdcs vaccine administered by the i.d. route; we believe that this would be both ethical and potentially of great importance for developing countries. k. g. n. was partly supported by an mrc-eli lilly travelling fellowship at the u.s. national center for disease control, atlanta, ga. g. s. t. was partly supported by mrc grant no. / . we thank dr c. charbonnier and l'lnstitut merieux for the gift of the vaccine requests for reprints should be addressed to k. g. n. successful protection of humans exposed to rabies infection postexposure treatment with the new human diploid cell rabies vaccine and antirabies serum post-exposure use of human diploid cell culture rabies vaccine deitch mw postexposure trial of a human diploid cell strain rabies vaccine immunization with a human diploid cell strain of rabies virus vaccine: two year results studies with human diploid cell strain rabies vaccine and human rabies immunoglobulin in man human diploid cell strain rabies vaccine rapid prophylactic immunisation of volunteers with small doses immune responses of humans to a human diploid cell strain of rabies virus vaccine: lymphocyte transformation, production of virus-neutralizing antibody, and induction of interferon l'injecteur sans aiguille "dermo-jet" presse m&eacute quantitative assay and potency test of antirabies serum and immunoglobulin macnaughton mr enzyme linked immunosorbent assay for detection of antibody in volunteers experimentally infected with human coronavirus e group viruses purification of human t and b lymphocytes immunogenicity and acceptability of a human diploid cell culture rabies vaccine in volunteers rabies prophylaxis simplified resultats de la vaccination antirabique preventive par le vaccin inactive concentre souche rabies pm/w - - m cultivee sur cellules diploides humaines developments in biological standardisation prophylactic immunization of humans against rabies by intradermal inoculation of human diploid cell culture vaccine a large scale antirabies immunisation study in humans using hdcs vaccine. who consultation on cell culture rabies vaccines and their protective effect in man immunoglobulin igg and igm antibody responses to rabies vaccine transformed the management of diabetes and it is now administered to about million diabetics throughout the world. although the frequency of side-effects is relatively low, efforts have been made over the years to improve the quality and extend the range of insulin preparations. the pace of these changes has accelerated during the past decade. introduction of high-purity insulin and of preparations of insulin from a single species of animal have been followed by developments of two kinds: the availability for therapy of insulin containing the aminoacid sequence of the natural human hormone and the construction of continuous-delivery systems to administer insulin under conditions that more closely mimic its natural secretion in the body. the changes in quality and type of insulin available have posed problems of nomenclature.recognition that the molecular structure of insulin can influence tolerance to, and the side-effects of, therapy led to the introduction in the british pharmacopoeia (bp) in ' of a requirement that all formulations be labelled with the species of origin. at that time, the bp contained no monograph for bulk insulin, but the marketing of a variety of purified insulins made such a monograph desirable, and it appeared in the bp . the monograph covers insulin of either porcine or bovine origin that has been purified beyond the stage of conventional crystalline insulin. this has had several consequences. first, the monograph required a title and "insulin" was taken. had the title been "purified insulin" or similar, to draw a distinction with crystalline insulin, the problem might arise of a name for material of yet higher quality (already available as "monocomponent" or "pro-insulin free" preparations). this is one reason why a *professor turner is vice-chairman and dr calam a member of the nomenclature committee of the british pharmacopoeia commission. monograph for a drug substance rarely contains any qualifying adjective indicating degree of purity. however, the title "insulin" had been for many years a synonym for insulin injection, and it was necessary to delete it as an alternative name for that preparation. second, a unique situation arose in that the monographs for formulations continued to specify a minimum potency of iu/mg for the insulin used, against the higher figure in the bulk monograph, thus allowing insulin not of bp quality to be incorporated into bp formulations. this was the result of decisions not to delete conventional formulations, satisfactory for many patients, from the pharmacopoeia and not to add a set of separate monographs for formulations containing the bp grade of insulin, which would require additional titles. another factor was involved in that control of six of the nine insulin formulations is exerted by monographs in the european pharmacopoeia. for these, no unilateral change in the requirements can be made by a national authority, but revision must await agreement by the european pharmacopoeia commission, with a further lapse of time before adoption. this factor illustrates the point that pharmacopoeial decisions in the united kingdom, including those involving nomenclature, cannot be taken without considering the international constraints that apply and the international implications that may result. during the past eighteen months another aspect of insulin nomenclature has been discussed by the british pharmacopoeia commission and its committees concerned with nomenclature and with hormones. this arose from availability, for testing and clinical trial, of insulin possessing the structure of the natural human hormone, the prospect of its wider use, and the eventual need for a monograph for it. that one method of production of such insulin uses geneticengineering techniques suggests that the wider implications must be considered. thus, in the following discussion, it should be remembered that the final outcome should, so far as possible, set a pattern that can be applied to other hormones and therapeutic substances (such as growth hormone and interferons) obtained by novel techniques.the structure of human insulin was established in and was found to differ from that of the porcine hormone only in the presence of threonine in place of alanine at position of the b chain. the total synthesis of insulin having the human sequence was achieved in an elegant manner by workers at ciba geigy in , but the process is not economically viable under present conditions. this material key: cord- -muvoo pe authors: chen, zhu title: biomedical science and technology in china date: - - journal: lancet doi: . /s - ( ) - sha: doc_id: cord_uid: muvoo pe nan advances in medicine in the th century, along with an ageing population and changes in lifestyles, have altered the nature of diseases. reform, economic issues were the major concern and deng xiaoping advocated the notion of "science and technology constituting a primary productive force". in the mid- s, when the national high-technology programme ( ) was launched, biotechnology was the main priority. since the mid- s, china has used science and education to improve its international competitiveness, with an increase in expenditure on research and development from · % of gross domestic product (gdp) in to · % in (a period during which the annual rate of growth in gdp reached more than %). at the same time, china set up policies to develop its talent pool in biomedical research, and is ranked fourth internationally in for patents granted and publications in indexed journals. more than % of the government's research and development budget was spent on life science and biotechnology, including health-related domains. while encouraging investigator-initiated projects by augmenting the budget of the national natural science foundation (a fi ve-fold increase over the past decade, rising to · billion renminbi [about £ · billion] in ), china has also launched the national key basic research programme ( ) and established major scientifi c facilities, including synchrotron light-sources and centres for genomics or protein science, drug screening, and biodiversity conservation. by combining resources in human genetics and traditional chinese and western medicine, a comprehensive medical research system has been developed. in addition to the contribution to sequencing of the human genome and the hapmap project, scientists sequenced the genomes of several important species (including rice, chicken, the domesticated silk-moth, and schistosoma japonicum). the molecular pathogenesis of infectious outbreaks, such as severe acute respiratory syndrome (sars) and avian infl uenza, and several chronic diseases has also been analysed. the development of selective diff erentiation or apoptosis induction in acute promyelocytic leukaemia is an example of how functional genomics can promote targeted cancer therapy. china has joined international research eff orts in proteomics and structural genomics. crystal structures of several protein complexes, including mitochondrial respiratory chain complex ii, have been characterised, and the fi rst human proteome catalogue for the liver has been generated. advances in other domains have also been made-eg, the eff ect of lymphoid microenvironments on dendritic cells and signal transduction, such as the involvement of β arrestin in the regulation of g-protein-coupled receptor signalling. biochips have been applied to clinical medicine and food safety. china is the fi rst country to issue approval through the government's regulator (the state food and drug administration [sfda]) for the use of biochips to screen for diseases such as hepatitis c. china approved the world's fi rst gene-therapy product (recombinant human serotype adenovirus, gendicine) for tp tumour suppressor. almost new drugs have either been introduced into the market or are in late-phase clinical trials, such as analogues of artemisinin (a key component in combination therapy for malaria, and recommended by who), and quick-test diagnostic reagents for hiv/aids. especially noteworthy are achievements in vaccines for sars and avian infl uenza, and the establishment of important platforms for antibody studies. in stem-cell research, there have been patents and the setting of standards for animal cloning, generation of human embryonic stem-cell lines, nuclear transfer of somatic cells, somatic stem-cell isolation or characterisation, expansion and directed diff erentiation of stem or progenitor cells, and tissue or organ engineering. for example, the use of mesenchymal stem cells to support haemopoiesis during bone-marrow transplantation is now in clinical trials, and the sfda has recently ratifi ed a certifi cate for a novel artifi cial skin. yet china faces several challenges, including: the need to develop a sound infrastructure for health-care insurance; a lack of eff ective partnership between the academic and industrial sectors; insuffi cient investment in drug research and development; and unsatisfactory support for the oversight of food and drug safety. with the move towards the outlook of scientifi c development and the aim of developing an equitable society, china has placed public health at the top of its agenda, with the aim of health for all by . at present, the country is concentrating on primary health care in rural areas and community medicine in cities. the initial goal is a framework for delivery of health care and an insurance system that will cover most people by , in which governmental funding will take the lead. by the end of , the new rural cooperative medicare scheme, with an % contribution from public coff ers, will cover all million farmers in china. new initiatives to cover all urban citizens have also been launched. to use biomedicine to boost accessibility and equal provision of health care, a strategy of "walking on two legs" has been advocated. this strategy suggests that excellence in cutting-edge technologies should be pursued along with a serve-all approach. in the guidelines on national medium-and long-term program for s&t development ( development ( - , drug innovation and prevention and control of major emerging infectious diseases have been listed as two of mega projects. in line with the notion of predictive, preven tive, personalised, and participatory medicine, disease prevention should be a priority, with importance attached to provision of clean drinking water, environ mental health, natural disasters and disaster prepared ness, large-scale production of good-quality food, drug, and vaccine production and regulation, production of reliable reagents for diagnosis and screening, and devel op ment of an e-health-care system to manage chronic non-communicable diseases. moreover, modern isation of traditional chinese medicine will be strengthened by multicentre clinical trials to evaluate effi cacy, and to implement standardisation and quality control, and also by studying systems biomedicine. china's translational research capacity will be improved by combining its clinical resources and research strength, while creating an environment that considers ethical, legal, and societal input. while encouraging indigenous innovation, china needs to further extend international collaboration through personal exchanges and joint projects. we believe that all these factors will contribute to the improvement of public health in the st century. minister of health, ministry of health, beijing, , china; and rui jin hospital, shanghai, china zchen@stn.sh.cn this comment benefi ted considerably from constructive discussion with zhan qimin, chinese academy of medical sciences. i declare that i have no confl ict of interest. life sciences and biotechnology in china science and technology constitute a primary productive force offi ce of implementing the strategy of developing the country through science and education the international hapmap consortium. a haplotype map of the human genome molecular evolution of the sars coronavirus during the course of the sars epidemic in china highly pathogenic h n infl uenza virus infection in migratory birds acute promyelocytic leukemia: from highly fatal to highly curable crystal structure of mitochondrial respiratory membrane protein complex ii splenic stroma drives mature dendritic cells to diff erentiate into regulatory dendritic cells a nuclear function of beta-arrestin in gpcr signaling: regulation of histone acetylation and gene transcription chinese gene therapy: splicing out the west? full text of hu jintao's report at th party congress. th cpc congress guidelines on national medium-and long-term program for science and technology development key: cord- - slh nbk authors: jacobs, j.w.; peacock, d.b.; corner, b.d.; caul, e.o.; clarke, s.k.r. title: respiratory syncytial and other viruses associated with respiratory disease in infants date: - - journal: lancet doi: . /s - ( ) - sha: doc_id: cord_uid: slh nbk diagnosis by virus isolation and serology was attempted in cases of respiratory-tract infection in infants under one year of age admitted to hospital during two winters. a diagnosis of infection with respiratory syncytial (r.s.) virus was made in %, rhinovirus in · %, adenovirus in · %, parainfluenza in · %, enterovirus in · %, and influenza in · %. r.s.-virus infections were more severe than others and occurred mostly in the first five months of life, with a peak at two months. rhinovirus infections occurred at all ages, and often involved the lower respiratory tract. of the deaths, only (due to r.s. virus) was not associated with a contributory cause. maternal antibody to r.s. virus did not notably affect the incidence or severity of r.s.-virus infections. there have been few intensive studies of respiratoryvirus infections of infants. - to prevent these infections, it is necessary to know which viruses cause the most severe illness and whether maternal antibody plays any part in their prevention. we report here the results of a survey of respiratory-virus infections in infants under one year of age in hospital. all infants under one year of age in southmead hospital and bristol children's hospital who had respiratory infections during a period covering two winters (nov. , , to july , , and sept. , , to april , ) were included. had respiratory infections on admission and developed respiratory infections in hospital. soon after admission (or onset) nose and throat swabs were taken by one of us (j. w. j.) from each infant. the throat swabs were taken with a gagging technique, so that the infants coughed over the swab. at the same time blood was taken from most of the mothers. paired serum samples were obtained from some of the infants with an interval of [ ] [ ] [ ] weeks. one throat swab from each infant was inoculated into bristol hela-cell tissue cultures at the bedside, and was examined thereafter in the university of bristol department of bacteriology. a second throat swab and the nose swab were put together into % milk-saline transport medium and inoculated in the public health laboratory into hela cells and primary monkey-kidney tissue culture within minutes. they were also inoculated (often after storage at &mdash; &deg;c, and if not already yielding a virus) into human embryo kidney and wi- human embryo fibroblast tissue cultures and into suckling mice. the methods used have already been described. , serology sera were tested by complement fixation (c.f.) against respiratory syncytial (r.s.) virus antigen but not against other viruses. the methods of preparing the antigen and conducting the test have already been described. , e this was graded retrospectively according to a scheme developed during the survey. signs in order of severity were: ( ) upper-respiratory-tract infection. ( ) specific treatment (excluding nasal drops but including humidified air, physiotherapy, or antibiotics) or temperature > - c. ( ) chest signs found by radiography, auscultation, or aspiration for less than three days. ( ) chest signs for three days or more unless the patient died. ( ) oxygen therapy for one or more days, or respiration-rate or more per minute, or peripheral cyanosis. ( ) digoxin therapy or heart-rate of or more per minute. ( ) additional treatment (cortisone, intubation, or tracheostomy). ( ) death. the grade was the most severe sign the patient showed, providing that all the less severe signs were also present. for example, an infant showing signs , , , and was said to have a severity grade of . in practice it was rare for an infant not to show an intermediate sign. in cases routine bacteriological examination was undertaken. staphylococcus aureus was isolated from %, and streptococcus pneumoniae from %. several &bgr;-haemolytic streptococci were isolated, but none were group a. haemophilus influen. was isolated from ( %), in of which r.s. virus infection was also diagnosed. twenty of the infants were admitted with respiratory infections twice, and two were admitted three times. from one infant, two different m rhino viruses were isolated-type b at the age of two months and type at the age of ten months. one infant, a premature baby, was admitted seven times over a period of four months (table ). different viruses were isolated. there was no evidence of hypogammaglobulinsemia. the infant's twin sister was in hospital once with a chest infection due to r.s. virus at the same time as her sister's first admission. subsequent infections of the twin were less severe and frequent, and she was not readmitted. fold or greater rise in titre between acute and convalescent specimens, or a change from passive maternal (secondary) type of antibody to an active (primary) type of antibody in a chequerboard c.f. test with a potent antigen. of the fifty-four infants in whom r.s.-virus infection was diagnosed and both isolation and serology attempted, the diagnosis was made in twenty-four by serology alone (nineteen infants showed a fourfold rise and five a change from secondary to primary antibody), six by isolation alone, and in twenty-four by both methods (twenty-two showed a fourfold rise and two a change from secondary to primary antibody). r.s. virus was isolated more frequently from throat swabs inoculated direct into tissue culture at the cotside ( / ) than from swabs put into transport medium and inoculated within ninety minutes ( / isolates). r.s. virus was isolated more frequently from specimens taken three to six days after the onset of the illness ( % of specimens) than from those taken before three days ( % of specimens) or after six days ( % of specimens) from onset. age table i shows virus infections diagnosed in infants of different ages. two-thirds of the specimens came from infants under six months of age. the rate of virus diagnosis was higher under six months of age, with a peak at three months. this was because most infections were caused by r.s. virus, and the peak for this virus was in the age range one to five months. parainfluenza and influenza viruses were found only over four months of age; and rhino viruses, enteroviruses, and adenoviruses were found at all ages. the viruses recognised in the first month of life were r.s. ( ), rhinovirus m, and coxsackie b . of the respiratory infections, ( %) were in boys and ( %) in girls (p< - ). there was no significant difference between the two sexes in the severity of the illness either in all the infants, or in those in whom r.s.-virus infections were diagnosed. rhinoviruses were often associated with lower-respiratory-tract illnesses. an eight-month-old boy was admitted with a ten-day history of wheezing getting worse two days before admission. coarse crepitations in right and left lower lobes. intercostal recession. pneumonia confirmed radiologically. chest signs persisted four days. respiration and heart rates up to and per minute. temperature up to more than - &deg;c. oxygen and cortisone given. discharged after ten days. nose and throat swabs taken on the second day in hospital yielded rhinovirus h. there was no evidence of r.s.-virus infection by either serology or isolation. no bacteria implicated. enteroviruses also were often associated with lowerrespiratory-tract illness. a four-month-old girl was admitted with a three-day history of worsening coryza. inspiratory wheeze and coarse rales. bronchopneumonia confirmed radiologically. no fever. respiration and heart rates up to and per minute, respectively. liver enlarged. cyanosis. chest signs lasted two days. discharged after nine days. echo- virus isolated from swabs taken on the second day in hospital. there was no evidence of infection with r.s. virus by serology or isolation. no bacteria implicated. the grade of severity was calculated for all illnesses in which definite viruses were implicated and in others (table iv). infants with r.s.-virus infection were more severely ill than other infants. illnesses due to rhinoviruses were of moderate severity. the small numbers of parainfluenza, influenza, and enterovirus infections were mild. there was a contributory cause of death in eleven; ten had congenital defects and one had gastroenteritis due to escherichia coli . the remaining infant was first admitted aged four months with severe bronchiolitis. discharged after twenty-five days, but readmitted two days later with bronchopneumonia. coarse rales in upper anterior chest and right axilla. temperature slightly raised. respiration and heart rates up to and per minute, respectively. no viruses or other organisms were implicated during the first admission, but the throat swab taken on the day of second admission yielded r.s. virus. no other organisms implicated. died three days after admission. at necropsy, muco-pus in larynx, trachea, and bronchi. generalised congestion of lungs. normal aeration in only a few small peripheral areas. the microscopical appearance resembled hyaline-membrane disease of newborn. no other abnormalities. in our hands the c.f. test was a more sensitive method than isolation for diagnosis of r.s.-virus infections in the infants where both methods were attempted. r.s.-virus infections were diagnosed by demonstrating a change from passive to active antibodies, for which it is necessary to do a cumbersome chequerboard titration, but most showed straightforward rises in titre when a large amount of antigen was used in the c.f. test. berglund and strahhnann conclude that isolation is better than serology. much will depend on the potency of the c.f. antigen, the number of antigen units used, and the time of taking the convalescent serum ; and the sensitivity of the cell line used for isolation and the timing of inoculation are also important. other respiratory pathogens the diagnosis-rate for all respiratory pathogens of % might have been higher if paired sera had been obtained from all the infants, and if serology for viruses other than r.s. virus had been performed. we did not look for mycoplasma pneumoniae & o a c u t e ; or coronaviruses or cytomegaloviruses, all of which are known to cause respiratory infections, especially cytomegalovirus in the first year of life. there is no convincing evidence that the bacteria we isolated (staph. aureus, str. pneumoniae, and hcemophilus infiuenzae) are a frequent primary cause of respiratory illness in infants. all are common in healthy infants. thiese were found on occasions. in double infections an adenovirus was isolated, but here the second virus (r.s. and influenza) probably caused the illness, the adenovirus being carried in the tonsils. the findngs in one patient (table ) support this. are subclinical. however, when one of these viruses is isolated from a child with a respiratory infection, it is probable that it is the cause of the illness. it is even more probable that illnesses associated with r.s. and parainfluenza viruses are due to these viruses. type of illness we found that rhinoviruses often produced a severe lower-respiratory-tract illness, as did hamparian et al. the finding of lower-respiratory-tract illness in association with echo virus is interesting in view of similar associations described by berkovich and smithwick. of the twelve infants who died with respiratory infections, eleven had a contributory cause of death. it seems, therefore, that respiratory viruses are not frequent killers of otherwise healthy infants in bristol. in newcastle only a quarter of infants who died with respiratory infections had congenital defects. r it seems that viruses, especially r.s. virus, are more important as a cause of severe illness and death among infants in newcastle than among infants in bristol. there may be socioeconomic reasons for this. in this survey, as in others, r.s. virus was the commonest cause of respiratory illness requiring admission at this age ( &deg; ), and the illnesses were more severe than those associated with other viruses (table iv). rhinoviruses were the next most important ( %) and often caused severe illnesses. in this age-group, adenoviruses, influenza, and parainfluenza viruses were relatively unimportant. this is supported by work with respiratory viruses in the bristol public health laboratory over the past nine years (unpublished). we found a heightened susceptibility of males to respiratory infections, previously noted by moss et al. effect of maternal antibody the few parainfluenza virus infections observed in this survey occurred only in infants more than four months of age. over the past nine years in the bristol public health laboratory, among large numbers of parainfluenza viruses isolated, parainfluenza types , , and have only occasionally been isolated from infants under four months of age, and type never. this is not a new observation, and there is evidence that maternal antibody protects against these viruses. our experience with influenza virus is similar, and in this survey there were no influenza virus infections below the age of four months. maternal antibodies probably played their role here also. on the other hand, rhinovirus infections were detected from a very early age, and this is to be expected because mothers would not have antibodies against all rhinovirus types at the time of delivery. indeed maternal antibody may protect against infections with this group of viruses. the position with regard to r.s.-virus infections is less clear-cut. for instance it is widely accepted that the majority of severe infections occur in the first three months of life. in our series the peak of incidence was at two months, and infections have been recorded as early as ten days after birth. there is no multiplicity of antigenic types to account for this early incidence as there is for rhinoviruses. on the other hand, the incidence of antibodies to r.s. virus in the adult population-and by implication exposure to r.s. virus-is very high. one would expect, therefore, the epidemiological features of this infection in infants to resemble influenza more closely than the common cold. the series we investigated may have been a selected group, in that for some reason we saw principally infants of mothers who lacked antibodies to r.s. virus. unfortunately a retrospective survey such as this cannot distinguish between maternal-antibody levels present before birth and those acquired at the time of, or just before, the infant's illness; and it is far more likely that the mother of an infected baby has just had an antigenic stimulus from the same virus. the high levels of antibody we observed in mothers of infected infants are thus meaningless in terms of protection afforded to the population studied. the vaccination studies carried out by some american workers, using killed virus vaccines - have often been quoted in support of the idea that antibody to r.s. virus actually increases the severity of a subsequent infection. however, other types of r.s.-virus vaccines prepared differently may not have the same effect. , ! neither is there any concrete evidence in table vil to support the hypothesis of antibody potentiation, for although at two months of age the geometric mean titre of antibody is higher in the group with r.s.-virus infections, as is the percentage of acute sera with antibody present, this trend is reversed at one month of age. similarly there is no correlation between high antibody titre and mean severity grade. although the numbers are extremely small, there was evidence in table v that in the first month of life infants had less severe r.s. infections than older infants. this could be taken as evidence that maternal antibody may actually have a protective effect. chanock et al. found that the titre of r.s.-neutralising antibody was two times lower in the acute sera of infants with r.s. infections than in those without, and suggests that antibody-antigen complexes in the lung may lead to depletion of antibody in the serum. gardner et al. present persuasive evidence in support of the postulate that the development of immediate hypersensitivity plays a dominant role in the pathogenesis of acute bronchiolitis in r.s. infections. however, they favour the idea of a gell and coombs type-i hypersensitivity response, and to sustain this argument they postulate a previous exposure to r.s.virus antigen. again we find no evidence to support this hypothesis, since, where antibody was detected in the acute-phase sera, it behaved like adult antibody in the c.f. test and was thus, presumably, maternal in origin. we thank the other clinicians for permission to study the infants under their care and dr. m. . roebuck for typing the rhinoviruses. financial support for one of us (j. w. j.) by the medical research council is gratefully acknowledged. requests for reprints should be addressed to j. w. j., department of pathology, royal veterinary college, royal college street, london n.w.i. one of the major problems in clinical organ transplantation is the detection and reversal of rejection episodes. centres differ in their methods of overcoming such episodes, but most administer an increased dose of oral steroids. - actinomycin c, - , antilymphocyte globulin and local graft irradiation , , have been used to the same end. at the start of our clinical renal-transplant programme we decided to use prednisolone given as a single g. intravenous dose over a period of hours for the treatment of acute rejection crises. this decision was made for several reasons. firstly, prednisolone at this dose level is lympholytic and has a short half-life of - minutes, , giving maximum lymphocyte damage with relatively little in the way of chronic side-effects. secondly, we were impressed by the results published by kountz and cohn, who used large doses of intra-arterial steroids, but we felt that this method was potentially dangerous and, perhaps, unnecessary. thirdly, we hoped to avoid the high oral doses of steroids normally used to control rejection and thereby avoid serious complications in the first few months after transplantation. the ability of a high dose of intravenous prednisolone to reverse acute rejection episodes was also investigated using the heterotopic rat-heart-transplant model. we present here the clinical and experimental results of this type of antirejection treatment. sixteen patients were transplanted over a -month period. three patients received kidneys from sibling medical research council working party on acute respiratory virus infections. ibid. , ii acta p&oelig;diat. scand "... we need to concentrate less on the reduction of infant mortality as a goal in itself than on assuring that children who survive are whole and healthy; and that it is fallacious to argue about whether the quality of medical care or the child's environment is the more important factor in relation to infant mortality. these cannot be separated. no matter how good the medical care system is, mortality rates cannot be lowered below a certain point unless certain changes are made in the social environment. the ability of single large ( g.) doses of intravenous prednisolone to reverse rejection episodes has been investigated clinically and experimentally. sixteen renal-transplant recipients have been treated in this way. the oral dose of prednisone was not increased during these episodes and no additional treatment was given. this therapy reversed % of rejection crises without any toxic effects. one patient has died from infection, month after transplantation. using the heterotopic rat-heart-transplant model the ability of intravenous prednisolone, antilymphocyte serum (a.l.s.), intraperitoneal prednisolone, and azathioprine to reverse rejection in recipients immunosuppressed with a single dose of a.l.s. at the time of transplantation were compared. intravenous prednisolone was the only successful agent and prolonged survival by &plusmn; days. key: cord- -hmfd xws authors: stein, h.; sperling, m.; dienemann, d.; zeitz, m.; riecken, e.-o. title: identification of a t cell lymphoma category derived from intestinal-mucosa-associated t cells date: - - journal: lancet doi: . /s - ( ) - sha: doc_id: cord_uid: hmfd xws cases of precursor t cell lymphoma and cases of peripheral t cell lymphoma were investigated for their reactivity with the monoclonal antibody (mab) hml- , which recognises human intestinal t lymphocytes but not lymph-node t cells. in all but one of the lymphomas studied, the tumour cells were unreactive with the mab hml- . the hml- (+) lymphoma was the only tumour that was primarily localised in the epithelium and lamina propria of the small intestine, and was associated with ulcerative jejunitis and coeliac disease. this result suggests that the hml- (+) lymphoma was derived from intestinal mucosa t lymphocytes and differs from precursor t cell lymphoblastic lymphomas and nodal and cutaneous peripheral t cell lymphomas. several groups have suggestedl- that the intestinal mucosa contains t cells that differ from those present in lymph nodes. this suggestion has been confirmed by generation of a monoclonal antibody (mab), designated hml- , that reacts with nearly all intraepithelial t cells and % of the lamina propria t cells of the intestine but with only occasional cells in lymph nodes, tonsils, blood, or skin. if the mucosa-associated t cells give rise to lymphomas, these should be identifiable with the mab hml- . to test this hypothesis, we investigated t cell (macrophage-specific) produced in our own laboratory. these antibodies were applied to acetone-fixed frozen sections. their binding was displayed by the apaap method,' slightly modified.s in addition, each case was histologically classified according to the updated kiel classification. case-report of pleomorphic t cell lymphoma of the jejunum a -year-old man presented with a -year history of weight loss ( kg) and diarrhoea. a biopsy revealed total villous atrophy. his severe malabsorption syndrome did not improve on a strict gluten-free diet, and laparotomy revealed a cm segment of thickened jejunum with enlarged mesenteric lymph nodes. when opened, the cm of resected jejunum showed some ulcers and multiple tumour nodules. postoperative healing was uncomplicated gray/week had to be abandoned after the fifth session because of a sharp deterioration of the patient's general condition. thereafter, staphylococcal sepsis developed, and he died of cardiovascular 'failure six months after first admission. tumour cells from all t cell lymphomas were unreactive with antibodies for b cells and macrophages. the tumour cells were positive for one or more t cell antigens. only one t cell lymphoma, that from the patient with jejunal tumour, reacted with hml- (table and figs and ). this lymphoma of pleomorphic t cell type was confined to the jejunum, growing mainly in the lamina propria and the epithelial layer. it was associated with ulcerative jejunitis and complete villous atrophy. discussion the findings in the case of jejunal lymphoma suggest that this tumour was derived from intestinal mucosa t lymphocytes. this conclusion is in keeping with the primary localisation of this lymphoma in the lamina propria of the jejunum and the spread of the hml- + tumour cells within the intestinal epithelium and the expression of cd and cd in the absence of cd , since the majority of intraepithelial t cells also carry cd and cd on their surface. the negative reaction of all other t cell lymphomas, including those with primary involvement of lymph nodes, skin, mediastinum, and stomach, indicates that the specificity of the mab hml- for intestinal mucosa t cells holds true for cells that have undergone malignant transformation. the hml- + t cell lymphoma is of particular interest because it was associated with ulcerative jejunitis and coeliac disease. malignant lymphomas occurring in association with ulcerative jejunitis and coeliac disease were first recognised in . in , isaacson and wrightll, reported evidence that this lymphoma is of a single histogenetic type. these workers regarded the lymphoma as a special form of malignant histiocytosis, because it met the criteria for a diagnosis of malignant histiocytosis and immunological analysis seemed to confirm the histiocytic properties of the malignant cells. in a joint immunohistological and genotype study in , when a wide range of mabs and a t cell receptor-specific dna probe were available, the t cell nature of this lymphoma was demonstrated. at the first meeting of the european society for haematopathology (april , ) isaacson reported another case of intestinal t cell lymphoma associated with coeliac disease that was reactive with the hml- antibody. it therefore seems possible that all t cell lymphomas of the small intestine that arise in coeliac disease will react with the mab hml- . might there be gastrointestinal tract t cell lymphomas that are not associated with coeliac disease, but express the antigen specific for intestinal mucosa t cells? to answer this question, a larger series of primary gastrointestinal lymphomas should be studied with the hml- antibody. whatever the results, it is already clear that hml- + primary intestinal t cell lymphomas should be included in classification schemes as a unique entity. this was a difficult book to review: on the one hand it offers fascinating analysis of clinical decision making; on the other it strays frequently into unnecessarily complex mathematical analysis. the latter feature is so off-putting that i found it almost impossible to finish a single chapter completely. the really annoying thing is that many of the formulae express quite simple concepts, and to un-numerate clinicians figures like this can be a real deterrent. the authors do say in their preface that they are also aiming at computer-equipped statistically minded doctors. there are many excellent aspects; it does a clinician good to stop to question how history-taking leads to differential diagnosis, how test results are weighed, how treatments are decided, and how outcome is measured. two particularly important subjects are presented in considerable depth. the first is bayes' theorem, by which the effects of a given test result on the probability of disease can be mathematically calculated. this leads not only to critical evaluation of the power of a test (based on its sensitivity and specificity) but also to the decision on whether to use it at all-there is no point if the diagnosis is already highly probable and the test is of low predictive value. the second important subject is decision making; here the authors use algorithms to show how a clinical decision can be reached with optimum results to the patient. each algorithm includes chance nodes (points in the decision tree where chance decides the next path), and decision nodes (points where there are choices for the clinician). at each node probabilities of outcome are quoted the mouse gut t lymphocyte, a novel type of t cell. nature, origin, and traffic m mice in normal and graft-versus-host conditions lymphocyte subpopulations in the human small intestine the findings in normal mucosa and in the mucosa of patients with adult coeliac disease intraepithelial leukocytes contain a unique subpopulation of nk-like cytotoxic cells active in the defense of gut epithelium to enteric murine coronavirus a monoclonal antibody specific for rat intestinal lymphocytes weissman il lymphocyte homing receptors a monoclonal antibody (hml- ) defining a novel membrane molecule present on human intestinal lymphocytes immunoenzymatic labeling of monoclonal antibodies using immune complexes of alkaline phosphatase and monoclonal anti-alkaline phosphatase (apaap complexes) use of freeze-dried paraffin-embedded sections for immunologic staining with monoclonal antibodies updated keil classification for lymphomas clinical and biochemical syndrome in lymphadenoma and allied diseases involving mesenteric lymph glands malignant histiocytosis of the intestine: its relationship to malabsorption and ulcerative jejunitis malignant histiocytosis of the intestine a t cell lymphoma we thank mr b. young for help with preparation of the text. key: cord- -be ap authors: su, lin lin; chan, jerry; chong, yap seng; choolani, mahesh; biswas, arijit; yong, el title: pregnancy and h n infection date: - - journal: lancet doi: . /s - ( ) - sha: doc_id: cord_uid: be ap nan these observations suggest that antivirals ought to be used to prevent and treat h n infection in highrisk pregnant women. indeed, the us centers for disease control and pre vention recommend chemoprophyl axis with either oseltamivir or zanamivir against h n infl uenza for people at risk of complications, including pregnant women. however, a survey has shown that oseltamivir has important side-eff ects (including gastrointestinal and neuropsychiatric symptoms) in more than half of treated children, raising serious questions about the wide use of this compound, not only in children, but also in pregnancy. this side-eff ect profi le, together with the detection of oseltamivirresis tant strains, suggests that novel safe com pounds are necessary for the treatment of h n infection in pregnan cy. two human anti-infl uenza a h n monoclonal anti bodies (hmabs) have been cloned, and their h n -neu tral ising potential has been assessed against highly pathogenic avian strains, indicating that powerful and safe treatment of infl uenza h n infections with hmabs is possible. from this point of view, a strategy for the treatment and prevention of h n infection in pregnancy based on neutralising human monoclonal antibodies should be planned in the future, being also aware of the effi cient protection of the fetus by circulating iggs. we declare that we have no confl icts of interest. denise jamieson and colleagues highlight high morbidity and mortality rates in pregnant women infected with the h n infl uenza virus. admission rates were % and the median time from symptom onset to receipt of antiviral therapy was days. could earlier initiation of antiviral treatment have resulted in a better outcome? in , singapore was notably aff ected by severe acute respiratory syndrome (sars), which led to the formation of a rapid response team, hospital quarantine, infect ious disease control measures, temperature screening at borders and in public buildings and spaces, timely public education, and constant communication with the public. , in response to the centers for disease control and prevention's advice on poorer outcomes in h n -aff ected pregnant women on may , , the above sars strategies, coupled with rapid access to quantitative reverse-transcriptase pcr within h of presentation and early institution of antiviral therapy, was started from june , , in singapore. between july and aug , , pregnant women were diagnosed with h n at the national university hospital in singapore. the time from symptom onset to initiation of oseltamivir treatment was a median of days. three women were admitted for observation, and one developed pneumonia; initiation of treatment was days after symptom onset in this woman. no deaths have been reported nationwide in pregnant women thus far. our experience suggests that timely medical attention with early recourse to antiviral therapy is associated with a better outcome in h n -aff ected pregnant women. infl uenza virus infection during pregnancy in the usa acute respiratory distress syndrome in critically ill patients with severe acute respiratory syndrome crisis prevention and management during sars outbreak public health measures implemented during the sars outbreak in singapore we declare that we have no confl icts of interest. department of obstetrics and gynaecology, national university singapore, lower kent ridge road, singapore , singapore we agree with roberto burioni and colleagues that novel treatment approaches for infl uenza virus infection such as use of antiinfl uenza monoclonal antibodies might hold promise and are certainly worth pursuing. however, most investigations have used animals, and treatment in human beings has mainly focused on the most severe cases. treatment with anti-infl uenza virus antibodies has not yet been shown safe and eff ective for use in non-pregnant people. it will probably be even longer before such treatment options would be considered for pregnant women since additional istockphoto the printed journal includes an image merely for illustration key: cord- -rwf bly authors: sutrisna, b.; frerichs, r.r.; reingold, a.l. title: randomised, controlled trial of effectiveness of ampicillin in mild acute respiratory infections in indonesian children date: - - journal: lancet doi: . / - ( ) -y sha: doc_id: cord_uid: rwf bly the recommended treatment for mild acute respiratory infections (ari) in children is supportive care only, but many physicians, especially in developing countries, continue to prescribe antibiotic treatment because they believe it prevents progression to more severe ari. to find out whether ampicillin treatment conferred any benefit over supportive care alone, a randomised, controlled trial was carried out among children (under years) with mild ari in indonesia. were randomly allocated ampicillin ( - mg/kg body weight three times daily for days) plus supportive care (continued breastfeeding, clearing of the nose, and paracetamol to control fever); were allocated supportive care only. the treatment groups were almost identical after randomisation in terms of age, sex, level of parental education, history of measles immunisation, and fever. after week the percentages cured were nearly identical ( [ %] ampicillin; [ %] control), as were the percentages of cases progressing to moderate ari ( [ %] vs [ %]). the effect of treatment was not modified by age, sex, measles immunisation status, or the educational level of the parents. at the -week follow-up, the percentages cured were % ( ) in the ampicillin group and % ( ) in the control group; % of both groups had progressed to moderate ari; and % ( ) and % ( ), respectively, still had mild ari. none of the differences in outcome between the ampicillin and control groups was statistically significant. thus, ampicillin plus supportive care offers no benefit over supportive care alone for treatment of mild ari in young indonesian children. the findings obtained in necropsy studies. information collated from five independent necropsy studies indicated that mean prostate weight reaches g in men between the ages of and years and remains essentially constant at this weight with increasing age unless bph develops. o table ii summarises the prevalence rates of bph and prostatic weights of patients with bph in the survey in comparison with necropsy findings among men in similar age-groups with histologically confirmed bph. a surprising finding is that prostatic weights from these two sources are remarkably similar despite the differences in self-selection betwen the community survey and necropsy sources, the absence of prior knowledge of urinary dysfunction in the necropsy cases, and the absence of pathological confirmation of the diagnosis in the community survey. what is also of interest are the higher age-specific rates for bph in the necropsy than in the community survey. this difference suggests that a substantial reservoir of bph may exist below the "threshold" of signs and symptoms of urinary dysfunction that were used in the survey. the operational defmition adopted for this survey will probably change over time as knowledge of the natural history of bph increases, in the way that perception of what level of blood pressure constitutes hypertension has changed over the past several decades. whether the total urinary symptom score and qmax cut-off points used are ideal for enabling early cases of bph to be picked up through screening cannot be established from this survey. this issue can be determined only in a study that sets out to assess prostate size in a representative sample of men who have not been selected on the basis of their likelihood of having bph. the validity of symptom scores and voiding flow rate as preliminary screening criteria will eventually be required for identifying those men most likely to benefit from treatment should non-surgical therapy for bph be shown to be effective in the community. the recommended treatment for mild acute respiratory infections (ari) in children is supportive care only, but many physicians, especially in developing countries, continue to prescribe antibiotic treatment because they believe it prevents progression to more severe ari. to find out whether ampicillin treatment conferred any benefit over supportive care alone, a randomised, controlled trial was carried out among children (under years) with mild ari in indonesia. were randomly allocated ampicillin ( - mg/kg body weight three times daily for days) plus supportive care (continued breastfeeding, clearing of the nose, and paracetamol to control fever); were allocated supportive care only. the treatment groups were may start in the upper respiratory tract and progress to a more severe lower respiratory infection, such as pneumonia or bronchiolitis.l in less developed countries, pneumonia is a major cause of death in young children - antibiotics such as procaine penicillin, ampicillin, or co-trimoxazole are useful for treatment of pneumonia , , which is most commonly caused by bacterial agents, mainly streptococcus pneumoniae and haemophilus influenzae. , , , antibiotics are not recommended for treatment of upper respiratory infections which are believed to be caused mainly by viruses, most likely rhinoviruses and coronaviruses. the world health organisation (who) has promoted case-management as the appropriate approach to control of ari in children. , part of this recommendation is that supportive care by the mother rather than antibiotics be used to treat mild ari. inappropriate treatment of mild ari in developing countries wastes the resources of government-sponsored health services and is believed to increase the occurrence of drug-resistant bacterial strains in the population." when the who case-management programme was introduced in indonesia, many physicians were reluctant to stop giving antibiotics to children with mild ari, because they believed that antibiotic treatment prevents the progression of mild ari to moderate or severe ari. this belief is not supported by any objective evidence. we decided to test the effectiveness of antibiotics for treatment of mild ari in indonesian children. we now present the results from a randomised, controlled comparison of supportive care alone and ampicillin plus supportive care as treatment for mild ari in children under years of age. we chose ampicillin on the basis of our earlier findings that % of indonesian physicians who treated mild ari with antibiotics used ampicillin (unpublished). subjects and methods children under years of age with mild ari, who attended government health clinics in two regions of east jakarta, indonesia, were included in the trial. mild ari was defined by who criteria: mild upper respiratory signs such as cough or runny nose, and/or fever ( > &deg;c), and breathing at a rate less than breaths per minute. we excluded children with asthma or infections that required antibiotics, those who did not live in a defined service area, and those who had recently been treated by medical personnel in other locations. parental consent was obtained for all eligible children. through random allocation, children were offered ampicillin powder and supportive care and were offered only supportive care. parents in both groups were advised to provide supportive care at home including continuation of breastfeeding, clearing of the nose as needed, and control of mild fever by means of paracetamol, an inexpensive analgesic and antipyretic drug ( mg/kg body weight daily; doses per day for days). in addition to the supportive care, children in the ampicillin group received ampicillin powder (age-dependent treatment packets of - mg/kg body weight per dose every h [except midnight] for days). parents were asked to bring their child back to the health centre after days. home visits were made by nurses or midwives within days to children who did not appear at the clinic on the scheduled day. based on the clinic or home examination the health status was classified as: cured or recovered; static (no change); worse (moderate or severe ari); or dead. moderate and severe ari were defined according to who and ministry of health criteria. moderate ari was diagnosed if there was a respiratory rate greater than breaths per minute but no chest indrawing, and severe ari if the child had a respiratory rate greater than breaths per minute and chest indrawing, with or without cyanosis. children not cured after week were either referred to the health clinic for further medical care or sent home with instructions for additional supportive care. all children ( ampicillin, control) had stopped taking ampicillin or paracetamol because of side-effects (diarrhoea in [ ampicillin, control] and an allergic reaction in [control]). statistical analyses were done by means of 'epi info' and 'epi log plus', two microcomputer-based statistical analysis programs for epidemiology. these included standard chi-square tests (two sided) and confidence intervals for risk ratios (taylor series % confidence limits). the randomisation procedure successfully achieved two nearly identical groups in terms of the potential confounding variables of age, sex, level of parental education, history of measles immunisation, or fever at the time of enrolment (table ). after week, the percentages of children who were cured, still had mild ari, or had progressed to moderate ari in the two groups were almost identical (table n). there was no significant difference in the course of the disease between the ampicillin-treated and control groups at either -week follow-up (&khgr; = . , df; p= - ) or -week follow-up (x = - , df; p = - ) (table ii). after week the percentage cured was similar at all ages, in both sexes, at various education levels for fathers and mothers, and by measles immunisation status (table iii) . ampicillin appeared beneficial only among a few subgroups, but in each case the % confidence intervals included - , so the risk ratios are more likely to reflect variation inherent in the sampling process rather than a real benefit of ampicillin. the percentage of cases of mild ari that progressed to moderate ari at the -week follow-up was also similar in the various subgroups (table iv). in some subgroups the control cases were more likely to progress, whereas in others the ampicillin-treated cases were more likely to become worse. the width of the confidence intervals makes it unlikely that any of the group-specific values are truly different. after weeks, % of ampicillin-treated and % of control children still showed signs of mild ari (table ii) . % in each group had progressed to moderate ari and were referred to the health clinic for additional care. the remaining % of controls and % of ampicillin-treated children were cured of ari, and nearly three-quarters of them had recovered during the first week. the randomisation process in our study effectively created two groups with the same inherent risk of ari outcome independent of treatment. thus, we were able to assess the unconfounded effect of ampicillin plus supportive care compared with supportive care alone on mild ari. we conclude that there is no beneficial effect of ampicillin on the clinical course of mild acute respiratory infections among young indonesian children. for children breathing less than times per minute and showing minor signs such as a cough or runny nose, addition of ampicillin to simple supportive care supplemented with paracetamol conferred no benefit. since mild ari is primarily or entirely caused by viruses, our finding that ampicillin is of no benefit for such illnesses is hardly surprising, and readers might wonder why we undertook this study. in our previous work on ari in indonesia (unpublished), we observed that many children with mild ari were being treated with ampicillin by physicians at government clinics despite the ministry of health guidelines (which accord with who recommendations) that only supportive care is required. in our discussions with physicians, it became clear that many believed antibiotics were effective at preventing the progression of mild ari to pneumonia or other forms of severe ari, which are frequently bacterial in origin. when challenged to present data refuting this notion, we were unable to find support in the indonesian medical or public health literature. thus, we felt it necessary to assess in indonesia the effect of antimicrobial therapy on progression of mild ari to more severe forms. clinical studies of antibiotic effectiveness have been carried out in other nearby' countries-for example, thailand and australia. , these studies of children with upper (or mild) respiratory infections showed no therapeutic value for ampicillin, erythromycin, penicillin, or tetracycline. although our data clearly show that the use of ampicillin for mild ari had no beneficial effect, what is not evident is the potential harmful effects of inappropriate antibiotic use. first, ampicillin used for mild ari will not be available to treat moderate or severe ari. if there is a limited supply of antibiotics, as is the case in many government health clinics, the resultant shortage could lead to the use of less effective treatment and higher case-fatality for moderate and severe ari. even if antibiotics are widely available, use of ineffective treatment for many mild ari cases will substantially reduce the cost-effectiveness of ari treatments in general. second streptomyces, and arthrobacter genera, and more weakly related to mycobacteria. the biopsy specimen was estimated to contain around cells of the organism. the probable aetiological agent for our patient's illness has not been identified previously in a patient with whipple's disease. whipple's disease is a systemic infection associated with a small, largely intracellular bacillus of uncertain identity. the nature of the whipple's bacillus has not been established because efforts to culture the organism have been unsuccessful. we report the results of sequencing the ribosomal dna of the predominant bacterium associated with a biopsy taken from the small bowel of a woman with whipple's disease. comparison of s rrna sequences is a powerful approach to phylogenetic analysis, and had led to a new phylogenetic tree of all life forms. it was thus possible to place the whipple's-associated bacterial organism (wabo) phylogenetically by comparing its s rrna sequence with known sequences. a -year-old woman presented with a -year history of diarrhoea, a kg weight loss, and iron-deficiency anaemia. she complained of abdominal distension, arthralgia, fatigue, and myalgia. on physical examination the patient was cachectic with a distended abdomen and thickening of the metacarpals and wrists. x-ray examination of the small bowel suggested malabsorption, and an abdominal computed tomography scan revealed paracaval and periaortic lymphadenopathy. upper gastrointestinal endoscopy showed a bowel mucosa with a granular infiltrated pattern. histologically, the small bowel lamina propria was expanded by foamy macrophages and had prominent lymphatic dilatation. material in the macrophages stained periodic acid-shiff-positive and did not contain acid-fast organisms. electron microscopy showed large numbers of intracellular and extracellular bacilli characteristic of those found in whipple's disease. after informed consent, an endoscopic biopsy specimen of the proximal small bowel was taken and frozen rapidly in dry ice-ethanol. nucleic acids extracted from the biopsy specimen were amplified in a polymerase chain reaction (pcr) for cycles. the pcr primers were designed to amplify specifically a -base segment of bacterial s rdna (identical to an organism's rrna sequence). the resulting pcr product was sequenced directly. a computer search of the genbank and embi databases was done to find the rrna sequences most similar to the one we had isolated, and all sequences were aligned. the alignment was used to find a site at which the sequence of the wabo differed from the detailed diagnosis and procedures, national hospital discharge survey some clinical aspects of uroflowmetry in elderly males. a population study the development of benign prostatic hyperplasia among volunteers in the normative aging study are doctors able to assess prostatic size symptom status and quality of life following prostatectomy a technical and clinical evaluation of the disa uroflowmeter a simple uroflowmeter tester reproducibility of uroflowmetry variables in elderly males transabdominal ultrasound in the evaluation of prostate size the development of human benign prostatic hyperplasia with age natural history of benign prostatic hypertrophy acute respiratory infections in the developing world: strategies for prevention, treatment and control validation of postmortem interviews to ascertain selected causes of death in children acute lower respiratory infections: a major cause of death in children in bangladesh acute respiratory infections are the leading cause of death in children in developing countries antimicrobial susceptibility patterns of haemophilus isolates from children in eleven developing nations trial of co-trimoxazole versus procaine penicillin with ampicillin in treatment of community-acquired pneumonia in young gambian children world health organisation. clinical management of acute respiratory infections in children: a who memorandium aetiology of pneumonia in children in goroka hospital world health organisation. guidelines for research on acute respiratory infections: memorandum from a who meeting world health organisation. a program for controlling acute respiratory infections in children: memorandum from a who meeting report of a symposium on use and abuse of antibiotics worldwide epi info, version : a word processing, database, and statistics program for epidemiology on microcomputers epi log plus, statistical package for epidemiology and clinical trials ministry of health. health worker manual for ari case management and diarrhea among children under five communicable disease control and environmental health the value of antibiotics in minor respiratory illness in children-a controlled trial evaluation of orally administered antibiotics for treatment of upper respiratory infections in thai children we thank the consultant urologists and other staff of stirling royal infirmary, the general practitioners and their staff at bridge of allan health centre, the forth valley general practitioner research group, and all other members of the bph natural history study group for their advice, cooperation, and support. funding for this work was provided by merck, sharp & dohme. key: cord- -ek rp kh authors: caul, e.o.; ashley, c.r.; clarke, s.k.r.; egglestone, s.i. title: coronavirus-like particles in diarrhoea stools date: - - journal: lancet doi: . /s - ( ) -x sha: doc_id: cord_uid: ek rp kh nan s:r,&mdash;dr dourmashkin and colleagues (nov. i, p. ) report that they have seen pleomorphic coronavirus-like particles in a specimen of human faeces and postulate that these may have derived from an intestinal yeast-like organism and suggest blastocystis (now believed to be a protozoon ). [ ] [ ] [ ] [ ] we have described coronavirus-like particles in human faeces. these are quite different from the cellular material with ill-defined fringes which is commonly present in human faecal material. to date one strain of the coronavirus-like particle has been shown to replicate in cell and organ culture systems producing ultrastructural changes which are indistinguishable from those produced by a bovine coronavirus in a similar intestinal organ culture system. , the sectioned particles seen inside the cells were typical of coronaviruses. we concluded that the particles were enteric coronaviruses. a common feature of these enteric coronaviruses is their pleomorphism, a finding which is not unusual with enveloped rna viruses, especially before they are adapted to in vitro culture. the above evidence of the viral nature of these particles must be considered against the findings of dourmashkin et al., who concluded that the particles they saw were probably not viruses. this conclusion was based on an interpretation of structural relationships obtained from a sectioned deposit of ultracentrifuged crude faecal suspension. we believe that interpretation of findings from these pilot experiments is not only difficult but also inappropriate to the question posed. sir,&mdash;dr berkowitz and colleagues (oct. , p. ) conclude that oral contraceptives do not increase the risk of proiiferative trophoblastic sequelae when taken after the evacuation of hydatidiform mole and before gonadotrophin values have fallen to normal. it is not clear how this conclusion can be drawn from a total of patients "selected at random" from their files. its statistical significance would seem highly questionable. the relevance of their data might also be questioned on the grounds that this group report elsewhere that they give cytotoxic drugs to all patients judged to be at risk of malignant sequelae even before the uterus is evacuated. such prophylactic therapy affects the issue in two ways. first, it ensures that a high proportion of mole patients receive potentially mutagenic cytotoxic agents during their childbearing period, whereas others think it desirable to avoid such exposure. secondly, it renders their series unsuitable for comparison with series of patients not given prophylactic therapy. the analysis of consecutively registered cases of hydatidiform mole on the registry of the royal college of obstetricians and gynaecologists suggested that taking oral contraceptives before gonadotrophin remission had been achieved increased the risk of invasive mole or choriocarcinoma almost -fbld compared with those not taking oestrogens and progestagens. these data are not conclusive since patients were not randomised to "pill" and "no pill" groups but they would seem to be a better basis for mole follow-up policy than the new england data. sir,-dr gorchein (july , p. ) comments on our letter.l perhaps we should have pointed out more clearly that we knew that induction of -aminolaevulinic acid synthetase is a dose related phenomenon. moreover, in general, there exists a large species variation in therapeutic or toxic effects of chemical substances, and additionally an interspecies difference exists in drug metabolism and pharmacological response, especially to liposoluble drugs -all of which points should be considered when extrapolating our findings in rats to man. nevertheless, we feel very strongly that those drugs which evoke a positive response in our rat model are potentially harmful in the hereditary porphyrias and should be avoided. we take exception to gorchein's suggestion that the safety of new drugs in the hereditary porphyrias should be evaluated by clinical trial. it would be irresponsible to subject a population at risk to potentially harmful agents. we have had a great deal of success, as evidenced by the remarkable decrease in the number of acute attacks, by education of affected subjects and their medical attendants about the dire consequences of exposure to potentially dangerous drugs. furthermore, good correlation exists between our clinical findings and those in our rat model with respect to the dangerous porphyrogenic drugs. sir,-dr hawkins and his colleagues in their study of thyroid microsomal antibodies (tma) (nov. , p. ) face a dilemma which bedevils much epidemiological research. this is the problem of studying individual subjects. out of subjects with tma had subclinical hypothyroidism (premyxoedema), according to hawkins and colleagues' criterion of a raised basal thyroid stimulating hormone (tsh) level. in our experience, % of patients with premyxoedema have a normal basal tsh but exaggerated response to thyrotrophin-releasing hormone (trh). blastocystis hominis, an intestinal protozoan parasite of man coronavirus particles in faeces from patients with gastroenteritis recognition of human enteric coronaviruses by electron microscopy coronavirus propagated from patients with non-bacterial gastroenteritis further studies on human enteric coronaviruses replication of an enteric bovine coronavirus in intestinal organ cultures the human enteric coronaviruses % of euthyroid subjects with an exaggerated response to trh have neither thyroid antibodies nor a history of partial thyroid ablation (unpublished) charing cross hospital relationship of oral contraception to development of trophoblastic tumour after evacuation of a hydatidiform mole drug safety in porphyria the value of determining the plasma concentration of drugs in animals and man. fundamentals of drug metabolism and drug disposition porphyria and the dangerous life-threatening drugs association between exaggerated responsiveness to thyrotrophin-releasing hormone and hypercholesterolaemia key: cord- - bee v authors: schoub, barryd title: enteric adenoviruses and rotaviruses in infantile gastroenteritis in developing countries date: - - journal: lancet doi: . /s - ( ) - sha: doc_id: cord_uid: bee v nan sir,-the letter by dr dowling and dr wynne (aug. , p. ) is of great interest to us. their disparate detection rates of adenovirus and rotavirus from stool samples taken in two different rural areas in south africa is intriguing and warrants further investigation. however, i would hesitate to ascribe an aetiological role to these adenoviruses merely on the basis of electron microscopy of stools of patients with diarrhoea and vomiting. further work is needed to differentiate these viruses from respiratory adenoviruses and commensal enteric adenoviruses. we are surprised that dowling and wynne "are aware of no other studies on the incidence of adenovirus-associated gastroenteritis in southern africa", apart from our report. since that time we have published papers on the aetiology of acute infantile gastroenteritis in our black urban communities in the pretoria and the johannesburg , areas. stools were examined by negative-staining electron microscopy and we were unable to detect adenoviruses in any of these specimens. the rates of rotavirus detection were low, varying from % to %, and this was thought at first to be due to patients reporting for medical care late in the course of their illness when the excretion of virus particles dropped below the detection limit of the electron microscope. in a recent study (unpublished) the low rotavirus detection rate in the black population ( %, out of ) was confirmed by enzyme-linked immunosorbent assay as well as by electron microscopy; in contrast, the figure for the white population was % ( out of ). adenovirus was again conspicuously absent. the reasons for this low frequency of rotavirus in the black population, which does not appear to be related to the high incidence of lactase deficiency in this population, are being investigated. whether our failure to detect adenovirus is due to technical factors or represents a real difference in incidence of infection between urban and rural populations needs further work. we have previously noted striking differences in detection rates of coronavirus-like particles between rural and urban black populations; these agents were seen in of stool samples taken sir,-we read professor with's letter (sept. , p. ) with interest and not a little dismay. he states that in his wide experience of acute porphyria he has never encountered an attack induced by alcohol and consequently does not advise his patients to abstain from drinking. his experience is completely contrary to our own. we strongly advise all of our patients with acute porphyria that alcohol may precipitate a porphyric attack. in the past three years alone our unit in glasgow has supervised the inpatient management of attacks of acute intermittent porphyria in twenty-four patients. of these attacks proved fatal. ( %) of the attacks were precipitated by alcohol ingestion, making alcohol the third commonest precipitating factor, preceded only by drugs and the premenstrual hormonal fluctuations. our experience in the management of porphyria over three decades is similar. on several occasions, we have been surprised by the small quantities of alcohol which have triggered attacks in some of our patients with frequently relapsing porphyria. two patients who have each had, over the past three years, an average of attacks per year, have independently discovered that drinking only one glass of vodka or two glasses of sherry is sufficient to precipitate an attack. on the basis of their personal experience of the effects of alcohol on their porphyria, both have become teetotal. the porphyrinogenicity of a substance is dependent on its ability to induce the initial and rate-controlling enzyme of haem biosynthesis, delta-aminolaevulinic acid (ala) synthase. ethanol is a well known porphyrinogen and induces hepatic ala synthase activity in laboratory animals. we have demonstrated in healthy non-porphyric subjects that the ingestion of ml vodka ( - mol ethanol), raises the activity of leucocyte ala synthase by a mean of % and similar distrubances of haem biosynthesis are observed in alcoholics. one should also remember that the primary aetiological agent in the development of cutaneous hepatic porphyria is ethanol, as a consequence of its effects upon haem synthesis. it is for these reasons that alcohol figures so largely on lists of drugs contraindicated in the porphyrias. with recommends more liberal use of drugs as well as of alcohol in porphyria patients. we agree that it is difficult to be certain of the safety or otherwise of certain drugs in acute porphyria. the response also varies from patient to patient. however, we must strongly advocate caution and avoidance of potential porphyrinogens when prescribing for and advising porphyria patients, as detailed in the recent international review. there is still no dependable form of therapy for the acute attack so prevention of such attacks is of paramount importance. diet and the faecal microflora of infants, children and adults in rural nigeria and urban u.k drugs and the hepatic porphyrias joubert sm effect of ethanol on liver delta-aminoaevulinate synthase in rats lancet a acute ethanol ingestion and haem biosynthesis in healthy subjects goldberg a abnormal haem biosynthesis in chronic alcoholics international review of drugs in acute porphyria goldberg a haematin therapy for acute hepatic porphyria key: cord- -kf a hix authors: mendenhall, emily title: the covid- syndemic is not global: context matters date: - - journal: lancet doi: . /s - ( ) - sha: doc_id: cord_uid: kf a hix nan what is driving coronavirus to move through the population in the usa and interact with biological and social factors, however, differs from other contexts. us political failures have driven covid- morbidity and mortality, and this cannot be divorced from our historical legacy of systemic racism or our crisis of political leadership. this matters because in other contexts covid- is not syndemic. new zealand's political leadership in response to the crisis has been exemplary. covid- is not syndemic there. in this sense, syndemics allow us to recognise how political and social factors drive, perpetuate, or worsen the emergence and clustering of diseases. recognising contexts are different matters a great deal. for instance, contexts throughout sub-saharan africa are doing much better than the most burdened contexts, like the usa, brazil, and india. many people have questioned, why? some have argued that this reflects a racist frame thinking that african contexts should suffer more. yet, many african governments acted more swiftly and confidently than wealthier countries. the political leadership in these contexts, therefore, prevented the extensive death tolls, compared to contexts like the uk and the usa, where political leadership failed. recognising political determinants of health is central to the syndemic construct. by calling the covid- syndemic global, we miss the point of the concept entirely. i do not write this to dampen horton's use of the term, as i believe covid- is syndemic in my country (the usa). this is precisely because pre-existing conditions such as hyper tension, diabetes, respiratory disorders, systemic racism, mistrust in science and leadership, and a fragmented health-care system have driven the spread and interacted with the virus. these synergistic failures have caused more death and devastation than many other contexts. recognising failures of wealthy countries is imperative as we think about where global knowledge and power sit within fields like global health. syndemic frames provide us with an opportunity to do this. i declare no competing interests. science, technology, and international affairs program, edmund a walsh school of foreign service, georgetown university, washington, dc, usa offline: covid- is not a pandemic syndemics and the biosocial conception of health beyond comorbidity: a critical perspective of syndemic depression and diabetes in cross-cultural contexts racial capitalism: a fundamental cause of novel coronavirus (covid- ) pandemic inequities in the united states understanding the us failure on coronavirus-an essay by drew altman three reasons why jacinda ardern's coronavirus response has been a masterclass in crisis leadership how to talk about covid- in africa key: cord- -gvkc hjd authors: chrystie, i.l.; totterdell, b.m.; banatvala, j.e. title: asymptomatic endemic rotavirus infections in the newborn date: - - journal: lancet doi: . /s - ( ) - sha: doc_id: cord_uid: gvkc hjd between may , , and may , , ( · %) of -day-old babies in newborn nurseries excreted rotaviruses. the infection-rate was highest during winter ( %). % of infected babies at this time were bottle-fed. % of neonates excreted low amounts of virus ( ( ) particles/g fæces); older children tended to excrete > ( ) particles/g fæces. infected breast-fed babies excreted less virus than those who were bottle-fed. stools of breast-fed babies often contained clumps of complete "smooth" rotavirus particles. when the newborn nurseries were transferred to a newly built hospital wing, infection appeared in the new wards, including those admitting only new patients, within a short period. infection was either mild ( %) or symptomless ( %), and even babies with symptoms required no treatment. in solid myeloma tumours but also for metastatic spread of myeloma. this notion is not in conflict with recent knowledge of the heterogeneity, development, and migratory habits of b-cell subpopulations. , there is no doubt about the presence of circulating tumorigenic cells in mice bearing myeloma tumours. however, the exact identity of these cells is not known. the simultaneous detection of malignant change and idiotypic structures in circulating lymphocytes is difficult. nevertheless, lymphocytoid cells bearing some tumour-cell markers have been demonstrated. the number of lymphocytes whose sig was altered by tumour r.n.a. ' is probably much greater than the number of tumorigenic cells estimated in other experiments. although it is highly likely that sig-id+ neoplastic stem cells circulate in human myeloma, the bulk of the sig-id+ lymphocyte population may be partially differentiated and therefore relatively benign. in addition, many circulating tumorigenic cells could be in a non-growth phase or equivalent state, and probably very few of those which are in the cell cycle successfully initiate a focus of tumour because of immunological inhibition and/or ecotactic preference. definitive experiments are needed to detect and isolate myeloma cfu-c stem cells from human peripheral blood, and attempts should be made to propagate these in nude mice. further characterisation of peripheral lymphocytes from myeloma patients must be undertaken because of their possible value in diagnosis and therapy. rotaviruses are the commonest cause of acute nonbacterial gastroenteritis in infancy and childhood,',' and a common cause of severe diarrhoeal disease in newborn calves and piglets. rotavirus infection is world-wide and iri children admitted to hospital is most common between months and years of age; virus is seldom detected in the stools of symptomless age-matched controls. in temperate climates, infection is most frequent in winter. after our first report of rotaviruses in the stools of newborn babies with mild diarrhoea we found that of ( %) newborn babies excreted rotaviruses. ' although the babies were infected as early as the third day of life, virus excretion was most frequent among - day-old babies, who showed few if any of the symptoms of infection found in older children.' this paper describes a -month study of the incidence of infection, the amount of virus excreted by breast-fed and bottle-fed babies, and the pattern of virus spread during the transfer of maternity wards to quarters in a newly built hospital wing. stools from -day-old babies were examined for virus particles by electronmicroscopy. during the first weeks of the study, the maternity wards (mary and mary a and b) were located in the old part of the hospital (south wing). in mid-june, patients were transferred to new wards (haydon and mary) in the new north wing, and the old wards were subsequently cleaned and reopened in early august under new names (garland, wrigley, and bowes) for mothers and babies of uncomplicated deliveries. garland and bowes were next to each other on the same floor and wrigley was one floor below. some patients were transferred from haydon and mary to bowes, but garland and wrigley accepted only new patients. mary ward in the new north wing was used for only months to provide additional accommodation while wards in the old south wing were being cleaned. in general, babies remained with their mothers during the day but at night were accommodated in the nurseries. between may , , and may , , stools from babies were examined, of which ( . %) &ccedil;ontained rotaviruses. bacteriophages but no other virus particles (astroyiruses, caliciviruses, coronaviruses, adenoviruses, small round virus particles) were detected, in contrast with our findings among older children. the number of rotavirus particles detected varied considerably : of consecutive rotavirus-positive infants studied during the winter months, % excreted - particles/g of fasces, but the stools of % of the infants contained more than o/g which is what we usually find in rotavirus-infected children with acute gastroenteritis. infection had a seasonal variation, reaching a peak during the winter of - and the lowest level in summer, ( fig. ) in haydon ward rotavirus infection among newborn babies was mild or more often symptomless. only of ( %) babies in this ward who excreted rotavirus passed frequent loose or offensive stools or vomited and there was no obvious correlation between the amount of virus excreted and the presence of gastrointestinal symptoms. such symptoms were noted in ( %) of the rotavirus-negative children in the ward. in other reports of rotavirus infection, - the proportion of newborns with diarrhoea was variable, but usually greater than in our series. however, the significance of this is difficult to assess since newborn babies, although apparently in good health, pass a variable and often frequent number of stools of varying consistency. the assessment of reports of "diarrhoea", "loose stools" or "frequent stools" is thus difficult particularly if, as in our study, assessment is made retrospectively by examining feeding-charts or case-notes. although we may have underestimated the frequency of diarrhoeal episodes, it is certain that no infant was sufficiently ill to require treatment. it is not known why rotavirus infection is mild or symptomless in the newborn human. it is often severe in newborn calves and piglets, particularly if they are colostrum-deprived," and unlike humans, these animals do not acquire antibodies transplacentally. rotavirus antibodies present in the sera of almost all human adults may protect the newborn after transplacental transmission. although it may appear surprising that serum antibody rather than secretory antibody protects against infection localised in the small intestine, vaccine-induced circulating antibodies protect the gut against cholera and the respiratory tract against influenza." however, although newborn infants are protected from disease, they are not protected from infection: % in our study excreted virus, occasionally in very large amounts. symptomless infection with excretion of large quantities of virus also occurs with cytomegalovirusi and hepatitis-b virus. holmes has suggested that the intestinal brush-border enzyme, lactase, acts as the host-cell receptor for rotavirus. in-vitro trypsin treatment enhances the in-vitro infectivity of porcinel and bovine , rotaviruses. however, there is no evidence that human neonates are deficient in these enzymes. it is possible that the rotavirus strains circulating in our nurseries were avirulent. pig rotaviruses may vary in virulence. o however, the demonstrations of mild or symptomless infection in newborn infants but frank diarrhoea in older children in the u.k., australia,'o and india i do not support this hypothesis. furthermore, in our hospital there is concurrent rotavirus infection among symptomless newborn infants and among older children with gastroenteritis in the ward only one floor above the newborn nurseries. breast-fed babies excreted rotavirus significantly less frequently and, when infected, generally shed less virus than bottle-fed babies. breast-fed babies may be protected by maternal secretory antibodies in colostrum , and breast milk during the newborn period, or by nonspecific antiviral factors distinct from antibody or interferon in breast milk. in a rural bangladesh environment heavily contaminated with rotaviruses admission to hospital with rotavirus-induced diarrhoeal disease is rare before the age of months. how rotaviruses induce diarrhoea in humans is not clearly understood but the newborn's gastrointestinal tract may have physiological characteristics not found in older children which allow symptomless infection. discovery of the mechanism by which young infants are protected might provide an alternative to vaccination. although it is uncertain how infection was introduced into the newborn nurseries, transmission of infection by medical or nursing staff from infected older children in the general wards seems likely. studies in toronto have shown that rotavirus infection, a common cause of hospital-acquired gastroenteritis among older children, was probably transmitted by medical staff. we found infection occasionally in infants in the newborn specialcare nursery. premature babies also had symptomless infections but in this unit many are in incubators and active measures are taken to prevent cross-infection, so rotavirus spread is likely to be rare. we are now investigating whether our newborn rotavirus-infected infants are "immunised" as a result of infection. follow-up studies on babies who excreted rotavirus neonatally have shown that had rotavirusinduced diarrhoea when aged this type appears to be the predominant serotype associated with symptomatic disease in most parts of the world. we thank the medical officers and nursing staff of the maternity wards at st. thomas's hospital for their cooperation. proc. staff meet. mayo clin h&aelig;mat semin. h&aelig;mat archs intern acute diarrhoea in childhood in acute diarrhoea in childhood oxford, and &dagger;hospital for sick children, great ormond street, london summary urinary iron excretion after single intramuscular (i.m.) bolus injections or h subcutaneous (s.c.) infusions of desferrioxamine (d.f.) was determined in sixteen homozygous &bgr key: cord- -tul bonh authors: nan title: rotaviruses of man and animals date: - - journal: lancet doi: . /s - ( ) - sha: doc_id: cord_uid: tul bonh nan the xtiological agents of most of the common viral infectious diseases have by now been identified, but until lately acute infantile gastroenteritis was an unhappy hunting-ground for virologists. this disease, one of the commonest causes of childhood illness throughout the world, is a leading cause of mortality in many underdeveloped countries. thus, in india - million children die each year from diarrhoeal diseases, cholera apart.' mortality in parts of africa is also particularly high, and preexisting malnutrition and other debilitating diseases are undoubtedly important contributing factors. certainly bacterial pathogens may cause both sporadic and epidemic gastroenteritis in children, but they cannot be isolated in up to % of cases. , whilst it is true that some investigations suggest that enteroviruses or adenoviruses may occasionally cause localised outbreaks of gastroenteritis, - others have shown that these viruses may be detected almost as frequently in controls as among patients. [ ] [ ] [ ] [ ] just over a year ago, bishop and her colleagues in melbourne detected reovirus-like particles in thin sections of theepithelium of duodenal mucosal biopsies in of babies in the symptomatic phase of acute non-bacterial gastroenteritis. their presence coincided with histological abnormalities and depressed duodenal mucosal disaccharidase levels. the viruses were originally classified as orbiviruses-a group of double-stranded-r.n.a. viruses which includes bluetongue, colorado , tick fever, and african horse sickness viruses. employing negativestaining techniques on fsecal extracts, flewett and his colleagues found similar particles in children with gastroenteritis in birmingham ; indeed, if virologists had only looked at such simply prepared specimens, there is no technical reason why these viruses could not have been detected, say, years ago. morphologically identical viruses were soon detected in fxcal extracts by numerous other workers in many parts of the world, - and in an analysis of these results on p. this week dr davidson and his colleagues report that these viruses were present in faecal extracts of of ( %) children with gastroenteritis but in only of controls. stools may be extremely rich in virus particles-there may be to particles per gramme of faeces. these viruses are rarely detected in children over the age of , and are more often encountered in winter, during which time virus may be detected in up to % of patients. , the disease has an incubation period of approximately hours. virus excretion is greatest during the third and fourth day of illness and is rarely detectable after the eighth day, , although it has exceptionally been recorded for as long as days after onset of symptoms. however, the incidence of infection by these viruses may be underestimated, for the number of particles may sometimes be below the critical threshold for detection by electron microscopy-particularly if specimens are not collected at the height of virus excretion. this may also perhaps explain failure to detect virus in nasopharyngeal secretions. these morphologically identical viruses detected in faecal extracts differ from reoviruses and orbiviruses antigenically , as well as in their fine structure. the virus consists of a core about nm. in diameter, surrounded by an inner layer of capsomeres which radiate outwards like the spokes of a wheel. an outer layer of capsomeres appears to be attached to the tops of the inner ones, and this gives rise to the characteristic appearance of a sharply defined rim surrounding the virus particle (diameter - nm.). , since these virus particles seem to be morphologically distinct from such diplorna-viruses as reoviruses and orbiviruses, and because of their wheel-like appearance, flewett and his colleagues suggested they be called rotaviruses, although the australian workers now suggest that duoviruses may be more appropriate. whichever term is eventually adopted, the viruses that cause epidemic diarrhoea of infant mice (e.d.i.m.) and some outbreaks of neonatal calf and pig diarrhoea, '- s as well as such viruses as the simian sa virus and the agent isolated from gut washings in sheep and cattle, are indistinguishable from the human virus and must therefore be included in this group. neonatal-calf-diarrhoea virus (a double-stranded-r.n.a. virus), like its human counterpart, has a world-wide distribution , and affects only young animals. calf diarrhoea is one of the most important causes of economic loss in both dairy and beef herds, mortality-rates varying from nil to %. - furthermore, calves which recover often fail to gain weight adequately. serological investigations show that babies with gastroenteritis acquire antibodies during the course of their illness. furthermore, complement-fixation (c.f.) and immunofluorescent (i.f.) lately been shown to replicate in fetal intestinal organ cultures, in which virus may be detected by electron microscopy. i.f. work shows that virus-specific antigen is localised in the epithelial lining of the intestinal villi. virus-infected organ cultures may be used for titrating antibody by i.f., and this provides a method that is rather more sensitive than c.f.; an effective c.f. antigen may be simply prepared from stool extracts rich in virus particles. techniques by which human rotaviruses may be propagated to high titres in cell cultures are eagerly awaited, since this is a step towards preparation of a vaccine. it is encouraging that an attenuated orally administered vaccine reduces the incidence of newborn-calf diarrhoea under field conditions ; probably this vaccine protects by inducing specific viral antibody at the gut mucosal surface. rotaviruses are only rarely encountered in specimens obtained from children who have experienced previous gastroenteritis, , which suggests that immunity may persist. thus, existing evidence suggests that rotaviruses are the most important cause of infantile gastroenteritis throughout the world, but as yet only a limited number of specimens have been examined from those tropical areas where mortality-rates are particularly high. although no other viruses have conclusively been shown to cause gastroenteritis in older children and adults, nm. diameter d.n.a. viruses (parvoviruses) may cause bovine enteritis, and viruses of this size have been detected by le.m. in human stools. however, they have been detected in patients with and without gastroenteritis, and their role in human disease must remain uncertain. during an outbreak of gastroenteritis in norwalk, ohio, nm. picornavirus-like particles were detected in faecal extracts. infection was transmitted to volunteers, and i.e.m. studies suggested that both naturally and experimentally infected persons developed antibody during their illness. in addition, cross-challenge studies elsewhere on volunteers with gastroenteritis suggest that the norwalk agent may be antigenically related to other viruses causing gastroenteritis. nevertheless, claims by some workers to have detected parvovirus-like or picornaviruslike particles in faeces by electron microscopy must be interpreted with caution, since it is difficult to be certain whether small isometric viruses are bacterial or human viruses, and such particles may be identified readily in both patients and controls. certainly le.m. detection of virus-agglutinating antibodies during convalescence, against virus present in the stools, provides useful circumstantial evidence of infection, but not until these viruses can be isolated and specific antisera raised against them can the specificity of the agglutination reaction be confirmed. in addition to rotaviruses, coronaviruses are important causes of enteritis in pigs (transmissible gastroenteritis of piglets) and calves, and it is tempting to speculate that coronaviruses may eventually be shown to cause human gastroenteritis. workers in melbourne and birmingham have opened a new vista in both clinical and comparative virology and, until such time as the human virus can be isolated in vitro, much may be learned from work in animals about virus transmission and the immune response it induces. rotaviruses may now be included in the list of such viruses as herpes, poxviruses, and hepatitis b which may be. reliably and rapidly detected in clinical specimens by electron microscopy. home blood-pressure recording although the case is far from proven, the indications are that substantial reductions in mortality and morbidity can be expected from effective treatment of mildly raised blood-pressure (diastolic - mm. hg). already the american heart association has called for a massive campaign of identification and treatment, and, despite the pessimism of epidemiologists, it is probable that population screening programmes will be started and that practitioners will be called upon to manage long-term therapy in many more symptomless patients than at present. as much as - % of the adult population may fall into this category, and if it is true that all these patients are at increased risk and would benefit from therapy then an enormous work-load will be generated. while the casual blood-pressure reading has proved to be an accurate predictor of morbidity and mortality from cardiovascular diseases, the risk will be highest amongst those patients who have a high blood-pressure throughout the day and least (perhaps negligible) in those who react briskly to the circumstances of the measurement. if the work-load is to be kept within reasonable bounds, and if unnecessary treatment of large numbers of essentially normal persons is to be avoided, we need . flewett some method of identifying the truly raised bloodpressure. this demands numerous recordings over long periods and at all times of the normal working day. the only practical way in which this can be achieved is by training the patient to record his own blood-pressure repeatedly , &mdash;a concept which also raises the possibility that such patients may be able to regulate their activities, and perhaps even their drug dosage, on the basis of their own recordings. it is not difficult to train lay persons to take their own blood-pressures with an acceptable degree of accuracy (defined as agreement with a doctor's readings), but there are obvious difficulties with technique and equipment. many different semiautomatic machines which substitute a sound detector built into the arm cuff for the human ears have come on the market and are offered for sale to the public. the accuracy of these instruments is very doubtful and few have come under professional scrutiny. the only published evaluations suggest that most are inaccurate and that they do not compare well with the stethoscope and mercury sphygmomanometer. evidently the human ear and its interpretive brain are still more accurate and sensitive than any electronic gadgets. as an alternative to elaborate and expensive equipment, a group of patients with hypertension living in the harrow area of london have been trained to record their bloodpressure twice daily using an anaeroid sphygmomanometer and a simple diaphragm stethoscope. all these patients were participating in clinic trials of antihypertensive agents. it was found possible to train all but a very few patients to record their pressures accurately, and, with encouragement, out of continued to keep records for periods of up to one year. during this time the therapy was changed, periods of active treatment alternating with periods of placebo therapy. the trials were conducted in a double-blind fashion, and the fact that the patient records followed precisely the direction of the clinic recordings suggested that the patient records were true and not biased by previous recordings or a desire to please the clinic doctor. the patient records were, however, consistently lower than the clinic recordings, and this was particularly so for those patients in whom the initial reading was only slightly raised. this is by no means a new observation, but it suggests that blood-pressures recorded by a simple technique by the patient can be as accurate acta p&oelig;diat oxprenolol in the treatment of non-accelerated essential hypertension key: cord- -v wlz fa authors: merianos, angela; peiris, malik title: international health regulations ( ) date: - - journal: lancet doi: . /s - ( ) - sha: doc_id: cord_uid: v wlz fa nan moderate exercise (eg, % of maximal capacity) and platelet adhesion reduces with regular exercise. although blood pressure often rises acutely during exercise, this response is attenuated by regular exercise. because reduction of peripheral vascular resistance was thought to be the principal mechanism for acutely lowering blood pressure with exercise, a reduction in cardiac output, stroke volume, and left ventricular end-diastolic volume were found to account for much of the acute blood pressure reduction after exercise in older people with hypertension. regular exercise improves myocardial contractility and coronary perfusion. in fact, exercise improves arterial compliance and endothelial function, in general. it is thought that greater sheer stress with exercise enhances synthesis of nitric oxide from endothelial cells. this nitric oxide might also slow the development of atherosclerosis, as well as reducing the risk of acute coronary events by relaxing smooth muscle and inhibiting the proliferation of smooth muscle, platelet aggregation, and leucocyte adhesion to vessel walls. regular moderate exercise can also reverse left ventricular hypertrophy. despite modest long-term compliance, advice to exercise has been shown to be effective and cost effective at increasing overall exercise levels for at least months, without adverse effects. for the people who can comply, adding exercise prescriptions to the management of hypertension has the extra value of reducing drug-related costs and adverse effects, and at the same time improving cardiovascular risk. thus the recommended exercise prescription for lowering blood pressure in hypertensive patients can be tailored, and can involve any intermittent or continuous aerobic activity of at least min a day, three or more times a week. on may , , the th world health assembly, consisting of the member states of who, adopted the revised international health regulations (ihr), the code of international regulations for the control of transboundary infectious diseases. the spread of severe acute respiratory syndrome illustrated the rapidity with which a new infectious disease can spread and affect today's interconnected world. the deliberate release of anthrax in the aftermath of the events of sept , , highlighted another dimension of microbial threats. neither event was adequately addressed in the previous ihr of . the key constraints of ihr ( ) were the limited scope of diseases (cholera, plague, yellow fever), the dependence on official notification to who by affected countries, the scarcity of mechanisms for collaboration in investigating such outbreaks, and the lack of specific riskreduction measures to prevent the international spread of disease. indeed, there was disincentive to reporting under the ihr because unaffected countries applied travel and trade restrictions far in excess of the true risks of the disease. the new ihr goes some way toward addressing these issues by establishing expert panels to review the risks to international public health and recommend evidence-based control measures. however, even the revised ihr show an inevitable compromise between national sovereignty and the collective international good; of trying to ensure the maximum security against the international spread of disease with minimum interference to travel and trade. new infectious diseases have been emerging at the unprecedented rate of about one a year for the past two decades, a trend that is expected to continue. , in the past years, new and emerging infectious diseases with a potential threat to international public health include ebola, lassa, and marburg haemorrhagic fevers in africa, variant creutzfeldt-jakob disease in europe, meningococcal meningitis w associated with returning hajj pilgrims, nipah virus in malaysia, west nile virus in the americas, severe acute respiratory syndrome, and the pandemic threat from avian influenza h n in asia. there is clearly a need for new approaches to confront these emerging threats from infectious disease. in , the who department of communicable diseases surveillance and response in geneva initiated the formation of the global outbreak alert and response network (goarn), which provides the operational and technical response arm for control of global outbreaks. in - , goarn responded to events in countries, and has grown to a partnership of over institutions and networks, including un and intergovernmental organisations. the network provided substantial support to affected countries during the outbreak of the severe acute respiratory syndrome and in response to avian influenza. it was clear that the ihr ( ) also needed to change to allow response to contemporary threats to international health. efforts towards achieving this response began in . the purpose and scope of the ihr ( ) are to prevent, protect against, control, and provide a public-health response to the international spread of disease in ways that are commensurate with and restricted to publichealth risks, while avoiding unnecessary interference with international traffic and trade. the ihr ( ) affirm the continuing importance of who's role in global outbreak alert and response to public-health events. the revised ihr spell out the responsibilities for who, other international agencies with a mandate to protect public health (including radiation health and chemical safety), and the member states themselves. a decision instrument has been developed to assist countries in determining whether an unexpected or unusual public-health event within its territory, irrespective of origin or source, might constitute a public-health emergency of international concern and require notification to who. criteria include morbidity, mortality, whether the event is unusual or unexpected, its potential to have a major public-health effect, whether external assistance is needed to detect, investigate, respond, and control the current event, if there is a potential for international spread, or if there is a significant risk to international travel or trade. the ihr ( ) explicitly recognise the need for intersectoral and multidisciplinary cooperation in managing risks of potential international public-health importance. key partners include intergovernmental organisations or international bodies with which who is expected to cooperate and coordinate its activities: eg, the un, international labour organization, food and agriculture organization, international atomic energy agency, international civil aviation organization, international committees and federations of the red cross and red crescent societies, and office international des epizooties. the revised ihr set out core capacities of a country's preparedness to detect and respond to health threats-early events detected by national surveillance system unusual diseases which must be notified: smallpox wild poliovirus human influenza (new subtype) severe acute respiratory syndrome any event of potential international public-health concern known epidemic-prone diseases which must be notified: cholera pneumonic plague viral haemorrhagic fevers yellow fever west nile fever other locally or regionally important diseases if yes to any two of these questions is public-health impact of event serious? is event unusual or unexpected? is there significant risk of international spread? is there significant risk of international travel or trade restrictions? figure: simplified decision instrument for assessment and notification of events that might constitute public-health emergency of international concern under international health regulations ( ) warning and routine surveillance systems, epidemiological and outbreak investigation skills, laboratory expertise, information and communication technologies, and management systems. who will continue its traditional role of providing support for national capacity building to achieve these core capacities. a short list of diseases (figure) needing mandatory notification to who are included in the decision instrument; however, countries are now also required to assess the international public-health threat posed by any unusual health event, including those of unknown causes or sources, and outbreaks caused by agents with the known ability to cause serious public-health effect and to spread rapidly internationally. importantly, who can now use a range of sources of health intelligence to raise an alarm and begin a process of verification with countries that have not voluntarily reported significant health events. parties capitalised to the ihr are required to inform who within h of the receipt of evidence of a public-health risk that might cause international spread of a disease. finally, if who obtains credible evidence that a public-health event of international importance has occurred and fails to obtain disclosure and cooperation by the affected state, it has discretionary power to release the public-health information required to protect global public health. the ihr work on the principle of global public goodprotecting public health through early detection and response to public-health emergencies benefits the nation concerned and reduces the risks of spread to other nations. their impact will be limited unless national governments accept their global public-health responsibilities. furthermore, because most human emerging infectious diseases are zoonotic in origin, there is a need for close collaboration between the veterinary, human health, and wildlife sectors. the regulations of the office international des epizooties, the veterinary counterpart of the ihr, face similar challenges as did the ihr ( ), and perhaps need a similar overhaul. the problems currently faced in confronting the threat to human and animal health posed by the outbreaks of avian influenza a h n in asia amply illustrate this contention. the ihr ( ) will enter into force in . effects of an intensive diet and physical activity modification program on the health risks of adults management of hypertension in older persons the acute versus the chronic response to exercise the role of exercise training in the treatment of hypertension: an update exercise characteristics and the blood pressure response to dynamic physical training accumulating brisk walking for fitness, cardiovascular risk, and psychological health auckland: faculty of medicine the effectiveness of exercise training in lowering blood pressure: a meta-analysis of randomised controlled trials of weeks or longer effect of aerobic exercise on blood pressure: a meta-analysis of randomized, controlled trials exercise and hypertension dose-response and coagulation and hemostatic factors postexercise blood pressure reduction in elderly hypertensive patients physical activity and cardiovascular disease effectiveness of counselling patients on physical activity in general practice: cluster randomised controlled trial world health organization. fifty-eighth world health assembly resolution wha . : revisions of the international health regulations world health organization microbial threats to health: emergence, detection and response world health organization. fifty-fourth world health assembly resolution wha . global health security: epidemic alert and response global outbreak alert and response: report of a who meeting world health organization. fifty-first world health assembly. revision of the international health regulations: progress report global public goods for health: health economics and public health perspectives global task force for influenza the nomenclature of epileptic seizures has always been confusing. many historic terms, still in use by the public and even by some physicians, convey little information about the anatomy or physiology of the event. "grand mal" and "petit mal" are hardly preferable to the simpler "big" and "little". in the international league against epilepsy (ilae) formed a commission to develop improved terminology, which led to the international classification of epileptic seizures (ices), last revised in . this document was supplemented in by the international classification of epilepsies and epilepsy syndromes, which takes into account causation and other clinical features. in the ices scheme, the fundamental dichotomy is between "partial" seizures (arising in a focal area of the brain) and "generalised seizures" ("those in which the first clinical changes indicate initial involvement of both hemispheres"). despite decades of effort, the ices terms remain hard to explain to naming seizures key: cord- - ddfywfa authors: assicot, m.; bohuon, c.; gendrel, d.; raymond, j.; carsin, h.; guilbaud, j. title: high serum procalcitonin concentrations in patients with sepsis and infection date: - - journal: lancet doi: . / - ( ) -n sha: doc_id: cord_uid: ddfywfa high concentrations of calcitonin-like immunoreactivity have been found in the blood of patients with various extrathyroid diseases. by means of a monoclonal immunoradiometric assay for calcitonin precursors, we have measured serum concentrations of procalcitonin in patients with various bacterial and viral infections. children (newborn to age years) in hospital with suspected infections were investigated prospectively. patients with severe bacterial infections had very high serum concentrations of procalcitonin at diagnosis (range - ng/ml) in comparison with children found to have no signs of infection (baseline concentrations < · ng/ml). serum procalcitonin values decreased rapidly during antibiotic therapy. patients with peripheral bacterial colonisation or local infections without invasive sepsis and ( %) of patients with viral infections had concentrations within or slightly above the normal range ( · - · ng/ml). among severely burned patients studied in an intensive care unit, the post-traumatic course of procalcitonin concentrations (range · - ng/ml) was closely related to infectious complications and acute septic episodes. concentrations of mature calcitonin were normal in all subjects, whatever procalcitonin concentrations were found. concentrations of a substance immunologically identical to procalcitonin are raised during septic conditions. serum concentrations seem to be correlated with the severity of microbial invasion. increased production of calcitonin by medullary thyroid carcinoma (mtc) is well known, and serum calcitonin is used as a marker of this cancer. high serum concentrations of calcitonin-like immunoreactivity have also been reported in various extrathyroid disorders, including many cancers, acute and chronic inflammatory disease of the lung, acute pancreatitis, renal failure, benign liver disease, and fulminating infantile meningococcaemia. [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] the presence of several circulating immunoreactive forms of calcitonin and its precursors in mtc patients has been shown by several groups ' , - but the nature of circulating immunoreactive calcitonin species in other disorders remains unknown. however, ghillani and colleagues lately showed that, unlike mtc, which produces both precursors and mature hormones, most of the extrathyroid diseases produce calcitonin precursors in the absence of mature hormone. we have investigated calcitonin species in patients with severe bacterial infections and sepsis. two groups of patients were studied. the first comprised newborn and older infants and children admitted to a paediatric unit with suspected infections (table) and the second included severely burned patients admitted to an intensive care unit (burn injuries - % of body surface area). blood samples were centrifuged for min at g and serum was stored at - &deg;c until analysis. procalcitonin was measured with a monoclonal immunoradiometric assay (m-irma). this assay uses two monoclonal antibodies, one directed against residues - of procalcitonin, as the capture antibody, and one recognising residues - , as the tracer antibody ( fig ) . this assay has a detection limit of pg/ml. serum calcitonin was measured with a commercial m-irma (cis bio-international, gif sur yvette, france) which is specific for mature calcitonin and has a sensitivity limit of pg/ml. circulating immunoreactive forms of calcitonin were analysed by reverse-phase high-performance liquid chromatography (hplc). after partial purification on a sep-pak cartridge, serum was injected into a c -nucleosil (macherey-nagel, diiren, germany) column equilibrated with - % (by volume) trifluoroacetic acid. the column was eluted at room temperature and at a flow rate of ml per min with a min gradient of - % acetonitrile in - % trifluoracetic acid. immunoreactivity of the fractions was tested by four assays: the two described above; a radioimmunoassay based on a polyclonal goat antiserum directed against residues - of procalcitonin, which recognises both procalcitonin and the putative cleavage peptide n-procti- ; and an irma that uses the polyclonal antiserum against procalcitonin - and the monoclonal antibody directed against residues - , which can detect only entire procalcitonin ( fig ) . fig shows the distribution of procalcitonin concentrations in the five subgroups of children with and without infection. procalcitonin was undetectable (< - ng/ml) in children without infection. at the time of diagnosis, newborn infants and older infants or children with severe bacterial infection ( %) had high serum concentrations of procalcitonin ( - ng/ml). antibiotic treatment rapidly decreased procalcitonin concentrations (days - of treatment). among the infants and children with locoregional infection and the newborn infants with skin bacterial colonisation and no sepsis, procalcitonin concentrations did not exceed - ng/ml ( - - - ng/ml). of the patients with viral infections, ( %) had values within or slightly above the normal range (maximum - ng/ml); children with gastroenteritis ( coronavirus, rotavirus) had values of - ng/ml and - ng/ml, and a child with acute hepatitis a had concentrations of ng/ml on admission and ng/ml on day . serum procalcitonin concentrations varied widely among the burns patients from -to ng/ml. three procalcitonin concentrations of ng/ml and ng/ml within days of the burn; concentrations then fell progressively to normal (subgroup i). these patients did not have any infectious complications during the hospital stay. patients (subgroup ii) had higher values, up to ng/ml. the peak concentrations were found at the onset of sepsis, confirmed by clinical and microbiological signs. in subgroup iii, serum concentrations of patients were high day after the burn ( ng/ml, ng/ml, and ng/ml) and continued to rise during the next few days, during acute septic episodes. of these patients, who had severe infectious complications (e coli positive blood culture on day , septic shock on day , pseudomonas aerwinosa positive culture on day ), had high concentrations of procalcitonin in all serum samples; the highest value ( ng/ml) was measured during septic shock. the th patient in subgroup iii had toxic shock syndrome days after the bum, and procalcitonin reached a maximum of ng/ml at that time. only burns patient (subgroup ii) died (pulmonary embolism days after injury). concentrations of mature calcitonin were normal at all times in both burns patients and children. analysis of serum extracts by reverse-phase hplc showed a major peak eluting at - min, as detected by several immunoassays (fig ) . it is likely that this immunoreactive peak corresponded to the whole molecule of procalcitonin. two other small peaks detected in some samples could not be identified. calcitonin was consistently undetectable by a specific m-irma. serum calcitonin-like immunoreactivity has been reported in various extrathyroid diseases. - our study shows that serum concentrations of a substance immunologically identical to procalcitonin increase at the onset of infections. in addition, serum concentrations of this substance seemed to be correlated with the severity of the infection. in all but children with procalcitonin concentrations above ng/ml, the diagnosis of severe bacterial sepsis was confirmed microbiologically. the study of bums patients suggests that bum injuries may lead to moderate systemic release of procalcitonin. however, among these patients, very high peak concentrations of procalcitonin were associated with septic complications, although no direct correlation was found between the post-bum course of the procalcitonin concentrations and the size of the bum or pulmonary injury. the correlation of procalcitonin with the severity of infection was confirmed by findings of serum concentrations up to ng/ml ( times the normal value) in patients with septic shock (data not shown). antibiotic treatment lowered procalcitonin rapidly. by contrast, high circulating procalcitonin concentrations persisted in burns patient who had overwhelming microbial invasion and a long septic episode. do the procalcitonin molecules originate from the thyroid gland or from other tissues in these patients? thyroid c-cells do not seem to be the production site of procalcitonin; indeed, burns patient who had undergone thyroidectomy years earlier had high procalcitonin values but no secretion of mature calcitonin. the finding that procalcitonin was detectable in the absence of mature calcitonin shows that the procalcitonin-producing cells are unable to process this precursor form to the mature hormone. mtc are capable of producing and secreting all the biosynthetic pathway products. - pulmonary neuroendocrine cells in the bronchial epithelium have been reported to be a major source of calcitonin immunoreactivity.'s however, most of our patients with sepsis did not have pulmonary injury. others have reported the isolated presence of calcitonin precursors in patients with benign liver diseases (such as hepatitis) or with hepatocellular carcinoma, and also the presence of calcitonin-related rna in this tumour. perhaps the liver is the site of procalcitonin production in patients with sepsis. since serum calcitonin-like immunoreactivity has been described in a wide variety of extrathyroid diseases, it is likely that inflammatory processes other than infection lead to the elaboration of calcitonin-like immunoreactivity by various types of cells. such immunoreactivity and a clinical picture resembling sepsis have been reported in some patients with acute pancreatitis.s the place, if any, of procalcitonin induction in the cytokine cascade that occurs in sepsis and other inflammatory processes remains to be investigated. rapid and substantial release of procalcitonin, at the same time as tumour necrosis factor alpha and before interleukin- , has been observed in patients with renal cancer after intravenous administration of interleukin- (unpublished). this observation could help elucidate the mechanism of rapid procalcitonin production in the septic process. our results, based on several specific immunoassays, strongly suggest that the molecule detected in the serum of patients with sepsis is procalcitonin. however, we cannot exclude the possibility that some of the aminoacids not involved in the recognised epitopes may differ. a second calcitonin messenger, encoding a procalcitonin bearing eight different aminoacid residues on the carboxy-terminal region, has been identified in the thyroid. concentrations of calcitonin gene-related peptide, the product of the calcitonin gene in nerve cells, are also increased in patients with sepsis. ? further studies are needed to elucidate the importance of procalcitonin production in association with infection and to assess a potential role in diagnosis and follow-up of patients with bacterial sepsis. we thank mr johny bombled and mr lionel fougeat for excellent assistance; dr walter bom (research laboratory for calcium metabolism, university of zurich) for progr - peptide and polyclonal antiserum; and dr jean-michel bidart for reviewing the manuscript. plasma immunoreactive-calcitonin in patients with non-thyroid tumours hypersecretion of calcitonin in neoplastic conditions increased serum and urinary calcitonin levels in patients with pulmonary disease hypercalcitoninemia in acute pancreatitis serum calcitonin in acute pancreatitis in man calcitonin levels in chronic renal disease immunoreactive parathyroidhormone and calcitonin in plasma and ultrafiltrate before and after haemodialysis identification and measurement of calcitonin precursors in serum of patients with malignant diseases hypercalcitoninaemia in fulminant meningococcaemia in children immunochemical heterogeneity of calcitonin in tumor, tumor venous effluent and peripheral blood of patients with medullary thyroid carcinoma immunochemical heterogeneity of calcitonin in plasma medullary thyroid carcinoma secretes a non-calcitonin peptide corresponding to the carboxylterminal region of preprocalcitonin diagnostic relevance of the amino-terminal cleavage peptide of procalcitonin (pas- ), calcitonin and calcitonin gene-related peptide in medullary thyroid carcinoma patients structural characterization of a high-molecular-mass form of calcitonin [procalcitonin-( - ) -peptide] and its corresponding n-terminal flanking peptide [procalcitonin-( - )-peptide] in a human medullary thyroid carcinoma immunocytochemical localization of calcitonin in kultschitzky cells of human lung a novel calcitonin carboxy-terminal peptide produced in medullary thyroid carcinoma by alternative rna processing of the calcitonin/calcitonin gene-related peptide gene calcitonin gene-related peptide levels are elevated in patients with sepsis endogenous fibrinolysis may play a part in acute upper-gastrointestinal-tract bleeding by causing digestion of haemostatic plugs. we assessed the predictive value of fibrinolytic tests for hospital outcome in a prospective study of patients with acute upper-gastrointestinal-tract bleeding who underwent endoscopy.serum fibrin degradation products (fdp) were above the normal range in % ( % cl - %) of patients who survived and did not require transfusion or surgery, in % ( - %) of patients who survived without surgery but required transfusion, and in % ( - %) of patients who required surgery or died. multivariate analysis showed that after adjustment for the effects of established risk factors (age, pulse rate, blood pressure, haemoglobin, site of bleeding, and stigmata of active bleeding at endoscopy), serum fdp was a powerful independent predictor of outcome (p= &middot; ). doubling of serum fdp was associated with a % increase in the risk of a poor outcome ( % cl - %).these findings are consistent with roles for endogenous fibrinolysis in gastrointestinal-tract bleeding, for fibrinolytic tests in prediction of adverse outcome, and for fibrinolytic inhibitors in treatment. lancet ; : - introduction about of the people admitted to hospital in the uk each year for acute upper-gastrointestinal-tract bleeding will die. prognostic indicators for outcome include: age, pulse rate, blood pressure, and haemoglobin at admission, and findings at endoscopy, such as presence, site, and nature of a bleeding lesion, and stigmata of recent bleeding. - one factor that may promote continued bleeding and hence an adverse clinical outcome is the fibrinolytic activity of the upper gastrointestinal tract, because fibrinolysis may lead to digestion of haemostatic plugs. consistent with this possibility, poller and colleaguess demonstrated increased serum fibrin degradation products (fdp) in a small series of patients with acute upper-gastrointestinal-tract bleeding; however, the prognostic value of serum fdp concentrations has not been reported in a prospective study. we therefore investigated the prognostic value of both serum fdp concentrations (a measure of in-vivo fibrinolysis) and the fibrin plate lysis area (fpla) of the plasma euglobulin fraction an in-vitro global test of the fibrinolytic potential of blood. we studied patients with acute upper-gastrointestinal-tract bleeding (haematemesis and/or melaena in the preceding h) who were admitted between april, , and april, , to the medical receiving unit of glasgow royal infirmary and who underwent emergency endoscopy. because of the known diurnal variation in fpla patients were assessed and blood sampled between h and h at the time of assessment for endoscopy. patients who had emergency endoscopy before this time or who were assessed on saturday or sunday mornings were not included in the study. patients were also excluded if they had haemostatic disorders or were receiving anticoagulant, antifibrinolytic, or recent thrombolytic therapy. clinical prognostic factors recorded included age, pulse rate, blood pressure, and haemoglobin on admission. endoscopic findings were recorded. patients were followed up until either discharge or death in hospital, and outcome was recorded in increasing order of adversity-ie, no blood or red cell transfusion, acute surgery, or death (group ); blood or red cell transfusion only (group ); or surgery and/or death (group ).a venous blood sample was taken from the arm contralateral to that used for intravenous access or infusions, anticoagulated with trisodium citrate, and kept on melting ice. platelet-poor plasma was obtained by centrifugation at &deg;c within min of sampling and aliquots stored at - &deg;c before assay. in addition, serum was obtained from a clotted blood sample for measurement of fdp as fibrin-related antigen by tanned red cell haemagglutinationinhibition immunoassay (wellcome fdp, wellcome diagnostics, key: cord- -pr x t authors: gaffney, adam w; mccormick, danny; woolhandler, steffie; himmelstein, david u title: us law enforcement crowd control tactics at anti-racism protests: a public health threat date: - - journal: lancet doi: . /s - ( ) - sha: doc_id: cord_uid: pr x t nan numerous videos document law enforcement officers' indiscriminate use of chemical irritants and kinetic impact projectiles (kips); striking peaceful protesters, and even jour nalists, with batons, fists, and vehicles; and corralling crowds in confined areas, making physical distancing impossible. chemical irritants, including tear gas and pepper spray, have been lobbed at protests nationwide. in one well publicised incident, officers used chemical irritants to chase peaceful protesters from a square near the white house to clear a path for president trump to attend a photo opportunity. such weapons, which are banned in warfare, carry substantial risks. a systematic review of studies found that among injuries from chemical irritants, • % were severe, two were lethal, and caused permanent disabilities. because chemical irritants provoke coughing and sneezing, their use during the covid pandemic raises particular concern about viral spread. the use of kips such as rubber bullets and bean bag rounds, sometimes shot from standard firearms, raises even more serious health concerns. a review of studies involving individuals wounded by kips showed that % died and • % suffered permanent disabilities, including vision loss and surgical abdominal injuries. in the last days of may, , alone, at least twelve protesters incurred grave injuries from kips according to media reports (appendix); several required intensive care, and five suffered severe ocular trauma resulting in partial or complete loss of vision. mass arrests of protesters, often for curfew violations, raise additional concerns. the usa incarcerates more people than any other nation, and its overcrowded jails have functioned as incubators for covid . as many as % of covid cases in illinois may be attributable to the cycling of community members into and out of jails. mass arrests, particularly combined with indiscriminate use of chemical irritants, risk accelerating the pandemic's spread. the medical profession must join in demanding an end to human rights abuses by law enforcement. police murders of people of colour and assaults on peaceful protesters must stop. a moratorium on the use of tear gas is needed. kip use should be banned. some of the us$ billion spent annually on law enforcement in the usa would be better spent on alternatives to policing, such as health, educational, and social programmes. all authors declare serving as leaders in physicians for a national health program, a nonprofit organisation that favours coverage expansion through a singlepayer programme. awg is reimbursed for some travel on behalf of the organisation; all other authors receive no compensation from the organisation. health impacts of chemical irritants used for crowd control: a systematic review of the injuries and deaths caused by tear gas and pepper spray death, injury and disability from kinetic impact projectiles in crowdcontrol settings: a systematic review incarceration and its disseminations: covid pandemic lessons from chicago's cook county jail tear gas use during covid pandemic irresponsible; moratorium needed, says police and corrections expenditures see online for appendix key: cord- - d abhg authors: herten-crabb, asha; davies, sara e title: why who needs a feminist economic agenda date: - - journal: lancet doi: . /s - ( ) - sha: doc_id: cord_uid: d abhg nan in september, , alan donnelly and ilona kickbusch called for a chief economist at who. such a position, they argued, would enable who to better advocate for greater recognition of, and thus action on, the interdependency of health and the economy. we support this proposal: recognition of the interdependence of health and the economy is vital for who to achieve its mandate: "the enjoyment of the highest attainable standard of health… without distinction of race, religion, political belief, economic or social condition". given this mandate, who should be more ambitious than the appointment of one economist. a more strategic and enlightened approach, especially in the aftermath of the coronavirus disease (covid- ) pandemic, would be for who to embrace and articulate a feminist economic agenda. a feminist economic agenda interrogates power dynamics and peoples' relative access to and use of wealth and resources. a feminist economic lens that incorporates intersectionality must address the power dynamics between genders and acknowledge the power relationships between nation states, ethnicities, ages, abilities, and other dimensions of diversity, and how they are interconnected with gender inequality and the economy. a feminist economic approach is consistent with how public health is taught and sometimes practised: that health, and access to health care, is interdependent not only on the economy but also on all other social and commercial determinants of health. , who has estimated a shortfall of million health workers by , largely in low-income and middle-income countries. women comprise more than % of the global health workforce, but who research into the state of gender equity in the health workforce has revealed systematic gender biases, inequities, and discrimination. a feminist economic approach recognises the systems of disadvantage and discrimination that lead to this inequality. minority ethnic status, class, education, and sexuality determine who is represented in unpaid community health-care worker roles. the unpaid and low paid labour of women has contributed to profits for private health-care providers and saved the bottom line of health spending in national budgets: capitalism and patriarchy combine to systematically undervalue social reproductive labour-ie, unpaid care roles as women's work. governments' ability to fund health-care services is dictated by their revenue and fiscal policy space. for the world's poorest countries, revenue and fiscal space have been largely controlled by the policy advice and loan conditionalities of international financial institutions such as the international monetary fund (imf) and the world bank. the imf, the world bank, the g , and the g have championed gender equality, while the g and g have highlighted the necessity of universal health coverage (uhc) and the world bank aims to support pandemic response through its pandemic emergency financing facility. yet the imf and the world bank continue to prioritise austerity measures and "private sector first" strategies that systematically undermine the ability of governments to provide public services and achieve uhc. mark henley/panos pictures on promotion of gender equality to the development of a systematic approach for evaluating the implications of its austerity policies on gender inequality, health delivery, or outcomes. , the key funders of the imf and the world bank, and those that hold the greatest number of executive board votes, are g and g members. these blocs comprise nations (canada, france, sweden, australia, and the uk) with domestic uhc and feminist or genderfocused development policies, although not without their criticisms. these same countries also fund the international financial institutions that promote austerity policies that reduce public spending on health services and wages. , the world's health care is largely delivered by women, but most decision making, including national budgets, lies in the hands of men. initiatives such as women in global health and women leaders in global health have raised the importance of increasing the numbers of women in health decision-making roles and institutions. however, undertaking a feminist analysis of health delivery and resourcing is not gender specific-men can be feminists, and not all women will be. a feminist economic approach to health requires that all people at all levels of healthcare decision making reorient their notion of wellbeing to include gender equality for women in all their diversities. feminist knowledge informs what we count as costs and savings: the national income saved from women's low wages or volunteerism as health-care workers; the benefit to national budgets and health outcomes when there are gender-based violence health-care prevention programmes; and the negative burdens carried by health-care workers exposed to violence, harassment, and exploitation when their work is located in unregulated environments, including homes, non-governmental organisations, and provincial health clinics. a who economic engagement strategy that does not address the social and political determinants of health delivery, resourcing, and decision making risks perpetuating the falsehood that health is a technical enterprise that can be achieved in a silo. health programmes that ignore gender, race, human rights, capitalism and corporatism, sovereign debt, donor influence, (neo)colonialism, and post-conflict transitions will fail to advocate for the necessary political economic interventions that underpin effective health delivery and outcomes. the question remains whether a feminist economic agenda led by who would hold sway over decision makers in governments, political blocs, and international financial institutions. the answer lies in political momentum and who's knowledge of the social and commercial determinants of health. as international financial institutions and donor groups like the world bank and the organisation for economic co-operation and development embrace gender equality and the uhc agenda, who has the opportunity to use its access to these institutions to demonstrate the necessity of a feminist economic approach to build better, more equitable ways to steer sustainable economies that prioritise health and gender equality as mutually inclusive. we declare no competing interests. a decision emerged after many hours of informal consultation at the who executive board in february, , on the next steps for global governance of harmful use of alcohol. clear evidence of increased alcohol consumption and attributable harm in many low-income and middleincome countries (lmics), and predictions of more harm to come if effective policy is not adopted, led a group of representatives from lmics to propose a working group "to review and propose the feasibility of developing an international instrument for alcohol control". the outcome of the executive board discussion illustrates the difficulty that alcohol control advocates face in the global governance environment; it is a compromise that might do more harm than good. the call for a working party to investigate an international control mechanism is not part of the final decision. instead there is a decision to develop an action plan ( - ) "to effectively implement the global strategy to reduce the harmful use of alcohol as a public health priority" and for a review of the global strategy by . this outcome gives the transnational alcohol corporations another years to expand their markets in lmics with emerging economies, the very countries that have been calling for investigation of a health treaty on alcohol, similar to that on tobacco, for several years. in these next years, the alcohol industry will benefit from the existing and future economic agreements, the effect of which is to chill the uptake of alcohol policies. without a framework convention, industry is expected to continue its unregulated marketing in the digital world, using big data to identify and target potential and current alcohol users, and increase profits. lobbying by industry and associated stakeholders is likely to prevent the uptake of effective policy. if we are to prevent the increase in alcohol-attributable harm in the emerging markets, the global health community needs to support national health sectors to protect abstention and reduce the extent to which alcohol is consumed in heavy drinking occasions. we need analysis to develop the content of an international control mechanism to support national governments and attract funding as the who framework convention on tobacco control (fctc) has done. , in this context, we question the executive board decision. how can the governing body of an evidence-based health-protection organisation not investigate the feasibility of an international response that is so clearly needed? perhaps the answer lies in the alcohol blind spot, a failure to respond to alcohol harm by the global health community, and behind that the profits made by the alcohol transnational corporations. industry-funded organisations were engaged in the lead-up to the executive board discussion. engaging america's global leadership argued: "the global strategy has so far been effective and should remain the leading international policy instrument to reduce harmful drinking...despite the constructive progress that has been made, who eb documents have instead started to emphasize that reducing alcohol consumption is an unmet goal, pushing for members to adopt and expand the use of 'best buys' policies. these policies-tax increases on alcohol, restrictions on alcohol marketing, and limitations on the physical availability of retailed alcohol-have unverified track records and can cause serious unintended consequences." uk (ah-c); and school of government and international relations why the who needs a chief economist covid- : the gendered impacts of the outbreak mapping the margins: intersectionality, identity politics, and violence against women of color social determinants of health series the commercial determinants of health delivered by women, led by men: a gender and equity analysis of the global health and social workforce. geneva: world health organization gendered health systems: evidence from low-and middle-income countries feminism for the %: a manifesto international monetary fund. things you need to know about the imf and gender world bank group gender strategy (fy - ): gender equality, poverty reduction, and inclusive growth making gender equality a major global cause g brisbane commitments global healthcare policy and the austerity agenda globalization and health equity: the impact of structural adjustment programs on developing countries the world bank and gender equality the imf and gender equality: operationalising change lessons from sweden's feminist foreign policy for global health declaration and platform for action, adopted at the fourth world conference on women how women contribute $ trillion to global healthcare. the conversation addressing violence against women: a call to action how do gender relations affect the working lives of close to community health service providers? empirical research, a review and conceptual framework key: cord- - edhhkt authors: calisher, charles; carroll, dennis; colwell, rita; corley, ronald b; daszak, peter; drosten, christian; enjuanes, luis; farrar, jeremy; field, hume; golding, josie; gorbalenya, alexander; haagmans, bart; hughes, james m; karesh, william b; keusch, gerald t; lam, sai kit; lubroth, juan; mackenzie, john s; madoff, larry; mazet, jonna; palese, peter; perlman, stanley; poon, leo; roizman, bernard; saif, linda; subbarao, kanta; turner, mike title: statement in support of the scientists, public health professionals, and medical professionals of china combatting covid- date: - - journal: lancet doi: . /s - ( ) - sha: doc_id: cord_uid: edhhkt nan we are public health scientists who have closely followed the emergence of novel coronavirus disease and are deeply concerned about its impact on global health and wellbeing. we have watched as the scientists, public health professionals, and medical professionals of china, in particular, have worked diligently and effectively to rapidly identify the pathogen behind this outbreak, put in place significant measures to reduce its impact, and share their results transparently with the global health community. this effort has been remarkable. we sign this statement in solidarity with all scientists and health professionals in china who continue to save lives and protect global health during the challenge of the covid- outbreak. we are all in this together, with our chinese counterparts in the forefront, against this new viral threat. the rapid, open, and transparent sharing of data on this outbreak is now being threatened by rumours and misinformation around its origins. we stand together to strongly condemn conspiracy theories suggesting that covid- does not have a natural origin. scientists from multiple countries have published and analysed genomes of the causative agent, severe acute respiratory syndrome coronavirus (sars-cov- ), and they overwhelmingly conclude that this coronavirus originated in wildlife, - as have so many other emerging pathogens. , this is further supported by a letter from the presidents of the us national academies of science, engineering, and medicine and by the scientific communities they represent. conspiracy theories do nothing but create fear, rumours, and prejudice that jeopardise our global collaboration in the fight against this virus. we support the call from the director-general of who to promote scientific evidence and unity over misinformation and conjecture. we want you, the science and health professionals of china, to know that we stand with you in your fight against this virus. we invite others to join us in sup porting the scientists, public health professionals, and medical professionals of wuhan and across china. stand with our colleagues on the frontline! we speak in one voice. to add your support for this statement, sign our letter online. lm is editor of promed-mail. we declare no competing interests. director-general's remarks at the media briefing on key: cord- -m kwgcg authors: chen, nanshan; zhou, min; dong, xuan; qu, jieming; gong, fengyun; han, yang; qiu, yang; wang, jingli; liu, ying; wei, yuan; xia, jia'an; yu, ting; zhang, xinxin; zhang, li title: epidemiological and clinical characteristics of cases of novel coronavirus pneumonia in wuhan, china: a descriptive study date: - - journal: lancet doi: . /s - ( ) - sha: doc_id: cord_uid: m kwgcg background: in december, , a pneumonia associated with the novel coronavirus ( -ncov) emerged in wuhan, china. we aimed to further clarify the epidemiological and clinical characteristics of -ncov pneumonia. methods: in this retrospective, single-centre study, we included all confirmed cases of -ncov in wuhan jinyintan hospital from jan to jan , . cases were confirmed by real-time rt-pcr and were analysed for epidemiological, demographic, clinical, and radiological features and laboratory data. outcomes were followed up until jan , . findings: of the patients with -ncov pneumonia, ( %) had a history of exposure to the huanan seafood market. the average age of the patients was · years (sd · ), including men and women. -ncov was detected in all patients by real-time rt-pcr. ( %) patients had chronic diseases. patients had clinical manifestations of fever ( [ %] patients), cough ( [ %] patients), shortness of breath ( [ %] patients), muscle ache ( [ %] patients), confusion (nine [ %] patients), headache (eight [ %] patients), sore throat (five [ %] patients), rhinorrhoea (four [ %] patients), chest pain (two [ %] patients), diarrhoea (two [ %] patients), and nausea and vomiting (one [ %] patient). according to imaging examination, ( %) patients showed bilateral pneumonia, ( %) patients showed multiple mottling and ground-glass opacity, and one ( %) patient had pneumothorax. ( %) patients developed acute respiratory distress syndrome and, among them, ( %) patients worsened in a short period of time and died of multiple organ failure. interpretation: the -ncov infection was of clustering onset, is more likely to affect older males with comorbidities, and can result in severe and even fatal respiratory diseases such as acute respiratory distress syndrome. in general, characteristics of patients who died were in line with the mulbsta score, an early warning model for predicting mortality in viral pneumonia. further investigation is needed to explore the applicability of the mulbsta score in predicting the risk of mortality in -ncov infection. funding: national key r&d program of china. since dec , , several cases of pneumonia of unknown aetiology have been reported in wuhan, hubei province, china. [ ] [ ] [ ] most patients worked at or lived around the local huanan seafood wholesale market, where live animals were also on sale. in the early stages of this pneumonia, severe acute respiratory infection symptoms occurred, with some patients rapidly dev eloping acute respiratory distress syndrome (ards), acute respiratory failure, and other serious complications. on jan , a novel coronavirus was identified by the chinese center for disease control and prevention (cdc) from the throat swab sample of a patient, and was subsequently named ncov by who. coronaviruses can cause multiple system infections in various animals and mainly respiratory tract infections in humans, such as severe acute respiratory syndrome (sars) and middle east respiratory syndrome (mers). [ ] [ ] [ ] most patients have mild symptoms and good prognosis. so far, a few patients with ncov have developed severe pneumonia, pulmonary oedema, ards, or mul tiple organ failure and have died. all costs of ncov treatment are covered by medical insurance in china. at present, information regarding the epidemiology and clinical features of pneumonia caused by ncov is scarce. [ ] [ ] [ ] in this study, we did a comprehensive exploration of the epidemiology and clinical features of patients with confirmed ncov pneumonia admitted to jinyintan hospital, wuhan, which admitted the first patients with ncov to be reported on. for this retrospective, singlecentre study, we recruited patients from jan to jan , , at jinyintan hospital in wuhan, china. jinyintan hospital is a hospital for adults (ie, aged ≥ years) specialising in infectious diseases. accord ing to the arrangements put in place by the chinese government, adult patients were admitted centrally to the hospital from the whole of wuhan without selectivity. all patients at jinyintan hospital who were diagnosed as having ncov pneumonia according to who interim guidance were enrolled in this study. all the data of included cases have been shared with who. the study was approved by jinyintan hospital ethics committee and written informed consent was obtained from patients involved before enrolment when data were collected retrospectively. we obtained epidemiological, demographic, clinical, laboratory, management, and outcome data from patients' medical records. clinical outcomes were followed up to jan , . if data were missing from the records or clarification was needed, we obtained data by direct communication with attending doctors and other health care providers. all data were checked by two physicians (xd and yq). laboratory confirmation of ncov was done in four different institutions: the chinese cdc, the chinese academy of medical science, academy of military medical sciences, and wuhan institute of virology, chinese academy of sciences. throatswab specimens from the upper respiratory tract that were obtained from all patients at admission were maintained in viraltransport medium. ncov was confirmed by realtime rtpcr using the same protocol described previously. rtpcr detection reagents were provided by the four institutions. other respiratory viruses including influenza a virus (h n , h n , h n ), influenza b virus, respiratory syncytial virus, parainfluenza virus, adenovirus, sars coronavirus (sarscov), and mers coronavirus (merscov) were also examined with real time rtpcr sputum or endotracheal aspirates were obtained at admission for identification of possible causative bacteria or fungi. additionally, all patients were given chest xrays or chest ct. we describe epidemi ological data (ie, shortterm [occasional visits] and longterm [worked at or lived near] exposure to huanan seafood market); demographics; signs and symptoms on admission; comorbidity; labora tory results; coinfection with other respiratory pathogens; chest radiography and ct findings; treatment received for ncov; and clinical outcomes. we present continuous measurements as mean (sd) if they are normally distributed or median (iqr) if they are not, and categorical variables as count (%). for laboratory results, we also assessed whether the mea surements were outside the normal range. we used spss (version . ) for all analyses. the funder of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report. the corresponding authors had full access to all the data in the study and had final responsibility for the decision to submit for publication. patients with ncov were included in this study, two of whom were husband and wife. in total, ( %) evidence before this study we searched pubmed on jan , , for articles that describe the epidemiological and clinical characteristics of the novel coronavirus ( -ncov) in wuhan, china, using the search terms "novel coronavirus" and "pneumonia" with no language or time restrictions. previously published research discussed the epidemiological and clinical characteristics of severe acute respiratory syndrome coronavirus or middle east respiratory syndrome coronavirus, and primary study for the evolution of the novel coronavirus from wuhan. the only report of clinical features of patients infected with -ncov was published on jan , , with cases included. we have obtained data on patients in wuhan, china, to further explore the epidemiology and clinical features of -ncov. this study is, to our knowledge, the largest case series to date of -ncov infections, with patients who were transferred to jinyintan hospital from other hospitals all over wuhan, and provides further information on the demographic, clinical, epidemiological, and laboratory features of patients. it presents the latest status of -ncov infection in china and is an extended investigation of the previous report, with extra cases and more details on combined bacterial and fungal infections. in all patients admitted with medical comorbidities of -ncov, a wide range of clinical manifestations can be seen and are associated with substantial outcomes. the -ncov infection was of clustering onset, is more likely to affect older men with comorbidities, and could result in severe and even fatal respiratory diseases such as acute respiratory distress syndrome. early identification and timely treatment of critical cases of -ncov are important. effective life support and active treatment of complications should be provided to effectively reduce the severity of patients' conditions and prevent the spread of this new coronavirus in china and worldwide. patients were clustered and had a history of exposure to the huanan seafood market. among them, there were patients with longterm exposure history, most of whom were salesmen or market managers, and two patients with shortterm exposure history, who were shoppers. none of the patients were medical staff. most patients were men, with a mean age of · years (sd · ; table ). ( %) patients had chronic diseases, including cardiovascular and cerebro vascular diseases, endocrine system disease, digestive system disease, respiratory system disease, malignant tumour, and nervous system disease (table ) . on admission, most patients had fever or cough and a third of patients had shortness of breath (table ) . other symptoms included muscle ache, headache, confu sion, chest pain, and diarrhoea (table ) . many patients presented with organ function damage, including ( %) with ards, eight ( %) with acute respiratory injury, three ( %) with acute renal injury, four ( %) with septic shock, and one ( %) with venti latorassociated pneumonia (table ) . on admission, leucocytes were below the normal range in nine ( %) patients and above the normal range in ( %) patients ( (table ) . platelets were below the normal range in ( %) patients and above the normal range in four ( %). patients had differing degrees of liver function abnormality, with alanine aminotransferase (alt) or aspartate aminotransferase (ast) above the normal range (table ) ; one patient had severe liver function damage (alt u/l, ast u/l). most patients had abnormal myocardial zymogram, which showed the elevation of creatine kinase in ( %) patients and the elevation of lactate dehy drogenase in ( %) patients, one of whom also showed abnormal creatine kinase ( u/l) and lactate dehydrogenase ( u/l). seven ( %) patients had different degrees of renal function damage, with elevated blood urea nitrogen or serum creatinine. regarding the infection index, procalcitonin was above the normal range in six ( %) patients. most patients had serum ferritin above the normal range (table ). patients were tested for creactive protein, most of whom had levels above the normal range (table ). all patients were tested for nine respiratory pathogens and the nucleic acid of influenza viruses a and b. bacteria and fungi culture were done at the same time. we did not find other respiratory viruses in any of the patients. acinetobacter baumannii, klebsiella pneumoniae, and aspergillus flavus were all cultured in one patient. a baumannii turned out to be highly resistant to antibiotics. one case of fungal infection was diagnosed as candida glabrata and three cases of fungal infection were diagnosed as candida albicans. according to chest xray and ct, ( %) patients showed bilateral pneumonia ( %) with just ( %) procalcitonin (ng/ml; normal range · - · ) · ( · ) figure) . additionally, pneumothorax occurred in one ( %) patient. all patients were treated in isolation. ( %) patients received antiviral treatment, including oseltamivir ( mg every h, orally), ganciclovir ( · g every h, intra venously), and lopinavir and ritonavir tablets ( mg twice daily, orally). the duration of antiviral treatment was - days (median days [iqr - ]). most patients were given antibiotic treatment (table ); ( %) patients were treated with a single antibiotic and ( %) patients were given combination therapy. the antibiotics used generally covered common patho gens and some atypical pathogens; when secondary bacterial infection occurred, medication was admin istered according to the results of bacterial culture and drug sensitivity. the antibiotics used were cephalo sporins, quinolones, carbapenems, tigecycline against methicillinresistant staphylococcus aureus, linezolid, and antifungal drugs. the duration of antibiotic treatment was - days (median days [iqr [ ] [ ] [ ] [ ] [ ] ). ( %) patients were also treated with methylpred nisolone sodium succinate, methylprednisolone, and dexametha sone for - days (median [ ] [ ] [ ] [ ] [ ] ). patients used noninvasive ventilator mechanical ventilation for - days (median days [iqr - ]). four patients used an invasive ventilator to assist ventilation for - days (median [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] ). the ventilator adopted psimv mode, the inhaled oxygen concentration was - %, and the positive end expiratory pressure was - cm h o. all four patients were still using ventilators at data cutoff. moreover, nine ( %) patients received continuous blood purifi cation due to renal failure and three ( %) patients were treated with extracorporeal membrane oxygenation (ecmo; table ). by the end of jan , ( %) patients had been discharged and ( %) patients had died; all other patients were still in hospital (table ). the first two deaths were a yearold man (patient ) and a yearold man (patient ). they had no previous chronic underlying disease but had a long history of smoking. patient was transferred to jinyintan hospital and diagnosed with severe pneumonia and ards. he was immediately admitted to the intensive care unit (icu) and given an intubated ventilatorassisted breathing therapy. later, the patient, having developed severe res piratory failure, heart failure, and sepsis, experienced a sudden cardiac arrest on the th day of admission and was declared dead. patient had severe pneumonia and ards after admission. the patient was transferred to the icu and given ventilatorassisted breathing, and received anti infection and ecmo treatment after admission. the patient's hypoxaemia remained unresolved. on the ninth day of admission, the patient died of severe pneumonia, septic shock, and respiratory failure. the intervals ( a) . the brightness of both lungs was diffusely decreased, showing a large area of patchy shadow with uneven density. tracheal intubation was seen in the trachea and the heart shadow outline was not clear. the catheter shadow was seen from the right axilla to the mediastinum. bilateral diaphragmatic surface and costal diaphragmatic angle were not clear, and chest x-ray on jan showed worse status ( b). case : chest x-ray obtained on jan ( a). the brightness of both lungs was decreased and multiple patchy shadows were observed; edges were blurred, and large ground-glass opacity and condensation shadows were mainly on the lower right lobe. tracheal intubation could be seen in the trachea. heart shadow roughly presents in the normal range. on the left side, the diaphragmatic surface is not clearly displayed. the right side of the diaphragmatic surface was light and smooth and rib phrenic angle was less sharp. chest x-ray on jan showed worse status ( b). case : chest ct obtained on jan ( a) showed mass shadows of high density in both lungs. bright bronchogram is seen in the lung tissue area of the lesion, which is also called bronchoinflation sign. chest ct on jan showed improved status ( b). between the onset of symptoms and the use of ventilator assisted breathing in the two patients were days and days, respectively. the course of the disease and lung lesions progressed rapidly in both patients, with both developing multiple organ failure in a short time. the deaths of these two patients were consistent with the mulbsta score, an early warning model for predicting mortality in viral pneumonia. of the remaining nine patients who died, eight patients had lymphopenia, seven had bilateral pneumonia, five were older than years, three had hypertension, and one was a heavy smoker. this is an extended descriptive study on the epidemiology and clinical characteristics of the ncov, including data on patients who were transferred to jinyintan hospital from other hospitals across wuhan. it presents the latest status of the ncov infection in china and adds details on combined bacterial and fungal infections. human coronavirus is one of the main pathogens of respiratory infection. the two highly pathogenic viruses, sarscov and merscov, cause severe res piratory syndrome in humans and four other human corona viruses (hcovoc , hcov e, hcovnl , hcovhku ) induce mild upper respiratory disease. the major sarscov outbreak involving patients occurred during - and spread to countries globally. , merscov emerged in middle eastern countries in but was imported into china. , the sequence of ncov is relatively different from the six other coronavirus subtypes but can be classified as betacoronavirus. sarscov and merscov can be transmitted directly to humans from civets and dromedary camels, respectively, and both viruses origi nate in bats, but the origin of ncov needs further investigation. [ ] [ ] [ ] ncov also has enveloped virions that measure approximately - nm in diameter with a single positivesense rna genome. clubshaped glycoprotein spikes in the envelope give the virus a crownlike or coronal appearance. transmission rates are unknown for ncov; however, there is evidence of humantohuman transmission. none of the patients we examined were medical staff, but medical workers have been reported with ncov infection, of whom are assumed to have been infected by the same patient. the mortality of sarscov has been reported as more than % and merscov at more than %. , at data cutoff for this study, mortality of the included patients infected by ncov was %, resembling that in a previous study. however, additional deaths might occur in those still hospitalised. we observed a greater number of men than women in the cases of ncov infection. merscov and sarscov have also been found to infect more males than females. , the reduced susceptibility of females to viral infections could be attributed to the protection from x chromosome and sex hormones, which play an important role in innate and adaptive immunity. additionally, about half of patients infected by ncov had chronic underlying diseases, mainly cardiovascular and cerebrovascular diseases and diabetes; this is similar to merscov. our results suggest that ncov is more likely to infect older adult males with chronic comorbidities as a result of the weaker immune func tions of these patients. [ ] [ ] [ ] [ ] some patients, especially severely ill ones, had co infections of bacteria and fungi. common bacterial cultures of patients with secondary infections included a baumannii, k pneumoniae, a flavus, c glabrata, and c albicans. the high drug resistance rate of a baumannii can cause difficulties with antiinfective treatment, leading to higher possibility of developing septic shock. for severe mixed infections, in addition to the virulence factors of pathogens, the host's immune status is also one of the important factors. old age, obesity, and presence of comorbidity might be associated with increased mor tality. when populations with low immune function, such as older people, diabetics, people with hiv infection, people with longterm use of immuno suppressive agents, and pregnant women, are infected with ncov, prompt administration of antibiotics to prevent infection and strengthening of immune support treatment might reduce complications and mortality. in terms of laboratory tests, the absolute value of lymphocytes in most patients was reduced. this result suggests that ncov might mainly act on lympho cytes, especially t lymphocytes, as does sarscov. virus particles spread through the respiratory mucosa and infect other cells, induce a cytokine storm in the body, generate a series of immune responses, and cause changes in peripheral white blood cells and immune cells such as lymphocytes. some patients progressed rapidly with ards and septic shock, which was eventually followed by multiple organ failure. therefore, early identification and timely treatment of critical cases is of crucial importance. use of intra venous immunoglobulin is recommended to enhance the ability of antiinfection for severely ill patients and steroids (methylprednisolone - mg/kg per day) are recommended for patients with ards, for as short a duration of treatment as possible. some studies suggest that a substantial decrease in the total number of lymphocytes indicates that coronavirus consumes many immune cells and inhibits the body's cellular immune function. damage to t lymphocytes might be an important factor leading to exacerbations of patients. the low absolute value of lymphocytes could be used as a reference index in the diagnosis of new coronavirus infections in the clinic. in general, the characteristics of patients who died were in line with the early warning model for predicting mortality in viral pneumonia in our previous study: the mulbsta score. the mulbsta score system contains six indexes, which are multilobular infiltration, lympho penia, bacterial coinfection, smoking history, hyper tension, and age. further investigation is needed to explore the applicability of the mulbsta score in predicting the risk of mortality in ncov infection. this study has several limitations. first, only patients with confirmed ncov were included; suspected but undiagnosed cases were ruled out in the analyses. it would be better to include as many patients as possible in wuhan, in other cities in china, and even in other countries to get a more comprehensive understanding of ncov. second, more detailed patient information, particularly regarding clinical outcomes, was unavailable at the time of analysis; however, the data in this study permit an early assess ment of the epidemiological and clinical characteristics of ncov pneumonia in wuhan, china. in conclusion, the infection of ncov was of clustering onset, is more likely to infect older men with comorbidities, and can result in severe and even fatal respiratory diseases such as ards. contributors nc, xd, fg, yh, yq, jw, yl, yw, jx, ty, and lz collected the epidemiological and clinical data and processed statistical data. nc and mz drafted the manuscript. jq and xz revised the final manuscript. xz is responsible for summarising all data related to the virus. lz is responsible for summarising all epidemiological and clinical data. we declare no competing interests. outbreak of pneumonia of unknown etiology in wuhan china: the mystery and the miracle the continuing ncov epidemic threat of novel coronaviruses to global health the latest novel coronavirus outbreak in wuhan, china clinical features of patients infected with novel coronavirus in wuhan, china clinical management of severe acute respiratory infection when novel coronavirus (ncov) infection is suspected: interim guidance sars and other coronaviruses as causes of pneumonia identification of a novel coronavirus in patients with severe acute respiratory syndrome isolation of a novel coronavirus from a man with pneumonia in saudi arabia clinical features predicting mortality risk in patients with viral pneumonia: the mulbsta score discovery of a rich gene pool of bat sarsrelated coronaviruses provides new insights into the origin of sars coronavirus crosshost evolution of severe acute respiratory syndrome coronavirus in palm civet and human middle east respiratory syndrome coronavirus in dromedary camels: an outbreak investigation evidence for camelto human transmission of mers coronavirus surveillance of bat coronaviruses in kenya identifies relatives of human coronaviruses nl and e and their recombination history origin and evolution of pathogenic coronaviruses fatal swine acute diarrhoea syndrome caused by an hku related coronavirus of bat origin evolution of the novel coronavirus from the ongoing wuhan outbreak and modeling of its spike protein for the risk of human transmission wuhan coronavirus has strong ability to infect humans. press release from sars to mers, thrusting coronaviruses into the spotlight prevalence of comorbidities in the middle east respiratory syndrome coronavirus (merscov): a systematic review and metaanalysis sexbased differences in susceptibility to severe acute respiratory syndrome coronavirus infection sexual dimorphism in innate immunity pathophysiology and burden of infection in patients with diabetes mellitus and peripheral vascular disease: focus on skin and softtissue infections clinical findings in cases of influenza a (h n ) virus infection clinical features of three avian influenza h n virusinfected patients in shanghai tcell immunity of sarscov: implications for vaccine development against merscov this study was funded by the national key r&d program of china (number yfc ). we thank all patients involved in the study. key: cord- - axms fp authors: nan title: ribavirin and respiratory syncytial virus date: - - journal: lancet doi: . /s - ( ) - sha: doc_id: cord_uid: axms fp nan experience in population medicine; management of the preventive health programme and information system described will require further training and a substantial time commitment. stocking o argues that in the absence of extra resources it may be preferable for general practitioners to relinquish some patient contact for a role as "central manager and referral agency" within the practice. clearly there is considerable scope for substituting less expensive (and in some instances more appropriate) manpower resources for many tasks currently undertaken by general practitioners." none of the obstacles is insurmountable, and some should be addressed for other reasons. however, ploughing money into fpcs to create the sort of management structure and proficiency that already exists in (often coterminous) health authorities would appear to be both exceptionally wasteful and extremely unlikely in the present economic climate. reintegration of fpcs and health authorities would be the sensible option, not only to provide a viable management structure for general practice but also to secure the advantages of planned community health care which a closer relation between general practice and community medicine would allow. ' even if a new contract was established linking remuneration to performance monitored by fpcs or district health authorities, would it lead to an improvement in the quality of care? preventive medicine lends itself to objective external assessment-it is possible to measure immunisation rates and screening coverage, for example, with the benefit of a computerised population register-and better care should follow. it is also probable that external audit of accessibility would be a major advance, especially in deprived urban areas. nevertheless, external audit of disease management is not without difficulty. lessons can be learned from the experience of recertification and peer review organisations in the usa. at best, external audit can monitor minimum standards, but the highest standards of care must ultimately depend on fostering enthusiasm and stimulating participation in continuing education and research in general practice. and good general practice demands qualities such as kindness and understanding which are not encompassed by performance indicators. the peer review procedure envisaged by the rcgp' appears to hold out the best chance of attaining this wider vision of quality of care, and would complement a more formal line of accountability. on balance, it seems likely that the people of newcastle will benefit if their general practitioners are contractually required to provide services to agreed standards of minimum performance, especially if the organisation to which the practitioners are accountable is not only equipped with teeth but also is capable of making a rational decision about whom to bite. but if we must wait for the end of the tripartite structure in order to achieve this, then perhaps "waiting for greenot" is a more apposite description of where we stand. ribavirin is an investigational synthetic triazole nucleoside of value in the treatment of lassa feverl and certain viral respiratory infections. first synthesised in , it possesses an unusually broad spectrum of antiviral activity, inhibiting under laboratory conditions a wide variety of rna and dna viruses, including among respiratory viruses influenza types a and b, parainfluenza types , , and , respiratory syncytial virus (rsv), and possibly coronavirus. its antiviral effect is expressed at various points in the replicative cycle but generally involves alterations of nucleotide pools and interference with the guanylation step required for ' capping of viral messenger rna. ribavirin has low cellular toxicity and is well tolerated by human beings, the primary adverse effects being haematological with raised unconjugated bilirubin levels in % of subjects on g orally per day and an occasional drop in haemoglobin on g daily. these effects are rapidly reversible and may be related to the accumulation of drug or metabolites in red blood cells. ribavirin is embryotoxic and teratogenic in laboratory animals, though not in baboons. in temperate climates, rsv is the most frequent cause of acute lower respiratory tract disease in infants and young children. in britain rsv accounts for yearly hospitaladmission rates of - to ' per among infants aged - months; and in north carolina it is responsible for - % of all admissions for pneumonia in children under years of age. in hospital roughly % of rsv-infected infants require intensive care and % need assisted ventilation.s although the mortality from rsv infection is generally low, it is especially high in infants with underlying congenital heart disease ( %, rising to % with concomitant pulmonary hypertension), and in the immunocompromised ( %), and is almost certainly raised in infants with bronchopulmonary dysplasia and cystic fibrosis. outbreaks among the elderly in nursing homes have also been associated with serious illness and a case fatality rate as high as &deg; o has been reported. the efficacy of aerosolised ribavirin in rsv-infected infants has been examined mostly in double-blind trials involving normal children and those with underlying disease. in normal infants with illness for several days, therapy over many -hours improved cough, rales, retractions, bronchiolitis, lethargy, overall severity scores, and arterial oxygen saturation by the second to fourth day. - o similarly rsv-infected infants with bronchopulmonary dysplasia and/or congenital heart disease improved more rapidly on ribavirin than on placebo and here benefit was most noticeable within the first h of treatment and the improvements in arterial po were substantia . , in these studies, there were no fatalities among ribavirin-treated infants with bronchopulmonary dysplasia and/or congenital heart disease or others requiring prolonged assisted ventilation, suggesting life-saving effects. a bonus of ribavirin is its effect against other important respiratory viruses. striking improvements were noted in infants treated with ribavirin aerosol for parainfluenza virus type infection complicating severe combined immunodeficiency disease , -a combination often causing respiratory failure and death. moreover, ribavirin aerosol therapy, when started within the first h of symptoms, reduces fever and symptoms from influenza type a (h n ) and type b in young adults, , but here the improvements are modest and insufficient to justify treatment in otherwise healthy subjects. the published work thus indicates the feasibility of broad-spectrum antiviral chemotherapy for three or possibly four potentially serious and often clinically indistinguishable repiratory pathogens. it is also noteworthy that resistance to ribavirin developed in none of the rsv strains isolated during treatment, and conceivably the modest reductions in viral shedding found in most investigations may lessen the incidence of nosocomially acquired infection. delivery of ribavirin via an infant oxygen hood, oxygen tent, inhalation tubing of a respirator, or face mask has the advantage of providing high drug concentrations at the site of viral replication and reduces the likelihood of systemic reactions. indeed no toxic or adverse effects of aerosol therapy were observed among any of infants or adults studied, many receiving an estimated ' mg/kg per hourl for periods of h over days. few otherwise healthy adults will feel that the accelerated clinical improvement is worth the inconvenience of many hours' confinement for this therapy, however safe. rather it should be considered for infants with bronchiolitis or pneumonia, and for high-risk patients with underlying cardiopulmonary disorders or immunodeficiency with probable rsv or influenza, and possibly parainfluenza infection. in high-risk patients early treatment seems indicated before onset of life-threatening disease or confirmation of the diagnosis by laboratory means. in britain, the drug is available on a named patient basis only. it is understandable that the idea of treating urinary incontinence by transferring it to another site should have been slow to gain acceptance, particularly when major surgery is involved. yet urologists, when faced with intractable cases of urethral leakage, have been making judicious use of uretero-ileo-cutaneous diversion for many years, fortified by the increasing safety of this operation and the improvement of collecting devices. the great majority of cases are women for whom no effective urinal is available. uncontrollable reflex detrusor activity due to vesicourethral neuropathy (especially in multiple sclerosis) is the commonest indication, followed by female stress incontinence persisting after multiple local operations. few surgeons deal with enough cases to make a convincing series and publications devoted to the subject are rare. in one report which appeared nine years ago, urinary diversion had been performed in cases of multiple sclerosis ( female) with very favourable results. it was concluded that urinary diversion should be considered much earlier in the treatment of incontinence in multiple sclerosis and not kept as a last resort. in a new report malone and co-workers again put urinary diversion in incontinence in a favourable light, stressing the great improvement in the patient's social acceptability that may be achieved. of the patients had uninhibited detrusor contractions associated with paraplegia (traumatic in and due to multiple sclerosis in ). in another case of multiple sclerosis an indwelling catheter had produced a patulous urethra. the remaining patients were obstetric cases in all of whom several local operations for stress incontinence had failed. there was no operative mortality and complications such as wound and chest infection and paralytic ileus were limited to the patients with multiple sclerosis. in only one case of this disease was any deterioration of neurological status noted postoperatively. before the operation of the patients had been unable to lead a reasonable social life, afterwards only ; the remaining .were inhibited more by fear of the stoma leaking or appearing conspicuous than by episodes of appliance failure. in fact, patients had either no leaks or only occasional leakage in the three months before interviews. patients had troublesome dermatitis around the stoma and in there was stomal ulceration with bleeding, but no one regretted having had the operation. the most common complication was pyocystis (in patients) which was relieved by vaginal vesicostomy performed with the aid of a payr's crushing clamp. malone et al suggest that prophylactic use of this operation should be considered especially in elderly or infirm patients. they also stress the importance of a stomatherapy service for all the patients, and of specialised nursing care and physiotherapy for those with multiple sclerosis. the importance of longterm follow-up is emphasised, for early detection of urolithiasis as well as stomal or uretero-ileal stenosis. in the future fewer diversions may be required, thanks to advances in artificial sphincters and techniques of bladder denervation. particularly promising in women with multiple sclerosis is the injection of phenol into the vesical plexus bilaterally through the vagina and perineum. in one series of lassa fever. effective therapy with ribavirin mechanisms of action of ribavirin report to the medical council subcommittee on respiratory syncytial virus vaccines respiratory syncytial virus infection: admissions to hospital in industrial, urban, and rural areas pneumonia: an eleven-year study in a pediatric practice respiratory syncytial viral infection in infants with congenital heart disease respiratory syncytial virus in immunocompromised children communicable disease surveillance centre. respiratory syncytial virus infection in the elderly - key: cord- -n i e q authors: peiris, malik; leung, gabriel m title: what can we expect from first-generation covid- vaccines? date: - - journal: lancet doi: . /s - ( ) - sha: doc_id: cord_uid: n i e q nan a first generation of covid- vaccines is expected to gain approval as soon as the end of or early . a popular assumption is that these vaccines will provide population immunity that can reduce transmission of severe acute respiratory syndrome coronavirus (sars-cov- ) and lead to a resumption of pre-covid- "normalcy". given an initial reproduction number of around · , which has since been revised to as high as about , and taking into account overdispersion of infections, perhaps about - % of the population would have to be immune to the virus to achieve suppression of community transmission. [ ] [ ] [ ] multiple covid- vaccines are currently in phase trials with efficacy assessed as prevention of virologically confirmed disease. who recommends that successful vaccines should show disease risk reduction of at least %, with % ci that true vaccine efficacy exceeds %. however, the impact of these covid- vaccines on infection and thus transmission is not being assessed. even if vaccines were able to confer protection from disease, they might not reduce transmission similarly. challenge studies in vaccinated primates showed reductions in pathology, symptoms, and viral load in the lower respiratory tract, , but failed to elicit sterilising immunity in the upper airways. sterilising immunity in the upper airways has been claimed for one vaccine, but peer-reviewed publication of these data are awaited. there have been reports of virologically confirmed sars-cov- re-infection of previously infected individuals, but the extent of such re-infection is unclear. whether re-infection is associated with secondary spread is unknown. the immunological correlates of protection from sars-cov- infection and covid- have yet to be elucidated. pre-existing neutralising antibody seemed to have afforded protection against re-infection in people on board a fishing vessel where there was an outbreak of sars-cov- with a high infection attack rate. in animal models, passive antibody transfer protected against covid- , , whereas neutralising antibody correlated with protection after inoculation. however, the roles of mucosal immunity, other biological antibody activities (eg, antibody-dependent cellular cytotoxicity), and t cells in protection conferred by natural infection or passive immunisation are unclear. the prevalence and duration of neutralising antibody responses after natural infection remain to be defined by gold-standard neutralisation assays that use live virus rather than pseudotype neutralising assays or nonfunctional elisa assays. the duration of protection against re-infection with seasonal human coronaviruses might last for less than a year. middle east respiratory syndrome coronavirus (mers-cov) re-infection occurs in dromedary camels, the natural host of that virus. whether re-infected camels are as infectious as those with primary infections is not known. the observation that mers-cov is enzootic in dromedary populations despite high (> %) seroprevalence in juvenile and adult camels implies that virus transmission may not be functionally interrupted by previous infection. also relevant is how influenza vaccines can reduce disease transmission, whereas inactivated polio vaccines are effective at protecting from disease but have less effect on reduction of faecal shedding of poliomyelitis virus and thus possibly on transmission. these observations suggest that we cannot assume covid- vaccines, even if shown to be effective in reducing severity of disease, will reduce virus transmission to a comparable degree. the notion that covid- vaccine-induced population immunity will allow a return to pre-covid- "normalcy" might be based on illusory assumptions. another important consideration is covid- vaccine allocation strategy. first principles would preferentially allocate vaccine supplies to people at high risk of severe morbidity and mortality. preliminary modelinformed analyses support this theoretical inference. however, vaccine allocation perspectives in addition to utilitarian considerations are important. the us national academy of medicine's preliminary framework for equitable allocation of covid- vaccines identified other foundational criteria, such as equal regard, mitigation of health inequities, fairness, and transparency, that should also determine vaccine allocation. alongside the risks of severe morbidity and mortality and of disease transmission, this framework stipulates two additional criteria for equitable vaccine allocation-namely, risks of acquiring infection and of negative societal impact. front-line health-care and essential workers, such as school teachers, belong in both these latter groups. policy makers must be vigilant of the possible impact of vaccine hesitancy. in the covid- response, the activities of some politicians have been incompatible with science and risk further eroding vaccine confidence among the general public. the potential disruption of a proportion of people declining vaccine uptake could be substantial. the likely heterogeneity of such abreactions to vaccination roll-outs between countries and across partisan divides within nations should not be underestimated. finally, if international travel were to fully recommence, vaccine allocation to different countries with varying means of access will require careful deliberation, based on moral grounds and because no country will be truly protected from covid- until virtually the entire world is. notwithstanding these caveats, covid- vaccines are needed, even if they have minimal impact on transmission and despite the challenges of vaccine allocation. what such vaccines are likely to achieve might not be herd immunity. if so, strategies for how we use such vaccines would have to be based on other considerations. will vaccines that protect healthy young adults also protect groups vulnerable to severe disease such as older adults and those with comorbidities? influenza vaccines are less effective in older populations than in younger populations, partly due to immune senescence, which might similarly affect covid- vaccines. however, the so-called original antigenic sin in influenza vaccines that arises from sequential infections by or vaccinations with antigenically closely related strains is not relevant to coronaviruses. if covid- vaccines have acceptable effectiveness in reducing morbidity and mortality in high-risk groups, they would have an important role, irrespective of impact on transmission and population immunity. if high-risk populations can be shielded by vaccination, covid- control measures could be recalibrated. crucially, it will be important to communicate to policy makers and the general public that first-generation vaccines are only one tool in the overall public health response to covid- and unlikely to be the ultimate solution that many expect. we declare no competing interests. individual variation in susceptibility or exposure to sars-cov- lowers the herd immunity threshold draft landscape of covid- candidate vaccines for the world health organization solidarity vaccines trial expert group. covid- vaccine trials should seek worthwhile efficacy chadox ncov- vaccine prevents sars-cov- pneumonia in rhesus macaques evaluation of the mrna- vaccine against sars-cov- in nonhuman primates novavax announces positive phase data for its covid- vaccine candidate covid- re-infection by a phylogenetically distinct sars-coronavirus- strain confirmed by whole genome sequencing neutralizing antibodies correlate with protection from sars-cov- in humans during a fishery vessel outbreak with high attack rate simulation of the clinical and pathological manifestations of coronavirus disease (covid- ) in golden syrian hamster model: implications for disease pathogenesis and transmissibility sars-cov- infection protects against rechallenge in rhesus macaques dna vaccine protection against sars-cov- in rhesus macaques longitudinal evaluation and decline of antibody responses in sars-cov- infection the time course of the immune response to experimental coronavirus infection of man longitudinal study of middle east respiratory syndrome coronavirus infection in dromedary camel herds in saudi arabia modification of an outbreak of influenza in tecumseh, michigan by vaccination of schoolchildren the degree and duration of poliomyelitis virus excretion among vaccinated household contacts of clinical cases of poliomyelitis model-informed covid- vaccine prioritization strategies by age and serostatus discussion draft of the preliminary framework for equitable allocation of covid- vaccine mapping global trends in vaccine confidence and investigating barriers to vaccine uptake: a large-scale retrospective temporal modelling study an ethical framework for global vaccine allocation vaccines to prevent infectious diseases in the older population: immunological challenges and future perspectives original antigenic sin responses to influenza viruses key: cord- -e qh xd authors: unger, jean-pierre; de paepe, pierre; ghilbert, patricia; de groote, tony title: public health implications of world trade negotiations date: - - journal: lancet doi: . /s - ( ) - sha: doc_id: cord_uid: e qh xd nan for personal use. only reproduce with permission from the lancet publishing group. the lancet • vol • january , • www.thelancet.com correspondence licensing requirements". claims that "the negotiations could reduce governmental discretion under gats by introducing international standards for the organisation of services industries" are completely unfounded. further, the authors' reference to the european community hormone ban in this context is largely irrelevant, given the distinct structure of the relevant sanitary and phytosanitary (sps) agreement. had pollock and price been interested in the potential outcome of the article vi: negotiations, they could have referred to a possible precedent in services, the disciplines on domestic regulation in the accountancy sector. assertions that "the wto's sole mandate is trade liberalisation" are mistaken. tellingly, the marrakesh declaration of starts by welcoming "the stronger and clearer legal framework . . . adopted for the conduct of international trade, including a more effective and reliable dispute settlement mechanism". impartial dispute settlement or, more generally, the rule of law in international trade might not be regarded as an important achievement for powerful members that have other-although less politically convincing-policy options. small countries might hold different views, however. of the complaints brought to the wto since , % were from developing countries. in conclusion, pollock and price refer to a process in which "governments lose rights to regulate and to protect economic values and the principles that shape provision of public services". although the gats has now been applied for almost years, pollock and price fail to describe any actual case in which governments would have deprived themselves of their sovereign right to regulate and to determine the scope of public service. these rights have never been questioned in a wto forum. since , the aid policies of industrialised countries has tended to restrict the public sector's functions to mere disease control. on the grounds of the private sector's supposed higher efficiency, this policy recommends marketing of curative care together with prioritisation of disease control within the public sector. gats article . .c. makes this recommendation compulsory: "a service supplied in the exercise of governmental authority means any service which is supplied neither on a commercial basis, nor in competition with one or more service suppliers". it could be invoked by powerful health services companies in countries with a weak bargaining position, to prevent publicly oriented services from receiving government subsidies or oblige subsidised public services to limit their activities to disease control. as a consequence, access to general care will further suffer in areas where private providers are scarce ( % of the population of low-income developing countries live in rural areas), or will become too expensive for most ( · % of south asians live on less than us$ per day ). article . .c. could also hamper disease control-the paradigm of contemporary international aid in health. it provides the legal basis to preclude integration of disease control with general practice. nevertheless, many commentators stress the convenience of integrating programmes into health facilities to achieve a reasonable prospect of successful disease control. such integration requires structures with patients, as journalists noticed while analysing causes of the severe acute respiratory syndrome (sars) epidemic in china. these patients, consulting for various symptoms, represent a pool of users that disease control programmes need for early case detection and sufficient coverage. subsidies to publicly oriented services owned by ministries of health, city councils, and non-governmental organisations could be barred on the ground of gats article . .c. politicians who endorse it carry a heavy moral responsibility. sir-in their seminar (nov , p ), andrew kingsnorth and karl leblanc discuss the prevention of incisional hernias, but overlook the most important way of avoiding incisional hernias-ie, by use of the lateral paramedian incision and the avoidance of midline incisions. there is clear evidence from randomised controlled trials - that the lateral paramedium incision is far superior to the midline incision, reducing the incidence of incisional hernia to as low as · % at year without a single dehiscence. the additional - min required by the lateral paramedian incision is far less expensive than the cost of repairing (often unsuccessfully) the roughly % or more hernias occurring in midline incisions. it is incredible in this age of emphasis on evidence-based medicine that the midline incision, with its attendant morbidity, is the most commonly employed means of access for this operation. harvard medical school, wellesley street, weston, ma , usa (e-mail: silenw@aol.com) peritoneal closure after lateral paramedian incision vertical abdominal incisions-a choice? key: cord- -bm nogig authors: su, shuo; wong, gary; liu, yingxia; gao, george f; li, shoujun; bi, yuhai title: mers in south korea and china: a potential outbreak threat? date: - - journal: lancet doi: . /s - ( ) - sha: doc_id: cord_uid: bm nogig nan first reported in september, , human infections with middle east respiratory syndrome coronavirus (mers-cov) can result in severe respiratory disease, characterised by life-threatening pneumonia and renal failure. countries with primary infections of mers-cov are located in the middle east, but cases have been occasionally exported in other countries (fi gure). human-to-human infections of mers-cov are rare and confi rmed cases are usually traced back to contact with camels, an intermediate host species for mers-cov. as of may , , worldwide, a total of cases and deaths (case fatality rate · %) have been reported, according to who. there is no approved vaccine or treatment. on may , , a -year-old male in south korea developed symptoms and sought medical care at a clinic between may - , before admittance into hospital on may . the patient had been travelling between april -may through bahrain, the united arab emirates, saudi arabia, and qatar. he was asymptomatic upon return to south korea on may , but tested positive for mers-cov on may , along with two additional cases: his -year-old wife, and a -year-old male who was a fellow patient. concerns of further mers-cov spread were confirmed when a -year-old male fellow patient, the daughter of the -year-old case, and two medical staff developed symptoms and were diagnosed with mers-cov infection (appendix). as of may , , south korea has laboratoryconfirmed cases of mers-cov, and more than additional contacts under surveillance. on may , a -year-old male traveller from south korea to huizhou, china was admitted into hospital. mers-cov infection was confi rmed on may , marking the fi rst laboratoryconfirmed case in china (appendix), and the patient was immediately put in isolation. this patient was the son of the -year-old south korean patient. he had visited his father in the hospital on may , developed symptoms on may , and travelled to hong kong by plane on may before arriving by road into mainland china via shenzhen. in response, the chinese health authorities promptly placed high-risk contacts under surveillance, but it is not known whether additional contacts exist and further mers-cov infections in china remains a possibility. this series of events highlighted issues with the current surveillance system put in place to prevent the importation of infectious diseases. the diagnosis for mers-cov infection was made on may for the -year-old patient. his -year-old son should have been monitored as a close contact of the laboratory-confi rmed case, with provisional quarantine and testing upon development of symptoms and isolation upon a positive diagnosis. such a high-risk case should not be travelling until after the incubation period, which is between - days for mers-cov. non-compliance by the patient regarding travel advice likely contributed to this scenario. these events serve as a timely reminder that natural geographical barriers against pathogens can now be easily overcome through trade and travel, and marks the fi rst mers-cov import case that did not come directly from the middle east. these developments are worrisome given favipiravir-a prophylactic treatment for ebola contacts? since the ebola outbreak began in march, , cases of ebola have been reported. to control spread of ebola in west african communities, vaccination campaigns have been proposed. however, the efficacy of candidate ebola vaccines for primary prevention has not been proven. furthermore, in communities in which ebola transmission might be ongoing, an important question is: how will such a vaccination be perceived if a vaccinated person develops ebola? such a scenario is possible in people who contract ebola virus before vaccination. if a person is infected with ebola virus before vaccination, the vaccine might have a post-exposure prophylactic effect. however, how effective this prophylaxis might be is unknown. moreover, if someone is infected more than h before vaccination, the post-exposure prophylactic eff ect is likely to be insuffi cient, leading to possible development of ebola after vaccination. this scenario is likely to result in serious issues relating to community trust and acceptance of an ebola vaccine. how to exclude ebola among people presenting with post-vaccination fever is also an issue. we make a case for the study of favipiravir (toyama chemical, japan), administered as directly observed therapy for contacts of patients with ebola. favipiravir has increased benefit in patients with low ebola viraemia compared with patients with high viraemia. as such, this drug could have a post-exposure prophylactic effect among recently infected contacts and a pre-exposure prophylactic eff ect among contacts exposed to, but not yet infected by, ebola virus. additionally, fever has not been reported as a side-effect of favipiravir (clinicaltrials.gov, nct ). furthermore, oral administration of prophylactic favipiravir gives people the choice to interrupt treatment if wanted. additional effects of prophylactic favipiravir might include increased openness of communities to use alert systems and to support contact tracing services (ie, contacts might be receptive to daily follow-up visits). finally, to reduce incidence of malaria, prophylactic artesunateamodiaquine could be administered to the contacts of patients with ebola. one disadvantage of proposed favipiravir prophylaxis might be the need to exclude pregnant women. to mitigate this problem, pregnancy tests could be included as a routine part of the favipiravir prophylaxis package. finally, prophylactic favipiravir could be field tested by measurement of incidence of ebola among contacts of patients with ebola before and after favipiravir is introduced. we declare no competing interests. that hong kong airport is a major international transport hub, and thus any potential infections can travel worldwide in a short time. after dealing with several pandemic threats over the past years, notably severe acute respiratory syndrome coronavirus (sars-cov) in , h n influenza in , and ebola virus in - , authorities now have ample experience in outbreak response compared with past years. in addition to the need for increased vigilance from health authorities, compliance by the public is crucial for the eff ective implementation of outbreak responses. everyone is responsible for upholding the principles of public health, and must play their part to minimise the chances of disease transmission across borders. middle east respiratory syndrome coronavirus: a case-control study of hospitalized patients middle east respiratory syndrome coronavirus: another zoonotic betacoronavirus causing sars-like disease evidence for camel-to-human transmission of mers coronavirus middle east respiratory syndrome coronavirus (mers-cov)-republic of korea international society for infectious diseases. mers-cov ( ): south korea middle east respiratory syndrome coronavirus (mers-cov)-china we declare no competing interests. key: cord- -vfandmy authors: usuelli, michele title: the lombardy region of italy launches the first investigative covid- commission date: - - journal: lancet doi: . /s - ( ) - sha: doc_id: cord_uid: vfandmy nan during the first months of , italy had the highest number of cases of covid- in europe and in the world. lombardy, with a population of million people, was the region of italy hit the hardest by the pandemic. according to the italian ministry of health's covid- dashboard lombardy had cases and deaths as of oct , , which is one third of all cases and half of all deaths in italy. lombardy, and the rest of italy reacted to the surge in cases too late. even a full lockdown could not slow down transmission of severe acute respiratory syndrome coronavirus . between march and april, , intensive care units treated up to ten times more patients than usual. in lombardy, due to a lack of personal protective equipment (ppe) and training in the proper use of ppe, health workers were infected, and health workers died. the covid- pandemic revealed problems inherent to italy's decentralised health-care system. because different political parties represent the national government and the regional government of lombardy, initial cooperation shifted quickly towards reciprocal blaming as the pandemic led to increased panic. within just days of the first covid- diagnosis on feb , , different guidelines were issued by regional health authorities, significantly deviating from the guidelines issued by the national ministry of health. for example, while the ministry of health suggested that all symptomatic patients in emergency rooms be tested, lombardy's welfare regional director, in official communication about covid- hospital management, asked that only those patients with severe symptoms and requiring admission be tested, and that all other patients be sent home without being tested. continuous wrestling between regional authorities and the central government caused confusion both among citizens and within hospitals. this delayed isolation of the highly industrialised towns of alzano, lombardo, and nembro in the bergamo area, leading to the most severe outbreak within italy. both national and regional authorities could have taken the decision, together or independently, to follow the suggestions of the national scientific committee. to this day, they blame each other. successive conservative governments in lombardy have promoted private health-care institutions for more than years. these have an important role within the welfare system, accounting for about % of the total health services provided. unfortunately, these lombardy governments have given free range to private health-care providers to develop excellent and profitable niches without demanding that those providers maintain social responsibility or invest in essential but less profitable services. certain fields of health care, such as hygiene, preventive primary health care, and public health, and networks of general practitioners and hospitals, with all the essential supportive disciplines like epidemiology, have therefore been neglected. this severely undermined lombardy's ability to respond to the pandemic. findings from a retrospective analysis of epidemiological data suggest that lombardy's first covid- cases occurred as early as jan , - days before the first official diagnosis on feb , , when primary health-care doctors, unsuccessfully, tried to report cases of what was described as strange pneumonia. the regional council of lombardy has now formed a covid- investigative commission within the regional assembly to analyse the sequence of events and the specific choices that led to so many infections and deaths in a region with an extremely high standard of health care. the mandate is political and not judicial. the commission is the first of its kind in all of europe and, to my knowledge, the first in the world. it is an essential step to learn from mistakes and to establish accountability to the italian people. many other countries are trying to set up similar organisational bodies. it took more than months to elect the president of the commission; by italian law, the president of such a commission must be a member of the opposition. the commission's objective is to retrace the series of events and decisions that were taken to respond to covid- , establishing the various degrees of responsibility involved in those decisions. this investigative commission's work, which will last year, will, if done well, be relevant to the entire italian and international community. it is also essential that the commission members, of which i am one, do not play the party-politics customary role of pointing fingers at each other, while overlooking the search for truth within each mistake. so many people have died and suffered-they and their families have a right to know what exactly has happened, good and bad, and i believe they will accept the commission's findings if presented with full transparency, considering the extremely difficult scenario. unless our work proves humble, inclusive, and free of party interests, consequences could be detrimental. cooperation with the scientific community will be essential. experts' counsel and research is crucial to understand the mistakes of the recent past. scientists not only have the duty to be objective observers, but also to speak up. a new call for action is needed now. i call for all political representatives to get involved and take into account the science as the first and main voice in the investigative process, being aware that true cooperation is needed in order to develop better strategies for the future. this is the only way to ensure that lombardy, italy, and all other countries are better prepared for pandemics and able to offer their people the protection they need and are entitled to. i am regional counsellor of lombardy, president of +europa/radicali, and a member of the regional council of lombardy's covid- investigative commission. michele.usuelli@consiglio.regione. lombardia.it lombardia mila medici e sanitari positivi, morti polmonite da nuovo coronavirus ( -ncov) in cina the early phase of the covid- outbreak in lombardy key: cord- -wj vhvxx authors: fananapazir, l.; edmond, elizabeth; eccleston, maureen; anderton, j.l. title: raised urinary fibrin-degradation products, complement, and igg during an influenza-like illness date: - - journal: lancet doi: . /s - ( ) - sha: doc_id: cord_uid: wj vhvxx urine from eight normal controls in whom an influenza-like illness developed contained high concentrations of fibrin-degradation products (f.d.p.), igg, and c( ). the study was carried out when influenza a was prevalent in the community. however, a wide range of serological investigations revealed no evidence for influenza a or other viruses. the infection may have been caused by other viruses which produce upper-respiratory-tract infections and which are not readily diagnosed by serology. urinary fibrin-degradation products are a well-known marker of glomerulonephritic activity and viral antigens may have induced an immune-complex glomerulonephritis in the controls in whom an influenza-like disease developed. a larger normal population should be investigated during a virus epidemic. of male and female blood-donors. their serum-bilirubin data were skewed but women with a bilirubin z mg/dl ( . p. j/l) and men with a bilirubin > . mg/dl ( . p. /l) were claimed to constitute a second, minor population who, owens and evans suggested, had gilbert's syndrome; if so about % of the population would have this disorder. they found two distinct linear sections when their data were plotted on normal-probability as distinct from log-probability paper. our data plotted on normal-probability paper yielded a smooth logarithmic curve with no evidence of bimodality. this difference could be due to sampling error in earlier study ; the upper end of owens and evans' distribution contains very few data points. in fact their data can be accommodated by a single log-normal distribution, thus weakening their case for bimodality. the men with a bilirubin > jjonol/ who were recalled had the usual criteria of gilbert's syndrome-i.e., their serum-bilirubin rose when they fasted, the bilirubin was mainly unconjugated, and gross haemolysis was excluded. the minor haemolysis demonstrated in some patients with gilbert's syndrome is not enough to account for the hyperbilirubinaemia. it is not surprising that the repeat bilirubins were slightly different from the first ones. in patients with a raised bilirubin the concentration does vary and the patients had not fasted before the second examination. is gilbert's syndrome a disease or merely an extreme expression of normality? a low uridine-diphosphate glucuronyl transferase,'s altered bilirubin kinetics, slightly reduced red-blood-cell survival, or even a genetic predisposition do not mean that it represents a disease state. one would expect to find differences in factors which control bilirubin concentration in a group of people with a high bilirubin if they are compared with those with a lower bilirubin. were it feasible to measure them in a large normal population these factors could also be expected to have a skew distribution. the frequency of symptoms in patients with gilbert's disease probably reflects the way they were diagnosed-i.e., by blood tests done to investigate vague lassitude or discomfort. our recalled patients had no such symptoms. we suggest that "constitutional hyperbilirubinaemia" be used in preference to "gilbert's disease" so that the patient can be reassured that the condition produces no symptoms and so that unnecessary investigations will not be ordered during any future non-associated illness in which the bilirubin may be found to be further increased. certainly, treatment with phenobarbitone' to lower the bilirubin and diminish vague symptoms seems misplaced. failure to recognise that the distribution of bilirubin concentration is skewed and the subsequent misapplication of gaussian statistical techniques can yield a misleadingly low upper limit of normal. an upper limit of &micro;mol/l (or - mg/dl) seems too low. the th percentiles in our population were plmol/ ( - mg/dl) for females and mol/ ( - mg/dl) for males, and these values more realistically define the upper limit of "normality". even on these strict criteria % of our screened men had abnormal bilirubin concentrations; almost all of them will have had no hepatocellular disease, but they would, in the past, have been diagnosed as having gilbert's disease. requests for reprints should be addressed to d. r., medical centre, pentonville road, london n ta. hospital, and regional virus laboratory, city hospital, edinburgh summary urine from eight normal controls in whom an influenza-like illness developed contained high concentrations of fibrin-degradation products (f.d.p.), igg, and c . the study was carried out when influenza a was prevalent in the community. however, a wide range of serological investigations revealed no evidence for influenza a or other viruses. the infection may have been caused by other viruses which produce upper-respiratory-tract infections and which are not readily diagnosed by serology. urinary fibrin-degradation products are a well-known marker of glomerulonephritic activity and viral antigens may have induced an immune-complex glomerulonephritis in the controls in whom an influenza-like disease developed. a larger normal population should be investigated during a virus epidemic. introduction the immunological basis for glomerulonephritis is well established and immunofluorescence studies have shown immunoglobulins in the glomeruli of patients with glomerulonephritis. immunoglobulins are produced in response to an antigen, but the nature of the antigen is often obscure and its demonstration difficult. however, numerous bacterial antigens (especially streptococci) may cause glomerular damage through immunological mechanisms. chronic viral infection of animals with lymphocytic choriomeningitis, the agent of aleutian dis-ease of mink coxsackie b , adenovirus/ and other viruses can result in immune-complex nephritis. in man the role of viruses in the aetiology of glomerulonephritis has been studied chiefly in cases or renal disease developing after viral illnesses caused by echovirus , coxsackie b, and varicella infections. raised titres of anti-epstein-barr have been demonstrated in patients with systemic lupus erythematosus glomerulonephritis, and parainfluenza type- antibody titres were raised in patients with immune-complex glomerulonephritis. intravascular coagulation with renal involvement has been reported in patients with influenza-a virus infection" and in a case of goodpasture's syndrome after influenza-a virus infection. urine fibrin-degradation products are an accurate marker of the activity of the glomerulonephritic process. in the present study high concentrations of urine fibrin-degradation products and immunoglobulins suggested that an immunological process consistent with a subclinical attack of glomerulonephritis had occurred during an epidemic of an influenza-like disease. sixteen normal healthy adult volunteers agreed to take part in an investigation to define the normal concentration of urine fibrin-degradation products (f.d.p.) for our laboratory. ml of urine was collected daily in the early morning for a month, dialysed against tap-water, concentrated in polyethylene glycol at &deg;c overnight, and stored at - &deg;c until assay. the tanned red-cell haemagglutination-inhibition im-munoassayl was used with the following modifications. the immunoassay was performed in the microtitre system (cooke engineering co.) and all reagents, fibrinogen standards, and sensitised cells were from the same batch. three concentrations of human fibrinogens (kabi pharmaceuticals ltd., lots no. and ) were included in each assay. the concentration of "clottable" protein in these standards was estimated by the method of ratnoff and menzie. the mean sensitivity of the assay calculated with these values was . mg/ . the concentrationofantisera was / (burroughs wellcomelot k ). the antigen/antibody incubation period was h at &deg;c. the incubation period after the addition of the sensitised cells was h (overnight) at &deg;c. human group- -negative, glutaraldehyde-fixed, fibrinogen ( g/ml) (kabi pharmaceuticals ltd., lot no. ) sensitised cells were used." the plates were read by two observers who agreed to within half a well. igg, igm, and c were measured by the mancini technique. because of the limited amount of urine available for analysis, urine was examined for protein content and blood by 'labstix' only. during the investigation clinical evidence of an influenzalike syndrome with acute upper-respiratory-tract symptoms (cough, sore throat, runny nose), general malaise, and arthralgia developed in eight controls. lymphadenopathy developed in one, and three were absent from work for or days. during the study there had been an epidemic of influenza in the community caused by parainfluenza a and b viruses. blood was taken for virus studies during the attack and one month later, and serum was investigated for antibodies to a wide range of viruses. complement-fixing antibody titres to the following antigens were determined: influenza a, b; parainfluenza type ; adenovirus; chlamydia group b; coxiella burneti ; mycoplasma pneumonice, and respiratory syncytial virus. antibodies to coxsackie bl- viruses were measured by a metabolic inhibition test. serum was tested for heterophil paul bunnell antibody and streptolysin antibody. during the influenza-like illness blood was also taken to measure serum-p.d.p., blood-urea, serum-creatinine, platelets, reticulocytecount, haptoglobulins, prothrombin index, and thrombin-time and a blood-film was studied for fragmented cells or burr cells to detect any evidence of intravascular coagulation. urinary f.d.p., igg, and c concentrations are shown in two of the controls who had an influenza-like illness ( fig. ). the mean urine f.d.p. concentration during the illness in eight controls was . mg/ (s.n.&plusmn; ) and this was significantly higher than the mean concentration in those controls who did not have the illness proteinuria was found in only two controls ( and mg/dl), but the method used to measure urinary protein was poor, there being insufficient urine to carry out a detailed protein estimation by the biuret method. blood not associated with menstruation was detected by microscopy in two consecutive urine samples from one woman during the illness. blood urea and creatinine were not raised in any of the controls at any time. serum antibody titres to the antigens tested were not raised in any of the eight controls. throat and nasal swabs were not taken. the paul bunnell test for heterophil antibody was negative in all eight cases. routine bacteriological cultures were negative and the anti-streptolysin titre was not raised in any of the eight controls. the results of all haematological investigations for disseminated intravascular coagulation were within normal limits. urine f.d.p., complement, and igg were raised in eight of sixteen adult controls studied. in all eight, the urinary changes were associated with an influenza-like illness. there were no changes in the urine of the other eight controls who remained well throughout the study. the possibility that a virus was responsible for the influenza-like illness was investigated. the infection occurred at the beginning of april, , when influenza-a infection was prevalent in the area. however, in the eight controls affected there was no serological evidence for influenza-a infection or for infection by a wide range of other viruses. however, the infection may have been caused by viruses&mdash;e.g. rhinovirus, echovirus, coronavirus, all known to cause upper respiratory infection-which are not readily diagnosed by serology. although there was no laboratory confirmation of viral infection, the clinical illness with upper-respiratory-tract symptoms, general malaise, fever, and arthralgia was compatible with such an infection. the excretion of f.d.p., complement, and igg in the urine is associated with glomerulonephritis. o immune complexes consisting of viral antigen and antibody may have been responsible for a glomerular nephritic process in the eight controls in whom urinary fibrin-degradation products, igg, and complement were raised. in man, as in laboratory animals, immune-complex disease due to deposition of viral antigen/antibody complexes in glomeruli may be of importance, since coxsackie-b antigen and australia antigen have been observed in glomeruli of patients with nephritis. others have used explant cultures in an attempt to isolate viruses directly from renal tissue obtained either at necropsy or by diagnostic biopsy.z z cytomegalovirus, adenovirus, measles, varicella, and coxsackie virus bl have been isolated from infant kidneys obtained at necropsy, but not from kidneys of older patients. particles with the characteristics of coronaviruses have been seen in the kidneys of patients with endemic (balkan) nephropathy. c-type r.n.a. viruses have been implicated in the aetiology of systemic lupus erythematosus, and kidneys from patients with lupus nephropathy have been found to contain antigens related to c-type virus from human cells (hel- virus).'" urine fibrin-degradation products, complement, immunoglobulin, and protein excretion should be measured prospectively and detailed virus studies should be carried out during an epidemic of influenza or other viral infection in a larger normal population. requests for reprints should be addressed to j. l. a., department of medicine, western general hospital, edinburgh eh xu. diseases of liver and biliary system communicable diseases scotland: weekly reports / and . c. d. s. unit, ruchill hospital nowos-&lstrok;awski, a. ibid. , ii key: cord- -dcdc sqi authors: kimball, am; thant, myo title: “what, me worry?” businesses and aids at davos date: - - journal: lancet doi: . /s - ( ) - sha: doc_id: cord_uid: dcdc sqi nan at the davos summit in february, , the world economic forum released its current survey on businesses and hiv/aids. in , we outlined the case for business in asia to play a pivotal role in preventing the epidemic. at that time, an estimated million people in asia had been infected with hiv. today that number is estimated at · million. aids is a preventable disease. the survey finds an absence of alarm in the business sector which, if true, bodes poorly for success in controlling this epidemic. beyond the tragic human costs, the economic and financial tolls of this epidemic are well known. costs to employers include: increased insurance premiums, larger expenditure on welfare benefits, decline in productivity, and increases in hiring and training costs. loss of skill base, institutional knowledge, and potential conflict in the workplace because of stigmatisation are more difficult to measure. at the macro level, the business environment, including markets and disposable income of consumers, savings rates, interest rates, and general education of the labour force, are put at risk. the findings in the survey from firms worldwide are a subset of global business surveyed annually by the world economic forum. firms appear less concerned this year than last year. this lack of concern is accompanied by conjecture rather than science as a basis for decision-making. informal policies prevail except in high-prevalence areas such as sub-saharan africa. why such complacency? the global epidemic has shown its inexorable nature in community after "what, me worry?" businesses and aids at davos pregnancy to any antiasthmatic drug), there is still much be learned. this need for information is particularly the case for systemic glucocorticosteroids and for recently introduced medications, such as salmeterol, formoterol, and leucotriene-receptor antagonists. one negative point is that, when systemic glucocorticosteroids are administered during the first trimester, the risk of an orofacial cleft is increased by about , although the power of the studies is poor and many confounding factors persist. one positive point is that more than women have been exposed to inhaled corticosteroids (mostly beclomethasone and budesonide) during pregnancy with no increase of outcomes in the infant (including congenital malformations). the higher reported risk of hypertension and pre-eclampsia in steroid-treated pregnant women is not related to the drugs but to uncontrolled asthma. thus, because many clinical trials on inhaled corticosteroids have shown efficacy in pregnant asthmatic women in terms of symptoms, lung function, and reduction of asthma exacerbations, maintaining asthma control during pregnancy is the goal; and, when the indication is clear (eg, severe asthma exacerbation), the benefit of systemic glucocorticosteroids is far greater than the risk. the main message of the update is that it is safer for the asthmatic pregnant woman to be treated with asthma drugs than to suffer from asthma symptoms and exacerbations, and that obstetricians and asthma-care providers should work together. guidelines for asthma during pregnancy should not differ from the guidelines for all asthmatic patients, but fetal toxicity should be monitored and an evidence-based search for drug treatment should be continued. community, country after country; will it now be business after business? in asia, the prospective new epicentre of the epidemic, the efforts of the thailand business coalition on aids and the tata group in india highlight roles business can play: prevention and education for workers; workplace programmes to prevent discrimination; and public-private collaboration and funding for effective programmes. the thailand business coalition on aids offers a range of tools for businesses to assure good-quality programming at all organisational levels. the tata group has focused on a full range of workplace programmes to ensure the sexual health of their employees, including an emphasis on nondiscrimination. leadership at the top of firms, coupled with government commitment, is key. the most populous countries in the global community, china and india, are now in the cross-hairs. projections for india are alarming: - million people living with hiv by , and a potential of million cases by . the epidemic is driven by commercial sex-work, and clients include businessmen who could benefit from education programmes in the workplace. there are peer-to-peer strategies that are effective in condom promotion. thai experience suggests that also addressing the clients ensures success. workplace programmes to secure the safety of the workforce would be a valuable contribution at this critical time. many economies are rural in asia; the effects of hiv on the household level are profound. the health infrastructure in china is crumbling, especially in rural areas, even as market reforms have created unprecedented economic growth. the business sector in china should lead the reinvigoration of preventive and health services. the march summit of the business coalition on aids, in beijing, was a perfect launch. the expansion of access to antiretroviral treatment in asia will not be a panacea. us experience shows that the reprieve from hiv is not forever, efficacy is not %, and people living with hiv face many obstacles in returning to work. from a business perspective, proactive prevention coupled with compassionate policies in the workplace and coverage of treatment through insurance is the wisest choice. there is a gulf between the public and private sectors that must be bridged in the fight against aids and other emerging infections. the urgency of robust public-private partnering is clear in the asia-pacific region, where the threat of new human infections, such as severe acute respiratory syndrome and avian influenza, challenge systems that have not received adequate investment to scale-up to successfully meet these new threats. the economics of intervention by the private sector are not always self-evident. much depends on the ability of the public sector to induce private firms to act for the common good. market incentives, such as tax breaks and subsidies, can lower the cost of training and help businesses provide information and education for workers. the reduction in duties and taxes on imports of equipment and reagents could reduce drug costs. the cornerstone of partnership is for each sector to understand the needs and motivations of the other. the world economic forum's survey is a pioneering work in progress. the kind of information it is positioning itself to capture is very important in the fight against the hiv epidemic. business has brought innovation, energy, and investment in creating value in economies across the globe. the ongoing struggle against hiv and other emergent infections requires no less. in south africa, where less than % of people who need antiretroviral treatment actually get it, private-sector companies are stepping in to fill the need. a growing number are supplying such drugs directly to employees who are hiv-positive or are facilitating access to drugs via third parties such as non-governmental organisations. while businesses in the rest of the world are becoming less concerned about aids, the contradictory trend in south africa is being driven, on the face of it, by two imperatives. the first is heightened social awareness in the postapartheid society. the second is more bankable: an often-compelling economic argument. behind these two driving factors, however, lies the darker reality of the south african government's slow and reluctant concession that it needed to intervene with drugs in the country's aids crisis, and its underperformance in rolling-out treatment with antiretrovirals since being pressed into doing so by, among other things, court rulings. this is where, increasingly, private companies are stepping in. "the corporate sector is shouldering more responsibility for the health of its workforce than it ever has in the past", says bernie clark of the health-care consulting team of alexander forbes, a firm that advises businesses on employee benefits and has helped several companies to develop aids policies (clark b, alexander forbes, johannesburg, south africa, personal communication). about aids, specifically, clark adds: "the perception is that the state is doing precious little to assist the formal work sector to stay at work." so the lesson is that necessity is the mother of drugs' provision. the unadorned bottom-line is that it is cheaper for a firm to supply antiretrovirals than to have an untreated aids patients die while on the payroll. the bottom-line is especially true when the prevalence of hiv positivity runs as high as % -as it does in many of south africa's mining companies which, not surprisingly, have pioneered inhouse aids treatment. for the same reasons of prevalence and financial reckoning, it may be that south african firms are presently leading where others elsewhere in the world will in time follow. a leading example of aids management in asia is thailand, where strong political backing for awareness and prevention campaigns has held the infection rate to · % -compared with south africa's %. in thailand, the thailand business coalition on aids has spawned its own umbrella organisation in the asian business coalition on aids. the coalitions' activities, though, are limited to education and prophylaxis, and do not include inhouse treatment. the most recent survey of the world economic forum's global health initiative shows that awareness by business that aids will affect operations and profits reflects the level of efforts to combat the disease. south african business leaders are well ahead of the rest of the world at % awareness; south and south-east asia, where the thai and asian coalitions are active, lags at %. then the levels fall off even more dramatically: in east asia, where, in china, one of the most worrying prevalences is developing, awareness is at a low %, as it is in latin america. the global health initiative worked with several south african firms to organise case studies, which vividly illustrate the imperatives and benefits for companies offering antiretrovirals to their employees. gold fields, for example, a mining house with mainly low-skilled workers in south africa, calculated that-with one in three of its miners hiv positive-failure to intervene would lead to losses of up to % of earnings by the year . we declare that we have no conflict of interest. global business surveybusiness and aids: commitment and action? world economic forum a role for business in hiv/aids in asia fact sheet: asia modelling hiv/aids epidemics in bostwana and india india's hiv epidemic the economic burden of illness for households in developing countries: a review of studies focusing on malaria, tuberculosis, and human immunodeficiency virus/acquired immunodeficiency syndrome china must prioritise health opportunities for all ministry of health and global business coalition on hiv/aids joint summit on business and aids in china perceived barriers to employment among persons living with hiv/aids key: cord- - mvzjrdg authors: nan title: balkan nephropathy date: - - journal: lancet doi: . /s - ( ) - sha: doc_id: cord_uid: mvzjrdg nan the natural history of balkan (endemic) nephropathy is one of the most fascinating topics in renal medicine. - a consensus view of some of the salient features may be summarised as follows. the clinical picture is one of progressive renal failure, insidious in onset and usually unaccompanied by salt retention or hypertension. the disease occurs principally between the ages of and and is very rare below or above . females predominate ( / ) in the younger age-groups but later the sex difference is lost. survival-times range from a few months to nearly years with approximately half the patients dying in years. a family history of balkan nephropathy is found in about in cases in the endemic area. the disease is rural rather than urban, and most of the patients are connected with farming. there is no association with socioeconomic status, nutrition, or hygiene. the incidence of balkan nephropathy within the endemic area is variable, but levels as high as % of the population have been claimed for some villages with perhaps % of individuals showing symptomless proteinuria. clustering of cases in certain parts of villages, even in individual houses, has been described. the endemic area is situated at an altitude of to metres and lies in the vicinity of the danube and its tributaries in adjacent parts of yugoslavia, bulgaria, and romania. it is a region of generally high humidity and high rainfall. no local peculiarities in geology have been described. important information is provided by the incidence of balkan nephropathy in individuals who move into or out of the endemic area. a history of residence in the affected area for at least years is usual, accounting for the development of nephropathy among incomers from disease-free regions who settle in the endemic areas and for the rarity of the disease among people who left the endemic areas when young. the pathology of balkan nephropathy is equally unusual. the major renal lesion is one of progressive tubular destruction and interstitial and capsular fibrosis. - gross renal atrophy results. the tubular damage is seen principally in the lower parts of the proximal convoluted tubule and the loop of henle. the status of glomerular changes in balkan nephropathy is disputed. - they were originally regarded as secondary to the tubular lesions and the interstitial fibrosis. recent work suggests a more distinct glomerular component in the disease process, with local deposition of immune complexes. the central importance of the tubular lesions in balkan nephropathy is, however, emphasised by the results of renal function tests. - the first detectable abnormality is tubular proteinuria, shown by an increase in urinary &bgr; -microglobulin and changes in electrophoretic patterns. defects in acidification and ammonia and urea excretion follow, then alterations in p-aminohippurate clearance and glycosuria culminating in a falling glomerular filtration-rate and renal decoxnpensation. overt proteinuria, detected by routine tests, is a late feature of the disease, and tests for early tubular proteinuria are essential. estimations of urinary &bgr; -microglobulin and urine electrophoresis have proved valuable in epidemiological surveys in the endemic areas. in the course of such investigations some patients have begun to have tubular proteinuria while others have shown an oscillating pattern with tubular proteins appearing only between october and february-an observation which could have important setiological implications. one final piece of information has to be added to the pathology. about a third of patients dying of balkan nephropathy in bulgaria and yugoslavia have papillomas and/or carcinomas of the renal pelvis, ureter, or bladder. the tumours are sometimes multiple and some-times bilateral. a proportion of these tumour patients, and of "healthy" individuals from the same geographical area, have raised serum &bgr; -microglobulin levels." the search for aetiological agents in balkan nephropathy has focused on possible local factors. studies of several trace elements in the soil and water, and in tissues from patients with the disease, have proved inconclusive: the trace elements in question include lead, copper, zinc, uranium, barium, cadmium, arsenic, fluorine, cobalt, and chromium. the disease existed before the advent of synthetic agrochemicals. there is no evidence to implicate bacteria such as &bgr;-haemolytic streptococci, leptospira ieterohaemorrhagiae, and brucellae. claims have been made for arborviruses and a coronavirus. reviewing the subject in , barnes drew attention to the possible role of nephrotoxic fungi occurring as contaminants on foodstuffs, a notion which gained support from the later observations of austwick and smith. these workers reported a statistically significant correlation in three endemic areas between variation in the late-summer and autumn rainfall and the number of local deaths from balkan nephropathy during the succeeding two years-the first clear association between a local environmental factor and the disease. they also described heavy fungal contamination of local foodstuffs, particularly by penicillium verrucosum var. cyclopium and fusarium spp. attempts to demonstrate mycotoxins were unsuccessful but in a new investigation, reported this week on p. , one strain of p. verrucosum var. cyclopium induced striking renal tubular lesions when force-fed to rats for only days. the lesions, located in the pars recta and junctional zone of the proximal convoluted tubule, are closely similar to the tubular changes in many patients with balkan nephropathy ; - and at present they seem to provide an acceptable experimental model for the disease. it is clearly a model rather than the model, and other nephrotoxin-producing fungi may be involved in the human disease as well as additional (non-fungal) setiological agents; one important mycotoxin which should be explored in more detail is ochratoxin a. a stumbling-block is the discrepancy between the wide distribution of the fungus and the apparently narrow distribution of the disease, though it is possible that balkan nephropathy is waiting to be discovered outside south eastern europe-for instance, in africa. a useful exercise would be to . sattler, t. a., dimitrov, ts., hall many possibilities are opened up by this work. the chemists and biochemists will want to characterise the putative nephrotoxin and establish its mode of action on the proximal tubular epithelium, the pathologists will be interested in the further evolution of the tubular changes and, above all, in the possible relation between balkan nephropathy and renal-tract tumours. the very recent demonstration of close similarities between balkan nephropathy and urothelial tumours with respect to geographical clustering, age, and sex within the vratza district is of particular interest. most importantly, the case for implicating fungi in the aetiology of balkan nephropathy seems to have been strengthened. more information is obviously required about p. verrucosum var. cyclopium and the other nephrotoxin-producing fungi which are almost certainly present in the endemic areas; but it would not be premature to reinforce measures aimed at preventing the local contamination of foodstuffs by potentially lethal fungi. hypertension in the elderly three months ago jackson and his colleagues' i reported on six previously healthy patients aged between and admitted to hospital within a few days of starting hypotensive medication. in each case a large fall in blood-pressure was associated with severe but mainly reversible consequences such as actual or near loss of consciousness. the subsequent correspondencez- has focused on several interrelated problems common to much of present medical practice. is there an increased risk associated with hypertension in the elderly and is this risk reversible with therapy? at what cost in iatrogenic disease might some increase in survival be purchased, and can the labour and expense of detecting and treating symptomless hypertension in this age-group be justified in social and economic terms? raised diastolic and systolic pressures are very common in old age and much of the argument that they can be ignored is based on the thesis that what is common must be normal and therefore safe, on descriptions of hypertensives who have reached a , , . . markovi&cacute;, b. isr key: cord- -efbjyuen authors: ravi, krithi title: ethnic disparities in covid- mortality: are comorbidities to blame? date: - - journal: lancet doi: . /s - ( ) - sha: doc_id: cord_uid: efbjyuen nan ethnic disparities in covid- mortality: are comorbidities to blame? on june , , public health england (phe) reported on the disparities in the risk and outcomes of covid- . after adjusting for sex, age, deprivation, and region, people from a black, asian, and minority ethnic (bame) background had a higher risk of death from covid- than white british people. this analysis did not adjust for comorbidities, and the phe report highlighted this to be an important limitation as comorbidities were postulated to be "more commonly seen in some bame groups". phe refers to a study from the covid- clinical information network (co-cin), led by harrison and colleagues, of the difference in survival from covid- associated with membership of an ethnic group. in this study, once comorbidities were accounted for, there was no difference in covid- mortality between ethnic groups. this initially appears to support phe's conclusion that differences in the distribution of comorbidities may account for the increased covid- mortality of bame patients. however, in co-cin's analysis of more than patients with covid- admitted to uk hospitals, bame patients were more likely to have diabetes, but less likely to have other comorbidities such as chronic cardiac, pulmonary, kidney, and neuro logical disease, malignancy, and dementia. in the multivariate analysis of risk factors for covid- mortality, the adjusted hazard ratio for diabetes ( • ) was less than that for chronic cardiac ( • ), pulmonary ( • ), and kidney disease ( • ), and dementia ( • ), and equal to the adjusted hazard ratio for malignancy ( • ). furthermore, age was by far the largest contributor to risk of death, with an adjusted hazard ratio of • for patients aged - years and • for those aged years and older, compared with people younger than years. • % of white patients admitted to hospital with covid- were aged years and older, compared with • % of black, • % of asian, and • % of minority ethnic patients. as patients from a white ethnic background were more likely to be older and have comorbidities associated with a higher risk of dying from covid- , it is very concerning that the case fatality at days after hospital admission for covid- appears to be the same in black and white patients. the lack of association between ethnicity and covid- mortality after adjustment for comorbidities is not reassuring. this suggests that research into ethnic disparities in covid- mortality must consider social as well as biological factors. disparities in the risk and outcomes of covid- investigating associations between ethnicity and outcome from covid- i declare no competing interests. i thank roba khundkar for her support and constructive criticism when writing this correspondence. department of surgery, southampton general hospital, university hospital southampton nhs foundation trust, southampton so yd, uk key: cord- -rh n u n authors: frumkin, howard; myers, samuel s title: planetary health and the us election date: - - journal: lancet doi: . /s - ( ) - sha: doc_id: cord_uid: rh n u n nan elections impact health through changes in both healthcare delivery and upstream social and environmental policies. the upcoming us election presents stark contrasts in environmental policies that will affect health in the usa and globally. here we examine these contrasts through the lens of planetary health. a hallmark of the current us administration has been its hostility to environmental stewardship and its embrace of an antiregulatory agenda. president donald trump has appointed administration officials from the ranks of polluting industries and their lobbying firms; eviscerated some key government agencies; and diluted or overturned environmental regulations (table) . notably, trump has called climate change a hoax and has cast doubt on established science. the democratic presidential candidate, joe biden, has stronger pro-environmental positions as evidenced by the actions of the obama administration in which he served and by his published election platform on a clean energy revolution and environmental justice. the candidates' environmental policy positions to date are outlined in the table. climate change policy provides one of the sharpest distinctions between trump and biden. climate change has extensive health implications through pathways that include severe weather events, infectious disease spread, hunger and reduced nutrition, mental health effects, and forced migration and conflict. the trump administration's denial of climate science, withdrawal from the paris accords, and dismantling of climate policy increase the risk of these outcomes in the usa and globally. , by contrast, biden's proposed climate change policies would be expected to yield health benefits; mitigation action delivers health co-benefits , and adaptation, such as disaster planning, heatwave preparedness, and planned relocation, can reduce human suffering. , the growing field of planetary health makes clear that other areas of environmental policy impact on health. protection of terrestrial and marine biodiversity may limit infectious disease exposure, promote mental health, facilitate pharmaceuticals discovery, and improve nutrition. protecting the recreational, cultural, and spiritual value of access to undisturbed public lands has a role in supporting mental and physical health. . safeguarding human health from pollution of air, water, and soil was a core reason for establishing the us environmental protection agency (epa) in , and the trump administration's weakening of these safeguards puts americans at increased risk of cardiorespiratory disease, endocrine and neurobehavioural abnormalities, and some cancers. some of the health consequences of post-election environmental policies will be felt in the near term, whereas others will be delayed. for example, adaptation actions such as pandemic preparedness are expected to be stronger under a biden presidency than under a trump presidency, as shown by the current administration's covid- response. action to reduce emissions from power plants and motor vehicles can yield reduced air pollution, and health benefits, within months to years. but some health benefits of policies that conserve land, water, and biodiversity will only manifest over many years. the environmental policies that are pursued after this election will be felt in the usa and globally. actions to protect rivers and streams, for example, will mainly benefit those in the affected watersheds, and continued soil loss will compromise local agriculture. but persistent toxic chemical emissions do not remain in place; they circulate globally in processes that are accelerating with climate change. the health implications of promoting versus obstructing climate action will be felt worldwide and across future generations. although a biden presidency would be expected to advance planetary health more than a second trump term, there are likely to be limits to these benefits. first, biden's policies do not go far enough for many environmentalists. for example, unlike some of his opponents in the democratic party presidential primary race, biden has stopped short of promising to ban fracking, despite its direct and indirect adverse health effects. critics have pointed to biden's continued reliance on advisers associated with the obama administration's "all of the above" energy strategy, some with links to the fossil fuel industry. second, although the us president has considerable power through agency appointments and executive orders, legislative solutions and budgeting rest with the us congress. a republican majority in either or both houses of congress could stymie progress. third, many us environmental policies face legal challenges and trump has established a highly conservative judiciary. this is a fraught historical moment. in the months leading up to the election, fires have consumed more than million acres of western forests in the usa. hurricanes in the atlantic and the gulf of mexico led to the deaths of over americans in states from north carolina to texas, and caused more than us$ billion in damages. efforts to move people to safety from these disasters have been hampered by the covid- pandemic. these emergencies arise in the context of the larger global climate emergency. according to the intergovernmental panel on climate change, the window for reductions in greenhouse gas emissions to avoid catastrophic climate change is rapidly closing. similarly, the intergovernmental science-policy platform on biodiversity and ecosystem services warns that there is only a short time to act on threats to biodiversity. continued reliance on fossil fuels, destruction of ecosystems, dissemination of persistent toxic chemicals, and other environmental depredations-many of them permitted, if not promoted, during the trump presidency-are inconsistent with a healthy future for humanity. the alternative is a transition to ways of living that protect both natural systems and the health of current and future generations. this path requires new approaches to generating energy, producing and consuming food, chemicals, and other manufactured goods, travelling, and designing and building cities. the vast public investments some governments are making during the covid- pandemic could spur this transition, and us leadership could be catalytic. the outcome of the us election will have far-reaching consequences for planetary health. we declare no competing interests. access to health care and the us election planetary health: protecting nature to protect ourselves president trump nominates acting epa chief andrew wheeler, a former coal lobbyist, to lead agency trump broke the agencies that were supposed to stop the covid- epidemic beijing says it is anything but. the new york times the biden plan for a clean energy revolution and environmental justice cop special report: health and climate change a breath of bad air: cost of the trump environmental agenda may lead to extra deaths per decade the undoing of us climate policy: the emissions impact of trump-era rollbacks public health co-benefits of greenhouse gas emissions reduction: a systematic review health benefits of policies to reduce carbon emissions adapting to climate change: thresholds, values, governance successful adaptation to climate change: linking science and policy in a rapidly changing world connecting global priorities: biodiversity and human health. a state of knowledge review. geneva: un environment programme, convention on biological diversity, world health organization nature and mental health: an ecosystem service perspective assessment and valuation of recreational ecosystem services of landscapes report of the lancet commission on pollution and health climate change and global cycling of persistent organic pollutants: a critical review the false promise of natural gas on climate policy, biden's advisers reveal more than his proposals do. the intercept atlantic hurricane season an ipcc special report on the impacts of global warming of . °c above pre-industrial levels and related global greenhouse gas emission pathways, in the context of strengthening the global response to the threat of climate change, sustainable development, and efforts to eradicate poverty summary for policymakers of the global assessment report on biodiversity and ecosystem services of the intergovernmental science-policy platform on who manifesto for a healthy recovery from covid- . geneva: world health organization key: cord- -p e authors: krogh, palle; elling, folmer title: fungal toxins and endemic (balkan) nephropathy date: - - journal: lancet doi: . /s - ( ) - sha: doc_id: cord_uid: p e nan all infants born during a two-month period in the maternity ward of our hospital. the results show (figure a) that in out of samples rt levels were - times above the normal adult range. all children were euthyroid. in the other cases (figure c) the rt was in the normal adult range. in these cases the slightly raised serum t levels and the normal serum t.s.h. levels suggested that the sera were from the mother since in cord-blood serum t levels are highly reduced and t.s.h. concentrations are normal or increased. the error could therefore be elucidated without further blood-sampling. the rt levels screened in the babies contrast greatly with undetectable t levels (figure b) found in cases of congenital hypothyroidism, diagnosed at one week and six weeks after delivery. both cases cannot be strictly compared with the results obtained at birth in cord blood. for reasons given above, however, it seems unlikely that maternal t could influence the level observed in cord blood. we conclude that screening for neonatal hypothyroidism with serum t could be of advantage and certainly deserves further investigation. this method is simple and hardly influenced by abnormal thyroxine-binding globulin, which greatly affects serum-t levels. it is likely that such a screening done at birth would permit early detection of congenital hypothyroidism and give the affected child the best chance of avoiding mental retardation. we want to draw attention to the hypothesis that e.n. is caused by ochratoxin a or other fungal toxins, proposed at the nd international symposium on endemic nephropathy and referred to in your editorial.s this hypothesis was based primarily upon the striking similarities between e.n. and ochratoxin-a-induced porcine nephropathy. ochratoxin a is a major disease determinant of naturally occurring nephropathy in pigs and poultry.' meat of pigs and poultry exposed to ochratoxin-a-contaminated feed contains residues of ochratoxin a, a heat-stable metabolite. ochratoxin a has been encountered in - % of homegrown cereals and pork meat in an endemic village in yugoslavia." in the search for an environmental cause of e.n. ochratoxin a seems a likely candidate. the possible role of fungal metabolites in the aetiology of e.n. is further supported by the highly significant correlation between excess of rainfall over evaporation in harvest and initial storage periods and the number of people who die ofe.n. during the succeeding two years, observed in all three e.n. countries (bulgaria, romania, and yugoslavia)." a high water content in foodstuffs favours fungal growth and mycotoxin formation. the possible association of pig husbandry and e.n. mentioned by apostolov et al. would be better explained by indicting ochratoxin a residues in pork meat, and hence a higher exposure for those people who eat pork meat compared with non-consumers of pork meat (the muslims). furthermore, if pig-borne coronavirus were the cause of e.n., would not one expect nephropathy among workers at pig slaughterhouses all over the world? to test the ochratoxin hypothesis information is needed on total exposure of the village population in endemic areas, based upon total diet studies. work of this type is now in progress at the institute for medical research, zagreb. also important in this context is the possible detection and localisation of ochratoxin a in kidneys from e.n. patients. work of this type, by use of immunofluorescence, is now in progress at our institutes. sir,&mdash;the concentrated form necessary for presentation of data in your excellent letters section may occasionally lead some of your readers to suspect that authors have overlooked important, and even elementary, facts. thus fuller and mccartney' find it difficult to judge the significance of our data n serum high-density lipoprotein (h.d.l.) levels in patients with coronary heart-disease (c.h.d.) because we did not give information on other variables. in fact we did not find any significant correlation between apo-ai-containing lipoprotein particles and other relevant indices (the fact that we did not measure h.d.l. cholesterol but apo-ai-containing particles is also relevant to the interesting letter by lopes-virella and colwell" clearly, we would not have stressed the potential usefulness of h.d.l. determination if the data had suggested that quantitative h.d.l. variation largely reflects variation in other lipoprotein indices. fuller and mccartney question our statement that "h.d.l. concentration is to a great extent independent of lipid and lipoprotein indices usually measured". obviously, our statement does not preclude the existence of correlations between h.d.l. level and other lipoprotein parameters. data in the papers cited by fuller relationship, that it "has varied between positive, negative, or non-significant". we think that our statement covers this situation adequately. proceedings of the second international symposium on endemic nephropathy; p. . sofia advances of veterinary science and comparative medicine key: cord- - bl ztuc authors: reid, michael j a; silva, sachin; arinaminpathy, nimalan; goosby, eric title: building a tuberculosis-free world while responding to the covid- pandemic date: - - journal: lancet doi: . /s - ( ) - sha: doc_id: cord_uid: bl ztuc nan in march, , the lancet commission on tuberculosis highlighted the opportunity to build a tuberculosis-free world. after years of neglect of this disease, the un high-level meeting on tuberculosis in september, , made ending tuberculosis a global priority; global leaders committed to important steps, including ambitious country-specific tuberculosis case-finding and prevention targets, and a revitalised research agenda. the lancet commission concluded that the prospect of a tuberculosis-free world was a realistic objective that could be achieved with sufficient accountability and resources, and detailed the catastrophic consequences of failing to build on that momentum. in india alone, deaths from tuberculosis would cost the economy at least us$ billion each year over the next years. in october, , however, the possibility of achieving a tuberculosis-free world seems challenging. even before the covid- pandemic, declines in tuberculosis incidence fell short of targets. despite consensus on the importance of global accountability, efforts to secure meaningful global accountability were mired in obfuscation and bureaucracy. moreover, the covid- response has reduced access to tuberculosis services worldwide, including in china, india, south africa, and nigeria. the potential advantages of physical distancing on tuberculosis transmission notwithstanding, covid- is also likely to reduce access to tuberculosis diagnostics, especially for those at greatest risk of drugresistant tuberculosis. the impact of the covid- response on care-seeking behaviour among people with tuberculosis is unknown, but available data suggest that fewer people are accessing tuberculosis services than would usually be expected. the potential impacts of these various challenges on tuberculosis transmission have been estimated; , even a temporary disruption resulting from covid- societal lockdowns might cause a long-term increase in tuberculosis incidence and mortality. in india, kenya, and ukraine, a -month lockdown, followed by a -month recovery period, is projected to lead to an estimated · million, , and additional incident tuberculosis cases in the next years, respectively, because of limited access to drugs, diagnostics, and prevention programmes in the past few months. the economic burden due to these additional incident tuberculosis cases is likely to be profound. we calculated the health spending due to these additional incident cases of tuberculosis using estimates of government tuberculosis spending per case and outof-pocket spending on tuberculosis care and projected the additional annual health-care costs that would result from these excess tuberculosis cases in india, kenya, and ukraine. after accounting for annual growth rates, we estimate that a -month lockdown, followed by a -month recovery, would result in an excess cost of $ · billion in india, $ million in kenya, and $ million in ukraine with an increase of · %, · %, and · % in average annual health spending on tuberculosis in each country over the next years (table) . if the disruptions were to extend by an additional months on top of the months of lockdowns and months of recovery ( months of lockdown and months of recovery), then these costs would health spending categories include national tuberculosis programme, outpatient care, inpatient care, and drugs purchased in addition to those purchased by the national tuberculosis programme. we used the estimates by cilloni and colleagues to estimate the additional incident cases of tuberculosis that would result due to a -month lockdown with a -month recovery and a -month lockdown with a -month recovery. we calculated health spending due to the additional cases using estimates of tuberculosis spending per case, per year, in , along with the annual growth rates reported by su and colleagues. all costs are reported in inflation-adjusted us$. additional incident tuberculosis cases values are reported with % bayesian credible intervals. increase to $ billion in india, $ million in kenya, and $ million in ukraine. in india, as much as % of that additional cost will be borne by individuals and households (appendix). our estimates do not take into account the excess health-system costs from covid- alone, which are likely to be substantially greater still. moreover, our estimates assume that the distribution of costs between the government versus the individuals and households, would remain unchanged over a -year period and that costs increase at a constant annual rate. despite these challenges, there are opportunities for synergy to expand tuberculosis programmes, strengthen tuberculosis response, and increase resources towards ending tuberculosis as governments mobilise covid- response efforts while maintaining existing tuberculosis programmes. furthermore, many of the messages of the lancet commission on tuberculosis are as relevant to national covid- responses as they are to national tuberculosis programmes. covid- and tuberculosis both require robust infection control strategies and similar diagnostic infrastructure. community engagement has been essential in tuberculosis control to address stigma, which has already been associated with covid- . mitigation strategies that proved successful in tuberculosis can also be deployed to assist in the community control of covid- , although the infection dynamics are different. moreover, peoplecentred models of care, community-based services, video-supported treatment, or home-based care that have been championed by tuberculosis care providers are relevant to covid- screening and management programmes. leveraging the extended capabilities of the private sector to improve access to testing capability while pursuing a social protection agenda are important components of the global response to both diseases. in addition, given the scale of testing needed in the covid- pandemic, the introduction of testing capabilities in low-income and middle-income countries should be used for tuberculosis and hiv as well. , as the lancet commission emphasised, global tuberculosis efforts must move beyond traditional siloed development assistance approaches towards greater country ownership and holistic, multisectoral global cooperation. that same approach is crucial for the global covid- response. in the short term, covid- has inevitably drawn attention away from tuberculosis services and might lead to an increase in tuberculosis burden and incidence. now is the time to leverage the political capital that exists for the global covid- response to enable lasting change in the tuberculosis response. covid- , like tuberculosis, reminds us of the importance of prioritising health and allocating financial and human resources for universal health coverage and addressing the needs of vulnerable populations. with sound science, effective collaboration, smart investments, and efficient synergies, covid- efforts could strengthen the global tuberculosis response and not undermine it. building a tuberculosis-free world: the lancet commission on tuberculosis un. political declaration of the un general assembly high-level meeting. united nations high-level meeting on the fight against tuberculosis who global progress report on tuberculosis elimination impact of covid- on tuberculosis control in china impact of covid- on tuberculosis services in india impact of covid- intervention on tb testing in south africa tuberculosis and hiv responses threatened by covid- the potential impact of covid- -related disruption on tuberculosis burden a decrease in tuberculosis evaluations and diagnoses during the covid- pandemic the potential impact of the covid- pandemic on tuberculosis: a modelling analysis potential impact of the covid- pandemic on hiv, tuberculosis, and malaria in low-income and middleincome countries: a modelling study tracking total spending on tuberculosis by source and function in low-income and middle-income countries, - : a financial modelling study to end tb, first ever high-level meeting on tuberculosis must address stigma new diseases and old threats: lessons from tuberculosis for the covid- response multicenter evaluation of the cepheid xpert xpress sars-cov- test leveraging the advances in hiv for covid- key: cord- - jugyncm authors: nan title: references and abbreviations date: - - journal: lancet doi: . /s - ( ) - sha: doc_id: cord_uid: jugyncm nan , (colover) (c) , (hendnckse) (c) , (clezy) (c) see also breast cancer chest-synopsis of diseases of the chest (pare and fraser) (r) child abuse (carmi and zimrin) (sibert) (r) child development services-and infant mortality rate in india (tandon et al) (c) child health-health visitors and (goodwin) (c) childbirth&mdash;in holland, ; injury to pelvic floor muscle innervation in (snooks et al) ; at weekends (cole) (c) , (newton) (c) , (paccaud et al) (c) , (macfarlane) (c) children&mdash;addiction to video games, ; child abuse (carmi and zimrin) (sibert) (r) ; child care law, working party and, , children (gray and cockburn) (moore) (r) ; cns symptoms with ramtidine in (de galcomo et al) (c) ; depression in (davis) (c) ; deprivation and hospital admissions (maclure and stewart) , (rosenberg) (c) , (west) (c) ; fictitious epilepsy in (meadow) ; in hospital, charter for, ; and medical research (pearn) ; mortality of in the gambia (lamb et al) , (lohse) (c) , (northrup) (c) ; pneumonia m. papua new guinea (shann et al) ; research and (pearn) , (silverman) (c) , sexual abuse of, report, children (gray and cockburn) (moore) (r) child-resistant packaging-for household goods, china-stomach cancer in, chlamydia trachomatis-rapid detection (taylor et al) (c) , (hawkins et al) (c) , (berr&oacute;n et al) (c) ; screening urine for (adger et al) chlorambucil-and chromosome damage (palmer et al) (c) chlorhexidineand who essential drug list (denton) (c) , (kahan et al) (c) , (fowler) (c) chlorophenols-and cancer (olsen and jensen) (c) , (gallagher and threlfall) (c) , (correction) chloroquine&mdash;intramuscular, in children (trigg et al) (c) ; response to immunisation and (greenwood) c cholecystectomy rates-and gallstone prevalence (bateson) , (mpherson et al) (c) cholera-alum in prevention of (khan et al) (c) chorion biopsy-and argininosuccinicaciduria diagnosis (vimal et al) (c) ; for citrullinaemia and methylmalonicaciduria (kleijer et al) (c ; haemophilia b diagnosis (tnnesen et al) (c) ; haemophilia diagnosis in twin pregnancy (mulcahy et al) (c) ; rhesus isoimmunisation and (kanhai et al) (c) chorionic gonadotropin-maternal serum, and down syndrome (chard et al) (c) chromosomes-abnormal in secondary ewing's sarco-ma (tilly et al) (c) (schiller) (c) . and mental confusion (flind and rowley-jones) (c) , (mam etal) (c) ; remission of mycosis fungoides with (mamus et al) (c) ; or ' vagotomy for luxtapyloric ulccr (strom et al) ; versus ramtidme in duodenal ulccr (gough et al) ciprofloxacin&mdash;intravenous, mtraprostatic levels of (boerema et al) (c) cirrhosis&mdash;prediction of (scirensen et at) , (correction) , (e) , (lindegard) (c) , (renwick) (c) ; primary biliary, aberrant bileduct hla-dr and (ballardini et at) cisplatin&mdash;intracavity. allergy and (markman) (c) citrullinaemia-chorionic biopsy in diagnosis (kleljer et al) (c) claudication, intermittent&mdash;ketanserin in (decree et at) , (fonseca et al) (c) 'cling film'&mdash;in central venous catheterisation (panning) (c clinical atlas of human chromosomes (grouchy and turleau) (ne) clinical biochemistry of the elderly (hodkinson) (brewin) (c) , (silverman) (c) ; zelen randomisation in (gore) (c) clinical tropical diseases (maegraith) (ne) clinicians-in management (chantler) (c) clofibrate-in prevention of ihd (oliver et al) , (green) (c) , (oliver et at) (c) clonidine&mdash;intrathecal, neurotoxicity of (tamsen and gordh) (c) , (coombs) (c) , (tamsen and gordh) (c) clostridium spp-two toxins from in diarrhoea (borriello et al) (c) cocaine-adolescent abusers (washton et al) (c) coccidiosis, see cryptospondosts; isospora belli coeliac dlsease&mdash;alpha-gliadin and suppressor-cell activity in (o'farrelly et al) ; k dglycoprotein as antigen in (maury andteppo) ; immune complexes in (maury and teppo) , (husby and svehag) (c) ; and sarcoidosis (douglas et al) , (macgregor) (c) , (correction) , (simpson) (c) , (lowe and johnston) (c) ; testing intestinal permeability and (selby et at) (c) , (bjarnason et al) (c) , (stevens et al) (c) ' cottus&mdash;during pregnancy (klebanoff et al) cold boxes-making of, colitis, ulcerative&mdash;cyclosporin in (gupta et al) (c) ; seasonality of (myszor and calam) (c) , (don and goldacre) (c) ; water-ski spill and (bundgaard and jarnum) (c) college of health-alternative medicine guide, colon cancer-and breast cancer (levine and witte) (c) , (wilhams) (c) (frohne and pfander) (hannmgton-kiff) (r) government statement, ; overheating and (stanton) , (cohen) (c) ; in se scotland (bain and bartholomew) (c) ; ventilatory dysfunction and (e) cotinine-urine levels in babies, maternal passive smoking and (woodward et al) (c) co-trimoxazole-toxicity of (jick et al) (c) , (lennon) (c) ,shann)(c) cotsides-use of (e) c-reactive protein&mdash;predictor m meningitis (borchsemus et al) (c) ; in bacterial with viral meningitis (zegher et al) (c) crohn's disease&mdash;seasonality of (myszor and calam) (c) , (don and goldacre) (c) cryptorehidism&mdash;circulating pituitary autoantibodies in (poupland-barthelaix et al) (c) cryptosporidosis&mdash;in aids, amprolium for (veldhuyzen van zanten et al) (c) ; in calves and handlers (rahaman et al) (c) (anderson) (c) ; metyrapone and sodium valproate for (glaser et al) (c) ; sodium valproate for (cavagnini et al) (c) cyclamates-carcinogenicity of, cyclophosphamide-in adjuvant breast cancer therapy (howell et al) cyclosporin-blood levels and complications (irschik et al) (c) ; interaction with rifampicin (daniels et al) (c) ; interstitial fibrosis with in renal graft (klintmalm et al) , (farnsworth et al) (c) , after liver graft, haemolytic uraemic syndrome with (bonser et al) (c) ; measurement of (holt and white) (c) , (albano et al) (c) , (woloszczuk et al) (c) (harper et al) (c) ; for red-cell aplasia (totterman et al) (c) ; in renal transplantation (salaman) , (ballardie et al) (c) ; in renal transplantation in children (klare et al) (c) , in ulcerative colitis (gupta et al) (c) cystic fibrosis-fetal cholecystokinin and (gosden and gosden) , (brock) (c) , (gosden and gosden) (c) , (cantor et al) (c) , (gosden and gosden) (c) ; meconium ileus and (muller et al) (c) , (barson et a]) (c) ; screening for (mastala et al) (c) ; survival in (anderson) (c) , (wilcken) (c) , (littlewood and miller) (c) cytarabine&mdash;and hla-dr antigen expression in leukaemia (pinto et al) (c) ; low-dose, for leukaemia in the elderly (harousseau et al) (c) (pedersen and m&oslash;lsted-pedersen) (c) ; sucrose in mixed meals (slama et at) , (ferner) (c) , (heaton et at) (c) , (slama) (c) (c) diazoxide-serum androgens with (hallengren and h&ouml;kfelt) (c) diet-and chd, dhss report (e) ; and chd mortality rates in usa (le fanu) (c) ; and hypertension (e) , (rosenberg and coleman) (c) ; and market forces, glc report, ; and myocardial metabolism (thuesen et al) , (frick) (c) ; protein restricted in renal failure (rosman et at) ) ; salt in, and hypertension (brown et at) (c) , (bush) (c) , (finn) (c) , (hughes-davies) (c) , (michell) (c) , (smith) (c) , (e) , (de wardener) (c) , (macgregor) (c) (watt and hart) (c) , (beard et al) (c) (swaminathan) ; antibiotic resistance (lacey) ; drugs, diagnostic aids and vaccines (murray) , human genetics (white) ; human molecular biology (weatherall) ; human perfectibility (rose) ; and immune system (rabbitts) ; message of (wolpert) ; oncogenes (weiss and marshall) ; probes in diagnosis (steel) (barnes) (c) , (mathews) (c) , (smith) (c) , (roddie) (c) , (schwartz) (c) (c) , (sargeaunt) (c) enteral and tube feeding (rombeau and caldwell) (goode) (r) environmental health-asphalt production and lung cancer (wilson (c) ; detergents and the gut (e) , (clark) (c) , (roe) (morgan et al) (c) , (stephenson) (c) damage to at bhopal disaster (andersson et al (c) , damage to from christmas trees (brazier) (c) (rowland et al) (c) ; and medical research (chye and ratnam) (c) ; ovulation induction in (porter et al) (c) , pregnancy from, oestrogens and prognosis in (emperaire et al) (c) ; see also warnock report fertility&mdash;after sex change (dewhurst and gordon) (c) &agr;-fetoprotein&mdash;maternal serum levels (johnson and lingley) (c) (mayne) (c) . (whitty) (c) ; intolerance to (gerrard) (c) (jenkins et al) (c) free radicals-and alcoholic hver disease (ryle) (c) t; and cell damage (garcia-brunuel) (c) , (singh and ghosh) (c) ; lipid peroxidation and ethanol hepatotoxicity and (halliwell and gutteridge) (c) (roe) ; see also aged gestational trophoblastic tumours-genetic origins of (e) giardia lamblia&mdash;culture of (gordts et al) (md) , (meyer) (c) glaucoma-bromocriptine in (mekki and turner) (c) ; intraocular pressure control in (e) ; and ipratropium bromide with salbutamol (packe et at) (c) glucagon-(i- )-peptide-for bihary colic pain (jacobson et at) (c) glucose-blood levels, measurement errors (de pasqua et al) (c) glue sniffing&mdash;advice on, glycoprotein&mdash;in immune compiexes (maury and growth hormone-(e) growth-hormone-releasing factor-radioimmunoassay of (saito et al) (c) grf-producing tumour-somatostatin analogue for (werder et al) (c) guide to alcohol and drug dependence, a (madden) (ne) guide to parenteral administration of drugs (hipwell et al) (beeley) (r) guillam-barre syndrome-plasma exchange m (oster- man et at) , (e) gynaecology-examination methods (amias) (c) (c) , (tomson) (c) (ramsey et at) (c) haemophilia a-dna probe for detection (harper et at) ; dx marker in prenatal diagnosis (tdnnesen et at) (c) transplantation of for babies (oliver) (c) ; prevention in haemodialysis (simon) (c) ; and reverse transcriptase in blood products (seto et (c) ; and antibodies to htlv- (stewart et al) (c) ; neoplastic cell lines and (popovic et at) (c) , parasites and missionaries and (hino et at) (c) , (karpas) (c) (hughes-davies) (c) , (michell) (c) , (smith) (c) , (e) , (de wardener) (c) , (macgregor) (c) (mitchell and fahey) (currie) immune system-dna in (rabbitts) immunisation&mdash;information on (hull and nicoll) (c) , response to, chloroquine prophylaxis and greenwood) (c) ; responsibility for vaccines (anand) (c) (patton and kistner) (ne) ; conception after embryo catheter passage (schulman) (c) (campbell) (c) language-in lancet, over years (bell) ; transatlantic english (spiers) laser-for sutureless extra-intracranial anastomosis (jam) (c) lassa fever-management of (e) , (emond et ; disease, protein load in (hirschberg et al) (c) ; ethanol, free radicals and (halliwell and guttendge) (c) (geisler et al) (c) lymphoid malignancies-distribution of (lloyd et at , (c) , (craft et (brahams) duty to care for nhs patients (brahams) insanity, definition of (wells) , (brahams) libel action and gmc proceedings (brahams) (fallon et al) (c) ; bacterial with viral (eglin et at) (c) ; bacterial with viral, c-reactive protein in (zegheretal) (c) ; bacterial, kits for diagnosis (e) ; c-reactive protein as predictor in (borchsenius et at) (c) (hayman) ; transmission of (barker) (c) myeobactenum xeitopi-distribution of (rahman and sinclair) (c) mycosis fungoides-remission with cimetidine (mamus et (comfort) (c) nitroglycenn-plasma levels of (taylor) (c) , (hirtz et al) (c) (brewerton) occupational health-cadmium workers, monitoring of (hughes) (c) ; chlorophenols and cancer (olsen and jensen) (c) (cox) (c) osteomalacia-creatine clearance in (fonseca et al) (c) , (williams and barnes) (c) , (decaux and delwiche) (c) , (lucas et al) (c) (warlow) (c) ovary--combination chemotherapy in cancer of (neijt et al) ; teratomas, genetic origins of (e) overdose, see poisoning oxfam-report on food, power and poverty, oxygen-domiciliary supply by nhs, , ; inspiration-phased (winter et (thomas et al) (c) papillomavirus-(greenspan et al) , (greenspan and greenspan) (c) , (madeley) (c) papua new guinea&mdash;pneumonia in children in (shann et al) parainfluenza virus-treatment of infection (nicholson) paraquat-plasma levels (hart et (nutt and carter) (c) (harrison and speller) (c) , (morris) (c) ; tumour marker tests, (mitchell) (c) ; in the wards (bamber) (c) pathophysiology-altered regulatory mechanisms in disease (frohlich) photosensitivty&mdash;to amiodarone, prevention of (ferguson et at) c) pneumococci-perinatal transmission of (shaw et al) (c ; sepsis from after splenectomy, fatal (bnvet et al) (c) , (gonzaga) (c) pneumocystis carinti-in aids, prophylaxis with pyrimethamme-sulfadoxine (gottlieb et al) (c) (fox) primary health care, promotion of (chabot) teaching hospitals' cash crisis (holland) traditional values and market forces in medicine (owen) uvulectomy in africa (wind) poisoning&mdash;carbon monoxide (quilliam) (c) , (james) (c) , (greenslade) (c) , carbon monoxide, in the home, video, ; carbon monoxide, late sequelae (brandon) (c) , (danel and barret) (c) , (swain) (c) ; melphalan, survival after (coates) (c) ; paraquat, plasma levels in (hart et (c) ; ultrasound in, cancer risk of (kinnier wilson and waterhouse) ; ultrasound in, report of working party, ; ultrasound in, warning, ; unwanted, costing of (gerber) (c) , (hall) (deitch) (c) , (deitch) (c) , (tagart) (c) , (marks) (c) , (williams and durdey) (c) regional health authorities-changes in (deitch) registrars-post registration experience of (cookson) (c) rehydration, oral-in low birth weight baby (abdalla et at) (c) , (sachdev) (burns-cox) (c) ; treatment of (e) retroviruses&mdash;factor viii concentrates and (levy et al) , (correction) ; lymphotropic in aids infant, from mother (vilmer et al) (c) rett's syndrome-and infantile autism, chromosome marker for (gillberg et al) (c) , (fitchett) (c) , (jenkms et al) (c) (simpson) (c) , (lowe and johnston) (c) (c) ; analogue for growth releasing factor producing xiii tumour (werder et al) (c) south africa-apartheid and psychiatry in (e) , (sashidharan) (c) , child health in (stuart) (c) ; health care in (dommisse) (c) , , (retief) (c) , (walker) (c) , (dommisse) (c) (allen) (c) ; film and report, ; speech therapy after (berman et al) (c) , (lincoln and mcguirk) (c) , (pickersgill) (c) ; food-induced dose dumping of (hendeleset al) (c) (c) , (watts) (c) , (gram et al) (c) (shaper and cook) (c) , (scott-samuel) (c) , (tilford) (c) wales, appointment, upper volta-yellow fever epidemic in (baudon et al) (c) uraemia-conjugated oestrogen for bleeding in (liu et al) ; glycosylation and (bruns and wills) (c) urethritis, see urinary tract infections urinary bags-formalin in (suryaprakash et at) (c) urinary stones--extraction of (e) urinary tract infections&mdash;ciprofloxacin for (boerema et al) (c) ; f i r s t -c a t c h urine screening for (adger et al) , (veeravahu and clay) (c) ; renal function after (verrier jones and asscher) (c) ; in schoolgirls, and later pregnancy (davison et (silver) ; see also round the world uterus&mdash;cervical cancer, depot medroxyprogesterone acetate and (who collaborative study) (c) , cervical cancer screening (deitch) ; cervical cancer screening for younger women (soutteret a)) (c) , (last andritchie) (c) ; cervical dysplasia, bromocriptine for (donath and schindler) (c) (berrino) (c) , (parkin and moss) (c) , (graafandzielhuis) (c) , (la vecchia et al) uvulectomy-in africa (wind) v v genes-and autoimmune disease (adams) (c) vaccines-meningococcal, safety of (zolhnger et al) (c) vaginosis&mdash;anaerobic, metronidazole for (blackwell) (c) vagotomy&mdash;proximal gastric, failure of (hoffman and jensen) (c) valproate-action in epilepsy (loscher and siemes) (c) ; tor cushion disease (cavagnini et al) (c) (compston and ledger) (c) vitamin ki-and femur neck fracture (hart et al) (c) , (mitchell) wilm's tumour-mutant genes in (crawfurd) (c) haemophilia b-chorionic biopsy in detection (ttinnesen et at) (c) haemophilus influenzae-epiglottitts and pericarditis due to (mier and shanson) (c) ; serious mfection in adult haemopoietic growth factor-role of premature babies (harrison and matthews) (c) , (e) , (cooke) (c) haemorrhagic fever with renal syndrome-in france (ligny et at) (c) ; genus hantavirus proposed (desmyter et al) (c) ; in scotland (walker et al) (c) ; see also hantaan virus handbook for clinical teachers, a (newble and cannon handbook of hypertension-review of (folkow et at) (c) handbook of ocular pharmacology (smith) (ne) handicapped, see disabled hantaan-related virus-in africa (gonzalez et at) (c) hantavirus-genus proposed (desmyter et at) (c) head injury&mdash;from fall, axonal injury and (adams et at) ; skull x-ray in (fowkes et at health care-ancillary support in (howard) (c) ; in belgium, , (farber) (c) , (nemery and piette) (c) health and illness (helman) (maclean) (r) ; government and in usa (silver) sir douglas black monograph (e) ; and insurance m usa (silver) , (klarman (c) ; presidential campaign and in usa c) , primary care and mental illness (e) ; primary, in the gambia (lamb et at) , (lohse) (c) c) , private, in usa (himmelstein and woolhandler) , (mccabe) (c) , (minuth) (c) ; race and survey, , and reduction of smoking health services-and politicians (middteton) (c) prescription for survival (kerr and poole) (mcewen) (r) health visitors-and child health (goodwin) (c) haites et at) ; disease of, nmr in, ; failure of heart disease in the elderly (martin and camm) (wedgwood) (r) ; the heart and rheumatic disease hypertrophic cardiomyopathy, adenosine receptors and (lohse et at) (c) ; lymphoproliferative disorders with transplantation ne) ; myocardial metabolism and diet (theusen et at) , (frick) (c) ; myocardial oxygen consumption (rees et at) (c) ; sudden cardiac death in the community c) &aring;sberg c) , (c) c) ' basten (c) , (correction) c) , rrtretttia l ll' c) , (c) ,(c) , a (r) c) , ' damsg&aring c) , (c) , (c) , c)lll c) , (r) , (c) g&uuml;llner c) loannides-demos c) k laarman l)oyd, l c) ,(r) c) , (correction) c) ,(c) ,(c) c) , ' o' oberholzer ' po))ock c) , r rabbitts c) ' rodeck, c c) sacks c) xxi salmon c) , ne) , smrth,m j (c) ' smith md) , (c) , (correction) c) , (correction) c) . (c) , published by the proprietors, the lancet limited, adam street godric square, maxwell road key: cord- -ob l bcf authors: bar-zeev, naor; inglesby, tom title: covid- vaccines: early success and remaining challenges date: - - journal: lancet doi: . /s - ( ) - sha: doc_id: cord_uid: ob l bcf nan in the lancet, denis y logunov and colleagues from the n f gamaleya research institute of epidemiology and microbiology in russia present findings from two phase / , non-randomised, open-label studies of a heterologous, replication-deficient, recombinant adenovirus vector-based vaccine in both frozen and lyophilised formulations. the researchers enrolled healthy adult volunteers (aged - years) into the two studies ( people in each study); ( %) participants were men and ( %) were women. the primary outcome measures of the studies were safety and immunogenicity (antigen-specific humoral immunity). in phase of each three-arm study, two groups of nine volunteers received one dose of either recombinant adenovirus type (rad ) vector or recombinant adenovirus type (rad ) vector, both carrying the gene for severe acute respiratory syndrome coronavirus (sars-cov- ) spike glycoprotein (rad -s and rad -s), in lyophilised or frozen form. in phase , another group of healthy adult volunteers in each study received sequential doses of rad -s followed by rad -s of one of the two formulations. adverse events were mostly mild, with the most common adverse events being pain at injection site ( [ %]), hyperthermia ( [ %]), headache ( [ %]), asthenia ( [ %]), and muscle and joint pain ( [ %]). adverse events occurred at similar frequency for each vaccine vector, with each formulation, and after each dose. serious adverse events did not arise in this small cohort. both formulations of the vaccine were immunogenic in all participants, inducing neutralising humoral and cell-mediated responses. in phase , % of participants had detectable antibodies at days after the priming dose, rising to % by day , with substantial titre rises after the boosting dose. the two studies by logunov and colleagues have several strengths. first, adenoviruses are ubiquitous, so humans might not be immunologically naive. previous immunity to the vector might interfere with adenovirusvectored covid- vaccine efficacy. indeed, findings of an adenovirus type -vectored covid- vaccine trial suggested such immunity could affect covid- responses. in another study, a chimpanzee adenovirus vector was used, since humans will presumably be naive to at least the first dose. logunov and colleagues used immunologically distinct (heterologous) vectors in their two-dose (prime-boost) regimen. they investigated cross-vector heterologous immunity and previous antivector adenovirus immunity, and neither affected covid- immunogenicity. a second strength is the threshold for neutralisation used in the two studies. neutralisation assays vary from study to study. neutralisation is tested by examining whether plasma from a recently vaccinated individual can prevent cellular damage on in-vitro exposure of cells to sars-cov- . both the degree of such protection (how many damaged cells are allowed) and the dose of the infecting virus vary across studies. expecting a vaccine to result in less than complete neutralisation is not inherently wrong but sets the bar low and makes it easier to claim neutralising activity. in logunov and colleagues' studies, however, the threshold for neutralisation was set high in two regards: the inoculating viral dose was large, and no arising cellular damage was allowable. essentially, the assay was set at full neutralisation. this high bar implies these researchers took an a-priori risk that their vaccine might fail the test. it did not. it remains to be seen if other manufacturers will set a similar high standard. a third strength is that the vaccine, similar to other adenovirus-vectored and mrna covid- vaccines before it, - induced broad immune responses. although not specifically discussed, the results imply a t-helper- -cell-weighted response that might be important for vaccine safety, potentially reducing the risk of antibodydependent enhanced disease. a fourth strength was development of two vaccine formulations, frozen and lyophilised. a lyophilised formulation could mean stability within the existing global vaccine refrigerated cold chain that is needed to maintain vaccine efficacy from factory to recipient, a hurdle other vaccines are yet to address. although more costly to produce at scale, product stability will maximise reach in remote terrain, a must if universal and equitable coverage is to be achieved. some limitations of the studies by logunov and colleagues are notable. in the study of the frozen vaccine formulation, the population included young military personnel. soldiers are likely to be fitter and healthier than the general population. moreover, in older adults, immune senescence might make vaccines less immunogenic, and this age group was absent from this study. sex imbalance occurred in the study arms because there was no random allocation. a control arm was conspicuously absent. two participants were of asian descent, with the rest of the participants of white european ethnic origin. clearly, much more remains to be learned from the phase randomised trial planned to include civilian volunteers and, hopefully, broadly inclusive of groups at risk. this covid- vaccine candidate from russia joins two other adenovirus-vectored covid- vaccine candidates, which have been reported in randomised trials in the lancet, , and an mrna vaccine candidate reported in a non-randomised trial. similar to these studies before it, logunov and colleagues' studies are encouraging but small. the immunogenicity bodes well, although nothing can be inferred on immunogenicity in older age groups, and clinical efficacy for any covid- vaccine has not yet been shown. a wide portfolio of early covid- vaccine candidates will hopefully provide more successful vaccines that are broadly protective across risk groups and that increase the global availability of what will be a precious limited commodity. showing safety will be crucial with covid- vaccines, not only for vaccine acceptance but also for trust in vaccination broadly. safety outcomes up to now are reassuring, but studies to date are too small to address less common or rare serious adverse events. unlike clinical trials of therapeutics, in which safety is balanced against benefit in patients, vaccine trials have to balance safety against infection risk, not against disease outcome. since vaccines are given to healthy people and, during the covid- pandemic, potentially to everyone after approval following phase trials, safety is paramount. licensure in most settings should depend on proven short-term and long-term efficacy against disease (not just immunogenicity) and more complete safety data, including rates of vaccine failure to prevent infection (not merely disease) and rates of occurrence of antibody-dependent enhanced disease, ideally from very large scale, flexible multivaccine trials with prolonged, blinded safety and efficacy follow-up. , safety assurance will then require further large-scale surveillance after licensure. such surveillance is not well established in many settings, and rapid efforts need to be made by governments, regulators, and global research funders to get those systems in place. surveillance will also be vital for showing transmission reduction, which is unlikely to come from phase trials since these are powered to detect covid- disease outcomes and not asymptomatic sars-cov- infection. to be sure, most past vaccines were designed to target disease and not infection as such, but with covid- , the general public could be expecting striking reductions in disease transmission after widespread vaccine introduction. such effects would be very welcome if they occur, but they are far from certain. a vaccine that reduces disease but does not prevent infection might paradoxically make things worse. it could falsely reassure recipients of personal invulnerability, thus reducing transmissionmitigating behaviours. in turn, this could lead to increased exposure among older adults in whom efficacy is likely to be lower, or among other higher-risk groups who might have lower vaccine acceptance and uptake. in view of the ongoing painful toll of the covid- pandemic and its magnitude, the more vaccine candidates that have successful early results the better. ultimately, all vaccine candidates will need to show safety and prove durable clinical efficacy (including in groups at greater risk) in large randomised trials before they can be put into widespread use. equitable access will require multiple vaccine producers and providers in a range of settings. each of their successes will together lead us towards our collective, longed for, new day. we declare no competing interests. *naor bar-zeev, tom inglesby nbarzee @jhu.edu safety and immunogenicity of an rad and rad vector-based heterologous prime-boost covid- vaccine in two formulations: two open-label, non-randomised phase / studies from russia immunogenicity and safety of a recombinant adenovirus type- -vectored covid- vaccine in healthy adults aged years or older: a randomised, double-blind, placebo-controlled, phase trial safety and immunogenicity of the chadox ncov- vaccine against sars-cov- : a preliminary report of a phase / , single-blind, randomised controlled trial an mrna vaccine against sars-cov- : preliminary report consensus summary report for cepi/bc march - , meeting: assessment of risk of disease enhancement with covid- vaccines vaccine confidence in the time of covid- covid- vaccine trials should seek worthwhile efficacy key: cord- - rfnt x authors: tsang, kenneth wt; eng, philip; liam, ck; shim, young-soo; lam, wah k title: h n influenza pandemic: contingency plans date: - - journal: lancet doi: . /s - ( ) - sha: doc_id: cord_uid: rfnt x nan a vaccine for h n will not be available in the foreseeable months. even if pharmaceutical manufacturing begins soon after an outbreak, there would not be a sufficient supply for the countries most in need-ie, the asian nations. antiviral drugs are consequently the only specific treatment, pending availability of effective vaccines. these include m inhibitors (amantadine and rimantadine), which are ineffective against h n in vitro, and the neuraminidase inhibitors (oseltamivir and zanamivir). the neuraminidase inhibitors reduce the severity and duration of symptoms, and prevent clinical influenza as post-exposure and seasonal prophylaxis. influenza contingency plans by the who and most governments generally advocate detection, isolation, staff protection, and the start of antiviral treatment for patients, and their contacts. many governments, including those of hong kong, thailand, singapore, malaysia, and korea, have already stockpiled, at a very substantial expense, vast quantities of oseltamivir to prepare for an outbreak. nonetheless, the efficacy of neuraminidase inhibitors, even for non-h n influenza a in healthy people and taken within h of disease onset, is only slight (table). [ ] [ ] [ ] [ ] [ ] [ ] the use of oseltamivir in five of the ten cases reported in vietnam did not show any obvious clinical efficacy, and the mortality was % in this cohort. the two neuraminidase inhibitors, oseltamivir and zanamivir, have not been directly compared in controlled trials. their pharmacological properties are compared in the table. [ ] [ ] [ ] [ ] [ ] [ ] although both have similar efficacy, zanamivir has fewer adverse reactions, and a favourable resistance profile. the resistance factor would be an important consideration in a pandemic situation. the reasons for zanamivir not being chosen for stockpiling might include concern that young children and patients with intellectual or coordination impairments would not be able to inhale zanamivir properly, although there are novel ways of giving the drug to children. the occurrence of bronchospasm and reduced lung function is very rare, and patients with asthma and chronic obstructive pulmonary disease (copd) seem to tolerate inhalation of zanamivir as well as the placebo. the inhaled flow rate needed to give the custom-designed inhaler for zanamivir ( - l/min) age approved for prophylaxis , Ͼ years Ͼ years age approved for treatment , Ͼ years Ͼ year renal impairment , no dose adjustment required adjustment if creatinine clearance - ml/min hepatic impairment , no dose adjustment required safety not established reduction of influenza symptoms , by median of · day by median of · day adverse reactions , allergy-very rare nausea · - · % bronchospasm and vomiting · - · % dyspnoea-very rare diarrhoea · - · % rash and urticaria-very rare bronchitis · - · % headache · - · % fatigue · - · % frequency of drug resistance none reported · and · - · % in adults and after treatment , children, respectively comment is similar to that for accuhaler ( - l/min), and turbohaler ( - l/min), which are popular drypowder inhalation devices used by many asthmatic and copd patients, even during exacerbations. , therefore governments should also consider stockpiling zanamivir as an anti-influenza agent in their pandemic plans. actual logistics for giving out antivirals to patients and close contacts need to be efficient and completed within h. it seems more appropriate for communitybased health-care personnel or even pharmacists, rather than hospital-based health-care workers, to handle such procedures. governments and health agencies should also consider planning for clinical trials, for instance a combination of both neuraminidase inhibitors, with or without other potential novel drugs, such as shortinterfering rnas and interferon. these trials, if initiated at the early stages of a pandemic, could provide useful information for further patient and outbreak management in later stages. the geographic location of vaccine manufacturers in developed countries would also delay poorer asian nations from obtaining the updated influenza vaccine. perhaps vaccine and neuraminidase inhibitor manufacturing activities should also begin in asia to deal with such deficiencies. the ethics of maintaining drug patents in a potential worldwide catastrophe is questionable. epidemiological modelling suggests that influenza is more infectious than severe acute respiratory syndrome, and that severe acute respiratory syndrome infection control measures might not be adequate for a pandemic of influenza. there will, therefore, be an overwhelming strain on health-care workers and hospitals in an h n pandemic, and staff could be rapidly demoralised and degenerate into deserters, if colleagues develop hospital-acquired h n infection, especially if not given adequate intensive-care unit treatment. protection of core personnel should also be planned to underpin recovery in the aftermath, when many key players in health care and governmental institutions would have perished. cumulative number of confirmed human cases of avian influenza a/(h n ) since probable person-to-person transmission of avian influenza a (h n ) avian influenza review of the use of neuraminidase inhibitors for prophylaxis of influenza world health organization. national influenza pandemic plans issue number core data sheet version . the mist (management of influenza in the southern hemisphere trialists) study group. randomised trial of efficacy and safety of inhaled zanamivir in treatment of influenza a and b virus infections efficacy and safety of the oral neuraminidase inhibitor oseltamivir in treating acute influenza: a randomized controlled trial. us oral neuraminidase study group management of influenza virus infections with neuraminidase inhibitors: detection, incidence, and implications of drug resistance resistant influenza a viruses in children treated with oseltamivir: descriptive study avian influenza a (h n ) in patients in vietnam new application method of zanamivir with a straw efficacy and safety of inhaled zanamivir for the treatment of influenza in patients with asthma or chronic obstructive pulmonary disease: a double-blind, randomized, placebocontrolled multicentre study pharmacoscintigraphic evaluation of lung deposition of inhaled zanamivir in healthy volunteers a comparison of the performance of two modern multidose dry powder asthma inhalers are we ready for pandemic influenza? nurses' professional care obligation and their attitudes towards sars infection control measures in taiwan during and after the epidemic key: cord- -ctx vhi authors: woo, patrick cy; lau, susanna kp; tsoi, hoi-wah; chan, kwok-hung; wong, beatrice hl; che, xiao-yan; tam, victoria kp; tam, sidney cf; cheng, vincent cc; hung, ivan fn; wong, samson sy; zheng, bo-jian; guan, yi; yuen, kwok-yung title: relative rates of non-pneumonic sars coronavirus infection and sars coronavirus pneumonia date: - - journal: lancet doi: . /s - ( ) - sha: doc_id: cord_uid: ctx vhi background: although the genome of severe acute respiratory syndrome coronavirus (sars-cov) has been sequenced and a possible animal reservoir identified, seroprevalence studies and mass screening for detection of subclinical and non-pneumonic infections are still lacking. methods: we cloned and purified the nucleocapsid protein and spike polypeptide of sars-cov and examined their immunogenicity with serum from patients with sars-cov pneumonia. an elisa based on recombinant nucleocapsid protein for igg detection was tested with serum from healthy blood donors who donated years previously and with serum positive for antibodies against sars-cov (by indirect immunofluorescence assay) from patients with sars-cov pneumonia. the seroprevalence of sars-cov was studied with the elisa in healthy blood donors who donated during the sars outbreak in hong kong, non-pneumonic hospital inpatients, and symptom-free health-care workers. all positive samples were confirmed by two separate western-blot assays (with recombinant nucleocapsid protein and recombinant spike polypeptide). findings: western-blot analysis showed that the nucleocapsid protein and spike polypeptide of sars-cov are highly immunogenic. the specificity of the igg antibody test (elisa with positive samples confirmed by the two western-blot assays) was %, and the sensitivity was · %. three of healthy blood donors who donated during the sars outbreak and one of non-pneumonic paediatric inpatients were positive for igg antibodies, confirmed by the two western-blot assays (total, · % of our study population). interpretation: our findings support the existence of subclinical or non-pneumonic sars-cov infections. such infections are more common than sars-cov pneumonia in our locality. background although the genome of severe acute respiratory syndrome coronavirus (sars-cov) has been sequenced and a possible animal reservoir identified, seroprevalence studies and mass screening for detection of subclinical and non-pneumonic infections are still lacking. methods we cloned and purified the nucleocapsid protein and spike polypeptide of sars-cov and examined their immunogenicity with serum from patients with sars-cov pneumonia. an elisa based on recombinant nucleocapsid protein for igg detection was tested with serum from healthy blood donors who donated years previously and with serum positive for antibodies against sars-cov (by indirect immunofluorescence assay) from patients with sars-cov pneumonia. the seroprevalence of sars-cov was studied with the elisa in healthy blood donors who donated during the sars outbreak in hong kong, non-pneumonic hospital inpatients, and symptom-free health-care workers. all positive samples were confirmed by two separate westernblot assays (with recombinant nucleocapsid protein and recombinant spike polypeptide). findings western-blot analysis showed that the nucleocapsid protein and spike polypeptide of sars-cov are highly immunogenic. the specificity of the igg antibody test (elisa with positive samples confirmed by the two western-blot assays) was %, and the sensitivity was · %. three of healthy blood donors who donated during the sars outbreak and one of non-pneumonic paediatric inpatients were positive for igg antibodies, confirmed by the two western-blot assays (total, · % of our study population). severe acute respiratory syndrome (sars) has now affected countries in five continents, with more than cases and more than deaths. a novel virus, the sars coronavirus (sars-cov), is known to be the aetiological agent. [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] the viral genome has been completely sequenced. , we have also reported the isolation of viruses resembling sars-cov from himalayan palm civets found in a live animal market in the guangdong province of china; this finding implied that animals could be a reservoir of the virus. detection of sars-cov from a non-pneumonic case in singapore (http://www.who.int/csr/don/ _ _ /en/) suggested that non-pneumonic and subclinical sars-cov infections are possible. however, extensive seroprevalence studies and mass screening for detection of subclinical and non-pneumonic infections are still lacking. at present, the most widely used methods for detection of antibodies against sars-cov are indirect immunofluorescence assay and elisa with cell-culture extract. , however, antibody detection by these methods is difficult to standardise and has not been compared with recombinant-antigen-based antibody-detection tests. a recent seroprevalence study, which used the indirect immunofluorescence assay for antibody detection, did not detect sars-cov antibodies in any of health-care workers from a hospital in which a sars outbreak had occurred. an approach of elisa-based antibody-detection tests using recombinant antigens with positive results confirmed by western-blot assays that use two different antigenic proteins offers higher sensitivity, specificity, and reproducibility than indirect immunofluorescence assay and elisa with cell-culture extract and is easier to standardise. [ ] [ ] [ ] [ ] [ ] [ ] in this study, we used a sensitive and specific elisa based on the highly immunogenic nucleocapsid protein of sars-cov and confirmed positive results by western-blot assays with recombinant nucleocapsid protein and recombinant spike polypeptide (another highly immunogenic protein) of sars-cov to examine the seroprevalence of non-pneumonic sars-cov in the general population, non-pneumonic patients in hospital, and health-care workers during the sars epidemic. pellet was resuspended in l dnase-free, rnase-free double-distilled water and was used as the template for rt-pcr. cloning and purification of (his) -tagged recombinant proteins to produce a fusion plasmid of the nucleocapsid protein of the sars-cov for protein purification, primers lpw and lpw (panel) were used to amplify the gene encoding this protein by rt-pcr. the sequence coding for aminoacid residues - of the nucleocapsid protein was amplified and cloned into the bamhi and ecori sites of expression vector pet- b(+) (novagen, madison, wi, usa) in frame and downstream of the series of six histidine residues. the (his) -tagged recombinant nucleocapsid protein was expressed and purified by means of the nickel-loaded hitrap chelating system (amersham pharmacia, piscataway, nj, usa) according to the manufacturer's instructions. roughly mg purified protein was routinely obtained from l escherichia coli carrying the fusion plasmid. for the spike protein of the sars-cov, primers lpw and lpw (panel) were used to amplify the gene encoding aminoacid residues - by rt-pcr. this portion of the spike protein was used because the complete protein could not be expressed in e coli. the pcr product was cloned into the bamhi and kpni sites of vector pqe- (qiagen, hilden, germany). the resulting clone was digested by psti, and the fragment that contained the gene encoding aminoacid residues - of the spike protein was cloned into expression vector pqe- (qiagen, hilden, germany) in frame and downstream of the series of six histidine residues. expression and purification of the (his) -tagged recombinant spike polypeptide were done as described for the nucleocapsid protein. western-blot analysis was done according to our published protocols, with slight modifications. [ ] [ ] [ ] briefly, ng purified (his) -tagged recombinant nucleocapsid protein or (his) -tagged recombinant spike polypeptide was loaded into each well of a sodium dodecyl sulphate % polyacrylamide gel, then electroblotted onto a nitrocellulose membrane (bio-rad, hercules, ca, usa). the blot was cut into strips, and the strips were incubated separately with in dilution of three serum samples, obtained from three patients with sars-cov pneumonia, positive for antibodies against sars-cov detected by our indirect immunofluorescence assay. antigen-antibody interaction was detected with an ecl fluorescence system (amersham life science, buckinghamshire, uk). serum samples from three healthy blood donors were used as controls. assessment of recombinant nucleocapsid protein elisa serum samples from healthy blood donors who donated blood years previously (aged years or older) and patients with pneumonia positive for antibodies against sars-cov detected by our indirect immunofluorescence assay were used for the assessment of the elisa-based igg antibody test. the test was modified from our previous publications. , briefly, each well of a nunc immunoplate (roskilde, denmark) was coated with ng purified (his) -tagged recombinant nucleocapsid protein for h, then blocked in phosphate-buffered saline with % bovine serum albumin. l diluted human serum ( in ) was added to each well of the protein-coated plates, and they were incubated at °c for h. after five washes with washing buffer, l horseradish-peroxidase-conjugated goat antibody to human igg ( in dilution; zymed laboratories inc, south san francisco, ca, usa) was added to each well, and the plates were incubated at °c for h. after a further five washes with washing buffer, l diluted , Ј, , Ј-tetramethylbenzidine (zymed laboratories) was added to each well and incubated at room temperature for min. l · mol/l sulphuric acid was added, and the absorbance at nm of each well was measured. each sample was tested in duplicate, and the mean absorbance for each sample was calculated. the presence of specific antibodies in positive samples was confirmed by retesting of the sample by the elisa based on recombinant nucleocapsid protein and western-blot assays with recombinant nucleocapsid protein and recombinant spike polypeptide separately. using the protocol described above, we tested for the presence of igg antibodies against the nucleocapsid protein in serum samples from healthy blood donors (aged years or older) who donated blood in march-may, ; non-pneumonic paediatric inpatients (aged less than years) and nonpneumonic adult inpatients (aged years or older) admitted to queen mary hospital in may, ; and symptom-free health-care workers. the presence of specific antibodies in all positive samples was confirmed by two separate western-blot assays, one with recombinant nucleocapsid protein and the other with recombinant spike polypeptide as the antigen. the study sponsors had no role in the study design; collection, analysis, or interpretation of data; or the writing of the report. the purified (his) -tagged recombinant nucleocapsid protein and spike polypeptide were separated on denaturing polyacrylamide gels followed by western-blot analysis with serum from three patients with pneumonia positive for antibodies against the sars-cov. prominent immunoreactive protein bands of about kda were visible on the western blots that used either antigen (figure ). these sizes were consistent with the expected size of · kda for the full-length (his) -tagged nucleocapsid protein and · kda for the (his) -tagged spike polypeptide. an elisa-based sars-cov antibody test was developed for the detection of specific antibodies against the (his) -tagged recombinant nucleocapsid protein. box titration was carried out with different dilutions of (his) tagged recombinant nucleocapsid protein coating antigen and pooled serum from three patients with pneumonia positive for antibody against the sars-cov. the results identified ng purified (his) -tagged recombinant nucleocapsid protein per elisa well as the ideal amount for plate coating for igg detection (data not shown). to establish the baseline for the tests, serum samples from healthy blood donors who donated blood years previously were tested in the elisa. for these samples, the mean optical density at nm for igg detection was · (sd · ). an absorbance value of · was selected as the cut-off value (the mean value for the healthy controls plus sd; figure ) . seven of the samples from healthy blood donors had values of more than · in the igg elisa (figure ), but none of them had the specific antibody when tested by the nucleocapsid protein or the spike polypeptide westernblot assay. the specificity of the igg antibody test (elisa confirmed by western-blot assays) was %. the mean value for the samples obtained from the patients with sars-cov pneumonia, positive for igg antibodies against the sars-cov by our indirect immunofluorescence assay, was · (sd · ). samples had optical density of more than · in the igg elisa (figure ). all were confirmed to have the specific antibody by both the nucleocapsid protein and the spike polypeptide western-blot assays. the sensitivity of the igg antibody test, with the immunofluorescence assay as the gold standard, was therefore · %. ( · %) of the healthy blood donors who donated blood in march-may, , eight ( · %) of the non-pneumonic paediatric patients, eight ( · %) of the non-pneumonic adult patients, and one ( %) of the symptom-free health-care workers who had cared for the patients with sars-cov pneumonia were positive for igg antibodies by elisa ( figure ) . however, only three ( · %) healthy blood donors who donated blood in march-may, , and one ( · %) non-pneumonic paediatric patient were confirmed to have specific sars-cov antibodies by both the nucleocapsid protein and spike polypeptide western-blot assays. up to the end of may, patients from a population of about seven million in hong kong ( · %) had developed sars-cov pneumonia, compared with a rate of non-pneumonic sars-cov infections in our study population of about · % (p< · by poisson exact test of equality). previous studies in animal coronaviruses, such as infectious bronchitis virus, have shown that the nucleocapsid protein and spike protein are highly immunogenic, are abundantly expressed during infection, and can be used for serodiagnosis of animal coronavirus infections. [ ] [ ] [ ] in this study, detection of igg antibodies to both proteins was highly sensitive and specific for sars-cov infections. six ( · %) serum samples that were seropositive by the immunofluorescence assay were negative by the elisa. the reason for this discrepancy may be that the nucleocapsid protein did not elicit antibody response in this minority group of patients. conversely, of five patients with sars-cov pneumonia who were seronegative by the immunofluorescence assay but rt-pcr positive for sars-cov, two were seropositive by our elisa, with clearly positive opticaldensity values of · and · and confirmation by western-blot assay (unpublished). furthermore, in four of patients with sars coronavirus pneumonia who had serial serum samples, igg was detected earlier by the elisa than by the immunofluorescence test (unpublished). in another study that used elisa based on cell-culture extract, five of patients with sars-cov pneumonia were positive according to that elisa but negative by indirect immunofluorescence during the time when the elisa titres were low. this finding accords with the results of a previous study on human coronavirus e, which showed that three of serum samples were positive by recombinant-nucleocapsid-protein-based western blot but negative by immunofluorescence, and six of serum samples were positive by immunofluorescence but negative by recombinant-nucleocapsid-protein-based western blot. all these findings show that our elisa may be able to detect additional cases that the immunofluorescence assay has missed. with this potentially more sensitive elisa for igg antibody detection, we assessed the seroprevalence of non-pneumonic sars-cov infections in both the general population and our hospital population; all positive serum samples detected by elisa were confirmed by two separate western-blot assays, with two immunologically unrelated antigens. the spike polypeptide was used in addition to the nucleocapsid protein for western-blot confirmation to eliminate the possibility of cross-reactivity between antibodies against the nucleocapsid proteins of other human coronaviruses and that of sars-cov. however, the aminoacid identities between the nucleocapsid protein of sars-cov and those of the human coronaviruses oc and e are only · % and · %, respectively, and there were no crossreactions between pairs of oc and pairs of e human coronavirus serum samples and the sars-cov. in fact, of the individuals who were igg positive by elisa, ( %) were positive by the nucleocapsidprotein-based western-blot assay, but only four were positive by both the nucleocapsid protein and the spike polypeptide western-blot assays. this apparent high rate of false-positive non-pneumonic cases, as detected by the recombinant nucleocapsid protein elisa, is due to the use of a single antigen for screening asymptomatic or nonpneumonic infections. it is well known that the positive predictive values of serological tests are much affected when the prevalence of the infection is low, especially in clinically incompatible cases. this is the reason why an immunologically unrelated antigen, the spike protein, has to be used for confirmation of the cases detected as "positive" by the nucleocapsid-protein-based assays. cross-reactivity with human coronavirus oc or other sars-cov-like viruses remains an important issue for future studies on sars-cov serology. three of the four individuals with non-pneumonic sars-cov infections were healthy blood donors, and one was a paediatric inpatient. this patient was a -month-old girl who was admitted to hospital in may, , because of fever for days. she was also noted to have had a cough for the previous weeks and repeated vomiting before admission. there had been no breathing difficulty or diarrhoea. the child had no history of direct contact with patients with sars-cov pneumonia. however, a colleague in her mother's workplace had recently been diagnosed as having sars-cov pneumonia. physical examination of the girl revealed only shotty (palpable but too small to be measured) cervical lymph nodes and congested throat. her chest radiograph was normal. apart from mild lymphopenia (lymphocyte count · ϫ /l), her blood results were normal. nasopharyngeal aspirate was negative for influenza viruses, parainfluenza viruses, adenovirus, and respiratory syncytial virus antigens. she was given antipyretic treatment and was discharged the next day. subsequent antibody testing showed that her serum was positive for both igg and igm antibodies against the nucleocapsid protein as well as igg antibodies against the spike polypeptide of sars-cov. the difference between the rate of non-pneumonic sars-cov infections in our study population and the rate of sars in hong kong suggests that non-pneumonic infections are more common than sars-cov pneumonia and may explain cases of sars-cov pneumonia in patients who had no obvious contact with other patients with sars. contributors p c y woo and k y yuen are coprincipal investigators, jointly wrote the report, and coordinated and supervised the study. s k p lau supervised the analysis of all serological data and corrected the report. h w tsoi cloned and purified the nucleocapsid protein and did the serological assays. k h chan supervised the immunofluorescence assay. b h l wong and v k p tam did the serological assays and analysed the data. x y che cloned and purified the spike polypeptide. s c f tam coordinated the collection of clinical specimens. v c c cheng and i f n hung managed the patients' database. s s y wong, b j zheng, and y guan corrected the report. none declared. coronavirus as a possible cause of severe acute respiratory syndrome development of a standard treatment protocol for severe acute respiratory syndrome prospective study of the clinical progression and viral load of sars-associated coronavirus pneumonia in a community outbreak lung pathology of fatal severe acute respiratory syndrome a novel coronavirus 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viral respiratory tract infections in pediatric patients this work is partly supported by a research grant council grant (hku / m), the sars research fund, and the university sars donation fund, the university of hong kong. we thank members of the clinical microbiology laboratory, queen mary hospital, and members of the department of medicine, united christian hospital, hong kong for their assistance. key: cord- -r qhfsj authors: tomlinson, brian; cockram, clive title: sars: experience at prince of wales hospital, hong kong date: - - journal: lancet doi: . /s - ( ) - sha: doc_id: cord_uid: r qhfsj nan the lancet • vol • may , • www.thelancet.com commentary the prince of wales hospital (pwh) has been at the forefront of the outbreak of severe acute respiratory syndrome (sars) in hong kong. we relate our experience at this hospital. a working definition of sars is important, although clinical conditions rarely remain within artificial boundaries. some patients might not have all features, others may present unusually. fever is a cardinal symptom but not always so, and is sometimes absent in elderly patients. some patients have presented with diarrhoea or, in at least two cases, with severe acute abdominal pain requiring exploratory laparotomy. all these patients developed typical sars. patients presenting with other respiratory infections must now all be regarded as potential sars cases until proven otherwise. contact with a known case is an important discriminator but, if emphasised too strongly in the diagnostic process, may lead to false positives or negatives. the difficulty of making a firm diagnosis until chest radiographic changes appear has important implications for health-care personnel and for surveillance. three major reasons for spread of infection to health-care workers have been: failure to apply isolation precautions to cases not yet identified as sars, breaches of procedure, and inadequate precautions. every patient must now be assumed to have sars, which has major long-term implications for the health-care system. another reason for spread among health-care workers is infected workers continuing to work despite symptoms, such as mild fever. such individuals must now cease working. however, staying at home can also have disastrous consequences for exposed family members. potential cases therefore require early isolation from both workplace and household. extreme measures are required to protect health-care workers, who account for about % of cases. early diagnosis by virus isolation or serological testing is essential to halt the spread of sars. progress has been made with the isolation of the coronavirus. [ ] [ ] [ ] a metapneumovirus was also identified in canada and in many of the cases at pwh. coronavirus appears to be the main pathogen, but dual infections may be possible. such situations are uncommon in human disease, apart from hiv-related infections, but in veterinary medicine combined infections with coronavirus and other agents have been described. , the first cases probably occurred in guangdong province in southern china in november, . the term sars appears to have been first used for a patient in hanoi who became ill on feb , , and was evacuated back to hong kong where he died on march . the physician who raised the alarm in hanoi, carlo urbani, subsequently contracted sars and died. the first case in hanoi had stayed at a hotel in kowloon, hong kong, at the same time as a -yearold doctor who had been treating pneumonia cases in southern china. this doctor was admitted to hospital on feb , and died from respiratory failure soon afterwards. he was the first known case of sars in hong kong and appears to have been the source of infection for most if not all cases in hong kong as well as the cohorts in canada, vietnam, singapore, usa, and ireland, and subsequently thailand and germany. the index patient at pwh was admitted on march , , and had also visited this hotel. he had pneumonia which progressed initially despite antibiotics, but after days he improved without additional treatment. on march , health-care workers at pwh were ill and potential cases among staff were identified later that day. further staff, patients, and visitors became ill over the next few days and there was subsequent spread to their contacts. by march , patients had been admitted to pwh with sars, all traceable to this index case. one important factor in the extensive dissemination of infection appears to have been the use of nebulised bronchodilator, which increased the droplet load surrounding the patient. overcrowding in the hospital ward and an outdated ventilation system may also have contributed. the second major epicentre in hong kong, accounting for over cases, has been an apartment block called amoy gardens. the source has been attributed to a patient with renal failure receiving haemodialysis at pwh who stayed with his brother at amoy gardens. he had diarrhoea, and infection may have spread to other residents by a leaking sewage drain allowing an aerosol of virus-containing material to escape into the narrow lightwell between the buildings and spread in rising air-currents. sewage also backflowed into bathroom floor drains in some apartments. spread to people in nearby buildings also occurred, probably by person-to-person contact and contamination of public installations. although the rapid spread of the disease in some situations may have been explained, many uncertainties remain. why the disease spread in the kowloon hotel has not been clarified, and there are many other important issues. "super-spreaders" may be prone to carry a high viral load because of defects in their commentary sars: experience at prince of wales hospital, hong kong immune system, as could be the case in the patient with end-stage renal failure implicated in the amoy gardens outbreak and another with renal failure at the centre of an outbreak in singapore. subclinical infections may also occur and will not be recognisable until reliable diagnostic tests are available. procedures causing high risk to medical personnel include nasopharyngeal aspiration, bronchoscopy, endotracheal intubation, airway suction, cardiopulmonary resuscitation, and non-invasive ventilation procedures. cleaning the patient and the bedding after faecal incontinence also appears to be a high-risk procedure. treatments have been empirical. initial patients were given broad-spectrum antibiotics but, after failing to respond for days, were given ribavirin and corticosteroids. patients who continued to deteriorate with progression of chest radiographic changes or oxygen desaturation, or both, were given pulsed methylprednisolone. steroids were used on the rationale that progression of the pulmonary disease may be mediated by the host inflammatory response, similar to that seen in acute respiratory distress syndrome, and produced by a cytokine or chemokine "storm". the clinical impression is that pulsed steroids sometimes produce a dramatic response. however, apparent benefits of steroid treatment have proven to be incorrect before, as in infection with respiratory syncytial virus. lack of knowledge of sars' natural history adds to the difficulty of determining the effectiveness of therapy. some patients have a protracted clinical course with potential for relapses continuing into the second or third week, or beyond. long hospital stays, even in less ill patients, are required, and the high proportion of patients requiring lengthy intensive care, with or without ventilation ( % in the cases from pwh ), and the susceptibility of health-care workers bodes ill for the ability of health-care systems to cope. even when the acute illness has run its course, unknowns remain. continued viral shedding and the possible development of long-term sequelae, such as pulmonary fibrosis or late post-viral complications, means that patients will require careful surveillance. this commentary is dedicated to the frontline health-care staff who have shown courageous devotion to duty throughout this epidemic. department of medicine and therapeutics, chinese university of hong kong, prince of wales hospital, hong kong sar, people's republic of china (e-mail: btomlinson@cuhk.edu.hk) world health organization. case definitions for surveillance of severe acute respiratory syndrome (sars) centers for disease control and prevention. cdc lab analysis suggests new coronavirus may cause sars identification of severe acute respiratory syndrome in canada coronavirus as a possible cause of severe acute respiratory syndrome coronavirus and pasteurella infections in bovine shipping fever pneumonia and evans' criteria for causation viral agents associated with poultry enteritis and mortality syndrome: the role of a small round virus and a turkey coronavirus severe acute respiratory syndrome (sars): multi-country outbreak-update a cluster of cases of severe acute respiratory syndrome in hong kong cdc update: outbreak of severe acute respiratory syndrome-worldwide main findings of an investigation into the outbreak of severe acute respiratory syndrome at amoy gardens a randomized, double-blind, placebo-controlled trial of dexamethasone in severe respiratory syncytial virus (rsv) infection: effects on rsv quantity and clinical outcome the dietary fibre debate: more food for thought this issue of the lancet contains two important papers that associate high intake of dietary fibre with a decreased risk of either colonic adenomas or colorectal cancer. the usa-based study done by the prostate, lung, colorectal, and ovarian cancer screening project team (plco) compared the dietary fibre intake of people who on sigmoidoscopy showed no polyps with people who had at least one histologically-verified adenoma in the distal large bowel. the study involved ten different us centres, with very different dietary practices. the european prospective investigation into cancer and nutrition (epic) consortium used a different approach to reach the same conclusion. they prospectively examined the dietary-fibre intake and incidence of colon cancer in people recruited from ten european countries. the findings of both research teams contrast with those of at least three other studies that have been published in the past years, - all of which found no protective effect of dietary-fibre intake on the development of either colonic adenomas or colorectal cancer. the new results give fresh impetus to fundamental research to determine the reasons for the protective action of dietary fibre, or to establish the definitive clinical trial.the us nurses health study was based on numbers of cases of colorectal cancer as large as in epic, and had a considerable impact on thinking. after its publication, doubts were expressed not only about population recommendations for health but even about the need for continued research. for example, santani-rim and dashwood posed the question about whether it was "time to discontinue antigenotoxicity studies of dietary fibre". of equal concern was the downturn in interest of commercial food companies to do applied research in such areas as high-fibre food products.why did these two groups of studies give such different results? although this question is obviously important, it is very difficult to answer. random variation is unlikely, given the numbers in the population groups involved. conflicting studies would be more difficult to explain if dietary fibre was a well- key: cord- -rb j dh authors: gu, jiang; xie, zhigang; gao, zhancheng; liu, jinhua; korteweg, christine; ye, juxiang; lau, lok ting; lu, jie; gao, zifen; zhang, bo; mcnutt, michael a; lu, min; anderson, virginia m; gong, encong; yu, albert cheung hoi; lipkin, w ian title: h n infection of the respiratory tract and beyond: a molecular pathology study date: - - journal: lancet doi: . /s - ( ) - sha: doc_id: cord_uid: rb j dh background: human infection with avian influenza h n is an emerging infectious disease characterised by respiratory symptoms and a high fatality rate. previous studies have shown that the human infection with avian influenza h n could also target organs apart from the lungs. methods: we studied post-mortem tissues of two adults (one man and one pregnant woman) infected with h n influenza virus, and a fetus carried by the woman. in-situ hybridisation (with sense and antisense probes to haemagglutinin and nucleoprotein) and immunohistochemistry (with monoclonal antibodies to haemagglutinin and nucleoprotein) were done on selected tissues. reverse-transcriptase (rt) pcr, real-time rt-pcr, strand-specific rt-pcr, and nucleic acid sequence-based amplification (nasba) detection assays were also undertaken to detect viral rna in organ tissue samples. findings: we detected viral genomic sequences and antigens in type ii epithelial cells of the lungs, ciliated and non-ciliated epithelial cells of the trachea, t cells of the lymph node, neurons of the brain, and hofbauer cells and cytotrophoblasts of the placenta. viral genomic sequences (but no viral antigens) were detected in the intestinal mucosa. in the fetus, we found viral sequences and antigens in the lungs, circulating mononuclear cells, and macrophages of the liver. the presence of viral sequences in the organs and the fetus was also confirmed by rt-pcr, strand-specific rt-pcr, real-time rt-pcr, and nasba. interpretation: in addition to the lungs, h n influenza virus infects the trachea and disseminates to other organs including the brain. the virus could also be transmitted from mother to fetus across the placenta. a pandemic outbreak of human infection with avian infl uenza h n currently poses a potentially serious health threat worldwide. since the outbreak of infection with avian infl uenza h n virus in , who has reported laboratory confi rmed cases in ten countries with a mortality rate of about %. so far the virus has spread only from animals to human beings. however, human-to-human transmission potentiated by viral genomic mutation and reassortment of genomic subunits could be imminent. recently, the fi rst cases of probable human-to-human transmission have been reported. , the h n infl uenza a virus is a negative-stranded rna virus in which the genome consists of eight segments encoding ten viral proteins including haemagglutinin, neuraminidase, polymerase proteins, and nucleoprotein. little is known about the specifi c eff ects in organs and cells targeted by the virus. the infection initially seemed to be restricted to the lungs, but later reports , have suggested that infl uenza a h n could disseminate beyond the lungs. for various reasons (eg, religion), full autopsies of h n -infected human cases can often not be obtained. accordingly, only a few reports , , - have described histopathology and virus distribution in h n cases. studies using in-situ hybridisation to detect viral genomic sequences in target cells have not been reported thus far. we present clinicopathological data from h n autopsies of two unrelated chinese cases, as well as the histopathological changes and pattern of infection in the placenta and fetus from one of the patients, who was pregnant at the time of death. to gain further insight into the tissue tropism of infl uenza a h n virus, we used in-situ hybridisation and immunohistochemistry to analyse viral localisation in various organs. reverse transcription (rt) pcr, real-time rt-pcr, and nucleic acid sequence-based amplifi cation (nasba) h detection assays were also done to detect viral rna in tissue samples, as well as strand-specifi c rt-pcr. the clinical data of patient have previously been published in detail. a -year-old chinese woman from china's anhui province who was months pregnant presented with a -day history of fever, cough, and dyspnoea. weeks before admission, she had handled birds, several of which had died. on admission, she was lymphopenic, confused, and irritable, had bilateral infi ltration on chest radiograph, and substantially reduced oxygen saturation. she was placed on a ventilator and treated with antibiotics, corticosteroids (hydrocortisone mg on day and day , and methylprednisolone mg on day and mg on day ), and fl uids, but died h after admission, days after the onset of symptoms. no antiviral treatment was given. *contributed equally to the study as fi rst authors patient was a -year-old chinese man from china's jiangxi province who had a -day history of fever and productive cough. he had participated in selling birds, of which several had died. on admission, chest radiographs showed evidence of pneumonia, and laboratory results showed abnormally increased hepatic-associated and cardiac-associated enzymes and lymphopenia. he was treated with antibiotics. corticosteroids were given initially with methylprednisolone mg on day and then mg per day for days. antiviral treatment was given, including rimantadine mg twice daily on days and and then oseltamivir mg per day from day for days. after admission, he became increasingly irritable and confused, followed by lowered consciousness. he developed respiratory failure and mechanical ventilation was initiated. in a sputum culture, several gram-positive microorganisms and candida albicans were isolated. antifungal drugs were added to his treatment. he developed multiple organ failure and died days after the onset of symptoms. the chinese centre for disease control and prevention confi rmed human infection with avian infl uenza h n in both patients. rt-pcr detected h n viral sequences in nasal swabs and nasopharyngeal aspirates, which were obtained on day of illness for patient and day for patient . viruses were isolated from the nasopharyngeal aspirate cultures, and designated as infl uenza a/anhui/ / virus in patient and a/jiangxi/ / virus in patient . the haemagglutinin genes of viruses in patient (genbank accession number: dq ) and patient (webappendix) were sequenced. the receptor-binding sites of both viruses were identical to those of previous h n isolates. h n viruses isolated from both patients were susceptible to both the m inhibitors amantadine and rimantadine, and the neuraminidase inhibitors oseltamivir and zanamivir. both cadavers were stored at ºc and underwent autopsy about - h after death. the autopsies were done following conventional protocols and strict safety procedures. tissue samples from all major organs and tissues were taken and fi xed in % formalin. the brain of patient was not available for investigation. immunohistochemistry was done on the basis of the technique of lin and colleagues, with antigen retrieval by a standard technique. , to detect viral antigen, tissue slides of μm thickness were incubated with mouse monoclonal antibodies to nucleoproteins and haemagglutinin. furthermore, monoclonal antibodies to the following cell markers were used: cd (for macrophages), cd (t lymphocytes), cd (b lymphocytes), cd (cytotoxic t cells), s (dendritic cells), cytokeratin ae /ae (epithelial cells), surfactant protein a (type ii pneumoncytes), tubulin-β (ciliated epithelial cells), placental alkaline phosphatase (plap, syncytiotrophoblasts), e-cadherin (cytotrophoblasts), neurofi lament (neurons), neuron-specifi c enolase (neurons), and factor viii (endothelial cells, webtable). for controls, we used unrelated antibodies in place of the primary antibody. for the development of probes, we used haemagglutinin (genbank accession number dq ) and nucleoprotein gene sequences (dq ) of the h n a/black-headed gull/qinghai/ / virus, which was recently isolated from a migratory bird at china's qinghai lake. plasmids were generated by cloning of the full haemagglutinin gene ( bp) and full nucleoprotein gene ( bp) into a plasmid vector pgem-t (promega, madison, wi, usa) yielding pgem-ha for haemagglutinin and pgem-np for nucleoprotein. both plasmids were linearised with appropriate restriction enzymes. two sense and two antisense rna probes were prepared by in-vitro transcription with t and sp rna polymerase (promega) in the presence of digoxigenin-utp (roche diagnostics, penzberg, germany). since h n is a negative-stranded rna virus, sense probes were defi ned as the probes that detect the viral rna (negative-stranded), whereas antisense probes detected mrna and complement rna (crna), which are both positive-stranded. briefl y, before hybridisation, all solutions were prepared with diethyl pyrocarbonate (depc)-treated water. after deparaffi nisation and rehydration, tissue sections of μm thickness were treated with proteinase k digestion or microwave heating. tissue sections were then incubated with a hybridisation cocktail containing μg/ml of one of the four sense and antisense probes at ºc for h. all sense and antisense probes were applied separately on consecutive tissue sections. after blocking with horse serum ( : ), sections were incubated with alkaline phosphatase-labelled digoxigenin antibody ( : , roche diagnostics, penzberg, germany) for h, and the reaction products were colourised with nitroblue tetrazolium/ -bromo- -choloro- -indolyl phosphate (promega). as a positive control, we used brain tissue samples of a black-headed gull, for which h n infection of the brain was confi rmed by viral isolation. we used lung tissues from a mouse infected with h n infl uenza virus as a negative control. negative controls also included an unrelated antisense probe against the fragment of the polymerase gene (r ab) of the severe acute respiratory syndrome-associated coronavirus (sars-cov), as well as h n in-situ hybridisation probes to tissues (including lung and tracheal) obtained from seven adults who died from infectious lung diseases other than h n infl uenza (four, sars; one, purulent bronchitis; two, pneumonia), one adult who died from a non-infectious disease (gastric ulcer), one pregnant woman who died from an amniotic embolism, and one aborted fetus. we identifi ed the cell types infected by the virus with double labelling by combining in-situ hybridisation for see online for webappendix see online for webtable viral genomic sequences and immunohistochemistry for one of the cell-associated markers. to identify placental cells and cerebral neurons containing viral sequences or antigens, consecutive sections adjacent to the sections used for in-situ hybridisation or immunohistochemistry were immunostained with cd , e-cadherin, plap, neurofi lament, or neuron-specifi c enolase. tissues from the pharynx, nose and paranasal sinuses, and lymph nodes other than hilar nodes were not available for investigation. on preliminary investigation of lung tissues, we noted a contrast between the extent of histological damage and the limited number of positive pneumocytes (patient ) or absence of positive pneumocytes (patient ) shown by in-situ hybridisation and immunohistochemistry studies. therefore, we did extensive pulmonary sampling for further histological assessment to ensure that the results were representative. after receptor-mediated endocytosis of the virus, the polymerase proteins, nucleoprotein, and encapsidated rna segments migrate to the nucleus of the infected cell. in the nucleus, rna segments are transcribed into mrna and crna. mrna is subsequently translated to viral proteins (eg, haemagglutinin and nucleoprotein) in the cytoplasm. newly synthesised nucleoprotein is transported back to the nucleus. crnas function as antigenomic templates for the production of progeny rna segments in the nucleus. assembly of progeny gene segments and proteins occurs in the cytoplasm. therefore, sense and antisense signals after in-situ hybridisation for nucleoprotein and haemagglutinin could be seen in both the nucleus and cytoplasm of infected cells, as well as immunohistochemical signals for nucleoprotein in the nucleus and for haemagglutinin in the cytoplasm. since antisense probes hybridise to mrna and crna, a positive signal would probably indicate active viral replication. rna was extracted from deparaffi nised tissue samples, or directly extracted from formalin-fi xed tissues after overnight incubation with proteinase k ( µg/µl, ameresco, cleveland, oh, usa). we did rna extraction with trizol (invitrogen, ca, usa), and pcr as previously described. the haemagglutinin gene of the h n virus was detected with h for as the forward primer and h rev as the reverse primer for h gene amplifi cation (panel). reamplifi cation was done for specifi c samples with the same set of primers if no band was seen in gel electrophoresis. we obtained negative controls for rt-pcr from uninfected tissues (eg, lung, brain, placenta, and intestine) from three patients who died from non-infectious diseases. rt-pcr for glyceraldehyde- -phosphate dehydrogenase (gapdh) was assessed in parallel as an internal control. to detect viral rna in fetal tissues, real-time rt-pcr (h avian infl uenza virus nucleic acid amplifi cation fluorescent quantitative detection kit, pg biotech, shenzhen, china) was used as recommended by the manufacturer and the national standards of the people's republic of china. −/− −/− n/a n/a n/a n/a cytotrophoblasts +/+ +/+ n/a n/a n/a n/a hofb auer cells +/+ +/+ n/a n/a n/a n/a circulating mononuclear cells −/− −/− −/− +/+ +/+ +/+ ish=in-situ hybridisation. ihc=immunohistochemistry. n/a=not applicable. plus sign=positive. minus sign=negative.*results presented for sense/antisense probes (identical results for nucleoprotein and haemagglutinin). †results presented for nucleoprotein/haemagglutinin signals (nucleoprotein mainly detected in nucleus and haemagglutinin in cytoplasm). ‡includes putative t lymphocytes. strand-specifi c rt-pcr was undertaken on the basis of the technique of yue and co-workers, with minor modifi cation. briefl y, two-part reactions were used. first, the rt reaction was done in the presence of tagged primer, tag-h for or tag-h rev (panel). a third of cdna products then underwent pcr with primers tag/h rev or tag/h for. we reamplifi ed under the same pcr conditions for a specifi c sample if no band was seen after gel analysis of the fi rst pcr reaction. virus-specifi c rna was also detected with the avian infl uenza virus (h subtype) nasba diagnostic test kit (mp version, hong kong dna chips, hong kong). the test was done as previously described with h -specifi c capture and detection probes (panel). absorbance of the amplifi ed product was measured at nm by an elisa plate reader (bio-rad, hercules, ca, usa). a negative control from the test kit was also included for h detection. the study was approved by the internal review board and ethics committee of the peking university health science centre. the sponsor of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report. the corresponding author had full access to all the data in the study and had fi nal responsibility for the decision to submit for publication. the microscopic features of both patients were similar, apart from more extensive fi broproliferative changes in the lungs of patient . both lungs of patient showed features of diff use alveolar damage (fi gure a) and focal desquamation of epithelial cells into alveolar spaces without evidence of type ii pneumocyte hyperplasia. in the lungs of patient , patchy foci of consolidated bronchopneumonia and areas of fi brosis were seen. we found variable numbers of macrophages in the alveoli (especially in patient ), and moderate numbers of scattered neutrophils and rare lymphocytes in the interstitial spaces. both patients had substantially depleted lymphoid tissue in the spleen, lymph nodes, and mucosal lymphoid tissue in the gastrointestinal tract. the liver in both patients had spotty necrosis. in both patients, we detected very low numbers of macrophages with haemophagocytosis in the spleen, lymph nodes, and liver. the kidneys showed extensive tubular necrosis. other organ systems showed no pronounced histological changes, apart from hypertrophy in the thymus of patient . the placenta showed development appropriate for the length of gestation. we saw scattered foci of syncytiotrophoblast necrosis, sometimes with associated dystrophic calcifi cation. whether this fi nding was induced virally or was the sole result of maternal shock is unclear. acute necrotising deciduitis was detected focally, and regarded as consistent with maternal shock. fetal tissues mostly showed no specifi c histopathological fi ndings, and development was also consistent with gestational age. however, sections of fetal lung showed oedema and very small numbers of scattered interstitial neutrophils, which raised the possibility of mild acute interstitial pneumonitis, although this appearance was notably less severe than that seen in patients and (webfi gure ). sense and antisense probes for in-situ hybridisation detected viral genomes focally in tissue samples from various organs (table ). the two sets of probes (for in the respiratory tract, we detected positive signals in tracheal epithelial cells and alveolar epithelial cells (fi gures b and c, webfi gure ). however, only an estimated - % of epithelial cells in the trachea and about % of epithelial cells in the alveoli showed positive signals. both bronchi and bronchioles were negative. double labelling combining in-situ hybridisation and immunohistochemistry with tubulin-β antibody showed that both ciliated (tubulin-β-postive) cells and non-ciliated (tubulin-β-negative) cells of the trachea had viral sequences (fi gure c, webfi gure ). we also found putative basal cells to be infected. double labelling with antibodies for cytokeratin and surfactant protein a showed that the positive alveolar cells were type ii pneumocytes (webfi gures c and d). in-situ hybridisation showed no positive staining in endothelial cells, macrophages, lymphocytes, fi broblasts, or any other cell type in the lungs or blood. however, we found positive viral signals in the cytoplasm of mononuclear cells in hilar lymph nodes (fi gure d). double labelling and consecutive sections showed that cells positive for in-situ hybridisation were t lymphocytes (ie, positive for cd and negative for cd , cd , and s , webfi gure ). additionally, positive signals of intracytoplasmic viral sequences were present in mucosal epithelial cells of the small intestine (> % in some intestinal segments, fi gure e). we also detected viral sequences in the cytoplasm (and to a much lesser extent in the nuclei) of brain cells from patient (fi gure f, webfi gure ). double labelling with neural markers neurofi lament or neuron-specifi c enolase showed that these h n -positive cells were neurons (webfi gures o and p). table shows the topographic distribution of cells with positive signals from in-situ hybridisation. no positive signals were seen in the heart, liver, spleen, kidneys, oesophagus, bone marrow, or stomach. placental tissue samples showed a large number of infected cells in chorionic villi (webfi gure ). most positive cells were localised in the connective tissue core of these villi. these cells were confi rmed (by labelling with monoclonal antibodies to cd and plap in consecutive sections) to be hofbauer cells but not syncytiotrophoblasts. a subgroup of the cells with positive signals was found in the periphery of chorionic villi (fi gure g), which morphologically resembled cytotrophoblastic cells and were confi rmed by immunostaining with e-cadherin antibody on consecutive sections. no positive signal was seen in syncytiotrophoblasts. in the fetus, in-situ hybridisation identifi ed viral sequences in the lungs, circulating mononuclear cells (webfi gure ), and mononuclear cells in the liver (fi gure h). the latter cells were identifi ed as macrophages (kupff er cells) by double labelling with antibody to cd (webfi gure ). both sense and antisense probes were distribution of immunohistochemical staining (table ) was consistent with that of in-situ hybridisation, apart from the absence of viral antigens in the intestines. positive staining for nucleoprotein and haemagglutinin was detected in pneumocytes (fi gure a) and cytotrophoblasts and hofbauer cells in the placenta (fi gure b) in patient ; as well as in tracheal epithelial cells (fi gure c), the brain (fi gure d), and t lymphocytes in hilar lymph-node tissue (fi gure e) in patient . the fetus showed positive staining in bronchial epithelial cells, pneumocytes (fi gure f), and circulating mononuclear cells. nucleoprotein was mainly detected in the nucleus and haemagglutinin in the cytoplasm. negative controls validated the specifi city of the immunohistochemistry protocol (webfi gure ). all organs tested showed positive rt-pcr results, apart from the lymph nodes of patient (tables and , fi gure ). all non-paraffi n-embedded samples were positive for h expression. however, paraffi n-embedded tissues only showed h expression after reamplifi cation of the rt-pcr products. nasba showed positive results on both types of samples without the need of reamplifi cation. with real-time rt-pcr, viral rna was detected in the lungs and liver of the fetus (table ) . gapdh was an internal control for successful rna extraction in these assays. positive-stranded rna was detected in the heart and placenta of patient and in the lungs, trachea, intestines, and brain of patient (table , fi gure ). the specifi cities of the rt-pcr and nasba were further confi rmed by use of the negative controls. our comprehensive investigation of the tissue tropism of h n infl uenza virus, based on two adult autopsies and one fetal autopsy, focuses on the localisation of viral genomic sequences and antigens. we present evidence suggesting that the virus disseminates beyond the respiratory system. in addition to the lungs, viral sequences and antigens were found in the cerebral neurons and lymphocytes. presence of viral sequences and antigens in the cns is consistent with the recent isolation of h n virus from cerebrospinal fl uid of a boy who died from encephalitis with neurological symptoms commonly seen in patients with h n infl uenza (gao zh, unpublished), including the two cases in this study. brain neurons were found to be infected by the virus. we also saw regional variations in positive neuronal distribution and negative neurons next to positive neurons. possible reasons might include diff ering densities of the avian infl uenza virus receptor in human beings, diff erences in blood supply pathways and nerve connections that allow virus-target cell contact, and diff ering viral loads and viral replication stages. the detection of positive-stranded rna by rt-pcr and in-situ hybridisation could indicate active viral replication in the brain. the virus could reach the cns by penetrating the blood-brain barrier or by invading the aff erent fi bres of the olfactory, vagal, trigeminal, and sympathetic nerves after replicating in the respiratory mucosa, as has been shown in animals. see online for webfi gure placenta y y y n/a n/a n/a n/a · y n/a n/a +/-, -, and + represent total, negative-stranded, and positive-stranded rna, respectively. y=positive result. n=negative result. n/a=not applicable. *samples regarded as h -positive if absorbance higher than · . our data imply that the virus also infects and actively replicates in the small intestines, which is consistent with previous studies. the origin of infection in the intestines could be blood-borne, which is lent support by previous studies isolating live h n virus from the serum and plasma. however, ingestion of infected respiratory secretion cannot be excluded as a possible route of infection, since h n infl uenza viruses maintain sialidase activity despite the low ph in the upper digestive tract. although in-situ hybridisation, nasba, and rt-pcr detected viral rna in the intestines, immunohistochemistry for viral antigens was negative. this discrepancy is consistent with the fi ndings of uiprasertkul and colleagues, although the reason is still unclear. in-situ hybridisation and immunohistochemistry detected viral sequences and antigens in lymphocytes in the lymph nodes, and fetal macrophages in the placenta. circulating mononuclear cells in the fetus and macrophages in the liver were found to harbour viral sequences. previous in-vitro experiments have shown infection of macrophages by h n , , and ex-vivo experiments have shown that the virus attaches to alveolar macrophages in human lung tissue. in addition to viraemia, infected immune cells could also carry the virus to extrapulmonary organs, which has been thought to participate in the pathogenesis of sars. the virus localised to type ii pneumocytes in the respiratory tract, which has also been reported previously. , , however, with double labelling, we found viral sequences and antigens in both ciliated and non-ciliated epithelial cells of the trachea (fi gure c), contrasting with previous in-vivo and ex-vivo studies. , in cultures of human tracheobronchial epithelial cells, h n infl uenza viruses have been reported to infect mainly ciliated cells, which express mainly avian infl uenza virus receptors (α- , -linked sialic acids), although a limited number of non-ciliated cells (< % of all infected cells) have also been reported to be infected. , some studies have detected only human infl uenza virus receptors (α- , -linked sialic acids) on non-ciliated cells, whereas others also have found avian infl uenza virus receptors in these cells, albeit to a lesser extent. , changes in receptor-binding properties of a/anhui/ / and a/jiangxi/ / viruses could, in theory, also account for the infection of non-ciliated cells. however, preliminary tests have not revealed any substantial changes in the receptor-binding sites of either virus, compared with previous h n isolates. notably, only a few scattered epithelial cells in the lungs were found to harbour the virus, contrasting with the severe and widespread histopathological changes in the lungs. since this contrast was unexpected, lung tissue was sampled and analysed extensively, but the number of cells with viral localisation was consistently low in both patients. with the technique's very high detection sensitivity (close to %), the percentages of positive epithelial cells recorded in this study could be reasonable estimates of h n -infected cells. in view of the low number of infected cells in patient and the absence of cells with positive signals after in-situ-hybridisation in patient , direct viral injury to the epithelial cells of the respiratory tract is, in our view, unlikely to cause such severe pathological changes. the lack of histopathological changes in the brain, despite our fi ndings indicating active viral replication in the region, also suggests that viral replication might not be specifi cally pathogenic. recent in-vitro and in-vivo studies have indicated that hyperinduction of cytokines and chemokines could take part in the pathogenesis of h n infl uenza. , , , , , despite the high number of infected cells in the fetal respiratory system, we saw no evidence of severe damage to the fetal lungs, which greatly contrasts with the extensive damage found in the adult lungs. the absence of severe pulmonary damage (ie, high numbers of infected cells) in the fetus probably indicated an immunological naive status, which would be expected to result in low concentrations of the cytokines or chemokines to which the fetal lung tissues were exposed, and thus reduce or eliminate their induction of tissue damage. this theory is supported by in-vitro experiments showing that h n -infected neonatal macrophages express much lower amounts of chemokines than h n -infected adult macrophages. although the intracellular distribution pattern of immunohistochemical signals conformed to our expectations, it did not for signals from in-situ hybridisation. probes hybridised mainly in the nuclei of pneumocytes and in the cytoplasm of other organs. in mice infected with h n infl uenza virus, nucleoprotein sense and antisense probes have also hybridised mainly in the cytoplasm of infected cells, although the reason for this fi nding is unclear. rna analysis with rt-pcr and nasba assays showed that h -specifi c rna was present in all tissues examined apart from the lymph nodes of patient , for which only nasba showed positive result. this result could be due to the higher sensitivity of nasba than that of rt-pcr. in fact, rt-pcr needed reamplifi cation of the pcr products on the paraffi n-embedded samples, which indicated a lower detecting sensitivity than nasba. rt-pcr and nasba results were generally consistent with those of in-situ hybridisation and immunohistochemistry. however, viral rna was also seen in viscera and some regions of the brain that showed negative results for both in-situ hybridisation and immunohistochemistry. a similar discrepancy has also been reported in a sars study, which was attributed either to very low copy numbers of rna and protein in these organs that might not be detectable or to false-positive rt-pcr results. false-positive results might be caused by the presence of virus in blood perfusing the organs without actual viral replication in the tissue parenchyma. detection of positive-stranded rna in the lung, heart, intestines, placenta, brain, and trachea in our study could imply that viral replication occurs in these organs. the absence of corresponding negative-stranded rna in the lung and heart could be due to a lower detecting sensitivity of rt-pcr for negative strands than for positive strands. this study has shown the capacity for human vertical transmission of the h n virus. transplacental transmission of the h n virus warrants careful investigation, since maternal infections with common human infl uenza virus are generally thought not to aff ect the fetus. a sero-epidemiological study showed no evidence of transplacental transmission in pregnant women with human infl uenza infection. our placenta autopsy showed viral genomic sequences in cytotrophoblasts and resident macrophages; furthermore, the virus infected the fetus. viraemia has been reported in avian infl uenza virus infections, , which is by contrast with the rare occurrence of viraemia in human infl uenza virus infections. therefore, the likelihood of virus reaching the uterus and placenta is probably higher in avian infl uenza than in human infl uenza. the vertical transmission route of avian infl uenza virus could be similar to that of human cytomegalovirus, which also targets cytotrophoblasts and hofbauer cells. two possible routes of transplacental transmission have been suggested: transcytosis across syncytiotrophoblasts to cytotrophoblasts in chorionic villi, or via infection of invasive cytotrophoblasts in the uterine wall (which could be infected after contact with maternal blood). these infected cells subsequently transmit the virus to the anchoring chorionic villi and could then be transmitted to hofbauer cells that enter the fetal circulation. the presence of viral sequences and antigens in cytotrophoblasts, hofbauer cells, and circulating fetal mononuclear cells supports this theory. we detected viral sequences in cytotrophoblasts of chorionic villi but not in syncytiotrophoblasts. diff erences in virus receptor expression could explain why cytotrophoblasts are susceptible to avian infl uenza virus infections but not human infl uenza virus infections. both syncytiotrophoblasts and cytotrophoblasts have been found to lack α- , -linked sialic acids, but whether the placenta expresses α- , -linked sialic acids is unknown. the relative number of infected cells in the fetal lungs, as detected by in-situ hybridisation and immunohistochemistry, was substantially higher than in the two adults, which could be explained by the dominance of avian-infl uenza-virus receptors over human-infl uenza-virus receptors in the bronchial and alveolar epithelia during the pseudoglandular stage of lung histiogenesis (up to the th gestational week). despite the long duration of the disease and antiviral treatment in patient , viral sequences and antigens were detected in the post-mortem tissues. this fi nding is diff erent from a previous study. the delayed clearance of viral antigens and sequences could be due to the immunosuppressive eff ect of the high-dose corticosteroids with which the patient had been treated for a long period before death. since viral cultures were not done on post-mortem tissues, whether the detection of antigens and sequences indicates active viral replication is unclear. positive results with in-situ hybridisation and rt-pcr have been reported in patients with sars who died late in the course of disease. , , however, these positive rt-pcr results have been ascribed to the presence of small amounts of residual genome, rather than to active viral replication. we have shown that the h n virus spreads beyond the lungs, infecting both ciliated and non-ciliated epithelial cells of the trachea, the placenta, t lymphocytes in lymph nodes, and cerebral neurons. we also report evidence of transplacental transmission, resulting in infection of fetal organs. these newly obtained data are important in the clinical, pathological, and epidemiological investgation of human h n infection, and have implications for public-health and health-care providers. jg initiated, designed, and coordinated the study, analysed the results, and took part in the writing of the manuscript. zx took part in the autopsies, tissue collection, and routine pathology. zhg was responsible for the clinical management and clinical data analysis. jliu took part in the probe-design molecular biology, viral test, and the writing of the manuscript. jy did the immunohistochemistry and in-situ hybridisation. ck took part in the study design, result and literature analysis, and writing of the manuscript. ltl took part in the rt-pcr and nasba, result analysis, and writing of the manuscript. jlu did the rt-pcr and nasba. zig took part in the autopsies, tissue collection, routine pathology, and clinical data analysis. bz did the molecular pathology, in-situ hybridisation, and probe design. mam took part in the routine pathology, clinical data analysis, and writing of the manuscript. ml took part in the autopsies, tissue collection, and routine pathology. vma did the fetoplacental pathology and molecular pathology. eg took part in routine pathology and tissue processing. achy designed and coordinated the rt-pcr and nasba study, analysed the results, and took part in the writing of the manuscript. wil had overall responsibility for the study design, and took part in the writing of the manuscript. we declare that we have no confl ict of interest. cumulative number of confi rmed human cases of avian infl uenza a/(h n ) reported to who probable person-to-person transmission of avian infl uenza a (h n ) human transmission but no pandemic in indonesia pandemic threat posed by avian infl uenza a viruses infl uenza a h n replication sites in humans fatal avian infl uenza a (h n ) in a child presenting with diarrhea followed by coma pathology of fatal human infection associated with avian infl uenza a h n virus re-emergence of fatal human infl uenza a subtype h n disease human disease from infl uenza a (h n ) lethal avian infl uenza a (h n ) infection in a pregnant woman in anhui province, china ha sequence of the virus establishment of multiple sublineages of h n infl uenza 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acid sequence-based amplifi cation methods to detect avian infl uenza virus the invasion routes of neurovirulent a/hong kong/ / (h n ) infl uenza virus into the central nervous system after respiratory infection in mice h n infl uenza a virus and infected human plasma duck and human pandemic infl uenza a viruses retain sialidase activity under low ph conditions diff erential expression of chemokines and their receptors in adult and neonatal macrophages infected with human or avian infl uenza viruses induction of proinfl ammatory cytokines in human macrophages by infl uenza a (h n ) viruses: a mechanism for the unusual severity of human disease? h n virus attachment to lower respiratory tract avian fl u: infl uenza virus receptors in the human airway infection of human airway epithelium by human and avian strains of infl uenza a virus human and avian infl uenza viruses target diff erent cell types in cultures of human airway epithelium infection of ciliated cells by human parainfl uenza virus type in an in vitro model of human airway epithelium fatal outcome of human infl uenza a (h n ) is associated with high viral load and hypercytokinemia time course and cellular localization of sars-cov nucleoprotein and rna in lungs from fatal cases of sars fatal infl uenzal pneumonia in pregnancy: failure to demonstrate transplacental transmission of infl uenza virus infl uenza virus infection in the second and third trimesters of pregnancy: a clinical and seroepidemiological study use of the polymerase chain reaction for demonstration of infl uenza virus dissemination in children human cytomegalovirus infection of placental cytotrophoblasts in vitro and in utero: implications for transmission and pathogenesis expression of gal beta , glcnac alpha , -sialyltransferase and alpha , -linked sialoglycoconjugates in normal human and rat tissues changes in sialic acid expression in the lung during intrauterine development of the human fetus fatal severe acute respiratory syndrome is associated with multiorgan involvement by coronavirus we thank hongquan shao and ning li for their assistance with the autopsies; lu yao, ruishu deng, and ruiqi xue for their assistance in the experiments; and ting zhang for helping with the photos. this study is supported partly by the lifu educational foundation, national basic research program ( ) of china (grant no cb ), national natural science foundation of china (grant no ), and awards from the national institute of allergy and infectious diseases, national institutes of health. ck is supported by grants from the prins bernhard cultuurfonds (wassink-hesp fonds and kuitse fonds), the netherlands. key: cord- -obeinwyq authors: horton, richard title: canada : what should global health expect? date: - - journal: lancet doi: . /s - ( ) - sha: doc_id: cord_uid: obeinwyq nan for south africa in , it is the world cup. for canada, it is the g -on jan , , canada takes over the g presidency. as the predicaments facing the world's leading economies grow ever more complex, canada's global leadership has never been more keenly needed. over the next months, canada has an opportunity to make a decisive impact on global health. canada could learn a great deal from japan's example. japan occupied the g presidency in . the country's foreign policy team, together with national health leaders, prepared early. in , japan's foreign minister signalled his commitment to international health through human security. the government proceeded to create an academic collaboration to propose action on health systems. that proposal fed directly into the g meeting itself and led to a post-g process that identifi ed key policy areas for priority action: the health workforce, fi nancing, and information. an attempt was made at a collaborative handover with italy in , but internal italian political distractions-the personal life of silvio burlusconi-made something of a dead year in g history. it is now time for canada to restart the g engine. prime minister stephen harper has already signalled four priorities: the global economy, climate change, development, and democratic governance. but canada's health community has so far been silent publicly on what canada's priorities should be. canada has many natural advantages to shape its international policyworld-class universities with global ambitions, a history of international policy infl uence (eg, the lalonde report, which redrew the boundaries of health), frontrank scientists and intellectuals who have redefi ned what is possible in health, - and increasing overseas development assistance. the most prominent anomaly canada has to address is the failure of the international institutional and donor architecture to address in any comprehensive and co herent way the catastrophic failure in progress towards the millennium development goals (mdgs). integrating funding for maternal, newborn, and child health into the global fund for aids, tuberculosis and malaria and the us president's emergency plan for aids relief is urgently needed if mdg targets are to be met in . but beyond rebalancing existing programmes, canada's unique experience as a nation could lead it to make important contributions in fi ve further dimensions of global health. first, health systems. canada's health service benefi ts from relatively low health disparities, high levels of public solidarity, and a strong commitment to equity. universal coverage is now top of the global health agenda. , canada must deepen and broaden g commitments to health-systems strengthening. second, climate change. this issue is already a canadian priority. but the health aspects of global warming are largely invisible. the lancet-ucl commission on the health eff ects of climate change argued that global warming is the biggest threat to health in the st century. this view has been backed by doctors' leaders. , health advocates in canada need to press this point on their politicians as additional evidence for concerted action. third, peace through health. canada has been the leading nation bar none to develop the concept of peace dividends through policies on health. [ ] [ ] [ ] this idea has catalysed governments to embrace health as a vital force in foreign policy. as suff ering escalates in zones of confl ict such as afghanistan, embedding health in political thinking is critical to promote peace and reconstruction. fourth, indigenous health. some canadian writers, such as john ralston saul, argue that canada is more aboriginal than european. in a fair country, saul suggests that canada's inclusiveness and egalitarianism stem from these indigenous roots and that if canada is to free the full creative energy of future generations, it must embrace its indigenous past. with million indigenous people living in disrupted, exploited, and marginalised circumstances today, canada's voice-as a country with an important indigenous population-has the potential to command respect and infl uence. , the recent commission on social determinants of health emphasised the importance of inclusion and empowerment for indigenous peoples in governmental policy making. and fi nally, global evidence and ethics. as the birthplace of evidence-based medicine, canada's health community should have a strong voice about the way health metrics are used to shape global health policies. to be fair, canada's health community has called for increased canadian awareness, involvement, and funding in international health. [ ] [ ] [ ] these calls need to be channelled into a more coherent response. perhaps it is time for a change-a canadian health action network for global equity. the creation of such a coalition of canadian academic and institutional health interests could contribute signifi cantly to canada's g agenda. a change could also off er a mechanism for sustained follow-up and continuitybetween diff erent political parties and as the g chair rotates between nations. canada's evolution as a nation through the lens of health reveals a deepening commitment to global aff airs. in the th century canadian doctors and public health offi cials reached out beyond canada's borders to attract health workers to help build a national health system. the country's planners broadened the reach of canada's health system westwards. health leaders identifi ed the crucial importance of reliable information to shape the progress of canada's development. severe acute respiratory syndrome illustrated the powerful fact that no nation can be immune from the global forces of disease. and canada's political leadership now recognises that the institutions that govern the world today need to become more democratic and representative. a long-forgotten but exemplary canadian public health leader, charles hodgetts, once wrote about "health as a foundation of government". this is as true today in a global context as it was in canada a century ago. it is up to the canadian health community to seize the opportunity that now off ers. the lancet, london nw by, uk a version of this comment was presented at the university of british columbia, vancouver, bc, canada, on sept , . i owe thanks to many canadian colleagues who off ered views on the arguments presented here. global health and japan's foreign policy global action on health systems: a proposal for the toyako g summit human security approach for global health g and strengthening of health systems: follow-up to the toyako summit italian g summit: a critical juncture for global health g summit : what approach will italy take to health? the case for expanding access to highly active antiretroviral therapy to curb the growth of the hiv epidemic globalisation and health: the need for a global vision avoidable global cancer deaths and total deaths from smoking what will it take to stop maternal deaths? all for universal health coverage who maximising positive synergies collaborative group. an assessment of interactions between global health initiatives and country health systems lancet-ucl institute for global health commission: managing the health eff ects of climate change health and climate change politicians must heed health eff ects of climate change health and peace: time for a new discipline the mcmaster-lancet health and peace conferences peace through health: key concepts oslo ministerial declaration-global health: a pressing foreign policy issue of our time suff ering, and mental health in afghanistan: a school-based survey a fair country indigenous health : determinants and disease patterns indigenous health : the underlying causes of the health gap commission on social determinants of health. closing the gap in a generation the rich-poor gap in global health research: challenges for canada coordinating canada's research response to global health challenges critical public health ethics and canada's role in global health department of health for canada key: cord- -cqbsmrpw authors: van ranst, marc title: chandipura virus: an emerging human pathogen? date: - - journal: lancet doi: . /s - ( ) -x sha: doc_id: cord_uid: cqbsmrpw nan these two trials provide important information on the natural history of node-negative oestrogen-receptor-positive breast cancer, and offer insights into our ability to alter that natural history. although node-negative patients are often referred to as low risk, it is clear from the % relapse rate in the placebo arm of nsabp b- that these patients are at significant risk for relapse. in that trial all patients benefited from tamoxifen use regardless of age or menopausal status, which translated into an overall survival benefit that was highest in the youngest cohort of patients. less clear is which patients warrant chemotherapy in addition to tamoxifen. a survival benefit has been seen with the addition of chemotherapy to tamoxifen in postmenopausal oestrogenreceptor-positive node-positive patients, but it is unclear whether this benefit can be extrapolated to all node-negative patients. nsabp b- showed significant benefits in terms of relapse-free survival in all age groups, but this resulted in a significant improvement in overall survival only in the youngest cohort. clearly the expectations and limitations of chemotherapy must be discussed with patients, especially the elderly, because competing health concerns, such as heart disease, might outweigh the small potential benefit of adjuvant chemotherapy. standard prognostic criteria, and ongoing work with molecular profiling may identify a subgroup of node-negative patients that has a particularly high risk for relapse and may benefit the most from adjuvant chemotherapy. this molecular profiling, with the current and planned intergroup and breast international group trials, will provide insights into the effectiveness and indications for chemotherapy in node-negative and elderly patients, and is congruent with the statement made by fisher et al that factors other than age and menopausal status must dictate systemic treatment. are these older trials relevant in the era of aromatase inhibitors? recent adjuvant trials have suggested that aromatase inhibitors are effective both as initial therapy, and after either - years or years of tamoxifen. both nodenegative and node-positive patients benefit from these newer hormonal agents, and from the published data, one cannot identify a subgroup that should not be considered for treatment. the latest reports from nsabp provide reassurance about the long-term efficacy of tamoxifen, data that we do not yet have for the newer agents. one benefit of reviewing this follow-up data is a reiteration of the need for long-term follow-up and persistent reporting to ensure that efficacy is maintained and unanticipated toxicities are not uncovered. it is a reminder that cooperative groups are committed to a relentless re-analysis of the data. adjuvant trials run by pharmaceutical companies must be held to the same standard. british columbia cancer agency, vancouver, british columbia, canada v z e kgelmon@bccancer.bc.ca we declare that we have no conflict of interest. chandipura virus is a member of the vesiculovirus genus of the family rhabdoviridae. it was first isolated in , from the blood of two adults with a febrile illness in a village in nagpur county, maharashtra state, india. the only other instance when the virus was isolated in human beings was in , in madhya pradesh, india, from a patient with acute encephalitis. the likely vector of chandipura virus is the female phlebotomine sandfly. during the outbreak, chandipura virus rna was detected by pcr in sandflies collected around the house of a patient with encephalitis. since , the virus has been reported in three adjoining states in central india: madhya pradesh, maharashtra, and andhra pradesh. the virus has probably been endemic in this region for decades, and might have been responsible for several earlier outbreaks of encephalitis that have been recorded in india since . however, the geographical distribution of the virus might extend well beyond india; it has also been detected in sandflies in senegal and nigeria. , do not feel too bad if you have never heard of chandipura virus before. since the discovery of the virus in , fewer than two articles a year have been published about it. in the year after the outbreak of severe acute respiratory syndrome (sars) in , more than articles were published on the sars coronavirus. i doubt if the chandipura virus outbreak in central india will be followed by a similar flurry of research activity. in the zoonotic animal virus farm, all viruses are equal, but some viruses are more equal than others. but, part of the explanation for the difference in research interests might be owing to the fact that koch's postulates were fulfilled for the causal role of a novel coronavirus in the sars epidemic, but not yet for the association of chandipura virus with the outbreak of encephalitis in . the story of the first discovery of the chandipura virus and its potential role in the outbreak can not be told without mentioning the national institute of virology (niv) in pune, india. this institute was established in , under the auspices of the rockefeller foundation and the indian council of medical research, to investigate arthropod-borne viruses. the niv is currently a who collaborating centre for arboviruses. only when regional surveillance networks are closely cooperating with regional reference diagnostic laboratories can they function as effective early-warning beacons for emerging infections. the us centers for disease control and prevention cannot, and should not, function as the ultimate global reference laboratory. the threshold for sending samples to a small regional laboratory is lower than that for sending it to a far away and often culturally incongruent mammoth laboratory. strengthening the regional diagnostic laboratory facilities in developing countries is an important global-health priority, and will result in a surveillance net with smaller meshes. a lot has already been achieved, and the diagnosis of the current outbreak of viral encephalitis is a good example of a sentinel system that worked. however, much more remains to be done: in the infectious disease sphere, there are (and i paraphrase the us secretary of defense donald rumsfeld slightly out of context here) a lot of "known knowns; there are things we know we know. we also know there are known unknowns; that is to say we know there are some things we do not know. but there are also unknown unknowns-the ones we don't know we don't know." the encephalitis outbreak in india taught us that the previously unknown chandipura virus joins the seemingly ever-growing list of the known important human pathogens. i bet there are still a lot of unknown unknown infectious diseases awaiting us. chadipura: a new arbovirus isolated in Ì ndia from patients with febrile illness isolation of chandipura virus from the blood in acute encephalopathy syndrome isolation of chandipura virus from sand flies in aurangabad first isolations of arboviruses from phlebotomine sand flies in west africa oligonucleotide fingerprints of rna species obtained from rhabdoviruses belonging to the vesicular stomatitis virus subgroup key: cord- -hv y x g authors: zumla, alimuddin; hui, david s title: infection control and mers-cov in health-care workers date: - - journal: lancet doi: . /s - ( ) - sha: doc_id: cord_uid: hv y x g nan the recent exponential rise in the number of reported cases of middle east respiratory syndrome coronavirus (mers-cov) is of major global concern. the fifth meeting of the international health regulations emergency committee concerning mers-cov was convened on may , , by who's director-general and concluded that, although the seriousness of the situation had increased, there was no evidence of sustained human-to-human transmission and that conditions for a public health emergency of international concern have not yet been met. mers-cov was fi rst reported in september, , when a novel β coronavirus was isolated from a saudi arabian patient in jeddah, who had died of severe (a third now exercise for at least min on days per week) would be expected to reduce blood pressure. comparison with data from the usa and canada suggests that the uk has some way to go in terms of cardiovascular disease prevention, but this must be set against the distinctly lukewarm evidence for benefi t from treatment of people with stage hypertension and no additional risk, on which uk guidance is based. , furthermore, there were important methodological diff erences between countries, particularly in the canadian data in which multiple measurements of blood pressure will have led to improved results compared with those from england. nevertheless, falaschetti and colleagues' data point to the potential for further improvements in both the detection and treatment of hypertension. people with hypertension and raised cardiovascular risk, albeit based on relatively small numbers in the study, might be undertreated. data from uk primary care suggests that many of these people will be elderly, who might go untreated because of lack of evidence (particularly for decreased targets and in the presence of comorbidities). we have previously shown that patients can self-monitor blood pressure and self-titrate their own medication; these and other new interventions can help to build on the improvements of blood pressure control that have been achieved so far. such improvements are worthwhile because treatment of blood pressure is cost saving. overall, however, physicians in primary care-who provide most hypertension management in the uk-seem to have made substantial advances in their management of hypertension, perhaps encouraged by the uk's pay-forperformance policy within which hypertension care has received a large and sustained proportion of the funding on off er. falaschetti and colleagues' study provides a welcome example of the combined eff ects of individual physicians and policy makers on a simple but important risk factor. after years of treatment, it seems that the drugs are working. the large number of mers-cov cases ( cases) reported between april , , and may , , by saudi arabia were probably seasonal (related to the camel birthing season), reminiscent of the clusters of hospital cases that were previously confi rmed in a hospital in jordan in april, , which involved haemodialysis units within hospitals in al hasa in april and may, . sequencing of the mers-cov isolates from the jeddah outbreak has shown no substantial genetic changes. the who emergency committee concluded that the increase in cases reported among health-care workers from hospitals in jeddah was amplifi ed due to overcrowding and inadequate infection control measures. , acute viral respiratory tract infections, such as severe acute respiratory syndrome (sars) and mers, are predominantly spread by large respiratory droplets (≥ μm in diameter) during coughing and sneezing, whereas contact with fomite (including hand contamination with subsequent self-inoculation) might be another potential route of transmission. , the sars outbreak in provided good lessons for the evaluation of environmental infl uences on the aerosol transmission of communicable respiratory diseases and the importance of good infection control measures in the prevention of nosocomial infections. one intriguing aspect of the sars epidemic was the occurrence of super-spreading events, which accounted for · % and · % of sars cases in hong kong and singapore, respectively. during the sars outbreak in , sars-coronavirus (cov) was moderately transmissible, with · secondary infections for every index case. however, infectivity was substantially increased when coupled with environmental factors: patients, many of whom were health-care workers, were infected within weeks as a result of exposure to one patient with community-acquired pneumonia who was admitted to a general medical ward. this super-spreading event seemed to be related to overcrowding and poor ventilation in the dry air-conditioned hospital ward, together with some contribution by the use of a jet nebuliser for the index case. evidence of airborne transmission of sars-cov was also supported by positive air samples of the virus obtained from a hospital room occupied by a patient with sars in toronto, canada. on the basis of analysis of data in a case-control study that involved medical wards in hospitals in guangzhou, china, and hong kong, the risk factors for super-spreading events of sars-cov in the hospital setting were: close separation between beds of less than m; performance of resuscitation; staff working while experiencing symptoms; and patients requiring oxygen or non-invasive ventilation therapy. this study also showed that the availability of washing or changing facilities for health-care staff was a protective factor. these fi ndings have important clinical implications in the prevention of nosocomial infections of mers-cov in health-care facilities in the middle east. a systematic review of fi ve case-control and fi ve retrospective cohort studies identifi ed tracheal intubation, tracheotomy, and manual ventilation before intubation as procedures associated with risk of transmission of sars-cov to health-care workers. opportunistic airborne transmission might occur through fi ne particle aerosols as an effi cient means of propagation under special environmental conditions, such as with aerosol-generating procedures in a ward science photo library environment with poor ventilation and insuffi cient air changes. the main infection prevention and control measures for managing acute viral respiratory tract infections are simple and well documented: droplet precaution (wearing a surgical mask within m of the patient) and contact precaution (wearing gown and gloves on entering the room and removing them on leaving). droplet precautions should be added to standard precautions for patients with symptoms of acute respiratory infection. contact precautions and eye protection should be added when caring for probable or confi rmed cases of mers-cov infection. airborne precautions should be applied when performing aerosol-generating procedures. , , , to reduce room contamination in the hospital setting, major health organisations have recommended the application of a minimum room ventilation rate of six air changes per hour in existing facility, whereas a higher ventilation rate of air changes per hour is recommended for new or renovated construction, especially when caring for patients receiving mechanical ventilation and during aerosol-generating procedures. , infection source and engineering control, including avoidance of aerosol generation with appropriate airborne precautions, and improvement of ventilation design in hospital wards warrant serious consideration for the prevention of nosocomial outbreaks. the mers-cov outbreak in jeddah, and the increasing number of health-care workers acquiring the infection as a result of poor infection control measures, remind us of the need to go back to the basics of infection control to help prevent mers-cov infection in health-care workers. az and dsh serve on the scientifi c advisory committee of the saudi ministry of health global centre for mass gathering medicine. we declare no competing interests who. who statement on the fifth meeting of the ihr emergency committee concerning mers-cov isolation of a novel coronavirus from a man with pneumonia in saudi arabia middle east respiratory syndrome coronavirus (mers-cov)-update hospital outbreak of middle east respiratory syndrome coronavirus severe acute respiratory syndrome vs the middle east respiratory syndrome infection prevention and control measures for acute respiratory infections in healthcare settings: an update transmission dynamics of the etiological agent of sars in hong kong: impact of public health interventions a major outbreak of severe acute respiratory syndrome in hong kong sars: experience at prince of wales hospital, hong kong detection of airborne severe acute respiratory syndrome (sars) coronavirus and environmental contamination in sars outbreak units why did outbreaks of severe acute respiratory syndrome occur in some hospital wards but not in others? aerosol generating procedures and risk of transmission of acute respiratory infections to healthcare workers: a systematic review guideline for isolation precautions: preventing transmission of infectious agents in healthcare settings interim infection prevention and control recommendations for hospitalized patients with middle east respiratory syndrome coronavirus (mers-cov) who guidelines on natural ventilation for infection control in health-care settings. geneva: world health organization guidelines for environmental infection control in health-care facilities. recommendations of cdc and the healthcare infection control practices advisory committee (hicpac) key: cord- - rzi x authors: boyd, rhea w; krieger, nancy; jones, camara phyllis title: in the us election, we can choose a just future date: - - journal: lancet doi: . /s - ( ) - sha: doc_id: cord_uid: rzi x nan when us voters go to the polls (what few are left) or attempt to mail our ballots (with what remains of the us postal service) in the election, we are not simply choosing between two parties or posturing about partisan politics. we are making a choice about the future. on the one hand, are the dangers of white supremacy, authoritarianism, and nationalism-lethal threats to our democracy, our lives, and the viability of the planet. on the other hand, is a rebuke of racist, autocratic politics, and the mandate to create a more equal, just, healthy, and habitable nation and world. the choice is stark and the stakes are high. in terms of health, the current us administration has intentionally lied about the grave risks of covid- , failed to implement a coherent national pandemic strategy, hamstrung and underfunded public health agencies, initiated the process to withdraw the usa from who, reversed and weakened health regulations, attacked abortion and contraception access, eroded transgender health protections, and aired racist, anti-asian, antiscience views. - furthermore, the us administration under president donald trump has cut food stamps, denied climate change, jeopardised the decennial census, undermined indigenous sovereignty, imposed discriminatory anti-muslim travel bans, unleashed federal force on peaceful protesters, openly appealed to white supremacists, and separated immigrant families and caged their children. - while black and indigenous communities, and people of colour more generally, are made vulnerable under the current us administration (panel), no one is fully immune to its harms. ultimately, unfettered racism, truncated rights, anaemic protections, and the resource inequities these exposures create shorten lives. anyone who doubts this needs to only consider the past months. home to only % of the world's population, the usa accounts for about a fifth of global covid- deaths. since february, , we have buried more than of our beloved neighbours, co-workers, family members, and friends. the age-adjusted covid- mortality rate among black and indigenous communities and people of colour in the usa is up to three times higher than among non-hispanic white populations. latinx and black children account for an astounding % of covid- deaths among people aged years and younger in the usa. as of oct , , more than non-hispanic white people have also died from covid- in the country. and every untimely death has occurred within the nation that spends more money on health care than any other country in the world. more exposure and less protection-eg, from racism, resource inequities, inadequate housing, and occupational and environmental hazards-not genetic differences, drive premature mortality from covid- and chronic illnesses such as heart disease and cancer. [ ] [ ] [ ] [ ] to make matters worse, in the face of the nation's cavernous inequalities, widespread economic immiseration, and the highest unemployment rate since the great depression, the current administration has proffered a one-time payment of us$ to limited households while giving tax breaks to the nation's wealthiest elites. , now, up to one in eight us households are food insecure. , an estimated - million people could risk eviction in the coming months. and in july, , the us gross domestic product had the largest drop on record. yet a month later, the stock market peaked. all of this is not a coincidence. it is a consequence of racial capitalism, the profitability of inequality, and the deadly policies of the current administration. , when it comes to this administration, "it is what it is". but seeing it clearly is essential. when torrential rain flooded parts of louisiana, extreme winds decimated parts of utah, and the us western seaboard spent weeks aflame, it is important to see this administration's enshrinement of fossil fuels as accelerants for climate catastrophe. when vice president mike pence asserted that "we will have law and order" as a condition of a second term of a trump presidency, it is crucial to see the rise in hate crimes, white vigilante terror, and human rights abuses that have been a condition of the first term of this administration. , seeing this clearly prevents tacit acceptance of a dangerous diversion. this type of diversion is how indigenous dispossession becomes "discovery", "settlement", and "columbus day". it is how vigilante mob violence against black communities become "race riots" with "fine people on both sides". in , us voters can choose a just future by first confronting our past. the usa began as a slave-ocracy, built on expropriated land and indigenous genocide. its first ruling class were white colonisers. its first enterprises were powered by slavery and premised on the ideology of white supremacy, environmental exploitation, and systems of governance, voter suppression, and policing that protected the right of the white, male, property-owning class to unilateral social, economic, and political control. this is the bedrock on which the "founding fathers" built their attempt at democracy. it is plutocracy perched atop precarity. the current administration only makes that more evident. but while the "founding fathers" anchored their fledgling democracy in inequality, the expansion of us democracy owes its fragile progress to many forebearers, chief among them are the indigenous, the formerly enslaved, and women. starting from this fuller, more inclusive understanding of who we are as a nation and how we got here, the possibilities for who we can become and where we can go are profound. racism saps the strength of the whole of society. and we each live within the limitations of the worlds we build for each other. but another world is possible. building on that conviction, since may, , black lives matter, a black-led, multiracial uprising for racial justice, has become one of the largest movements in us history. together, demonstrators across the country are asserting that our collective losses are not inevitable and our nation's deep grief need not be immutable. so whether shrouded in a booth or the privacy of our own homes this november, us citizens who can vote must affirm these self-evident truths: white nationalism and authoritarianism imperil democracy; democracy and equality are co-constitutive; equality is essential to health; the social, economic, and political conditions necessary to advance equality safeguard the planet; and thriving societies require sustainable environments and equitable economies. all these issues are on the ballot. we hope us voters choose a just future. we declare no competing interests. the views expressed in this comment are our own personal views and do not necessarily represent those of the institutions to which we are affiliated. civil and human rights rollbacks read the full transcript from the first presidential debate between joe biden and donald trump covid world map tracking the global outbreak the color of coronavirus: covid- deaths by race and ethnicity in the us sars-cov- -associated deaths among persons aged < years-united states deaths involving coronavirus disease (covid- ) by race and hispanic origin and age, by state the american health care paradox: why spending more is getting us less occupational safety and health administration (osha) and worker safety during the covid- pandemic coronavirus disease discriminates. our health care doesn't have to levels of racism: a theoretic framework and a gardener's tale trends in premature deaths among adults in the united states and latin america the employment situation the cares act sent you a $ , check but gave millionaires and billionaires far more. propublica the new york times magazine. america at hunger's edge. the new york times magazine measuring household experiences during the coronavirus pandemic national low income housing coalition. the covid- eviction crisis: an estimated - million people in america are at risk racial capitalism: a fundamental cause of novel coronavirus (covid- ) pandemic inequities in the united states dying in a leadership vacuum coronavirus is "under control". axios full transcript: mike pence's r.n.c. speech. the new york times hate-crime violence hits -year high, f.b.i. reports. the new york times trump defends white-nationalist protesters: "some very fine people on both sides one person, no vote: how voter suppression is destroying our democracy black lives matter may be the largest movement in us history. the new york times key: cord- -sv xhxb authors: hogan, william; frost, stephen; johnson, lissa; schulze, thomas g; nelson, e anthony s; frost, william title: the ongoing torture and medical neglect of julian assange date: - - journal: lancet doi: . /s - ( ) - sha: doc_id: cord_uid: sv xhxb nan from a medical standpoint, the risks to mr assange's life and health have only grown more acute since professor melzer's warnings, for two main reasons. one involves the continued abuses of mr assange's fundamental human and legal rights at the hands of judicial, prison, and contracted security authorities, during his extradition proceedings. the second concerns the grave medical risks posed to vulnerable prisoners during the covid- global health emergency, and the exacerbation of mr assange's psychological torture under covid- prison lockdown measures. pattern of abuses contributing to torture. since our previous letter, mr assange has been the subject of six legal hearings ( ) ( ) ( ) ( ) march, april, april, may, and june), which form part of our detailed timeline of events provided (table ) . mr assange's treatment during the first phase of his extradition proceedings in february was described as "shocking and excessive" by the international bar association's human rights institute (ibahri), which likened the abuses to those of the abu ghraib prison scandal ( ) . throughout these and subsequent hearings, mr assange has been unable to engage in his own defence. he was held in a bulletproof glass enclosure at the back of the courtroom ( ; ) during the four days of extradition proceedings, and objected repeatedly that, consequently, he could not hear the proceedings nor communicate with and instruct his lawyers. responding to a formal application by mr assange's lawyers, the judge denied mr assange permission to leave the enclosure to sit with them, despite the prosecuting lawyers' assent to the application ( ) . when he returned to belmarsh after the first day of the extradition hearing, prison authorities strip-searched mr assange twice, handcuffed him times, and moved him successively to five different holding cells ( ; ; ) . mr assange's court documents were also seized, including legally privileged, client-lawyer communications. subsequently, mr assange attended only one of the five following hearings, and did so by videolink. the videolink was terminated early, before the hearing had concluded. mr assange has since missed four following hearings because of covid- -related restrictions and medical risks and has not been seen in court either in person or by videolink since march , . moreover, with the second phase of his extradition proceedings imminent, uk prison lockdowns due to covid- have eliminated prison visits ( ; ), preventing mr assange from meeting with his lawyers to prepare for future proceedings. in a further stripping of self-protection, during an emergency bail hearing in light of covid- , the judge lifted an anonymity order, despite the objections of mr assange's lawyers, which was in place to protect the privacy of mr assange's fiancée, stella morris, and their two children ( ; ) . shortly before the protection afforded by the court order was due to lift, ms morris made the family's story public. these events and others have intensified the pattern of irregularities and excesses documented by professor melzer, causing escalations in imposed helplessness, arbitrariness, threat and isolation, all key components of mr assange's psychological torture. given the rapid spread of covid- in the uk, with prisons acting as a "breeding ground" for infectious diseases, mr assange is at grave risk of contracting, and succumbing to, coronavirus. medically, the risk must be assumed to be elevated significantly beyond that of the general prison population, due both to his chronic respiratory condition and to his history of psychological torture and medical neglect, resulting in high likelihood of his immune system being severely compromised. further, mr assange is non-violent, he is being held on remand, he is not serving a sentence for a crime, and he is being arbitrarily detained according to the un working group on arbitrary detention ( ) . thus, he meets the criteria for prisoner release recommended internationally by human rights and lawyers' associations to contain the spread of covid- and to protect the vulnerable ( - ). accordingly, a bail plan was presented to the court involving monitored home detention for mr assange, with his fiancée and their children. nevertheless, district judge vanessa baraitser denied mr assange bail. this decision, as we stated following the bail hearing ( ), has meant that under prison lockdown mr assange is held in solitary confinement for hours a day ( ). he was also denied a radio for several months. having first ordered a radio from a prison catalogue six months ago, and after a friend of mr assange had tried to send one to him, only for it to be returned, mr assange received a radio on june ( ). isolation and understimulation are key psychological torture tactics, capable of inducing severe despair, disorientation, destabilisation and disintegration of crucial mental and psychological functions ( ). as a person incarcerated solely for publishing activity, continuing to hold mr assange under these conditions represents the torture of a publisher and journalist. in the context of attacks against and arrests of journalists at the recent global protests, his treatment and the precedent it sets are of international concern. call to action. we have witnessed these unfolding developments with alarm. since our we therefore reiterate our demand for an end to the torture and medical neglect of julian assange. we join the world's leading authorities on human rights and international law calling for his immediate release from prison. it is not possible to treat torture victims without first removing them from the circumstances of their torture. we note that ibahri has stated that, in view of mr assange being a victim of psychological torture, his extradition to the us would be illegal under international human rights law. a world psychiatric association (wpa) position statement emphasises the fact that withholding appropriate medical treatment can itself amount to torture ( ) . thus, the ongoing failure to properly treat mr assange may amount to an act of torture in which state officials, from parliament to court to prison, risk being judged complicit. under the convention against torture those acting in official capacities can be held complicit and accountable not only for perpetration of torture, but for their silent acquiescence and consent ( ) . in the uk, such complicity is prohibited not only under the convention against torture but also under article of the european convention on human rights (echr) and section of the criminal justice act . under the latter, it is an offence for any public official to "intentionally inflict severe pain or suffering on another in the performance or purported performance of his official duties ( )." as ibahri co-chair, the hon michael kirby ac cmg, commented on march , : "the ibahri is concerned that the mistreatment of julian assange constitutes breaches of his right to a fair trial and protections enshrined in the united nations convention against torture and other cruel, inhuman or degrading treatment or punishment, to which the uk is party. it is deeply shocking that as a mature democracy in which the rule of law and the rights of individuals are preserved, the uk government has been silent and has taken no action to terminate such gross and disproportionate conduct by crown officials. as well, we are surprised that the presiding judge has reportedly said and done nothing to rebuke the officials and their superiors for such conduct in the case of an accused whose offence is not one of personal violence. many countries in the world look to britain as an example in such matters." dr allen keller, director of the bellevue/nyu program for survivors of torture, has said that "as physicians, we have a crucial role to play in promoting human rights ( ) ," and professor leonard rubenstein, of the john hopkins berman institute of bioethics, stresses that "the medical community as a whole needs to speak out far more forcefully against torture ( ) ." we have a professional and ethical duty to speak out against torture, report past torture, to stop present torture and to prevent future torture. assange's torture may well facilitate his death ( ) . the silence must be broken. if not now, then when? please join us, before it is too late ( ) . ( ) amnesty international. uk: assange bail application highlights covid- risk to many vulnerable detainees and prisoners. https://www.amnesty.org/en/latest/news/ / /uk-assange-bail-application-highlights-covid -risk-to-many-vulnerable-detainees-and-prisoners/ . - - . ( ) reporters without borders. uk: adjournment of julian assange's us extradition hearing considered amidst coronavirus concerns. https://rsf.org/en/news/uk-adjournment-julianassanges-us-extradition-hearing-considered-amidst-coronavirus-concerns . - - . ( ) reporters without borders. #free assange: sign against julian assange's extradition to the united states! https://rsf.org/en/free-assange . - - . ( ) the freedom of the press foundation. the trump administration's indictment of julian assange threatens core press freedom rights. https://freedom.press/news/trumpadministrations-indictment-julian-assange-threatens-core-press-freedom-rights/ . - - . ( ) amnesty international. usa must drop charges against julian assange. https://www.amnesty.org/en/get-involved/take-action/julian-assange-usa-justice/ . - - . formal application, which she would hear on day d. on day , following assange's lawyers' submissions, which were reportedly not contested by the opposing lawyers, the judge, reportedly reading from a pre-prepared ruling, denied the application for assange to leave the enclosure and sit with his lawyers e. the judge further ruled that assange would remain in the glass enclosure for the duration of the extradition hearing, including phase f. https://www.wsws.org/en/articles/ / / /assa-f .html g. https://www.craigmurray.org.uk/archives/ / /thearmoured-glass-box-is-an-instrument-of-torture/ . on day of the hearing, one of assange's lawyers left the courtroom and moved to "shake hands" with assange through a slot in the glass enclosure a. as assange stood to meet the gesture, the security guards in the enclosure physically forced him back into his seat, preventing any contact with his lawyer b. https://www.craigmurray.org.uk/archives/ / /your-man-inthe-public-gallery-assange-hearing-day- / . the extradition treaty between the uk and the us proscribes extradition on the basis of political offenses, and the domestic uk extradition act was passed into law on the basis of this treaty. nevertheless, the judge asserted that: a. the domestic uk extradition act does not mention political offenses as an exemption b. the court was not bound by the us-uk treaty under which extradition is being sought, only the uk extradition act c. therefore, she appeared to indicate that she would extradite defendants to the us for purely political offences . the court heard that the us will place assange under "special administrative measures" in the us if extradited a. https:// stcenturywire.com/ / / /pilger-julian-assangemust-be-freed-not-betrayed/ . special administrative measures (sams) are among the most extreme forms of solitary confinement and isolation known, described by the centre for constitutional rights as "far more restrictive than even the most severe conditions found in most established legal systems" https://ccrjustice.org/sites/default/files/attach/ / /sams% report.final_.pdf b. a yale law school report from details sams' violations of both us and international law: https://law.yale.edu/sites/default/files/area/center/schell/docum ent/sams_report.final.pdf end torture and medical neglect of julian assange state responsibility for the torture of julian assange international bar association. ibahri condemns uk treatment of julian assange in us extradition trial your man in the public gallery -assange hearing day julian assange asks to sit with lawyers for extradition case the armoured glass box is an instrument of torture live updates from london: assange extradition hearing adjourned until wikileaks founder julian assange misses uk hearing as 'unwell with respiratory problems julianassange's partner @stellamoris says he's in his cell at hmp belmarsh hours a day judge refuses to grant wikileaks founder's partner anonymity in extradition case united kingdom: working group on arbitrary detention expresses concern about assange proceedings wpa position statement on banning the participation of psychiatrists in the interrogation of detainees united nations office of the high commissioner for human rights. convention against torture and other cruel, inhuman or degrading treatment or punishment human rights and advocacy: an integral part of medical education and practice the medical community's response to torture doctors for assange general surgery forensic child and adolescent psychiatrist ma md frcp independent writer and humanitarian physician; visiting lecturer in nephrology at the university of ulster dental surgeon assange to exercise in the prison gymnasium with other inmates c. https://www.theguardian.com/media/ /feb/ /julianassange-was-harassed-by-cell-search-claims-father d. https://www.youtube.com/watch?v=f_dj nll xw . on assange's return to hmp belmarsh after day , authorities: a. strip searched assange twice, moved him between holding cells, and handcuffed him times b. seized his legal papers including privileged communications . when assange's lawyers objected to this treatment, the judge claimed no authority to ensure humane treatment of prisoners, despite both assange's and the us' lawyers noting that such practice is commonplace and urging her to "send a message" to prison authorities that his treatment was unacceptable https://assangecourt.report/day- -morning . assange, as a defendant in a us extradition request relating to his work as a journalist, was forced to sit in an armoured glass enclosure, which inhibited his ability to hear the proceedings and communicate with his lawyers a. assange made appeals regarding his inability to participate in his own defence on days and b. on day , his lawyers requested that assange be permitted to leave the enclosure to sit with them c. the judge refused, inviting assange's lawyers to make a . phase of extradition hearing set to begin may . assange will be confined to the glass enclosure for future phases of extradition hearing key events . assange's lawyers requested bail on the basis that assange is non-violent, he is being held only on remand, he is not convicted of a crime, he is not awaiting sentencing, and he is at increased risk for contracting covid- and suffering severe sequalae and/or death . his lawyers also presented a bail release plan to live with his partner, their children, and his own father (mr shipton) . assange himself appeared by videolink, which was terminated after about an hour, rendering him unable to follow the remainder of his own hearing . the judge denied reason to question existing prison procedures regarding covid- , despite widespread concern about poor management of coronavirus in prisons at the time; https://www.theguardian.com/society/ /mar/ /releaseprisoners-or-face-jail-pandemic-says-chief . the judge ignored assange's increased risk for covid- result . assange to remain in hmp belmarsh, his bail request being denied despite all the arguments in favour . first uk prisoner death due to covid- announced the next day . uk bureau of prisons (bop) announces policy for the release of up to , prisoners . the policy requires that a prisoner is serving a custodial sentence . prisoners on remand awaiting sentencing will have their sentencing expedited . the policy thereby excludes assange, because he is neither serving a custodial sentence nor is he awaiting sentencing . a reporter asked the bop specifically about assange, and received an official statement that assange is not eligible as he is not serving a custodial sentence and therefore will not be released https://www.sbs.com.au/news/despite-prisoner-coronavirus-fearsuk-government-won-t-release-julian-assange resultassange not released from hmp belmarsh as covid cases and deaths within and without uk prisons rapidly mount more issues with open justice: during the postponement, the court placed on hold seven journalists and observers participating by phone. court clerk reportedly failed to unmute the call after the delay and the journalists and observers missed the proceedings entirely d. the six journalists and members of the public above includes i) reporters without borders (rsf) uk bureau director rebecca vincent ii) stefania maurizi iii) doctors for assange observers . assange was reported to be too unwell to appear in person or by videolink . lewis said july was not good for prosecution a. dobbins for prosecution assisting w/child abuse inquiry b. american prosecutors need to fly over and flights doubtful c. lewis has some "public duties" at end of july . fitzgerald said november too late and july "perhaps unworkable" a. mr summers and a key witness not available in july b. a further date in august is a problem too . the judge acknowledged july will not work; noted good availability in august . fitzgerald said first three weeks of august unworkable . lewis said prosecution prefers september . hearing date set for "approximately" september . hearing will be moved to another crown court a. possibly outside london b. judge said it will "take some negotiation" to find another court that is willing and available in september because of "current climate" . assange protest outside westminster magistrates court was broken up by uk special operations officers and metropolitan police within minutes after the hearing ended a. the police deemed the protest "unlawful" under covid- legislation b. documentation of special operations involvement in addition to the metropolitan police: i) https://twitter.com/tareq_haddad/status/ ii) https://thewatchdog.net/ / / /special-operationsofficers-disperse-assange-supporters-as-u-s-extraditioncase-delayed-for-months/ results . search on for a court for the hearing in september a. judge said she would have a new date/location by friday may , and communicate that information by email to the two parties then b. likely it will be a court outside london . it is likely that the new restart date is september . next "callover" for assange will take place on june new date and court venue will not be confirmed on friday , a. both psychiatric reports on assange -prosecution and defence -will be due on july . b. new defence skeleton argument due on august c. new prosecution skeleton argument due on september . assange remains at extreme risk for covid- . assange remains unable to participate in his own case proceedings key events . guardian publishes article detailing the impact of the collateral murder video . the event depicted in the video was a us apache helicopter gunning down iraqi civilians and two reuters journalists . the helicopter also shot up a van that came to rescue the victims who were still alive after the first round of gunfire . that van had two children as passengers who were both severely wounded . the article describes the reuters station chief in baghdad--dean yates--seeking answers from the us military about the killings . two us army generals lied about the event and denied him the video . yates filed freedom of information act requests for the video, which were turned down . yates recounts how the wikileaks release of the video exposed the us military's lies and cover up of the events depicted in the video key: cord- -hahqwt x authors: alwan, ala title: responding to priority health challenges in the arab world date: - - journal: lancet doi: . /s - ( ) - sha: doc_id: cord_uid: hahqwt x nan the arab world today faces major challenges to health development, which are captured by papers in this series. after my election as who regional director for the eastern mediterranean in january, , my fi rst task was to work closely with who member states to agree on an agenda to address these challenges. a series of high-level consultations was held with countries and experts, after a process of objective analysis of the health situation in the countries of the region. it is a region of great diversity. although many countries, both arab and non-arab, have made great gains and have built extensive modern networks of health infrastructure with wide deployment of medical technologies, these gains have not been shared across and within countries. many of the challenges cut across the health sector and are shared by all countries. in october, , health ministers of the region agreed on fi ve key priority areas-highly relevant to all countries-and on strategic directions for public health action to tackle them. , the priority areas were aligned with the fi ve categories for priority setting that were endorsed by all who member states during the world health assembly in may, . although these directions were intended to guide the work of who, their focus and nature make them applicable for a much broader range of stakeholders and partners. one of the fi ve priorities is strengthening of health systems. accelerating progress towards universal health coverage by reforming health systems is top priority for who in the region. the aim is to ensure access for all people to quality health services without risk of fi nancial hardship. this is a diffi cult challenge considering the current low levels of prepayment schemes and high out-of-pocket health expenditures in many countries. with support from who, and working closely with the world bank and other partners, countries are beginning to develop a vision, responding to priority health challenges in the arab world i owe special thanks to a large network of arab scientists who have contributed to this series. special thanks go to huda zurayk, rita giacaman, samer jabbour, and iman nuwayhid for their persistent and exceptional commitment to this project. thanks also to idrc for fi nancial support, and to the faculty of health sciences at the american university of beirut for hosting our planning and peer review meetings. evidence-based strategies, and road maps to move toward universal health coverage. some countries have started to plan comprehensive reforms, including in health fi nancing, adopting a multisectoral approach. another priority is the unfi nished agenda of communicable diseases. despite commendable progress in past decades in reducing the burden of these diseases, important challenges remain and new ones continue to emerge. the coverage and quality of immunisation programmes vary. viral hepatitis and malaria are major health problems in some countries. the region has the fastest rate of increase among who regions in the number of hiv infections and the lowest coverage with antiretroviral therapy. it also has two of the world's three remaining pockets of polio. recent outbreaks in countries that had been free of polio for many years represent a major impediment to global eradication eff orts, and led ministers of health to declare polio a regional emergency and mount a comprehensive response. new infections, such as the middle east respiratory syndrome, also continue to emerge. although the international health regulations provide a framework for countries to respond to acute public health threats, countries need to do more to meet the requirements set by the world health assembly for achieving the core capacities for surveillance and response by june, , at the latest. a third priority is maternal and child health; chil dren younger than years and mothers needlessly die each year in the region from avoidable causes. at the present rate of action, the region as a whole will not be able to achieve millennium development goals and . a regional response, the dubai declaration for saving the lives of mothers and children, has been launched, and national acceleration plans are being implemented in high-burden countries, which include seven arab countries. non-communicable diseases are also a crucial challenge, particularly cardiovascular diseases, cancers, and diabetes-the burden of each continues to escalate. in some countries, up to % of those dying from noncommunicable diseases are aged younger than years. the response of countries to the very clear road map for addressing non-communicable diseases outlined in the global strategy and the political declaration of the united nations general assembly of september, , is, so far, inadequate. however, countries have adopted a regional framework for action specifying commitments to implement strategic interventions in governance, prevention of risk factors, surveillance, and health care. some progress is being made but gaps in action remain. the fi fth priority is emergency preparedness and response. protracted emergencies seem almost to have become a way of life in some parts of the region, and more than half of the countries are currently facing either acute or chronic crises. the major source of emergencies is civil unrest and violent confl ict. the consequences are clear in the expanding humanitarian crisis in syria and its neighbours, with rising numbers of people displaced. health systems in all countries aff ected are facing major diffi culties in coping with the demands. collective action and solidarity are needed to deliver health services to refugees and host communities, and to increase the resilience of countries to emergencies and ensure eff ective public health responses during crises. much work is still ahead of us in each of these fi ve areas. health goals in the arab world will only be realised through the building of strong health systems, solid commitment to health promotion, and ensuring that health is con sidered in all government policies. solidarity among countries is of crucial importance. the contribution of high-income countries in the region to achieve better health in low-income countries needs to be scaled up. world health organization, regional offi ce for the eastern mediterranean, nasr city, cairo , egypt alwana@who.int i declare that i have no confl icts of interest. the calls for freedom, social justice, and human dignity that resonate within the arab world have been heard loud and clear but, as yet, are not refl ected in a new development paradigm. the legitimate aspirations of the arab population are suff ocated by deeply polarised societies and a very narrow interpretation of social justice. these two deterrents are a manifestation of failure of the development trajectory to embrace fairness and inclusiveness as core prerequisites for individual and social wellbeing. development has emphasised economic growth and access to services, and employed a narrow translation of social justice in terms of provision of minimum basic needs to the poorest populations. as a result, many arab countries (eg, those of the persian gulf, libya, lebanon, algeria, and tunisia) have been placed in very high or high ranks in terms of the human development index. other arab countries, including those in the low human development index rank, have managed to achieve great improvements on economic and health fronts. notably, before the uprisings in tunisia and egypt, these countries were complimenting themselves on such economic and health improvements and on commitments to poverty reduction. , so where did the arab world go wrong? the people of the region provided the answer to this question. protesters on the streets of cairo, egypt, and in tunisia were asking for fair employment, and recognising that jobs and rewards are off ered on the basis of family connections and political affi liations. young women were making their voices heard by objecting to the continuous assault on their public spaces. lowincome and underserved communities were asking for their just entitlements. they all demanded freedom of expression, political voice, and protection from police brutality. they recognised social justice as fairness in the creation of participatory opportunities, and in empowerment not restricted to remedial welfare handouts. clearly, past failures underlie frustrations with the status quo, and have eroded social fabrics and bred extremism and polarisation in society. overall economic growth, which is equitably distributed, and accessibility to public services are necessary but not suffi cient to bring about social changes that can lead to refutation of ideas such as superiority of one religious group over another, or tolerance to discrimination by sex. arab countries must ensure the foundations of citizenry and non-discrimination by sex, religion, and ethnic or social background. i propose that targeting health equity as a central development goal and as a measure of societal success can go a long way in avoiding the failures of the past. health equity needs to capture people's aspirations for wellbeing, and must be grounded in a transformative understanding of social justice on the basis of fairness and inclusiveness for all. this proposal is in full accordance with the global development discourse. it draws on a rich evidence base linking systematic inequalities in health to their structural causes. such a foundation is, at present, evolving into a growing movement pushing health equity to the forefront. this movement is explicit in crystallising the key diff erences between a social determinants approach to health and a social justice approach to health equity. the social justice approach is not about the size of resources, but their fair allocation and distribution, and contributes an additional value judgment to health equity. it considers health inequality as unfair, not only because it involves denial of a human right, but also because it expresses the inequitable distribution of power, money, and resources. the discourse has now moved from eff ective government into good governance. another distinctive feature of the present health equity movement is its concern with wellbeing and not health equity in the arab world: the future we want the state of health in the arab world, - : an analysis of the burden of diseases, injuries, and risk factors public health in the arab world governance and health in the arab world non-communicable diseases in the arab world the path towards universal health coverage in the arab uprising countries tunisia changing therapeutic geographies of the iraqi and syrian wars health and ecological sustainability in the arab world: a matter of survival health and contemporary change in the arab world importance of research networks: the reproductive health working group, arab world and turkey state formation and underdevelopment in the arab world responding to priority health challenges in the arab world health equity in the arab world: the future we want research and activism for tobacco control in the arab world the making of the lancet series on health in the arab world global action plan for the prevention and control of noncommunicable diseases political declaration of the high-level meeting of the general assembly on the prevention and control of non-communicable diseases the political declaration of the united nations general assembly on the prevention and control of non-communicable diseases: commitments of member states and the way forward. resolution adopted at the fifty-ninth session key: cord- -d uera authors: kuiken, thijs; fouchier, ron am; schutten, martin; rimmelzwaan, guus f; van amerongen, geert; van riel, debby; laman, jon d; de jong, ton; van doornum, gerard; lim, wilina; ling, ai ee; chan, paul ks; tam, john s; zambon, maria c; gopal, robin; drosten, christian; van der werf, sylvie; escriou, nicolas; manuguerra, jean-claude; stöhr, klaus; peiris, j s malik; osterhaus, albert dme title: newly discovered coronavirus as the primary cause of severe acute respiratory syndrome date: - - journal: lancet doi: . /s - ( ) - sha: doc_id: cord_uid: d uera background: the worldwide outbreak of severe acute respiratory syndrome (sars) is associated with a newly discovered coronavirus, sars-associated coronavirus (sarscov). we did clinical and experimental studies to assess the role of this virus in the cause of sars. methods: we tested clinical and postmortem samples from sars patients in six countries for infection with sarscov, human metapneumovirus, and other respiratory pathogens. we infected four cynomolgus macaques (macaca fascicularis) with sars-cov in an attempt to replicate sars and did necropsies on day after infection. findings: sars-cov infection was diagnosed in ( %) of patients fitting the case definition of sars; human metapneumovirus was diagnosed in ( %) of , and other respiratory pathogens were diagnosed only sporadically. sars-cov was, therefore, the most likely causal agent of sars. the four sars-cov-infected macaques excreted sars-cov from nose, mouth, and pharynx from days after infection. three of four macaques developed diffuse alveolar damage, similar to that in sars patients, and characterised by epithelial necrosis, serosanguineous exudate, formation of hyaline membranes, type pneumocyte hyperplasia, and the presence of syncytia. sars-cov was detected in pneumonic areas by virus isolation and rt-pcr, and was localised to alveolar epithelial cells and syncytia by immunohistochemistry and transmission electron microscopy. interpretation: replication in sars-cov-infected macaques of pneumonia similar to that in human beings with sars, combined with the high prevalence of sars-cov infection in sars patients, fulfill the criteria required to prove that sars-cov is the primary cause of sars. published online july , http://image.thelancet.com/extras/ art web.pdf severe acute respiratory syndrome (sars) is an emergent disease that was first reported in guangdong province, people's republic of china, in november, , from where it spread to other asian countries, north america, and europe. [ ] [ ] [ ] [ ] [ ] by july , , this epidemic had resulted globally in reported cases, of which were fatal. pulmonary lesions in sars patients have been diagnosed as diffuse alveolar damage. histological changes include desquamation of pneumocytes, formation of hyaline membranes, flooding of alveolar lumina with oedema fluid mixed with inflammatory cells, and the presence of enlarged pneumocytes and syncytia. alveolar walls are thickened by mild mononuclear infiltrate, and in later stages air spaces contain fibromyxoid-organising exudate. , , , , coronaviruslike particles have been detected by transmission electron microscopy in cells from a lung biopsy sample and a bronchoalveolar lavage sample, and in pneumocytes from a postmortem lung sample. until now, immunohistochemical detection of sars-associated coronavirus (sars-cov) in sars-associated lesions has not succeeded. identification of the causal agent of sars is essential to make an accurate case definition, to diagnose the disease accurately, and to develop appropriate preventive and curative treatment. several agents have been proposed in the course of investigation of sars. during initial investigations in china, mycoplasma pneumoniae and chlamydia sp were suggested as possible causes. , subsequent studies ruled out these agents and other known viral and bacterial pathogens, , except for human metapneumovirus. a previoulsy unknown coronavirus was identified in patients with sars. , , it was suggested that this coronavirus, alone or in combination with human metapneumovirus or other causal agents, might be the primary cause of sars. we investigated the causal role of the newly discovered sars-cov by analysis of the results of investigations done by the who network of laboratories, showing that sars-cov was the only agent seen consistently in patients with probable sars. we also investigated whether respiratory lesions of sars could be replicated in experimentally infected cynomolgus macaques (macaca fascicularis). replication was based on histopathology, as in a preliminary report, and on localisation of sars-cov to the typical pulmonary lesions by immunohistochemistry and transmission electron microscopy. newly discovered coronavirus as the primary cause of severe acute respiratory syndrome all patients in this study fitted the who case definition for sars (table ). some of the data on various proportions of patients in cohorts , , , [ ] [ ] [ ] [ ] and , , and have been published previously. antibody to sars-cov was detected in paired acute and convalescent sera by use of an indirect immunofluorescence assay for patients in all cohorts. in addition, an enzyme-linked immunosorbent assay was used with minor modifications in cohorts and . antibody to human metapneumovirus was detected in paired acute and convalescent sera by use of an immunofluorescence assay on human-metapneumovirusinfected fetal rhesus monkey kidney (frhk- ) cells for patients in cohort , and for all patients who were human-metapneumovirus culture positive in cohorts and . iga-specific and igg-specific eia were used for the remaining five patients in cohort , and for all patients in cohort . an iga-specific eia was used for patients in cohort . these tests are under development for commercial distribution (meddens diagnostics, vorden, netherlands). the clinical samples from which rna extracts were obtained varied among cohorts and included swabs from nose, pharynx, or conjunctiva, aspirates from nasopharynx or trachea, bronchoalveolar lavage fluid, faeces, urine, sputum, and blood. samples included postmortem lung tissue in cohort , and from various organs in cohort . the rt-pcr for sars-cov on clinical samples was done according to peiris and colleagues' method for cohorts - , and according to that by drosten and colleagues for cohorts , , and . comparable tests that used primer pair cor- /cor- were used for cohorts [ ] [ ] [ ] primer pairs cor-p-f /cor-p-r and bp/ bm for cohort , , and primer pairs cor- /cor- and sar s/sar as for cohort . virus isolation procedures for sars-cov were done by inoculation of samples on to vero cells for cohorts - , and on to hela, human embryonic lung, llc, madin-darby canine kidney cells, and vero cell lines for cohort . presence of virus was confirmed by immunofluorescence, rt-pcr, or both. the rt-pcr for human metapneumovirus on clinical samples was done according to peiris and colleagues' method for cohorts and , with use of primer pair l ( Ј-catgcccactataaaaggtcag- Ј) and l ( Ј-caccccagtctttcttgaaa- Ј) for cohorts - , according to the method of peret and colleagues, with conventional and real-time pcr for cohort , with use of a family-specific primer pair according to drosten and colleagues for cohort , for cohort with use of n and f gene-based primers, and by nested pcr with use of the outer primer pair p ( Ј-gatcaacatatct tcagtccagac- Ј) and p ( Ј-aaaagcatgatc cgatatgaaccc- Ј) and l and l as inner primer pair for cohorts and . in addition, for cohort samples were inoculated onto hela, human embryonic lung, llc, madin-darby canine kidney, and vero cell lines for days at ºc. for cohort , nasopharyngeal aspirate samples were inoculated onto llc-mk rhesus monkey kidney cell and human laryngeal carcinoma cell (hep- ) monolayers and incubated at ºc for - days (hep- cells) or days (llc-mk cells) in a roller tube culture system. these cell lines were selected based on the results of an initial assessment. irrespective of the presence of cytopathic effect, cell culture supernatants were testd for human metapneumovirus by nested rt-pcr with use of the outer primer pair ( Ј-agctgttccattgg cagca- Ј) and ( Ј-atgctgttcrccytcaac ttt- Ј; r=a or g, y=c or t) and the inner primer pair ( Ј-gagtagggatcatcaagca- Ј) and ( Ј-gct tagctgrtatacagtgtt- Ј). all pcr products were confirmed by nucleotide sequencing. in addition, all cell cultures positive for human metapneumovirus rtpcr were passaged on to another llc-mk rhesus monkey kidney cell culture tube and incubated for days. randomly selected supernatants of cell cultures with cyopathic effect were examined by electron microscopy for the presence of virus particles. we made the virus stock used to inoculate cynomolgus macaques from the fourth passage of a sars-cov isolate, obtained from patient , who died of sars, and inoculated it on to vero cells cultured in iscove's modified dulbeco's medium (bio whitaker, walkersville, md, usa). after centrifugation at g for min, ml samples were made from the supernatant and from the pelleted cells, which were resuspended in ml medium. the titre of this virus stock was ϫ median tissue culture infectious dose (tcid ) per ml. all cell cultures were done under biosafety level conditions. four adult cynomolgus macaques, two males and two females, were placed in negatively pressurised glove boxes. they were infected with ϫ tcid of sars-cov suspended in ml phosphate-buffered saline. ml was applied intratracheally, · ml intranasally, and · ml on each conjunctiva. we checked the macaques daily for clinical signs. just before infection and at days , , and after infection, we anaesthetised the macaques with ketamine and collected ml blood from inguinal veins, and took nasal, oral, pharyngeal, and rectal swabs, which were placed in ml virus transport medium. from macaques and , we also collected sputum samples by use of swabs under the tongue and sponges placed in the buccal cavity during anaesthesia. we extracted fluid from the sponges by centrifugation. the macaques were euthanised days after infection by exsanguination under ketamine anesthesia. we did necropsies of the macaques according to a standard protocol. for histological examination we collected the following tissues: adrenal gland, aorta, axillary lymph node, brachial biceps muscle, brain stem, caecum, cerebellum, cerebrum, colon, duodenum, eye, tissues for light-microscope examination were fixed in % neutral-buffered formalin, embedded in paraffin, and m sections were stained with haematoxylin and eosin. selected lung sections were stained with monoclonal antibody ae /ae (neomarkers, fremont, ca, usa) for the identification of epithelial cells, and monoclonal antibody cd (dako, glostrup, denmark) for the identification of macrophages according to standard immunohistochemical procedures. we developed an immunohistochemical method for detecting sars-cov antigen. duplicate sections of all tissue samples were stained with an avidin-biotin complex peroxidase method. paraffin was removed from sections, which were rehydrated and pretreated with protease (sigma, st louis, mo, usa) for min at ºc. endogenous peroxidase was revealed with -chloro- -naphthol (sigma). endogenous biotin was blocked with an avidin-biotin blocking kit (vector laboratories, burlingame, ca, usa). slides were briefly washed with · % phosphate-buffered saline tween (fluka, buchs, switzerland) and incubated with biotinylated purified human igg from a convalescent sars patient, negative control biotinylated purified human igg, or the dilution buffer (phosphate-buffered saline containing % bovine serum albumin) for h at room temperature. after washing, sections were incubated with avidin-biotin complex-horseradish peroxidase (dako) for h at room temperature. horseradish peroxidase activity was revealed by incubating slides in -amino- -ethylcarbazole (sigma) solution for min, resulting in a bright red precipitate. sections were counterstained with haematoxylin. tissue sections from cynomolgus macaques that had not been infected with sars-cov were included as negative controls. we included formalin-fixed, paraffin-embedded sars-cov-infected or uninfected vero cells in each staining as positive and negative controls, respectively. for negative contrast electron microscopy, samples of tissue culture supernatants were centrifuged at g at ºc, after which the pellet was resuspended in phosphatebuffered saline and stained with phosphotungstic acid. samples of lung from macaque were fixed for transmission electron microscopy in % formaldehyde and % glutar(di)aldehyde after brief fixation in % neutral-buffered formalin, and post-fixed in % osmium tetroxide. after embedding in epoxy resin, thin sections were prepared, stained with % saturated uranyl acetate and lead citrate, and examined with a philips morgagni d electron microscope. samples from lung, duodenum, jejunum, kidney, liver, and spleen were collected post mortem for virus isolation and rt-pcr. additionally, we collected the following samples for rt-pcr only: cerebellum, cerebrum, ileum, intestinal contents from the colon, mesenteric lymph node, nasal septum, pancreas, skin, spleen, stomach, tonsil, trachea, tracheobronchial lymph node, urinary bladder, and urine. from macaques and , samples of intestinal contents from the jejunum, ileum, and caecum were also collected for rt-pcr. intestinal contents were pretreated with stool transport and recovery buffer (roche diagnostics, mannheim, germany) before further processing. tissue samples were homogenised in ml transport medium with polytron pt tissue grinders (kinematica, littau-lucerne, switzerland). after lowspeed centrifugation, the homogenates were frozen at - ºc until inoculation on vero cell cultures in logarithmic dilutions. the infectious virus titres were expressed as tcid /g of tissue. the identity of the isolated virus was confirmed as sars-cov by rt-pcr of supernatant. we developed an rt-pcr with primers and probe specific for the nucleoprotein gene of sars-cov because the nature of the coronavirus replication cycle suggested that such an assay may be more sensitive than rt-pcrs based on the polymerase gene, which are currently in use for diagnostics. nucleic acid isolation was done on the magnapure lc automated nucleic acid isolation system (roche diagnostics). swabs, faeces, and serum were processed with the magnapure lc total nucleic acid serum plasma blood isolation kit. postmortem tissue samples were processed with the magnapure lc rna isolation kit i on the magnapure lc station using the external lysis protocol. sars-cov rna was detected on the abi prism , with use of the ez rtth rna amplification kit (applied biosystems, foster city, ca, usa). primers sarsnp fpr ( Ј-caaacattggccg caaatt- Ј), sarsnp rpr ( Ј-caatgcgtgaca ttccaaaga- Ј), and probe sarsnp prb ( Ј-cacaatttgctccaagtgcctctgca- Ј) (eurogentec) specific for the nucleoprotein (np) gene of sars-cov were used for amplification. amplification parameters were min at ºc, min at ºc, min at ºc, and cycles of s at ºc, and min at ºc. we compared the sensitivity of the sars-cov np rtpcr with a sars-cov polymerase rtpcr that used essentially the same methods with primers and probe specific for the sars-cov polymerase (sarstm fpr . serial dilutions of the sars-cov virus stock and sars-cov-infected vero cells from patient were made and tested with the np and polymerase-specific rt-pcrs. samples from the respiratory tract (nasal swabs, pharyngeal swabs, postmortem trachea, and lung samples) were also monitored for influenza a and b virus, respiratory syncytial virus a and b, rhinovirus, coronavirus (oc and e), and human metapneumovirus with use of essentially the same rt-pcr methods but with specific primers. we detected antibody to sars-cov in macaque sera by use of an indirect immunofluorescence assay. sars-cov-infected vero cells that had developed cytopathic effect were used to coat microscope slides. after incubation of the serum for min at ºc, slides were washed with phosphate-buffered saline and incubated with antihuman igg, iga, and igm, conjugated with fluorescein thiocyanate (dako). after washing and drying, slides were examined with a fluorescence microscope (zeiss axioscope, oberkochen, germany). we the sponsors of the study had no role in the study design, data collection, data analysis, data interpretation, or in the writing of the report. overall, % of patients who had suspected sars according to the who case definition were diagnosed as being infected with probable sars-cov, whereas % were diagnosed as having human metapneumovirus infection (table ). the high proportion of patients diagnosed with human metapneumovirus infection could be attributed mainly to cohort , in which % of patients were positive for this infection. without this cohort, the overall proportion of human metapneumovirus diagnoses decreased to %. alternative diagnoses in patients who tested negative for sars-cov infection were influenza (five), m pneumoniae infection (one), and legionella sp infection (one). three macaques ( , , and ) became lethargic from days - after infection onwards. macaques and developed a temporary skin rash at day after infection. macaque had respiratory distress, consisting of an increased respiratory rate and dyspnoa, from day after infection onwards. macaques - had multiple foci of pulmonary consolidation in both lungs. the consolidated lung tissue was grey-red, firm, level, and less buoyant than normal. the tracheobronchial lymph nodes and spleen in these macaques were about twice the normal size. the other organs in these three macaques, as well as the respiratory tract and other organs of macaque were normal on microscopic inspection. the main lesion in the consolidated pulmonary tissue of macaques - involved the alveoli and bronchioles, and consisted of areas with acute or more advanced phases of diffuse alveolar damage. in such areas the lumina of alveoli and bronchioles were variably filled with proteinrich oedema fluid, fibrin, erythrocytes, and cellular debris, a moderate number of alveolar macrophages, and fewer neutrophils and lymphocytes (figure ). the cytoplasm of some of these macrophages contained erythrocytes or pools of oedema fluid. there was extensive loss of epithelium from alveolar and bronchiolar walls. in areas with more advanced diffuse alveolar damage, the alveolar walls were moderately thickened and lined by cuboidal epithelial cells (type pneumocyte hyperplasia), and the alveolar lumina contained mainly alveolar macrophages (figure ). regeneration of epithelium was seen in some bronchioles, visible as one irregular layer of squamous to high cuboidal epithelial cells with hyperchromatic nuclei. in some areas, the alveolar walls were lined by deep eosinophilic hyaline membranes (figure ). there were occasional multinucleated giant cells (syncytia) in bronchioles and alveoli, either attached to the wall or free in the lumen (figure ). these syncytia had up to about peripheral nuclei, abundant hyaline eosinophilic cytoplasm, and, based on positive cd staining and negative pan-keratin staining, originated from marcophages. enlarged type pneumocytes with large vacuolated nuclei, prominent nucleoli and abundant vesicular cytoplasm were frequently found attached to the alveolar walls (figure ). the epithelial origin of these cells was confirmed by keratin expression (figure ). by contrast, alveolar macrophages had smaller nuclei, less prominent nucleoli, and were generally loose in the alveolar lumina (figure ). the identity of these cells as macrophages was confirmed by cd staining (figure ). alveolar and bronchiolar walls were thickened by oedema fluid, mononuclear cells, and neutrophils. there were aggregates of lymphocytes around small pulmonary vessels. moderate numbers of lymphocytes and macrophages were present in the lamina propria and submucosa of the bronchial walls, and a few neutrophils in the bronchial epithelium. changes in other tissues of macaques - were diffuse lymphoid hyperplasia and sinus histiocytosis of the tracheobronchial lymph nodes. macaques and also had diffuse intrafollicular hyalinosis of the spleen. there were minimum multifocal inflammatory lesions in the pulmonary tissue of macaque , consisting of increased numbers of alveolar macrophages (about ten per alveolus) and occasional syncytia in alveoli and bronchioles. with use of a biotinylated igg fraction from a sars patient, sars-cov expression was detected in a few to moderate numbers of alveolar epithelial cells (type pneumocytes; figure ) and rare intrabronchiolar and intra-alveolar syncytia ( ultrastructurally, coronavirus-like particles measuring about nm in diameter with typical internal nucleocapsid-like structure and club-shaped surface projections were found in enlarged alveolar epithelial cells (type pneumocytes) of inflamed lung tissue from macaque . the particles were localised within smoothwalled vesicles, often closely associated with the golgi apparatus ( figure ) . the particles in inflamed lung tissue were similar in size and structure to coronavirus particles in vero cells infected with sars-cov ( figure ) . the np-specific rt-pcr was about -fold more sensitive than the polymerase-gene-based rt-pcr on the virus stock and the infected cell dilution series. the np rt-pcr also was more sensitive based on detection of viral rna in samples obtained from the sars-covinfected macaques (data not shown). the macaques shed sars-cov from sputum, nose, and pharynx from days after infection onwards (table ) . sars-cov was isolated from the nasal and throat swabs from macaque at days after infection, from the throat swabs of macaque at days , , and after infection, and from sputum samples of macaque at days and after infection. the virus titre in these samples was not measured. several other clinical samples were positive only by rt-pcr (table ) . by negative-contrast electron microscopy, coronavirus particles were seen in cell cultures obtained from nasal swabs (figure ) and closely resembled those in the virus stock used to infect the macaques ( figure ) . virus was not detected in rectal swabs. sars-cov was isolated from the lung ( ϫ tcid /g tissue) and kidney ( ϫ tcid /g tissue) of macaque , and from the lung ( ϫ tcid /g tissue) of macaque . no virus was isolated from the postmortem samples of macaques or . several other tissues were positive only by rt-pcr (table ) . no macaque had detectable antibody to sars-cov by day after infection. virological examinations of nasal and pharyngeal swabs, and tracheal and lung samples from all four macaques by rt-pcr for influenza a and b virus, respiratory syncytial virus a and b, rhinovirus, coronavirus (oc and e) and human metapneumovirus were negative. no relevant pathogens were identified on bacteriological culture of lung and blood samples. the lung homogenates tested negative for chlamydia sp and c pneumoniae by pcr. according to koch's postulates, as modified by rivers for virus diseases, six criteria need to be fulfilled for a particular micro-organism to be the causal agent of a disease. laboratory investigations of clinical and postmortem samples from sars patients, as presented here and in earlier studies , , , already fulfilled the first three criteria-isolation of the virus from diseased hosts, cultivation in experimental hosts or host cells, and proof of filterability (to exclude larger pathogens). the results of our studies on sars-cov-infected macaques fulfill the remaining postulates-production of a comparable disease in the original host or a related species, and reisolation of the virus. detection of a specific immune response to the virus after experimental infection was already reported. together, these findings prove that sars-cov is the primary cause of sars. the primary role of sars-cov in the cause of sars is suggested by the cumulative studies at who laboratories, in which most sars patients were diagnosed as having sars-cov infection, frequently in the absence of other respiratory pathogens. the most common co-infection in sars patients was with human metapneumovirus. the sars patients in cohort co-infected with human metapneumovirus were mostly health-care workers from the same ward and who shared resting areas. the circulation of this infection among them during the sars outbreak probably explains the frequency of the infection in cohort . similarly, four sars patients from canada were infected with sars-cov and human metapneumovirus. the clinical symptoms of human metapneumovirus infection vary from mild upper-respiratory-tract disease to severe bronchiolitis and pneumonia. the possible role of human metapneumovirus infection in exacerbating sars remains to be assessed. alternative diagnoses, such as influenza, were occasionally made among patients fitting the case definition of sars but testing negative for sars-cov infection. on the basis of the current case definition, therefore, disease from sars-cov infection overlaps with respiratory illnesses of other causes. alternative diagnoses are most likely in geographical areas where sars is not endemic. the pulmonary lesions in sars-cov-infected macaques are comparable to those in sars patients, , , , , and to those in other respiratory coronavirus infections, such as sialodacryoadenitis virus infection in rats, n d ---- - results from rt-pcr or virus isolation. nd=not done. syncytia were found commonly in bronchioles, and less frequently in alveolar ducts and alveoli, of sars-covinfected macaques. syncytia also were prominent in the alveoli of sars patients. , , based on expression of cd and pan-keratin, the syncytia were of histiocytic origin in macaques (this study), and of histiocytic or epithelial origin in sars patients. the formation of syncytia in these macaques may have been induced by sars-cov infection, because some syncytia were positive for sars-cov by immunohistochemistry, and the spike protein of coronavirus induces cell to cell fusion. pneumocytes showing cytomegaly, enlarged nuclei, and prominent nucleoli were common both in sars-cov-infected macaques (this study) and in sars patients. , such enlargement and cytologic atypia of hyperplastic type pneumocytes occurs commonly in organising diffuse alveolar damage, and is non-specific. the development of a specific immunohistochemical test to identify sars-cov antigen in histological samples allowed us to assess the cell tropism of sars-cov infection in macaques. expression of sars-cov in the lung was restricted to pneumonic areas and localised to the cytoplasm of type pneumocytes and syncytia. the infection of type pneumocytes by coronavirus was confirmed by transmission electron microscopy. these findings correspond to the detection of coronavirus-like particles in pneumocytes of a postmortem lung sample of a sars patient, and with the tropism of respiratory coronaviruses in pigs and rats for respiratory epithelium, and occasionally alveolar macrophages. , on the basis of histological changes, sars-cov infection in the macaques primarily affected the epithelium of alveoli and bronchioles. at the time of euthanasia, days after infection, most pneumonic areas showed early to advanced type pneumocyte hyperplasia, indicating repair of alveolar walls after loss of type pneumocytes. the temporal sequence of the histological changes corresponds with that of experimental infection with porcine respiratory coronavirus in pigs, in which acute changes (loss of epithelium, presence of macrophages and fibrin in airway lumina) were seen at days - after infection, and more advanced changes (type pneumocyte hyperplasia, interstitial mononuclear cell infiltration) were seen from days - after infection. because diffuse alveolar damage from different causes follows a common pathway, , more chronic changes in these macaques probably would have included organisation of the intra-alveolar exudate, resulting in alveolar fibrosis and bronchiolitis obliterans, as seen in sars patients who died later in the course of disease. [ ] [ ] [ ] the development of fibrosis is dependent on the deposition of fibrin in the alveoli rather than on the continued presence of virus infection. onset of fibrosis is a critical feature of chronic diffuse alveolar damage, because it leads to loss of alveolar function and is irreversible. in respiratory coronavirus infections in pigs and rats, viral infection of respiratory epithelium is maximum at days - after infection, and is no longer measurable by days - . , the rapid disappearance of infected cells after initial infection might explain why sars-cov was not found in type pneumocytes, and was only occasionally found in type pneumocytes in these macaques. it also might decrease the chance of detecting sars-cov by immunohistochemistry in postmortem lung tissue of sars patients who die after a protracted course of disease. the lymphoid depletion of splenic follicles in experimentally infected macaques corresponds to that seen in a sars patient and in pigs infection with porcine respiratory coronavirus. based on these findings, together with the leucopenia observed in sars patients, [ ] [ ] [ ] [ ] we speculate that sars-cov infection suppresses immunity and may predispose infected hosts to secondary infections, such as in measles virus infection. virological examination of clinical and postmortem samples of experimentally infected macaques indicates that the respiratory tract was the most important source of virus, as is probably the case in human beings. unlike in sars patients, sars-cov was not detected in urine or faeces of these macaques, although faeces did test positive in a previous experiment. this finding may be partly explained by the early cut-off point of the experiment ( days after infection), because sars-cov rna was detected in the faeces of sars patients in the late convalescent phase. the sporadic detection by rt-pcr of sars-cov in the urinary bladder, stomach, duodenum, cerebrum, and spleen in infected macaques in the absence of evidence of viral replication-based on virus culture or immunohistochemistry-suggests overspill from other tissues, for example via blood. the isolation of sars-cov from the kidney of one macaque suggests viral replication at that site, but this theory could not be confirmed by immunohistochemistry. the rt-pcr based on nucleoprotein primers proved to be about -fold more sensitive than the existing rt-pcr, based on polymerase primers. presumably, this difference is due to the gradient in the transcription of coronavirus rna, with high concentrations of nucleoprotein rna and low concentrations of polymerase rna. collectively, these results of laboratory studies of sars patients and experimental infections of macaques prove that the newly discovered sars-cov is the primary causal agent of sars. based on histopathological and immunohistochemical analysis of postmortem tissues of these macaques, sars-cov infection primarily affects epithelium of the lower respiratory tract, with potentially severe consequences for respiratory function. none declared. t kuiken and r a m fouchier participated in the joint planning and coordination of the study. t kuiken wrote the report and supervised and interpreted the pathology, immunohistochemistry, and electron microscopy components of the experimental infections. r a m fouchier and m schutten developed, supervised, and assessed the rt-pcr for sars-cov. g f rimmelzwaan and g van amerongen planned and carried out the infection experiments. d van riel and j d laman were involved in the design, execution, and assessment of the immunohistochemistry test to detect sars-cov in tissues. t de jong did the electron microscopy and detected sars-cov in pneumocytes. g van doornum supervised the virological analyses of samples from the experimental infections. k stöhr participated as secretary of the who laboratory network on sars diagnosis and played a substantial part in the initiation of the study. a d m e osterhaus was the principal investigator and was responsible for the overall planning and coordination of the study. all other researchers were involved in the development, application, assessment of diagnostic tests on samples from sars patients, or a combination of these. berend niemeyer, georgina aron, and judith guldemeester for virological assistance; rob van herwijnen, european veterinary laboratory, woerden, for purification and biotinylation of primary antisera for immunohistochemistry; frank van der panne for assistance with preparation of figures; a m burguière for contributions to analysis of the data; s azebi, c batejat, g coralie, b crescenzo-chaigne, f fichenick, s gerbaud, v lorin, c rousseaux, and m tardy-panit for technical assistance; n tordo for the design of primers p and p and for helpful discussions; and f freymuth for providing free the human severe acute respiratory syndrome (sars) coronavirus as a possible cause of severe acute respiratory syndrome a major outbreak of severe acute respiratory syndrome in hong kong a cluster of cases of severe acute respiratory syndrome in hong kong identification of severe acute respiratory syndrome in canada cumulative number of reported probable cases of severe acute respiratory syndrome (sars) a novel coronavirus associated with severe acute respiratory syndrome lung pathology of fatal severe acute respiratory syndrome no::f _p _check_display,f _p _pub _mail_id:x, no::f _p _check_display,f _p _pub _mail_id:x, identification of a novel coronavirus in patients with severe acute respiratory syndrome koch's postulates fulfilled for sars virus clinical progression and viral load in a community outbreak of coronavirus-associated sars pneumonia: a prospective study children with respiratory disease associated with metapneumovirus in hong kong pcr primers for sars developed by who network laboratories phylogenetic analysis of a highly conserved region of the polymerase gene from coronaviruses and development of a consensus polymerase chain reaction assay characterization of human metapneumoviruses isolated from patients in north america detection of human metapneumovirus from patients with severe acute respiratory syndrome: a methodological evaluation detection of influenza a viruses from different species by pcr amplification of conserved sequences in the matrix gene coronaviridae: the viruses and their replication detection of chlamydia trachomatis in clinical specimens by the polymerase chain reaction rapid and standardised detection of chlamydia pneumoniae using lightcycler real-time fluorescence pcr a dictionary of virology a newly discovered human metapneumovirus isolated from young children with respiratory tract disease experimental infection of adult axenic rats with parker's rat coronavirus pathogenicity of experimental infection with 'pneumotropic' porcine coronavirus common pathways and patterns of injury the respiratory system pathogenicity of porcine respiratory coronavirus isolated in québec measles virus and immunomodulation: molecular bases and perspectives we thank, at the erasmus medical centre, rotterdam, the staff of the histology and immunohistochemistry laboratories of the department of pathology for technical assistance; alewijn ott and arjen van vliet, diagnostic unit, department of medical microbiology and infectious diseases, for bacteriological examination of macaque tissues; and alex van belkum and liesbeth van der zwaan, department of medical microbiology and infectious diseases, for examination of macaque lung homogenates for chlamydia. we thank theo bestebroer, metapneumovirus. we thank the french medical team, the medical staff of the hanoi french hospital, and the medical teams at the hospitals in tourcoing, besançon, strasbourg, bordeaux, montpellier, hôpital d'instruction des armées, brest, rennes, chu bichat claude bernard, paris, and chu pitié-salpétrière, paris for providing the samples. we thank the staff of the department of pathology, virology section, singapore general hospital, who did the bulk of the investigations there; and the staff of the defence medical research institute, who did some of the stool pcr tests. key: cord- -tdx ccj authors: bradley, benjamin t; maioli, heather; johnston, robert; chaudhry, irfan; fink, susan l; xu, haodong; najafian, behzad; deutsch, gail; lacy, j matthew; williams, timothy; yarid, nicole; marshall, desiree a title: histopathology and ultrastructural findings of fatal covid- infections in washington state: a case series date: - - journal: lancet doi: . /s - ( ) - sha: doc_id: cord_uid: tdx ccj background: severe acute respiratory syndrome coronavirus (sars-cov- ) is the cause of an ongoing pandemic, with increasing deaths worldwide. to date, documentation of the histopathological features in fatal cases of the disease caused by sars-cov- (covid- ) has been scarce due to sparse autopsy performance and incomplete organ sampling. we aimed to provide a clinicopathological report of severe covid- cases by documenting histopathological changes and evidence of sars-cov- tissue tropism. methods: in this case series, patients with a positive antemortem or post-mortem sars-cov- result were considered eligible for enrolment. post-mortem examinations were done on people who died with covid- at the king county medical examiner's office (seattle, wa, usa) and snohomish county medical examiner's office (everett, wa, usa) in negative-pressure isolation suites during february and march, . clinical and laboratory data were reviewed. tissue examination was done by light microscopy, immunohistochemistry, electron microscopy, and quantitative rt-pcr. findings: the median age of our cohort was · years (range – ; iqr · – · ). all patients had clinically significant comorbidities, the most common being hypertension, chronic kidney disease, obstructive sleep apnoea, and metabolic disease including diabetes and obesity. the major pulmonary finding was diffuse alveolar damage in the acute or organising phases, with five patients showing focal pulmonary microthrombi. coronavirus-like particles were detected in the respiratory system, kidney, and gastrointestinal tract. lymphocytic myocarditis was observed in one patient with viral rna detected in the tissue. interpretation: the primary pathology observed in our cohort was diffuse alveolar damage, with virus located in the pneumocytes and tracheal epithelium. microthrombi, where observed, were scarce and endotheliitis was not identified. although other non-pulmonary organs showed susceptibility to infection, their contribution to the pathogenesis of sars-cov- infection requires further examination. funding: none. in december, , severe acute respiratory syndrome coronavirus (sars-cov- ) was identified in wuhan, china from a cluster of severe pneumonia cases. the virus and the disease it causes (covid- ) have now spread globally and are responsible for an ongoing pandemic that has claimed hundreds of thousands of lives. in the months after its emergence, the community of health-care workers and researchers acted quickly to sequence the virus, establish transmission chains, elucidate the receptor, and test therapeutics. , these efforts have revealed similarities and differences between sars-cov- and the related virus, severe acute respiratory syndrome coronavirus (sars-cov). both viruses have similar clinical presentations, with the highest viral load identified in lower respiratory samples. , viral rna has also been detected in blood, stool, and urine samples, suggesting the potential for extrapulmonary spread and multiorgan involvement. , the viruses also share a common cellular entry receptor, angiotensin converting enzyme (ace ). despite their similarities, sars-cov was responsible for a restricted disease outbreak with high mortality, whereas sars-cov- has caused a greater number of infections with relatively lower mortality. post-mortem studies have shown pulmonary, renal, and small vessel injury, with particles resembling virus observed in the kidney by electron microscopy. [ ] [ ] [ ] [ ] one study described two complete autopsies without tissue-based methods for detection of sars-cov- . our study expands the literature by documenting a series of fatal covid- cases that occurred in washington state during february and march, . systematic evaluation of all major organs was done by a combina tion of light microscopy, immunohistochemistry, electron microscopy, and quantitative rt-pcr. our findings serve as a basis for generating further discussion related to the tropism, mechanisms of dissemination, and pathophysiology of severe sars-cov- infection. in this case series, patients with a positive antemortem or post-mortem sars-cov- result were considered eligible for enrolment. preliminary testing for sars-cov- was done at the washington state department of health public health laboratory (shoreline, wa, usa). confirmatory testing was done by the us centers for disease control and prevention (cdc) in atlanta (ga, usa). both locations used the cdc-designed ncov real-time rt-pcr assay for virus detection. autopsies were done at the king county medical examiner's office (seattle, wa, usa) and snohomish county medical examiner's office (everett, wa, usa) in negative-pressure isolation suites during february and march, . given safety concerns, in-situ dissection was done for patients , , , , , , and . patients , , , , , , and were examined by standard autopsy procedure. three to blocks were submitted per autopsy case. limited autopsies submitted two blocks containing sections from the left and right lung lobes, whereas complete autopsies submitted at least four blocks of lung-containing sections from central and peripheral locations of both lungs. resource limitations led to fresh tissue collection for patients , , and only. institutional review board approval was requested and waived for this study (study ). autopsy material was fixed in % neutral buffered formalin and submitted for standard processing with haematoxylin and eosin staining. select kidney sections were stained with periodic acid schiff and jones methenamine silver. evaluation of haematoxylin and eosin sections was done by consensus agreement by four board-certified forensic pathologists (ny, tw, jml, and dam) with expert guidance provided in cardiothoracic pathology (hx and gd) and renal pathology (bn). immunohistochemical staining was done on formalinfixed, paraffin-embedded -µm sections following citrate ph · antigen retrieval, endogenous biotin, and peroxidase block. immunohistochemistry for sars-cov- was done using a monoclonal antibody to the spike protein ( : ; genetex; irvine, ca, usa) on the ventana benchmark ultra ihc (roche diagnostics; basel, switzerland). images were visualised and captured with a digital camera mounted on a nikon eclipse i microscope using nis-elements advanced research software version . (nikon instruments; tokyo, japan). samples from patients and were placed in halfstrength karnovsky fixative. tissue was then post-fixed in % osmium tetroxide, processed according to standard transmission electron microscopy procedures, and embedded in polybed (polyscience; warrington pa, usa). suitable sections were identified by toluidine blue staining. thin sections were examined using a tecnai g spirit bio-twin transmission electron microscope (fei; hillsboro, or, usa) and digital images and measurements were acquired using amt image capture software (version . ). rna was extracted from · µg of tissue using the direct-zol rna miniprep plus kit (zymo research; irvine, ca, usa). complementary dna was synthesised using the iscript cdna kit (biorad; hercules, ca, usa). samples were tested in triplicate using itaq evidence before this study we searched pubmed and medline for peer-reviewed articles published between database inception and may , , that described the histopathological features of severe covid- infections, with the search terms "sars-cov- ", "covid- ", "autopsy", "postmortem", and "histology". our search was restricted to studies published in english. of the eight studies identified by our search, one documented complete histopathological findings from all major organs in two autopsies. other series showed evidence of diffuse alveolar damage, endothelial injury, and viral particles within renal cells. tissue quantitative rt-pcr (rt-qpcr) was used as an ancillary technique to identify virus in one study. this study provides crucial information related to the natural history of fatal covid- from early in the us outbreak. our analysis used multiple methods, including clinical chart review, histopathological evaluation, electron microscopy, immunohistochemistry, and quantitative rt-qpcr to examine all major organ systems. to our knowledge, no previous studies have used all these techniques simultaneously. our results support previous studies, which suggested that diffuse alveolar damage is the major source of pulmonary injury in covid- ; however, we found no evidence of widespread microvascular injury. additional investigations raised the possibility of extrapulmonary involvement in renal, intestinal, cardiac, and lymphoid tissues. in addition to the results of previous studies, our findings provide a histological explanation for physiological derangements observed by clinicians in patients who died with covid- . further investigation is required to characterise the extent of extrapulmonary injury caused by severe acute respiratory syndrome coronavirus infection. universal probes supermix (biorad) with the cdc ncov n and n primer/probe set and sarbeco e gene primer/probe set (idt; coralville, ia, usa). cycle threshold values less than were considered positive. the limit of detection was estimated to be copies per reaction based on serial dilutions of a positive control plasmid (cov ; exact diagnostics; fort worth, tx, usa). negative control reactions included on each plate repro ducibly showed no amplification. pcr was done on patients , , and . tissues examined included lung, trachea, subcarinal lymph node, heart, spleen, liver, large intestine, kidney, and whole blood. there was no funding source for this study. the median age of our cohort was · years (range to ; iqr · - · ). seven members of the cohort were part of a single cluster from a long-term care facility. all patients had clinically significant comorbidities, the most common being hypertension, chronic kidney disease, obstructive sleep apnoea, and metabolic disease, including diabetes and obesity (table ) . the most frequent presenting symptoms were respiratory distress, fever, and cough. less commonly encountered initial symptoms included altered mental status and gastrointestinal symptoms (nausea, vomiting, or diarrhoea). during hospital admission, six patients had acute kidney injury shown by elevated creatinine and three patients had elevated troponins. additional respiratory pathogens were isolated from two patientspatient had influenza a and meticillin-sensitive staphylococcus aureus and patient had sputum cultures positive for pseudomonas aeruginosa. excluding those who declined resuscitative measures (six patients), all patients were intubated. patient was electively extubated less than a day before death. the median time from symptom onset to intubation was · days (iqr - ; eight patients), with most intubations occurring at the time of admission. time to death after symptom onset varied from day to days, with a median time of days (iqr - ). for patients , , and , fresh tissue was collected at the time of autopsy for molecular and ultrastructural examination. patient was a -year-old woman who presented with cough and malaise for days after returning from international travel. on admission, the patient was hypoxic with elevated troponins and leukocytosis. her x-ray showed extensive bilateral opacities and testing was positive for sars-cov- , influenza a, and meticillin-sensitive s aureus. the patient had increasing oxygen demands and died days after admission. patient was a -year-old man with a complex cardiovascular history, end-stage renal disease, and chronic pulmonary fibrosis who presented with shortness of breath, delirium, and new onset atrioventricular node block. given his respiratory symptoms and lymphopenia, sars-cov- testing was done and returned a positive result. days after admission, the patient developed worsening hypoxia followed by sudden cardiac arrest and died. patient was a -year-old woman who presented after days of progressive shortness of breath while travelling abroad. on admission, she had clinically significant respiratory distress with hypoxia and signs of shock with elevated lactate, leukocytosis, and initial normal troponin. her chest x-ray showed diffuse lung disease and sars-cov- testing was positive. the patient's clinical course was complicated by multifactorial encephalopathy, new atrial fibrillation, and presumed ventilator-associated pneumonia and she died days after admission. all seven decedents examined by gross standard autopsy had heavy, oedematous lungs, with an average weight of g for the right lung and g for the left lung. intraparenchymal haemorrhage was observed in patient and pulmonary consolidation was present in patient . the volume of pleural fluid was highly variable and ranged from ml to ml per pleural space. patients and had evidence of central pulmonary emboli (figure ). splenomegaly was observed in patients and ( g and g, respectively), whereas splenic atrophy was observed in patient ( g). scattered punctate subarachnoid haemorrhages were observed in the brain of patient . additional gross findings showed changes including varying degrees of cardiac and atherosclerotic disease, hypertensive renal surface changes, and hepatic congestion in most patients. organ weights and gross obser vations are available in the appendix (p ). histopathological examination of the pulmonary system showed a spectrum of diffuse alveolar damage in ( %) of patients, which was evidenced by the presence of intra-alveolar fibrin, hyaline membranes, or loosely organising connective tissue in the alveolar septal walls. ( %) of patients with diffuse alveolar damage showed acute or acute and organising diffuse alveolar damage ( figure a, b) . for patient , only organising diffuse alveolar damage was observed. airways and alveolar spaces contained large, reactive multinucleated cells that stained positive for the epithelial marker ttf- and negative for the macrophage marker cd (figure c, d). microscopic haemorrhage was identified cardiac findings were mostly non-specific and associated with pre-existing comorbidities. the most common changes observed were fibrosis in ( %) patients and myocyte hypertrophy in ( %) patients. in patient , myocarditis was present with aggregates of lymphocytes surrounding necrotic myocytes ( figure c, d) . sars-cov- s protein immunohistochemistry was negative in patient . amyloid was identified in small vessels in patient and within the myocardium in patient . patients , , and had splenic white pulp depletion, which was confirmed by cd staining in patient (figure e). patient had a small sub-centimetre splenic infarction. subcarinal lymph nodes showed normal follicular architecture with haemophagocytosis observed in patients , , and . sars-cov- immunohistochemical staining was negative in the subcarinal lymph node from patient and spleen from patient . lymphoid tissue from additional patients was not available for testing. the kidneys showed mild to severe arterione phrosclerosis and diabetic nephropathy. although restricted by autolysis, features suggestive of acute tubular injury, including extensive tubular epithelial vacuolisation, were identified in patients. in patient , chronic inflammation of the renal parenchyma and focal segmental glomerulosclerosis were present. sars-cov- immunohistochemical testing in patients and showed patchy, granular cytoplasmic staining of the renal tubular epithelial cells (figure f). virus was not visualised in the endothelial cells or glomeruli by immunohistochemistry. pathological findings in the liver showed predominantly chronic changes associated with pre-existing comorbidities, with variable degrees of acute congestion. centrilobular necrosis consistent with hypoperfusion injury was identified in four patients (patients , , , and ). liver inflammation was not prominent, although some patients had mild periportal lymphocytic inflammation. weak sars-cov- immunohistochemical staining in the liver was indistinguishable from background. sam ples of the thyroid gland, pituitary gland, adrenal glands, and pancreas were largely unremarkable. post-mortem autolysis prevented thorough investigation of the gastro intestinal system and assessment by sars-cov- immunohistochemical staining. brain examination was done in five patients (patients , , , , and ). patient had acute pathology with scattered punctate subarachnoid haemorrhages and rare microhaemorrhage in the brainstem. neuropathological examinations were otherwise unremarkable. focal pulmonary micro thrombi were identified in five patients (patients , , , , ; figure ) . patient and patient also had microthrombi in the trachea, although in patient this was qualified by chronic tracheostomy. an organising thrombus was identified within a small renal vein in patient . microscopic involvement by grossly observed pulmonary emboli was seen in patient and patient . pathological findings for individual patients are provided in table . by electron microscopy, aggregates of uniform, round enveloped particles ranging in size from around nm to nm with peripheral spike-like projections consistent with the morphology described for sars-cov- were observed in the lung, trachea, kidney, and large intestine of patient and patient . , when confined to vesicles or in the extracellular space, structures with these characteristics were designated coronavirus-like particles. for simplicity, we refer to these coronavirus-like particles as viral particles. viral particles were present both inside tracheal epithelial cells and the extracellular space adjacent to the cell membrane or mixed with the luminal mucus ( figure a, b) . in the lung, extensive sloughing of pneumocytes into alveolar spaces was observed. some of these pneumocytes contained abundant autophagosomes, and occasionally viral particles were observed within the vesicles. viral particles were seen both in type and type pneumo cytes ( figure c, d) . aggregates of viral particles were found in enterocytes; however, the membranes of the surrounding vesicles were often disrupted and the tissue affected by post-mortem artefact (figure e, f). in the kidney, viral particles were observed in tubular epithelial cells, and more rarely in endothelial cells ( figure g, h) . some viral particles were associated with double membranes, and resembled double membrane vesicles (figure g). rare ill-defined round particles were also observed in podocytes. definitive viral particles were not observed in the other examined organs, including the heart, spleen, and liver. sars-cov- rna was detected in the lung, trachea, subcarinal lymph node, kidney, large intestine, and spleen of all three tested patients (patients , , and ) . viral rna was also detected in the liver, heart, and blood for patient and patient . in all three patients, the lungs and trachea had the lowest cycle threshold values. the spectrum of pathological findings in people who die from covid- is only beginning to emerge. [ ] [ ] [ ] [ ] we present a case series of autopsy findings in patients who died after sars-cov- infection. our results show the central role of lung damage and provide evidence that suggests extrapulmonary involvement of sars-cov- during severe infection. the major histopathological observation in our series of patients who died with covid- was diffuse alveolar damage-type lung injury in the acute or organising phases ( [ %] of patients). lung tissue from most decedents showed pulmonary oedema, prominent reactive type pneumocytes, intra-alveolar fibrin, and hyaline membranes. these findings are similar to those described during the - sars-cov outbreak and more recent covid- studies. , , [ ] [ ] [ ] in contrast to sars-cov, in which organising diffuse alveolar damage was predominantly observed in those with longer hospitalisations (> to days), we found evidence of organising diffuse alveolar damage in a patient with covid- who died days after symptom onset (patient ) and observed acute and organising diffuse alveolar damage in patients and , who died within a week of symptom onset. compared with the study by franks and colleagues, our patient cohort also had a shorter interval from symptom onset to death (median days vs · days). we hypothesise that there was a subclinical period during which lung injury was occurring in covid- patients with organising diffuse alveolar disease who died in the week after symptom onset. the hypothesis that lung injury might occur in covid- patients before symptom onset is supported by evidence of abnormal pulmonary ct findings in asymptomatic patients. these findings could have implications for screening patients at the time of admission to identify and aggressively manage those with pre-existing diffuse alveolar disease-type injury. additionally, we noted mostly focal sars-cov- immunohistochemical staining in the lungs of tested patients. in areas with less severe diffuse alveolar damage the virus was more readily visualised in pneumocytes. the absence of strong diffuse viral staining might indi cate that most cytotoxic damage caused by sars-cov- occurs early on in infection, with diffuse alveolar damage seen later as part of an exuberant host response. whether covid- patients are at increased risk for endothelial injury causing pulmonary microthrombi has become central to the discussion of patient management. this theory is based on the observed mismatch between lung compliance and oxygen saturation in ventilated patients. these results have led to the proposal that covid- acute respiratory distress syndrome (ards) might represent a novel type of lung injury. an early pathology report documenting three patients with covid- found active endotheliitis and endothelial cells containing coronavirus-like particles, supporting the claims of microvascular damage during infection. however, the observation of virally infected endothelial cells has been called into question. although our findings document coronavirus-like particles in the endothelial cells of the kidney, we did not observe endothelial cell infection in other organs surveyed by electron microscopy or immunohistochemistry. additionally, no histological evidence of endotheliitis was observed in our cohort. given the scarcity of these findings, we propose that the lung injury observed in our cohort presented the typical ards lung phenotype and not a novel type of injury. infection of endothelial cells by sars-cov- is hypothesised to cause dysregulation of the clotting system, which particularly affects small vessels and leads to pulmonary microthrombi and altered ventilatory patterns in intubated patients. , around a third of our cohort (five patients) had infrequent microthrombi. as no formal grading scale for the severity of microthrombi in tissue exists, we would classify the presence of microthrombi in our cohort as less than one per low power ( ×) field and within the scope of what is seen in other causes of diffuse alveolar damage. most microthrombi were seen when a full autopsy was done, and we suspect rare microthrombi might also be present in our cohort of limited autopsies. however, this factor is unlikely to have changed our overall findings or final cause of death. macroscopic pulmonary arterial thrombi were identified in two patients (patient and patient ). patient showed evidence of organisation with adherence to the pulmonary artery wall, indicating an event that probably predated covid- infection. an organising thrombus was also found in a small renal vein on microscopic evaluation of patient and was considered probably unrelated to covid infection. cardiac injury in covid- is common, although our results do not provide direct evidence of myocardial injury by sars-cov- . in a study that documented the clinical course of patients in the intensive care unit in kirkland, wa, % of patients had cardiomyopathy of unclear cause. previous post-mortem examinations have detected viral rna in cardiac tissue from a single patient, although histopathological evidence of myocarditis was not present. in our cohort, patients , , and had elevated troponin; however, only patient had histologically apparent lymphocytic myocarditis. myocardial tissue from this patient was positive for viral rna by pcr, but immunohistochemistry and electron microscopy results were negative. as the patient was also viraemic, the low rna level detected in the cardiac tissue might represent contamination by circulating virus rather than direct infection. patient also tested positive for influenza a, a known cause of viral myocarditis, before death. contamination by viral rna could also explain the results in the liver and spleen, where no definitive virus was identified by electron microscopy or immunohistochemistry. tubular epithelial cells, endothelial cells, and podocytes express ace , making kidneys a candidate target for sars-cov- infection. direct infection of kidney cells by the virus has been proposed as a mechanism for acute kidney injury observed during sars-cov- infection. two studies reported sars-cov- in tubular epithelial cells and podocytes. , these studies depended on ultrastructural findings, which carry a risk of confusion with cellular structures if used without immunolabelling. therefore, we labelled the observed structures as coronavirus-like particles, although positive pcr (three of three patients) and immunohistochemistry (two of four patients) data support our assertion that infection of renal cells occurs by covid- . multiple orthogonal approaches, including pcr, immunohistochemistry, and electron microscopy were used to help identify tissues that harboured viral particles. the pattern of virus distribution seen in our cohort raises questions about the mechanism of viral dissemination during severe infections, specifically whether sars-cov- can be transported by lymphocytes. current data support this hypothesis, with viral rna detected in blood samples and in vitro data showing pseudotyped sars-cov- capable of infecting lymphocytes. , in our study, two of three whole blood samples and three of three lymph nodes tested positive by pcr, in addition to sars-cov- immunohistochemistry highlighting lymphocytes in the tracheal submucosa of patient . if sars-cov- is capable of productive infection in lymphocytes, this could provide a mechanistic explanation for the poor survival and cytokine derangements of severe covid- cases with lymphopenia. the extent to which our findings of extrapulmonary involvement of sars-cov- are generalisable to nonsevere covid- infections is uncertain. as sars-cov- has been detected in urine and stool of non-severe covid- cases, there is evidence suggesting productive infection of non-pulmonary sites. , these questions raise concerns for susceptible groups, including those with chronic renal injury or inflammatory bowel disease. whether these patients are at increased risk for more serious complications during sars-cov- infection requires close monitoring. another patient group that requires close monitoring are those undergoing organ transplantation. although extrapulmonary infection might be less common in mild or subclinical disease, it is unclear whether active extrapulmonary infection can exist in a patient without concurrent respiratory infection. our study has several limitations. electron microscopy was limited to patients and , pcr to patients , , and , and immunohistochemical testing to patients , , , and . future studies will reveal whether the relatively consistent findings in this small number of patients are borne out in larger samples. as safety limitations in place during february and early march, , precluded complete autopsies of seven patients, our ability to detect rare findings was restricted for part of the cohort. in some situations, there was an extended postmortem interval before examination. as post-mortem autolysis reduces the sensitivity of electron microscopy and pcr, patient samples collected several days after death might generate false negative results. however, we could detect viral particles and viral rna from specimens up to h post mortem (patient ). extended postmortem intervals should not be an absolute criterion for exclusion in future studies. in conclusion, our findings show the central role of diffuse alveolar damage-type lung injury in patients with severe covid- . microthrombotic disease and endothelial injury were not as pronounced as reported in previous studies. we found broad tropism for sars-cov- with coronavirus-like particles identified in the pulmonary system, kidneys, and gastrointestinal tract. our results also raise the question as to whether sars-cov- can cause direct myocardial injury and whether direct infection of lymphocytes promotes viral dissemination and immune dysregulation. these findings provide histological context for clinical observations and help characterise the pathophysiology of sars-cov- , hopefully 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injury in covid- : emerging evidence of a distinct pathophysiology sars-cov- infects t lymphocytes through its spike protein-mediated membrane fusion longitudinal characteristics of lymphocyte responses and cytokine profiles in the peripheral blood of sars-cov- infected patients prolonged viral shedding in feces of pediatric patients with coronavirus disease we thank the technical staff of king county medical examiner's office (seattle, wa, usa) and snohomish medical examiner's office (everett, wa, usa) for their assistance with autopsy procedures. we thank jennifer swicord, gianni niolu, and the electron microscopy laboratory at the university of washington (seattle, wa, usa) for preparation of electron microscopy specimens. key: cord- -zb ih dl authors: chongsuvivatwong, virasakdi; phua, kai hong; yap, mui teng; pocock, nicola s; hashim, jamal h; chhem, rethy; wilopo, siswanto agus; lopez, alan d title: health and health-care systems in southeast asia: diversity and transitions date: - - journal: lancet doi: . /s - ( ) - sha: doc_id: cord_uid: zb ih dl southeast asia is a region of enormous social, economic, and political diversity, both across and within countries, shaped by its history, geography, and position as a major crossroad of trade and the movement of goods and services. these factors have not only contributed to the disparate health status of the region's diverse populations, but also to the diverse nature of its health systems, which are at varying stages of evolution. rapid but inequitable socioeconomic development, coupled with differing rates of demographic and epidemiological transitions, have accentuated health disparities and posed great public health challenges for national health systems, particularly the control of emerging infectious diseases and the rise of non-communicable diseases within ageing populations. while novel forms of health care are evolving in the region, such as corporatised public health-care systems (government owned, but operating according to corporate principles and with private-sector participation) and financing mechanisms to achieve universal coverage, there are key lessons for health reforms and decentralisation. new challenges have emerged with rising trade in health services, migration of the health workforce, and medical tourism. juxtaposed between the emerging giant economies of china and india, countries of the region are attempting to forge a common regional identity, despite their diversity, to seek mutually acceptable and effective solutions to key regional health challenges. in this first paper in the lancet series on health in southeast asia, we present an overview of key demographic and epidemiological changes in the region, explore challenges facing health systems, and draw attention to the potential for regional collaboration in health. southeast asia consists of the ten independent countries located along the continental arcs and off shore archipelagos of asia-brunei, singapore, malaysia, thailand, the philippines, indonesia, vietnam, laos, cambodia, and myanmar (burma) (fi gure )-collectively known as the association of southeast asian nations (asean). the region contains more than half a billion people spread over highly diverse countries, from economic powerhouses like singapore to poorer economies such as laos, cambodia, • the diversity of geography and history, including social, cultural, and economic diff erences, have contributed to highly divergent health status and health systems across and within countries of southeast asia. • demographic transition is taking place at among the fastest rates compared with other regions of the world, whether in terms of fertility reductions, population ageing, and rural-to-urban migration. rapid epidemiological transition is also occurring, with the disease burden shifting from infectious to chronic diseases. • rapid urbanisation, population movement, and highdensity living raise concerns about newly emerging infectious diseases, but these outbreaks have stimulated regional cooperation in information exchange and improvement in disease surveillance systems. • southeast asia's peculiar geology contributes to it being the most disaster-prone region in the world, more susceptible to natural and man-made disasters aff ecting health, including earthquakes, typhoons, fl oods, and environmental pollution. climate change along with rapid economic development could exacerbate the spread of emerging infectious diseases. (continues on next column) (continued from previous column) • health systems in the region are a dynamic mix of public and private delivery and fi nancing, with new organisational forms such as corporatised public hospitals, and innovative service delivery responding to competitive private health-care markets and growing medical tourism. • the health-care systems are highly diverse, ranging from dominant tax-based fi nancing to social insurance and high out-of-pocket payments across the region. there is a greater push for universal coverage of the population, but more needs to be done to ensure access to health services for the poor. • private health expenditure is increasing relative to government expenditure, where new forms of fi nancing include user charges, improved targeting of subsidies, and greater cost recovery. health-care fi nancing could be further restructured in response to future demographic shifts in age-dependency, as in introduction of medical savings and social insurance for long-term care. • there is potential for greater public-private participation with economic growth through asean integration and further regional health collaboration, despite the current division of the region under two who regional offi ces. and myanmar (table) . [ ] [ ] [ ] [ ] [ ] [ ] [ ] by comparison with india and china, southeast asia is less visible in global politics and economics. the same is also true of global health. in the fi rst paper in this lancet series on health in southeast asia, we analyse the key demographic and epidemiological transitions of the region to delineate the challenges facing health systems and to emphasise potential for regional collaboration in health. this regional overview sets the scene for more detailed discussion of specifi c health issues presented in the fi ve subsequent reports in this series, profi ling maternal and child health, infectious diseases, non-communicable diseases, health workforce challenges, and health-care fi nancing reforms. southeast asia contains about million people, or % of the world's population, with indonesia having the largest population (and fourth largest in the world) and brunei the smallest (see table) . nearly half ( %) of the region's population live in urban areas, which is less than the world average, but there is much variation between countries, from % in cambodia to % in singapore. the region's average population density of people per km² also masks substantial intercountry and in some instances intracountry diff erences. population densities range from a low of people per km² in laos to a high of per km² in singapore. population densities in southeast asia's only two megacities, jakarta and manila, are much higher, at more than people per km². although their population sizes are similar (around million), the greater sprawl of manila and jakarta make them less densely populated (ranked th and th in the world) than mumbai and delhi (ranked st and th, respectively). the next largest city in southeast asia, bangkok, is ranked th. although urbanisation is expected to continue to rise in the region, urban slum populations seem to be less deprived than they are elsewhere, with about a quarter living in extreme shelter deprivation (defi ned by un habitat as a slum household lacking three or more of the following conditions: access to water, access to sanitation, access to secure tenure, a durable housing structure, and suffi cient living space). , although life expectancy in all countries in the region has improved, there have been signifi cant variations in the rate of progress. most countries have enjoyed continuous rises in life expectancy since the s, and these are converging. in some cases (myanmar, cambodia) political regimes and history of confl ict have aff ected progress, as has hiv in thailand (fi gure ). where life expectancy gains have slowed, this trend has been mainly attributable to slow progress in reduction of adult mortality. there has been little progress towards reduction of intercountry diff erence in life expectancy during the past years, with the gap remaining at around years. as elsewhere, decreased fertility has been the main factor contributing to ageing of the populations in these countries. the speed and timing of fertility reduction has varied widely across the region (webappendix p ). singapore had the earliest and sharpest reduction-the total fertility rate fell from more than six children per woman in to · in the mid- s, and since , it has ranked among countries with ultra-low fertility (table). thailand's fertility decrease mirrors that of singapore, although beginning somewhat later; it is currently the only other country in the region with we used quantitative and qualitative data from academic and grey literature to review the health situation in southeast asia. search terms used were "health", "health statistics", "health systems", "socio-economic development", and "southeast asia". data were gathered after a call for information from regional experts on selected subthemes related to health (geography, history, demography, epidemiology, and health systems rapid socioeconomic development and strong family planning programmes are likely to have driven this reduction. interestingly, this statement was true for indonesia, but less so for brunei and malaysia, although all three countries share a common dominant religion, islam. malaysia adopted a pronatalist policy in the late s under the then prime minister mahathir mohammad. catholicism has been a major contributing factor to the slow uptake of family planning programmes in the philippines, alongside the persistence of cultural norms that support large family sizes. the high fertility rates recorded in cambodia and laos are related to low educational levels, as refl ected in their low proportion of enrolment in secondary school- - % compared with - % elsewhere in the region (including % in vietnam). according to cleland, although literacy confers cognitive abilities to use contraception, the social and psychological skills conferred by higher education probably enable people to "translate the desire to postpone or limit childbearing into contraceptive practice… [and] they are also more likely to use allopathic health services for a range of needs including ante-and natal-care, child immunization and curative care [that lead to better child survival]". economic and demographic developments have prompted the movement of people across the region, mainly for short-term employment, but also for settlement. rapid economic growth and the slowing of domestic population and labour force growth due to fertility reduction have prompted countries such as singapore to open its doors to in-migration of foreigners at all skill levels for employment, with the option of permanent settlement for the highly skilled. the philippines, indonesia, and vietnam are major labour-exporters, whereas malaysia and thailand both receive and send nationals abroad. besides this internal labour market, countries in southeast asia also send and receive migrants from outside the region. since the s, however, destinations within asia have replaced labour migration to countries such as the usa and to the middle east. there is signifi cant undocumented or illegal migration as well as movement of displaced people in the region. , these groups are particularly vulnerable since "[u]ndocumented migrants are disproportionately more exposed to health risks due to inadequate working conditions and irregular movements, but are unlikely to seek medical attention because of their status, and are also often left out of assistance programmes in times of disasters and emergencies". population age structures of countries in the region vary widely as a result of past diff erences in fertility, mortality, and migration trends (fi gure ). these trends are in turn aff ected by economic, social, cultural, and political developments. singapore and thailand have among the fastest ageing populations in the world, with the proportion of elderly residents projected to double from % to % in and years, respectively-shorter than the years expected for japan - because of more rapid fertility reduction in these two countries. with increasing longevity, the pace of increase in numbers of the oldest old, aged years and older, in southeast asia is projected to exceed that of east asia over the period - . the other major factor contributing to population ageing has been the decrease in mortality. figure shows estimated trends in risk of child death (ie, between birth and age years) in countries of the region during the past four decades. child survival has improved substantially in all countries, but particularly in indonesia, vietnam, thailand, malaysia, brunei, and singapore, where the risk of child death is now typically less than about · %, compared with - % in the s. measured by the risk of dying between ages and years, regional diversity in levels of adult mortality is even greater than for child mortality (fi gure ). typically, the risk of dying at these ages for men is - %, and is higher ( %) in cambodia, laos, and myanmar ( - %), and signifi cantly lower in singapore, where the level is similar to those in australia and japan ( - %). this regional diversity in risk of adult death is similar for women, but with rates typically - % less than those for men. increasing longevity is a result of diminishing burden from communicable, maternal, and perinatal diseases (group diseases; webappendix p ), whereas countries with aged populations have a higher burden of noncommunicable diseases (group diseases). interestingly, mortality rates from these two groups of diseases, as well as from injuries, are correlated. countries with high mortality rates from communicable diseases also have high death rates from chronic diseases (webappendix p ). deaths from communicable diseases are still prominent in cambodia, myanmar, and laos. injuries are an important cause of death in all countries, but less so in singapore and brunei. few countries in the region have complete cause of death data systems to inform health policy and planning, and of those that do only singapore has reliable cause of death certifi cation and coding. although not representative of present health conditions in neighbouring countries, understanding of how leading causes of death have changed in singapore during the past years or so can provide important insights into what other countries of the region could expect to achieve, provided there is a similarly strong public health commitment to disease control and injury prevention. figure summarises trends in selected causes of death for both sexes in singapore since . in the early stages of transition, striking reductions in infectious diseases such as tuberculosis were achieved, off set by increases in non-communicable diseases including cardiovascular diseases and cancers, as well as injuries. although deaths due to road traffi c accidents have subsequently decreased and cardiovascular diseases seem to have reached a plateau, breast cancer has continued to rise. except for stomach and cervical cancer, mortality from all other cancers is still rising (data not shown). these data illustrate the success of singapore in reducing mortality from the diseases of poverty, as well as the eff ects of inadequate chronic disease control programmes, although there is evidence of some success in control of lifestyle-related diseases in recent years. as other countries in the region succeed in bringing communicable diseases under control, the importance of injury prevention and chronic disease control programmes will become increasingly pressing. the region as a whole does not have reliable longitudinal data for disease trends. however, evidence from studies of disease prevalence shows a strong inverse association with national wealth, which can be largely attributed to the social determinants of health, including the provision of more effi cient health systems with greater population coverage. the fi gure provided on p of the webappendix shows the relation between prevalence of tuberculosis and per head income (log-log scale). the regression equation (not shown) suggests that a doubling of per head income is associated with a reduction in tuberculosis prevalence of %. for diabetes mellitus prevalence, countries can be roughly divided into three groups that are positively correlated with income, although the eff ect tapers off at higher levels of per head income, (webappendix p ), possibly because of more eff ective disease control programmes with greater coverage. hiv was introduced into the region in the s. transmission peaked in the early s in thailand, followed by myanmar and cambodia. hiv/aids has been a major cause of death in some countries of the region (eg, thailand), although its spread has been partly controlled by the promotion of condom use. in the early s, more eff ective antiviral therapies emerged, followed by the introduction of compulsory licensing. although universal access to treatment has been attempted, patient compliance and losses to follow-up care are still prevalent. , aids mortality in southeast asia has stabilised since the mid- s, although prevalence remains high in myanmar, laos, and cambodia. the environment continues to be an important contributing factor to disease and mortality in the developing world, including countries in southeast asia, accounting for up to a quarter of all deaths. regular monsoons and typhoons occur in southeast asia. the el niño and la niña phenomena also intensify the annual variation of the hot and wet climate, leading to droughts, fl oods, and the occurrence of infectious diseases such as malaria and cholera. countries in the northern part of the region such as the philippines and vietnam are badly aff ected by seasonal typhoons that have increased in intensity over time. the philippines and indonesia are located on the pacifi c ring of fire, a zone of earthquakes and volcanoes where around % of the world's earthquakes occur. southeast asia is one of the most disaster-prone regions in the world; the indian ocean earthquake off the coast of sumatra in caused a devastating tsunami in aceh, indonesia, and countries on the fringe of the indian ocean, one of the worst natural disasters ever recorded. uncontrolled forest fi res raged in the indonesian states of kalimantan and sumatra in . the severity of the fi res was also closely linked to the occurrence of the el niño southern oscillation, which has historically brought severe drought conditions to southeast asia, creating conditions ripe for fi res. in , the severity and extent of haze pollution was unprecedented, aff ecting some million people across the region. the health-related cost of the haze was estimated to be us$ million. the health eff ects of the haze in southeast asia have been well documented. , an increase in concentration of particulate matter with diameter μm or less from μg/m³ to μg/m³ was signifi cantly associated with increases of % in upper respiratory tract illness, % in asthma, and % in rhinitis from public outpatient care facilities in singapore. time-series analyses in people admitted to hospital in kuching, malaysia, showed that signifi cant fi re-related increases occurred in respiratory hospital admissions for chronic obstructive pulmonary disease and asthma. survival analyses suggested that people older than years who had been previously admitted to hospital for cardio respiratory and respiratory diseases were signifi cantly more likely to be readmitted during the haze episode. climate change could exacerbate the spread of emerging infectious diseases in the region, especially vector-borne diseases linked to rises in temperature and rainfall. southeast asia has been identifi ed as a region that could be vulnerable to eff ects of climate change on health, because of large rainfall variability linked to the el niño and la niña oscillation, with attendant consequences for health systems. southeast asia's rich history and recent industrialisation and globalisation have raised new challenges for the region's health systems. modern medical technology is available in the world market but at costs higher than most of the region's population can aff ord. many traditional health practices persist alongside the use of new medical technologies and pharmaceutical products, presenting regulatory problems in terms of safety and quality. with increasing educational levels, ageing populations, and growing consciousness of human rights in the recently developing democratic environment, the demand for better care is increasing. health systems in the region face more serious adjustment problems than ever before. health services have become an important industry, with a mix of public and private non-profi t and for-profi t actors, along with the growth of trade and medical tourism. the provision, fi nancing, and regulatory functions of the public sector have to adapt accordingly to these transformations. the need to restructure healthcare delivery and fi nancing systems becomes crucial to balance new demand and supply equilibriums. , countries in southeast asia and their health system reforms can thus be categorised according to the stages of development of their health-care systems. a typology of common issues, challenges, and priorities are generated for the diverse mix of health systems of southeast asia at diff erent stages of socioeconomic development (see webappendix pp - ). the pressures placed on national health-care systems by the recent demographic and epidemiological transitions that we have described are amplifi ed by the growing demands of an increasingly educated and affl uent population for high quality health care and the supply of the latest medical technology. before the east asian fi nancial crisis in - and the recent global economic recession, an expanding middle class in the urban populations of the larger cities pushed their demand for high quality care into a booming private sector. as a result, market forces have turned many aspects of health care into a new industry in countries such as singapore, malaysia, and thailand, contributing to labour-force distortions for the production and distribution of health workers both within and across countries. the s began with the opening up of socialist states and rapid growth among market economies in the region. while they were each fi nding ways to reform their health systems, the asian fi nancial crisis in - posed more challenges for countries of the region. the depreciation of local currencies resulted in increased costs of imported drugs and other essential supplies, at the same time as access to basic health care was reduced for the most vulnerable population groups. however, reported spikes in suicides and mental illnesses in the other aff ected east asian economies such as south korea, taiwan, and hong kong were not as signifi cant in southeast asia. following the lessons learnt from the past fi nancial crisis, most countries have strengthened their social protection mechanisms and essential health services. there is a greater push among countries to increase universal coverage of basic health services, especially to vulnerable and disadvantaged populations. , throughout the region, many innovative pro-poor fi nancing schemes were implemented, such as the health card and -baht schemes in thailand, the health fund for the poor in vietnam, health equity funds in cambodia and laos, and, even in affl uent singapore, the medifund, a meanstested hospital fees subsidy scheme for indigent patients. so far, the health-care systems with dominant tax funding are fairly stable, in view of the strong role of governments and eff ective controls by health agencies to overcome inequity problems. however, crucial issues involve rising costs, future sustainability of centralised tax-fi nanced systems, effi ciency and quality of the public services, and higher public expectations. in both malaysia and singapore, the health-care systems are changing from government-dominated health services towards greater private-sector involvement. attempts to privatise public hospitals have been controversial, thus resulting in many hybrid forms of corporatised entities that continue to be controlled or subsidised by governments. [ ] [ ] [ ] [ ] some of the most innovative and advanced forms of publicprivate mix in health services have developed within the region, for example the restructuring or corporatisation of public hospitals in singapore from as early as and the later swadana (self-fi nancing) hospitals in indonesia. with the anticipated rise in the ageing population and future problems of intergenerational funding through pay-as-you-go mechanisms, there are experiments with new health-care fi nancing such as compulsory medical savings and social insurance for long term care. [ ] [ ] [ ] some countries such as the philippines, vietnam, and indonesia have radically decentralised their health-care systems with the devolution of health services to local governments, a restructuring that has aff ected aspects of systems performance and equity even though the impetus for cardiovascular diseases excluding rhd breast cancer tuberculosis road traffic accidents decentralisation was mainly political. consequently, to ensure increased fi nancial coverage and aff ordability, many governments have passed laws to establish national health insurance systems and mandated universal coverage, although implementation is problematic. with existing policies of decentralisation and liberalisation, equity issues and poor infrastructure will continue to challenge the development of the health sector. , the severe acute respiratory syndrome (sars) epidemic has emphasised the need to strengthen regional health collaboration. this cooper ation has occurred via two channels-direct bilateral collaboration by individual countries (ministries of health and foreign aff airs) and those under the aegis of asean. the mekong basin disease surveillance project is an example of successful health cooperation. it was established under the collective agreement of each ministry of health of member states of the greater mekong subregion to share important public health information. the emergence of infl uenza a h n and h n outbreaks has led to common eff orts to strengthen epidemiological surveillance and stockpiling of antiviral drugs. enthusiasm for regional economic collaboration continues to grow, evident from the explicit goal of the asean free trade area to increase the region's competitive advantage as a production base geared towards the world market. asean leaders have identifi ed health care as a priority sector for region-wide integration. from an economic perspective, opening of health-care markets promises substantial economic gains. at the same time, however, this process could also intensify existing challenges in promotion of equitable access to health care within countries. it could also lead to undesirable outcomes whereby only the better-off will receive benefi ts from the liberalisation of trade policy in health. health and trade policy can and do appear to contradict each other. tobacco use is the major preventable cause of non-communicable disease and death among the populations of asean countries. all asean members except indonesia have embraced the framework convention on tobacco control (fctc) and all countries endorse some form of tobacco control policy. however, most of these states are, to varying degrees, still involved in investment in or promotion of the tobacco industry, often using the justifi cation of poverty alleviation. there are clear contradictions inherent in the state seeking to prevent tobacco use in the interests of health, while actively promoting tobacco for the economic benefi t of its population, resulting in both substantial and symbolic harm to eff orts to implement the fctc. for example, tobacco production is legitimised; rational policy principles are violated, and direct cooperation between the state and multinational tobacco corporations is made possible by modifi cation of control policies. tobacco exports within asean also threaten the group's health solidarity. divestiture of state ownership of capital in tobacco corporations and a much stronger commitment by states to control the use and promotion of tobacco are urgently required in asean countries. issues of intellectual property rights surrounding products such as essential pharmaceutical drugs as public health goods are also of concern to countries. thailand started compulsory drug licensing in . indonesia has called for the urgent development of a new system for virus access and a fair and equitable sharing of the benefi ts arising from the use of the infl uenza virus in research (now commonly referred to as viral sovereignty). additionally, indonesia has pressed for the development of medical products to replace the existing patent system in global health governance. with globalisation, ensuring of accessible health services for citizens is no longer the sole responsibility of the state; health care in southeast asia is fast becoming an industry in the world market. the private sectors in singapore, thailand, and malaysia have capitalised on their comparative advantage to promote medical tourism and travel, combining health services for wealthy foreigners with recreational packages to boost consumption of such health services. patients from elsewhere, including the developed countries, are choosing to travel for medical treatment, which is perceived to be high quality and value for money. because of poor local economic conditions, the philippines had a policy to export human resources for health to the world and to richer countries in the region as an income-generating mechanism. although the fi nancial returns from this strategy seem substantial, equity issues have surfaced concerning the negative eff ects of international trade in health services and workforce migration on national health systems, especially in widening disparities in the rural-urban or public-private mix. regional collaboration in standards of data collection and health systems analysis is hampered by who's division of the asean region into two areas under separate regional offi ces: the south-east asia regional offi ce, encompassing indonesia, myanmar, and thailand, and the western pacifi c regional offi ce, consisting of the remaining countries. potential benefi ts from enhanced who regional cooperation include improved health surveillance, information-sharing, and health systems strengthening in all asean countries. southeast asia is a region characterised by much diversity, including public health challenges. social, political, and economic development during the past few decades has facilitated substantial health gains in some countries, and smaller changes in others. the geology of the region, making it highly susceptible to earthquakes and resultant tsunamis, along with seasonal typhoons and fl oods, further increases health risks to the population from natural disasters and longterm eff ects of climate change. public policy in these countries cannot ignore such risks to health, which could have important social and economic consequences. regional cooperation around disaster preparedness and in the surveillance of and health systems response to disease outbreaks has obvious advantages as a public health strategy. concomi tantly, all countries in the region are faced with large or looming chronic disease epidemics. even in the poorest populations of the region, non-communicable diseases already kill more people than do communicable, maternal, and perinatal conditions combined, with many of these deaths occurring before old age. greatly strengthened health promotion and 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contradictions in health system pluralism constraints on the retreat from a welfare-oriented approach to public health care in malaysia the politics of privatization in the malaysian health care system innovations in health service delivery: the corporatization of public hospitals saving for health the savings approach to long term care fi nancing in singapore western pacifi c regional offi ce and south-east asia regional offi ce for who east asia decentralizes: making local government work south-east asia regional offi ce and western pacifi c regional offi ce for who measuring the accumulated hazards of smoking: global and regional estimates for global health, equity and the who framework convention on tobacco control the political economy of tobacco and poverty alleviation in southeast asia: contradictions in the role of the state the framework convention on tobacco control and health promotion: strengthening the ties pandemic infl uenza preparedness: sharing of infl uenza viruses and access to vaccines and other benefi ts this paper is part of a series funded by the china medical board, rockefeller foundation, and atlantic philanthropies. key: cord- -zxx m kz authors: heymann, david l; aylward, r bruce; wolff, christopher title: dangerous pathogens in the laboratory: from smallpox to today's sars setbacks and tomorrow's polio-free world date: - - journal: lancet doi: . /s - ( ) -x sha: doc_id: cord_uid: zxx m kz nan the lancet • vol • may , • www.thelancet.com commentary less than a year after an unprecedented international public-health effort interrupted human-to-human transmission of the coronavirus that causes severe acute respiratory syndrome (sars-cov), some human beings are again infected. sars-cov does not seem to have reentered the human population from the exotic wildanimal markets of china that have preoccupied publichealth officials worldwide, nor from some other source in nature not yet understood. rather, the latest outbreak seems to be from a laboratory source. this scenario is reminiscent of the often forgotten footnote to the smallpox eradication effort when the last human infections did not occur in somalia, the last country with naturally occurring smallpox, but a year later in birmingham, in the uk, originating from a laboratory with inadequate biosafety facilities. auspiciously, the new sars cases are occurring as who's biosafety advisory group prepares to examine the long-term containment of poliovirus stocks, the risks of which will rapidly increase after interruption of transmission and the ending of immunisation with oral poliovirus vaccine. the recent outbreak of nine cases of sars in china, with one death, underlines again the challenges of maintaining appropriate biosafety conditions in laboratories working with dangerous pathogens. in this outbreak, two researchers at the institute for viral disease control and prevention in beijing developed sars in late march and mid-april. all subsequent second-generation and thirdgeneration cases have now been linked to close contact with one of these researchers. investigation of the source of the outbreak, jointly by the chinese ministry of health and who, continues to focus on this virology institute. if the laboratory source is confirmed in china, this will be the third known incident of laboratory-acquired sars-cov infection, the first having occurred at the national university of singapore where a postgraduate developed an illness consistent with sars in late august, . during the investigation that followed, it was concluded that the student most probably acquired the infection in the bsl- laboratory in which he was studying the west nile virus · days before the onset of his illness, which is consistent with the expected incubation period of sars. (biosafety conditions are described as biosafety levels in four categories , with bsl- and bsl- recommended for work with pathogens that cause serious human and animal disease). it seems that transmission occurred as a result of inappropriate laboratory procedures that led to cross-contamination of the west nile virus specimen with sars-cov. no other workers in the laboratory, and none of the medical staff who cared for the student while he was ill, became secondarily infected, nor did household and other contacts. the second reported incident similarly resulted in an isolated case of sars in early december, . it occurred at the institute of preventive medicine, national defence university, taipei, in a laboratory scientist who had been working intensely in a bsl- laboratory, over a long period and for long hours each day. it seems that transmission occurred after exposure to sars-cov from contact with droplets when cleaning the spill of a sars-containing specimen in the laboratory's transport chamber. accidental transmission of a dangerous pathogen from a laboratory can occur when a susceptible and unprotected laboratory worker is exposed to the agent during laboratory procedures. these conditions were met in the smallpox laboratory in birmingham in , and in at least two of the laboratories associated with the recent cases of sars during . if the resulting human infection causes viral shedding, with exposure to susceptible workers in the laboratory, health-care system, or community, an outbreak can result. in the outbreak in brimingham after the smallpox laboratory accident, infection spread from the initial case to a close family member and one other. in the current outbreak of sars, chains of transmission seem to have moved from the laboratory, to a close family member, and to a hospital, from where a nurse who treated the laboratory worker then transmitted infection to five others. proven measures to minimise the risk of reintroducing dangerous pathogens include: limiting the number of sites where they are stored and studied to those that are absolutely necessary; protection of laboratory workers with available vaccines, protective clothing, and safe equipment; closely monitoring illnesses in laboratory workers; and adhering to standard operating procedures. hundreds of years of combined experience in high and maximum containment laboratories have proven these biosafety measures effective if rigorously and faithfully followed-with strict national procedures to verify that appropriate conditions and procedures are maintained. after certification of smallpox eradication, known stocks of variola virus were destroyed or transferred to one of two who reference laboratories where biosafety is periodically verified by the who biosafety advisory group. during the sars outbreak last year, many specimens were obtained from human cases of sars commentary dangerous pathogens in the laboratory: from smallpox to today's sars setbacks and tomorrow's polio-free world and sent to many different national and international laboratories for various studies. in april, , who provided guidelines for handling, packing, and shipping sars specimens, and listed laboratory practices that could safely be done under bsl- and those that required bsl- . these guidelines were reviewed and updated during later who consultations, and laboratory research activities continue at many of these sites. unfortunately, adherence to these guidelines has now failed at two, and possibly three, different laboratories, reaffirming the importance of strong national, and possibly international, monitoring of their implementation. the predictable emergence of new dangerous pathogens in the future further highlights the need for such action. if activities to eradicate poliomyelitis remain on target, interruption of human-to-human transmission will occur sometime during the next months, and the wild poliovirus will be moved from the list of endemic infections to that of dangerous pathogens. that poliovirus reintroduction could occur was seen in when a reference strain of wild-poliovirus type i that is used in the production of inactivated poliovirus vaccine was isolated from a young child being investigated for diarrhoea. the subsequent epidemiological investigation found that the child's father was employed at a production site for inactivated poliovirus vaccine where an accident had occurred. fortunately the child was fully immunised against poliovirus. but the child served as a healthy carrier of poliovirus to the community, although sanitation was adequate and poliovirus vaccination coverage was high enough to prevent an outbreak. a similar poliovirus reintroduction from a laboratory or production facility for poliovirus vaccine to one of the many countries that have indicated their intention to stop poliovirus immunisation after certification of global eradication could result in future outbreaks of poliomyelitis. recognising the risks that would be associated with a poliovirus reintroduction, who and its technical partners in poliomyelitis eradication began the process of establishing a global action-plan for the long-term laboratory containment of wild polioviruses in the mid- s. by , international consensus had been established and the process of surveying and inventorying laboratories for wild poliovirus and infectious or potentially infectious materials began in the three who regions that had interrupted indigenous transmission of wild poliovirus. through the comprehensive surveys of national laboratories that are underway or completed in countries in five continents, over facilities have been inventoried to date. about facilities have reported wild-type poliovirus or potential infectious materials. at the same time, technical and engineering solutions have allowed the continued production of inactivated poliovirus vaccine from wild poliovirus under enhanced bsl- conditions to ensure that such a vaccine is available to the countries that choose to continue routine immunisation against the poliovirus after eradication has been certified globally and the routine use of oral poliovirus vaccine stopped. the current who plan for the period after the global interruption of wild-poliovirus transmission specifies bsl- conditions for wild-poliovirus infectious materials and bsl- for potentially infectious materials in nonvirology laboratories, on the basis of a now outdated assumption of continued universal immunisation. in september, , an expert group recommended that because circulating vaccine-derived polioviruses would, like wild poliovirus, compromise the goal of poliomyelitis eradication, the use of oral poliovirus vaccine for routine immunisation should eventually stop. , this decision, combined with the recognition that many countries plan to forego future routine immunisation with inactivated poliovirus vaccine, has led to the understanding that sabin poliovirus strains will also need to be stored and handled under appropriate biosafety conditions. a biosafety strategy for minimising the risk of a laboratory accident with the sabin poliovirus is under development. in addition, consensus is being sought on the mechanisms and procedures for ensuring that the necessary stockpiles of oral poliovirus vaccine are available should poliovirus be reintroduced into human populations because of a laboratory accident. although an increasing number of pathogens are referred to as dangerous, in reality different pathogens present different laboratory risks. sars-cov seems to represent a high laboratory risk. unlike sars-cov, poliovirus is not efficiently transmitted by droplets from person to person, and a vaccine is available that fully protects laboratory workers from disease and reduces the risk of infection, thereby providing additional assurances against substantial consequences should a laboratory accident occur once routine immunisation with oral poliovirus vaccine has stopped. it is also reassuring that no further accidents have occurred with the smallpox virus stored in two reference laboratories for over years. nevertheless, the recent laboratory accidents with sars-cov are a stark reminder that the security of public-health achievements requires greater investment to ensure that global biosafety standards for dangerous pathogens in laboratories are universally adopted, strictly adhered to, closely monitored, and rigorously enforced. we have no conflict of interest to declare. polio eradication initiative who, geneva , switzerland (e-mail: heymannd@who.int) the basis of five longitudinal studies. the authors conceded that only one of these studies was able to record whether prodromal manifestations of schizophrenia preceded cannabis use. the results of the study indicated that "cannabis users at age years had elevated scores on the schizophrenic symptom scale only if they had reported psychotic symptoms at years", and that people who used cannabis at age years had a higher risk for adult schizophreniform disorder at age years even if psychotic symptoms at age years were controlled for. the researchers concluded that cannabis was a causal factor for psychosis in "vulnerable youths". there is some reason to believe that cannabis contributes to psychosocial problems in adolescents and young adults, and no responsible adult would want young people to take drugs. there is no question that this issue is an important candidate for education and prevention, but there is a fierce debate on the place repressive measures should have in this context. there is little reason to believe that criminalisation has had a strong effect on the extent of cannabis use by young people. moreover, prohibition itself seems to increase the harmfulness of drug use and cause social harm. by stopping all cannabis users from being treated as criminals, i believe this year's change by the british government of its cannabis law (a declassification from class b to c) is a sensible attempt to balance the possible harms caused by cannabis and its prohibition. the concern expressed by peter maguire of the british medical association and others, that "the public might think that reclassification equals safe", is based on the wrong assumption that cannabis became illegal because its use is unsafe and dangerous. many unsafe activities are legal, including skiing downhill, having sex, drinking beer, eating hamburgers, and taking aspirin. cannabis did not become illegal because it was shown to be dangerous but, more likely, because harry anslinger, commissioner of the us bureau of narcotics - , and his colleagues needed a new target and battlefield after the end of alcohol prohibition in . reputed dangers, presented in his statements before the us senate in , were used as a shocking means of manipulation-eg, "a man under the influence of marijuana actually decapitated his best friend; and then, coming out of the effects of the drug, was as horrified as anyone over what he had done." the representative of the american medical association strongly opposed the marijuana tax act of : "to say . . . that the use of the drug should be prevented by a prohibitive tax, loses sight of the fact that future investigation may show that there are substantial medical uses for cannabis." we live in a time in which the unrealistic and unproductive paradigm of complete abstinence from drugs is slowly dissipating. proponents of a drug-free society find this fact hard to accept, and responsible politicians and doctors can find achieving an appropriate position in the debate difficult. however, we must learn to deal with drugs and their possible dangers without fear. i have no conflict of interest to declare. nova-institut gmbh, d- huerth, germany (e-mail: franjo.grotenhermen@nova-institut.de) cannabis can cause anxiety, agitation, and anger among politicians. the consequences of this cannabis-induced psychological distress syndrome (cipds) include overreaction with respect to legislation and politics and a lack of distinction between use and misuse of cannabis. in times of a war against drugs, this distinction might even be regarded as unpatriotic, as irresoluteness in the face of the enemy. one trend associated with cipds involves taking away the driving licence of people who drive and are discovered to have inactive tetrahydrocannabinol metabolites in their urine. in a more severe state of paranoia even medicinal use can be perceived as a threat to society, since it might "destabilize the societal norm that drug use is dangerous", ignoring the fact that many prescription and over-the-counter drugs are potentially harmful. exaggerated laws on cannabis made by anxious individuals could be regarded as a modern version of the generational conflict. rationality and factuality are needed to calm down politicians affected by cipds. that cannabis might cause infertility, cancer, cognitive decline, dependency, traffic accidents, and heart attacks, and that it can lead to the use of more dangerous drugs, are all arguments that have been used to justify the war on cannabis. drugs can be harmful, whether they are legal or illegal, but claims about the dangers of cannabis are often overstated. , one main justification for today's war on cannabis is its possible detrimental effect on the mental health and social wellbeing of adolescents. in this week's lancet, john macleod and colleagues show that the causal relation is less certain than often claimed, and point out several common misunderstandings about the difficulties encountered when studying drug use, such as the limits of confounder adjustment. the results of one often-cited swedish study, for example, indicate a crude odds ratio of · for schizophrenia risk at age years in individuals who used cannabis more than times before age years. this finding suggests cannabis is an important contributor to schizophrenia. after adjustment for several possible confounders, however, the risk decreased to · , a strong indication of residual confounding-ie, the presence of factors that would further reduce the risk if included in the statistical model but that could not be included because of a lack of data. another review details the findings of an investigation into the association between cannabis and psychosis on world health organization. sars in china-updates smallpox and its eradication. geneva: world health organization polio control after certification: major issues outstanding china confirms sars infection in another previously reported case; summary of cases to date. world health organization sars situation update severe acute respiratory syndrome (sars) in singaporeupdate . sars case in singapore linked to accidental laboratory contamination severe acute respiratory syndrome in taiwan, china world health organization. who biosafety guidelines for handling of sars specimens world health organization. who post-outbreak biosafety guidelines for handling of sars-cov specimens and cultures genetic analysis of wild-type poliovirus importation into the netherlands ( - ) • www.thelancet.com commentary poliovirus vaccine production sites be effective for global certification? global action plan for l aboratory containment of wild poliovirus world health organization. guidelines for the safe production and quality control of ipv manufactured from wild poliovirus the role of routine polio immunization in the post-certification era report of an informal consultation on identification and management of vaccine-derived polioviruses key: cord- - h si authors: sharpstone, d; gazzard, b title: gastrointestinal manifestations of hiv infection date: - - journal: lancet doi: . /s - ( ) - sha: doc_id: cord_uid: h si the harrowing picture of emaciated terminally ill aids patients is a reminder of our lack of understanding of immunological mechanisms that normally control opportunistic infections. many gastrointestinal pathogens in patients with aids are resistant to treatment and lead inexorably to weight loss and death. although knowledge of the pathogenesis and clinical significance of weight loss has improved considerably, this has not yet led to a sustained effort to improve nutritional status during early stages of disease. most of the morbidity and mortality of late aids is associated with gastrointestinal disease. whilst oesophageal candidosis responds readily to treatment and cytomegalovirus enteritis may be cleared by antiviral agents, the two commonest protozoal pathogens-microsporidia and cryptosporidia-cannot be eradicated. these protozoa cause disruption of small-bowel villus architecture by unknown mechanisms and severe malabsorption, maldigestion, and diarrhoea. weight loss is a major contributor to death in most patients with aids and is commonly caused by protozoal gut infection. the host metabolic response to these infections is typical of starvation and patients are likely to respond to the provision of additional calories, ideally by the enteral route. by contrast, weight loss associated with other opportunistic infections-mycobacterium avium intracellulare and cytomegalovirus-is characterised by cachexia and is unlikely to respond to simple refeeding. the commonest cause of oesophageal symptoms is candidosis; odynophagia or dysphagia with oral candidosis is an aids-defining diagnosis and can be treated empirically with a systemic azole. the second most frequent cause is cytomegalovirus (cmv), which produces either diffuse oesophagitis or discrete ulceration. the aetiology of these lesions can be confirmed by biopsy of the centre of ulcerated areas. detection of cmv inclusion bodies is enhanced by immunoperoxidase staining. oesophagoscopy occasionally reveals vesicles typical of herpes simplex oesophagitis, diagnosed either by biopsy or smears from brushings showing typical giant cells. as many as % of oesophageal ulcers leading to dysphagia are idiopathic, possible causes being unknown opportunistic viruses or hiv itself. these ulcers may respond to thalidomide. pathogenesis hiv was initially believed to cause intestinal symptoms since hiv-seropositive individuals free from intestinal pathogens commonly have diarrhoea. however, the frequency of "pathogen-negative diarrhoea" depends on the extent of the diagnostic investigations and the definition of diarrhoea. in a prospective study of pathogen-negative diarrhoea, follow-up revealed an unsuspected pathogen in only a minority. most patients had low-volume diarrhoea that either resolved spontaneously or was controlled with antimotility agents, a response that accords with the features of irritable bowel syndrome. hiv-seropositive persons free from intestinal pathogens do have minor abnormalities of villus architecture, characteristically a mild villus atrophy associated with either crypt hypoplasia or hyperplasia. these minor abnormalities are unlikely to cause diarrhoea since they occur in symptom-free individuals and are associated either with no or with very mild malabsorption of carbohydrates. however, there is a consistent increase in small-bowel permeability in hiv-seropositive individuals; this functional abnormality and the minor structural abnormalities of the small bowel mucosa may be due to the immunological changes produced by hiv infection of lamina propria lymphocytes. activated t cells cause villus atrophy in fetal gut explants, and hiv causes activation of these cells. hiv can be identified in the lamina propria of both the large and small intestine but its detection or quantification is not related to diarrhoea. whether hiv also infects small-bowel mucosal cells, as was initially shown by in-situ hybridisation, is unknown. other possible mechanisms for villus damage include ingress of foreign antigens because of the increased permeability that sets in motion a vicious circle of release of cytokines and other inflammatory mediators. alternatively, bacterial overgrowth in the small intestine of hiv-seropositive patients, as reported in some small studies, might produce an inflammatory response and villus atrophy. bacterial overgrowth might occur because of the hypochlorhydria reported in aids patients. hypochlorhydria is common in those with starvation and systemic infection and may therefore occur in advanced aids without any hiv-induced defects in gastric secretion. neither hypochlorhydria nor bacterial overgrowth is a universal finding in patients with advanced hiv infection, so these mechanisms are unlikely to have an important role in villus atrophy. the harrowing picture of emaciated terminally ill aids patients is a reminder of our lack of understanding of immunological mechanisms that normally control opportunistic infections. many gastrointestinal pathogens in patients with aids are resistant to treatment and lead inexorably to weight loss and death. although knowledge of the pathogenesis and clinical significance of weight loss has improved considerably, this has not yet led to a sustained effort to improve nutritional status during early stages of disease. fluoresce with agents such as calcofluor, thereby providing an excellent screening test. results can be confirmed with giemsa staining. cryptosporidia in the stool is diagnosed by a modified ziehl-neelsen or auramine stain. enteric bacteria are usually detected by routine stool cultures but are occasionally found only in the blood. stool culture of mycobacterium avium intracellulare is tedious and of uncertain pathogenic significance since colonisation can occur without diarrhoea. the value of stool electron microscopy for enteroviruses is debatable since in some studies these organisms have a similar prevalence in individuals with solid stools and in those with diarrhoea. detection is of limited value because enteroviruses produce a self-limiting infection, even in most hiv-seropositive persons, and are untreatable. mucosal biopsy: although diagnosis by stool analysis alone has been suggested by johanson and sonnenberg, this study may have overestimated the value of symptomatic treatment and ignored the possibility that cytomegalovirus infection sometimes responds to therapy. gut biopsy is the only way to diagnose infection with cmv or adenovirus. infections are commonly found in the large intestine, and sigmoidoscopy with rectal biopsies is probably the best initial invasive gastroenterological investigation in patients with diarrhoea. - % of cases of cmv colitis affect only the right side of the colon or small intestine, so colonoscopy or small-intestinal biopsy may be indicated in individuals with persistent diarrhoea and negative rectal biopsy. starvation, and diarrhoea is often out of proportion to the mucosal abnormalities, so a secretory component is likely. a secretory response was shown in isolated segments of human jejunum exposed to faeces from calves infected with cryptosporidia but not in patients with moderately increased stool volumes due to cryptosporidiosis. decreased intestinal transit time may exacerbate diarrhoea in protozoal infection, but whether this is a primary motility defect or a consequence of malabsorption or enteric nerve damage is unclear. another possibility is that motility changes or nerve damage are mediated by nitric oxide release as a result of stimulation of nitric oxide synthase in macrophages infected by hiv or opportunistic organisms; this possibility remains unexplored. changes in the immunological responses in the gut mucosa allow the persistence of protozoal infection in hiv-seropositive individuals, and abnormal immune responses themselves may be important in the pathogenesis of diarrhoea. the cd lymphocyte population of the lamina propria in hiv-seropositive patients shows a disproportionate reduction compared with the circulating cd count. experiments in immunocompromised mice have shown that cd -positive cells are essential for the eradication of cryptosporidia. cd responses may be important in controlling infection in cd -count-depleted mice, and interferon-gamma released from macrophages may also have a role. altered cd or macrophage responses in hiv-seropositive individuals who are unable to mount a cd response to cryptosporidial infection may lead to aberrant cytokine release and consquent intestinal damage. increased concentrations of tumour necrosis factor-alpha have been reported in the faeces but not in the mucosa of patients with protozoal diarrhoea. studies of the complex balance between various cytokines and their tissue receptors are awaited. stool analysis is the initial investigation for hivseropositive subjects with diarrhoea and three samples will identify about % of pathogens. cryptosporidia may not always take up appropriate stains in the stool and some infections are diagnosed only by histological examination of small or large bowel biopsy specimens. histological examination of duodenal biopsy specimens may also reveal previously unsuspected microsporidia, giardia, m avium intracellulare; or isospora. ultrastructural examination of enteric biopsy specimens by electromicroscopy is not done routinely but enables speciation of organisms such as microsporidia and maybe a useful addition to light microscopy ( figure) . analysis of six stool samples and histological examination of small and large bowel biopsy speicmens detect more than % of infectious causes of diarrhoea in hiv-seropositive individuals. most individuals in whom no pathogens are found by these initial investigations have minor symptoms that usually resolve spontaneously. a few have continued large-volume diarrhoea, and in some of these widespread kaposi's sarcoma of the gut or lymphoma is subsequently diagnosed. after stool analysis, acutely ill individuals with diarrhoea should be treated with ciprofloxacin, to which most enteric bacteria in hiv-seropositive individuals are sensitive. in those with chronic diarrhoea, antimotility agents reduce symptoms. oral rehydration therapy may also be important to maintain electrolyte balance. the somatostatin analogues octreotide and vapreotide are used in hiv-seropositive individuals with diarrhoea because of a motility effect and possibly because hiv has aminoacid sequences similar to vasoactive intestinal peptide (vip) and may induce diarrhoea by upregulating vip receptors. increased concentrations of vip have been shown in some patients with pathogen-negative diarrhoea, in whom octreotide has likewise been successful. somatostatin analogues are most effective for pathogen-negative diarrhoea and less so in protozoal diarrhoea, with one placebo-controlled study showing no effect. these expensive agents are unlikely to have a wide role in the treatment of hiv-related diarrhoea. microsporidiosis: two genera of microsporidia are associated with diarrhoea. enterocytozoon bieneusi is found only in human beings. there is no known effective treatment, although uncontrolled studies suggest that some patients may respond to albendazole, thalidomide, or atovaquone. encephalitozoon spp are much less commonly associated with diarrhoea, but infection with these organisms can also cause disseminated disease; organisms are eradicated by albendazole, with resolution of symptoms. cryptosporidiosis: there are many anecdotal reports of treatment for cryptosporidiosis that are difficult to interpret in view of the variable natural history of this infection. in at least a third of patients, diarrhoea resolves spontaneously, especially in those with an initial cd count above /l. investigation of suitable therapeutic agents is hampered by inability to culture the organism in vitro and the major differences between animal models and human infection. although many agents have been used, the only one with proven efficacy is paromomycin, which reduces stool volumes by about %. quantitative stool analyses have shown some reduction in oocyst excretion with therapy but the organism is seldom eradicated. because therapy of this infection is so difficult, primary prophylaxis would be a highly desirable goal. human cryptosporidiosis is a waterborne infection. since the minimum infectious dose is low-between one and five oocysts in gnotobiotic animals and - oocysts in healthy human beings -standard screening tests of metropolitan water supplies may not be sensitive enough for detection. boiling water eliminates infective oocysts, so this strategy is sensible for hiv-seropositive patients with cd counts of less than /l. enteritis: the treatment of cytomegalovirus enteritis remains controversial. both ganciclovir and foscarnet reduce symptoms and improve macroscopic and microscopic appearances of the colon with weeks' therapy. however, relapse with a median time of weeks is very common. both initial treatment and the decision to give maintenance therapy will therefore depend on the initial severity of symptoms. since diagnosis of cytomegalovirus enteritis is improving, patients with milder symptoms are being detected and the quality of life with treatment-anti-cmv agents have to be given intravenously and have considerable toxicitymay not be enhanced compared with no therapy. whether such patients left untreated will develop complications of cmv enteritis such as toxic dilation and perforation, which were common in the early years of the epidemic, remains to be determined. oral ganciclovir in a high dose to overcome problems of bioavailability may have a limited role as primary prophylaxis in preventing the development of cmv disease. nevertheless, such therapy has major toxicity, only limited benefit, and is extremely expensive. widespread use of primary prophylaxis must await the development of more effective agents or of other markers that allow better prediction of patients who are most likely to develop cmv disease. mycobacterium avium-intracellulare (mai): about % of severely immunosuppressed hiv-seropositive patients have mai-induced diarrhoea. primary prophylaxis with rifabutin of clarithromycin may reduce the incidence of mai but established small-bowel infection necessitates treatment with conventional quadruple therapy. such treatment must include the most effective agentsclarithromycin or azithromycin. resistance to these drugs will probably be limited by the addition of rifabutin and their efficacy improved by ethambutol. weight loss is a common feature of late hiv infection. initially wasting was thought to be a feature of hiv infection per se. however, although there is a slight increase in resting energy expenditure (ree) in individuals at most levels of immunosuppression, weight and lean body mass are normal unless an opportunistic infection supervenes. the pattern of weight loss characteristic of starvation, with decreased ree and relative preservation of lean body mass, is seen with enteric protozoal infection. the starvation response is probably caused by a combination of voluntary reduction of intake to reduce diarrhoea and anorexia related to malabsorption. certain opportunistic infections, especially m avium intracellulare and cmv, produce a cachectic response in which the ree is further raised and there is a more pronounced loss of lean body mass, likely to be related to inappropriate cytokine release. although increase in fat mass may improve body image, repletion of lean body mass is probably required to improve locomotor function and many aspects of quality of life. hiv-seropositive individuals losing weight because of starvation are likely to respond to food supplements given orally, parenterally, or enterally via a nasogastric tube or percutaneously by gastroenterostomy tube. such patients may also benefit from appetite stimulants. however, refeeding is likely to be ineffective in those with cachexia, who may improve lean body mass in response to anabolic agents (eg, recombinant human growth hormone). abdominal pain cmv infection is associated with an arteritis and the consequent ischaemia may be associated with acalculous cholecystitis or appendicitis. cmv colitis commonly gives rise to abdominal pain with bloody diarrhoea and rebound tenderness. the other origin of abdominal pain unique to hiv-seropositive patients is an aids-related sclerosing cholangitis caused by various opportunists including microsporidia, cmv, and cryptosporidia. this condition is associated with sclerosis of both the intrinsic and the extrinsic hepatic system and with changes in the pancreatic duct. sclerosing cholangitis may also be common in those without pain, but it is usually the discomfort that leads to investigation. since the natural history of this pain is variable, how frequently sphincterotomy improves symptoms is unclear. background low adherence of patients to prescribed, selfadministered medical interventions is ubiquitous. low adherence limits the benefits of current medical care. efforts to assist patients to follow treatments might improve the efficiency of care and substantially enhance benefits. our objective was to summarise the results of randomised controlled trials (rcts) of interventions to help patients follow prescriptions for medications. methods a previous systematic review was updated through computerised searches in medline, international pharmaceutical abstracts, psychinfo, and hstar online databases; bibliographies in articles on patient adherence; articles in the reviewers' personal collections; and contact with authors. articles were judged of interest if they reported original data concerning an unconfounded rct of an intervention to improve adherence with prescribed medications, with one or more measure of medication adherence, one or more measure of treatment outcome, at least % follow-up of each group studied, and, for longterm treatments, at least months of follow-up for studies with positive initial findings. information on study design features, interventions and controls, and findings were ex tracted by one reviewer (rk) and checked by the other two reviewers. findings relevant citations and abstracts were screened, full text articles were reviewed in detail, and rcts met all criteria. the studies were too disparate in clinical problems, adherence interventions, measures and reporting of adherence, and the clinical outcomes studied to warrant meta-analysis. seven of interventions were associated with improvements in adherence and six interventions led to improvements in treatment outcomes. for short-term treatments, one study showed an effect on adherence and outcome of counselling and w ritten information. the interventions that were effective for longterm care were complex , including various combinations of more convenient care, information, counselling, reminders, self-monitoring, reinforcement, family therapy, and other forms of additional supervision or attention. even the most effective interventions did not lead to substantial improvements in adherence. interpretation although adherence and treatment outcomes can be improved by certain-usually complexinterventions, full benefits of medications cannot be realised at currently achievable levels of adherence. it is time that additional efforts be directed towards developing and testing innovative approaches to assist patients to follow treatment prescriptions. lancet ; : - introduction non-adherence with prescribed treatments is very common. typical adherence rates for prescribed medications are about % with a range from % to over %. to the extent that treatment response is related to dose, non-adherence reduces treatment benefits and can bias assessment of the efficacy of treatments. with increasing numbers of efficacious self-administered treatments, the need is apparent for better understanding and management of non-adherence. in previous reviews, we have examned the accuracy of clinical measures of non-adherence, interventions to improve attendance at appointments for medical services, and interventions to enhance medication adherence. in the last review some of the included trials were acute hiv infection presenting with painful swallowing and esophageal ulcers natural history and prognosis of diarrhoea of unknown cause in patients with acquired immunodeficiency syndrome (aids) effects of zidovudine treatment on the small intestinal mucosa in patients infected with the human immunodeficiency virus intestinal absorptive capacity, intestinal permeability and jejunal histology in hiv and their relation to diarrhoea t-cell activation can induce either mucosal destruction or adaptation in cultured human fetal small intestine intestinal mucosal inflammation associated with human immunodeficiency virus infection human immunodeficiency virus detected in bowel epithelium from patients with gastrointestinal symptoms duodenal mucosal t cell subpopulation and bacterial cultures in acquired immunodeficiency syndrome association of gastric hypoacidity with opportunistic enteric infections in patients with aids decreased gastric acid secretion and bacterial colonisation of the stomach in severely malnourished bangladeshi children prevalance of enteric pathogens in homosexual men with and without acquired immunodeficiency syndrome infectious diarrhea in patients with aids gastrointestinal symptoms in patients infected with human immunodeficiency virus: relevance of infective agents isolated from gastrointestinal tract prevalence of intestinal protozoans in french patients infected with aids prevalence of intestinal microsporidiosis in hiv-infected individuals referred for gastroenterological evaluation faecal tumour necrosis factor-alpha in hiv-related diarrhoea the diagnosis of aids-related chronic diarrhoea: a prospective study in patients light and electron microscopic appearances of pathological changes in hiv gut infection enterotoxic effect of stool supernatant of cryptosporidium-infected calves on human jejunum jejunal water and electrolyte transport in aids-related cryptosporidiosis small bowel transit in hivseropositive individuals autonomic denervation in jejunal mucosa of homosexual men infected with hiv loss of mucosal cd lymphocytes is an early feature of hiv infection mechanisms of innate and acquired resistance to cryptosporidium parvum infection in scid mice cryptosporidium infection in an adult mouse model: independent roles for ifn-␥ and cd + t lymphocytes in protective immunity faecal tumour necrosis factor-alpha and faecal alpha-one-antitrypsin in hiv infection diarrhoea in hiv-infected patients: no evidence of cytokine-mediated inflammation in jejunal mucosa an algorithm for the investigation of diarrhoea in hiv infection use of the fluorochrome calcofluor white in the screening of stool specimens for spores of microsporidia salmonella, campylobacter and shigella in hiv positive patients gastrointestinal viral infections in homosexual men who were symptomatic and seropositive for human immunodeficiency virus efficient management of diarrhea in the acquired immunodeficiency syndrome (aids): a medical decision analysis cytomegalovirus in aids: presentation in patients and a review of the literature spectral and sequence similarity between vasoactive intestinal peptide and the second conserved region of human immunodeficiency virus type envelope glycoprotein (gp ): possible consequences on prevention and therapy of aids elevated plasma levels of vasoactive intestinal peptide in aids patients with refractory idiopathic diarrhea: effects of treatment with octreotide octreotide therapy of large volume refractory aids-associated diarrhea: a randomized controlled trial treatment with albendazole for intestinal disease due to enterocytozoon bieneusi in patients with aids thalidomide for microsporidiosis atrovaquone is effective treatment for the symptoms of gastrointestinal microsporidiosis in hiv- infected patients paromomycin for cryptosporidiosis in aids: a health information research unit intestinal function and injury acquired immunodeficiency syndrome-related cryptosporidiosis infective dose size studies on cryptosporidium parvum using gnotobiotic lambs the infectivity of cryptosporidium parvum in healthy volunteers treatment of aids-associated gastrointestinal cytomegalovirus infection with foscarnet and ganciclovir: a randomized comparison the microbial causes of diarrhea in patients infected with the human immunodeficiency virus body composition studies in patients with the acquired immunodeficiency syndrome prospective analysis of patterns of weight change in stage iv human immunodeficiency virus infcction the metabolic sequelae of specific opportunistic infections in aids anabolic effects of recombinant human growth hormone in patients with wasting associated with human immunodeficiency virus infection natural history of aids related sclerosing cholangitis: a study of cases key: cord- -bcyotwkf authors: alkire, sabina; chen, lincoln title: global health and moral values date: - - journal: lancet doi: . /s - ( ) - sha: doc_id: cord_uid: bcyotwkf nan shaped differently depending on the morals espoused. a rights-based or equity approach, for example, would be expected to differ from a utilitarian or humanitarian approach. also, an initiative is only partly justified by its moral expediency. of critical importance are factors shaped by knowledge and by institutional interests. moral soundness about why particular global programmes should be advanced may need to be balanced against the imperative of achieving consensus among people of many different moral views. yet, as we argue in the conclusion, moral clarity-as well as knowledge and institutional interests-can usefully shape what, when, and how health initiatives should best proceed. to stimulate discussion, we have selected four major schools of moral values commonly used to justify global health initiatives: humanitarianism, utilitarianism, equity, and rights. we could have analysed other schools, but these four, we believe, encompass a good range of moral positions. there are, of course, both large and important variations within each school. the appeal for charitable acts to meet pressing humanitarian needs is arguably the most common ethical basis for global health action. humanitarianism can be a form of virtue ethics but it also often a humanistic response to evident social problems. the ethos of humanitarianism is embedded in nearly all religions. in a humanitarian approach, people respond to human suffering and realise human fulfilment by acting in a virtuous manner based on compassion, empathy, or altruism. the virtues might be specific or broad. examples of specific acts are charitable tithing among baptists or zakat (charitable donations) among muslims. broadly proscribed virtues encompass such human qualities as generosity, honesty, trustworthiness, integrity, and fairness. among the wealthy, these virtues might be expressed as philanthropy, which often focuses on health. humanitarianism provides the primary ethical basis of voluntary action undertaken by non-governmental organisations (ngos), and is also an important base of public support for official foreign aid. us president george bush in announcing us$ billion in assistance for hiv/aids control described the pledge as a "work of mercy". public opinion polls in the usa consistently show that alleviating world hunger and providing drinking water are worthy of foreign aid from the usa. emphasis on voluntary generosity and self-expression (rather than on duties or obligations) gives humanitarianism a broad appeal to many social groups, corporations, and governments. contemporary appeals to people's humanitarian impulses focus on the giver: who a person becomes by acting well, and how a person realises a sense of accomplishment or fulfilment. there are dangers that those who are helped can be placed in a dependent position, treated as victims not agents. also, the underlying societal rules and structures that generate the social ills are not necessarily addressed. this approach might be more relevant to humanitarian catastrophes than structural approaches that attempt to correct the root causes of social problems. in a utilitarian framework, the value of health is determined by the subjective utility (happiness, pleasure, or desire satisfaction) that it creates for an individual. across all individuals in a society, the ideal state is one that maximises the aggregate utility. health could be valued because it generates utility directly, or because good health is instrumental to other utilitygenerating states, including opulence, or both. many contemporary health policies are based on a form of utilitarianism in which good health is valued as instrumental to maximising aggregate utility. for example, the who commission on macroeconomics and health calculated the costs and benefits of burdens of disease and argued that investing in health would generate economic growth, thereby enhancing incomes and aggregate utility. the utilitarian approach underscores important interconnections between health and other variables. it can show how improving the health of the deprived can be "in everybody's interest"-including the self-interest of people not inclined to altruism. its difficulties, however, are several. first, the instrumental valuation of health demeans it as an intrinsically valued goal in all societies. second, people's self-assessments do not www.thelancet.com vol september , rights were not granted to include this image in electronic media. please refer to the printed journal. necessarily match their observed health status. for example, the self-reported morbidity rates in the indian state of kerala, where life expectancy is - years, are significantly higher than in bihar, where life expectancy is significantly lower; and self-reported morbidity in the usa is higher still. third, it is rather difficult, even theoretically, to aggregate very different kinds of utility together into a single entity. finally, a utility-maximising approach is not directly sensitive to distributional concerns. equity is a relational concept in which ethical assessments are-at least in part-based on distributional features of one or more variable. fortunately, considerable intellectual work has recently been done on health equity and social justice. , building on the work of political philosopher john rawls, amartya sen has addressed some key features of health equity. first, he poses the question of "equity of what?" should equity be evaluated with reference to health achievement or access to health care? sen argues that equity in health should be assessed in terms of health capabilities and achievements rather than healthcare activities. after all, health care is a human activity; what people actually value is the capability to attain good health. he further notes that equitable social processes should inform evaluations of equity in the health space. in some equity domains, such as gender, completely equal distribution of health achievement could be considered unfair because women-whose lifespan in the absence of gender discrimination exceeds that of men-should, under an equity framework, enjoy longer life expectancies. an equity-based evaluation considers not only allocation of a fixed set of health resources, but also allocation of resources between health and other social objectives. equitable approaches to health have carried considerable power in mobilising support for health components of international development. striking disparities in health achievement and emotively powerful arguments of preventable suffering can animate the public and political leaders. an example is the recent call for public funds to expand antiretroviral treatment to hiv-positive people in poor countries. the disparity between the health of those with access to lifesaving drugs and the avoidable deaths among all others evokes the moral imperative to alleviate preventable human suffering caused by the inequitable access to antiretroviral drug therapy. human rights in health are embedded in several un declarations, and they have deep and wide moral bases. legal formulations were created to specify what was argued in the th century to be an inalienable moral claim grounded in the ontological dignity of human beings. human rights can be described as "things which are owed to man because of the very fact that he is man". some human rights can be expressed in the space of capabilities-for example rights to health, or to inclusion. yet rights also add to the capability perspective by invoking duties and obligations on the part of others. because each human being is recognised as an "end", human rights demand obligatory behaviour on the part of the state, firms, groups, and individuals. obligations may be "perfect" (as enshrined in law) or "imperfect" (a general duty to do what one can to help). calls for a rights-based approach to global health have recently grown. extensions of human rights to children and women both contain references to freedom from preventable suffering and freedom to exercise health choices. , the application of human rights to good health has drawn attention to the duties and obligations that people and institutions have towards human beings, viewed squarely as an "end" worthy of dignity. a human rights approach often assumes some health minimum that all people should be able to realise for human dignity. the challenge is to implement the corresponding "incomplete obligations" among communities, institutions, and states where good health depends upon resources, knowledge, technologies, and social action. these ethical schools do not track precisely to any specific health initiative. none of the schools dominates any specific health action, and several schools are often relevant to any single initiative. at present, whether the by initiative was evaluated according to aggregate utility (increasing the utility of people with hiv/aids) or distributional equity (increasing the numbers of people in developing countries who are given antiretroviral treatment), human rights (for health care), or the need www.thelancet.com vol september , rights were not granted to include this image in electronic media. please refer to the printed journal. for humanitarianism (to alleviate the suffering of those with hiv/aids), in all cases action is morally imperative. ensuring a minimal threshold of health might similarly fit well with humanitarianism and human rights, and equity and justice values will require action on behalf of the most disadvantaged. beyond moral values, the selection of global health initiatives is shaped by other, often implicit but no less valid, factors. among these are knowledge and institutions. to a large degree, ethical assessments will rest not only on the ethical perspective chosen, but also on the information selected for examination. the selection of information is shaped by political and scientific forces as well as by moral theories. paul farmer has written eloquently about the selective scrutiny of information that shapes health action. tuberculosis, especially multidrug-resistant tuberculosis, became recognised as a health crisis when it achieved rapid transmission in new york city. yet tuberculosis-before, during, and after the new york crisis-kills million people annually, most of whom are poor. because of informational selectivity, tuberculosis is a silent crisis among the world's poor, invisible to the rich and powerful. similarly, severe acute respiratory syndrome (sars) achieved front-page news because of its lethal nature and the paralysing effect it had on global commerce. yet, "sars-like" health catastrophes take place daily in thousands of rural villages in low-income countries. these health problems likewise severely affect families and communities, who are invisible to better-off and protected communities. scientific knowledge provides the basis for research and development of health technologies, such as vaccines and drugs. breakthroughs in health research raise moral challenges because they make feasible treatment for conditions that were hitherto incurablefor example, antiretroviral drugs for hiv. morally, there is a big difference between inevitable human calamity and suffering that can be prevented by modern technology. growing knowledge gaps between technological potentiality and health realities present huge ethical challenges. contention is further fuelled if the gap is accentuated by commercial interest. recent debates over affordable access to life-saving antiretroviral drugs have focused on the fairness of international regimes of intellectual property rights that are perceived to favour commerce over human health. global health, like other fields, has a cluster of institutional stakeholders. governments and intergovernmental agencies like the un and the world bank are mandated to play technical, financial, and operational roles. since health is a major component of the global economy, corporations have interests in profits as well as in protecting their public reputations. civil society organisations have many roles, ranging from the direct delivery of services to advocacy on public policies. institutions, like all actors, are endowed with certain capabilities and also seek to advance their bureaucratic, political, and financial agendas. one typical driver of organisational behaviour is to gain command over resources that can translate into more jobs, higher status, and more numerous activities. tracking of financial flows in global health initiatives can help reveal institutional winners and losers. historical studies have examined these institutional motivations in global health. the work of the rockefeller foundation overseas, for example, was often linked to corporate interests and political propagation of capitalism. in an excellent historical analysis of tuberculosis control in mid- th century, sunil amrith postulated that the conduct of tuberculosis programmes was primarily shaped by the state of knowledge and the capabilities of global institutions. field research had shown that directly observed therapy (dots) was highly effective in curing tuberculosis in home-based settings. endowed with new knowledge, yet limited by institutional capacity and scarce funding, who decided to pursue tuberculosis control through vertical programmes involving cadres of specifically tasked field workers rather than attempt to build holistic villagebased primary services. the latter approach would have been far more demanding institutionally and financially. a common usage of moral values is to mobilise public support. sometimes, however, advocates of global health do not give an accurate representation of distinct ethical schools, simply because they want everyone to agree. braveman and groskins, for example, argued that the concepts of equity and rights are essentially identical, and lead to similar strategies. their aim seems to have been advocacy for certain types of health actions rather than for clarification of distinctive moral schools. de cock argued that a public health rather than a human rights approach should frame responses to hiv/aids in africa, but again this analysis is based on a very narrow example of both ethical schools. we argue that clarity in thinking is essential, because different moral schools do indeed raise distinct considerations and it can be useful to evaluate these carefully. at the same time, the urge to seek consensus is also valid, and can be sought without either exaggerating differences, or claiming (inaccurately) that differences between moral schools do not exist. a common usage of moral values is advocacy, often to rich and powerful leaders, institutions, and nation states with the goal of mobilising resources-finance, political will, human motivations-on behalf of particular health action. but here we run into an apparent paradox: how can one use moral values as advocacy tools, when the moral schools are distinct, and when people argue passionately among them? in order to achieve the support, global health programmes also must build consensus among a diverse constituency of resource-holders as to the central value of the initiative. so when it comes to the language of why support for global health is important, we recognise, with cass sunstein, the wisdom of seeking "incompletely theorized agreements" in the moral discourse surrounding global health. in his tanner lectures in human values, sunstein argued that in some cases consensus can be achieved if participants refrain from elaborating their moral positions, because if they scrutinised these positions in depth, consensus could fracture. by contrast, he advocates an approach that "enlists silence, on certain basic questions, as a device for producing convergence despite disagreement, uncertainty, limits of time and capacity, and heterogeneity". sunstein's approach has the advantage of opening space for dialogue, exchange, and discussion, thereby promoting deliberative democracy, political accountability, and reason-giving. incompletely theorised agreements satisfy diverse constituencies who might have very different reasons, including incompatible values, for supporting a particular activity. there is a further point against requiring everyone to agree on only one ethical justification for global health. for not only might different approaches appeal to different groups, different people might also have distinct understandings of what the terms "rights", "equity", or "humanitarianism", actually mean. after all, the support base of global health initiatives is diverse, ranging from heads of state to private-sector executives to religious leaders to activists from ngos to opinion-setters and journalists. it is highly unlikely that these constituencies will share an identical understanding of ethical terms. a global health initiative can receive emphatic support from people who do not necessarily agree on the ethical foundations for their support, and in fact may very clearly disagree with one another as to why a programme should proceed-ie, its ethical or metaphysical justification. advocates of global health initiatives would thus do well to proceed with a general appeal to moral concepts such as social justice and compassion, and this generality belies prudence rather than a lack of moral rigour. yet an eclectic appeal to moral values in order to garner support of global health initiatives is not to imply that distinctions among moral values are trivial. beyond clarifying why an action is important, adopting a particular moral approach can influence health action in other deeply important ways. first is the scope of health action. an example is the programmatic implication of pursuing access to health care versus equitable distribution of health outcomes. in the former case, the programme would invest heavily in building health clinics and outposts, and perhaps in increasing the ratio of medical personnel per citizen. this sounds very appealing until one recognises that a country may have many rural health outposts, and many doctors on salary role, but if these doctors do not turn up to work, and the outposts do not have adequate pharmaceutical supplies, the population's health outcomes might remain very poor. on the contrary, to achieve an equitable distribution of health outcomes it would be necessary to make sure that the investment in health care results in better health across the population. it would also then be necessary to address broader social determinants of health, such as that raised in michael marmot's intriguing research on the under-recognised relation between socioeconomic inequality and health. second, different ethical schools (and different groups within them) may shape how global health programmes are undertaken. charitable acts might treat people as passive recipients of generosity, whereas rights-based approaches would encourage "voice" and participation to strengthen the agency of people for achieving their inherent rights. third, advocacy might use moral values to advance a global health agenda-because they are effective in advancing a global agenda. to mobilise a compassionate response, a picture of a feeble, emaciated, and large-eyed child might be used to stir pity among donors. such advertisements tend to view the poor as helpless victims, rather than people who could be empowered to care for themselves. arguably, much harm has been done by such dehumanising advocacy techniques. yet, it could be argued that such moral approaches are legitimate to use because they are more effective in evoking public support than other moral approaches. when people speak of ethics, the contribution that most readily leaps to mind is motivational: that an appeal to moral values will motivate people to support a set of actions. yet this is only one of the ways in which moral values can support global health initiatives, and is not necessarily the most powerful. discussions on whether to frame the objective of global health initiatives in terms of access to health care, or capabilities for good health, or utility maximisation, help to clarify what global health initiatives seek to accomplish. criteria such as efficiency, or equitable treatment for men and women, clarify which alternative actions to realise similar goals should be selected. consideration of how health activities contribute to or block non-health objectives such as the support of agency, or the rights to self-determination, clarify the importance of how health initiatives are carried forward. thus global health may be far easier to achieve if we pause to follow through different moral analyses and thereby clarify what, which, and how global health initiatives can best proceed. science and the health of the poor speech at the world health assembly health at the world summit on sustainable development philanthropy and health. london: king's college introduction to the principles of morals and legislation. london: the athlone press, . who commission on macroeconomics and health. macroeconomics and health: investing in health for development health: perception vs observation inequality reexamined challenging inequities in health: from ethics to action public health, ethics, and equity why health equity? the rights of man and natural law. london: geoffrey bles, the centenary press human development and human rights: human development report convention on the rights of the child vienna declaration and programme of action informational analysis of moral principles infections and inequalities: the modern plagueupdated edition with new preface rockefeller medicine men: medicine and capitalism in america plague of poverty? the world health organization, tuberculosis and international development, c - poverty, equity, human rights and health: policy and practice shadow on the continent: public health and hiv/aids in africa in the st century legal reasoning and political conflict aristotelian justice and health policy: capability and incompletely theorized agreements is inequality bad for our health key: cord- -ezu j tc authors: wang, lin-fa; anderson, danielle e; mackenzie, john s; merson, michael h title: from hendra to wuhan: what has been learned in responding to emerging zoonotic viruses date: - - journal: lancet doi: . /s - ( ) - sha: doc_id: cord_uid: ezu j tc nan as the world watches the rapid spread of the novel coronavirus ( -ncov) outbreak, it is important to reflect on the lessons that can be learned from this and previous emerging zoonotic viruses (ezv) in a comparative and analytic way. although the source of -ncov is yet to be confirmed, early findings suggest a high possibility of a bat origin. there have been six major ezv outbreaks in the past years caused by proven or suspected bat-borne viruses (table). [ ] [ ] [ ] [ ] [ ] [ ] with these in mind, four major points are worth considering in the context of the -ncov outbreak. first, are koch's postulates still relevant in the era of next-generation sequencing (ngs)? in the heat of the debate about the early response to the -ncov outbreak, insufficient attention was paid to how the initial aetiological evidence came from ngs analysis requested by clinicians. to our knowledge, all previous ezv outbreak investigations started with a live virus isolation, including the middle east respiratory syndrome coronavirus (mers-cov) discovery. the preliminary sequence data indicating the presence of a severe acute respiratory syndrome (sars)-related coronavirus in patients' lung lavage samples were obtained on dec , , by ngs. the chinese authorities ruled out sars and mers, as well as a few other non-coronaviruses, on jan , , and confirmed a novel coronavirus as a potential cause on jan , . however, the genome sequence-crucial for rapid development of diagnostics needed in an outbreak response-was not released until jan , , days after the preliminary sequence data were obtained. these events raise challenging questions. should a national response team report a highly suspected pathogen sequence before confirming an aetiological live agent? are current national and interna tional policies and regulations adequate to deal with a sequence-based outbreak reporting system? while they have evolved over time, the postulates formulated by robert koch and friedrich loeffler in included the isolation of a live agent as a key criterion. we believe that it is time to establish an ngs-based reporting system that can alert to the presence of a new aetiological agent(s) rather than requiring the isolation of aetiological agents. second, clinicians and scientists have a crucial role in responding to such ezv outbreaks. in past ezv outbreak investigations, clinicians have largely had supportive roles. this situation is likely to change now that more clinician scientists are better trained and have academic appointments, especially in china. in fact, it was the clinicians who led to the early detection of and warning about the -ncov outbreak in china. in investigating severe pneumonia cases of unknown cause, clinicians in two hospitals in wuhan independently sent lung lavage samples from patients for ngs analysis by commercial ngs companies. alarm bells rang, not only through the different levels of the official chinese center for disease control and prevention (china cdc) reporting system but also through social media traced back to eight doctors who were wrongly accused of spreading "fake news". these doctors were later cleared of any wrongdoing and praised by the government authorities for their brave action in early alerting. achieving the right balance between information sharing and scientific publication is important during an ezv outbreak response. this is not a new challenge but greatly amplified in the -ncov outbreak when anger in china was directed towards a few leading scientists who were alleged to have held back sharing data about the virus to publish their findings. these unsubstantiated allegations consumed media attention and created media panic that was counterproductive to the outbreak response. clear national and international guidelines are needed on how to achieve the right balance in the leadership provided by public health and research experts facing an outbreak of an ezv. third, a one health approach in ezv outbreak responses and control is vital. in august, , after who declared the end of the sars outbreak, it organised a special mission with international and chinese scientists to investigate the origin and early transmission events of sars-cov. among the eight international experts invited, seven were veterinarians or those working in animal health. by contrast, the six-member chinese team only had one participating veterinarian or animal scientist. while recognising the tremendous effort by the china cdc team in the early response to the -ncov outbreak, the small number of team members trained in animal health was probably one of the reasons for the delay in identifying an intermediate animal(s), which is likely to have caused the spread of the virus in a region of the market where wildlife animals were traded and subsequently found to be heavily contaminated. unfortunately, what animal(s) was involved in transmission remains unknown. there is an urgent need to know the risks associated with the presumed animal to human transmission of -ncov, and the measures that can be taken to prevent such transmission in the future. for example, should the sale of wild animals be restricted in chinese wet markets? we recommend that a comprehensive one health team be involved in all future ezv investigations. indeed, this approach has international implications, with risks of exotic zoonotic diseases associated with the huge quantities of illegal bush meat from central and west africa being imported into europe and north america. finally, naming of a new virus is important not only for virologists in the long term but also for effective communication to the general public. in all the major ezv events over the past years, naming of the new virus has not been straightforward and most went through a renaming process (table) . this is also true for the -ncov outbreak. there has been intensive discussion now among virologists worldwide about an alternative name for -ncov. to continue the tradition of using a syndrome, as in sars and mers, and to avoid the sensitivity of using a city name, we propose to name this new virus han acute respiratory syndrome coronavirus (hars-cov). han is the abbreviation of wuhan in chinese. such a name is, we believe, preferable to the names being used in media headlines, such as "wuhan virus" or "china virus", and it retains the historical fact that the outbreak started in wuhan. now is not a time for blame. rather, there are lessons the global health community can and should learn and act on so that we can better respond to the next ezv event, which is almost certain to happen again. these lessons are definitely not unique to china. programme in emerging infections diseases, duke-nus medical school singhealth duke-nus global health institute a pneumonia outbreak associated with a new coronavirus of probable bat origin a morbillivirus that caused fatal disease in horses and humans nipah virus: a recently emergent deadly paramyxovirus the severe acute respiratory syndrome isolation of a novel coronavirus from a man with pneumonia in saudi arabia reflections on early investigations into the ebola virus a novel coronavirus outbreak of global health concern genomic characterisation and epidemiology of novel coronavirus: implications for virus origins and receptor binding causation and disease: a chronological journey. the thomas parran lecture praise for chinese doctors who coronavirus blew whistle. the australian detection of emerging zoonotic pathogens: an integrated one health approach screening for viral pathogens in african simian bushmeat seized at a french airport key: cord- -tijcxtwx authors: wang, chen; horby, peter w; hayden, frederick g; gao, george f title: a novel coronavirus outbreak of global health concern date: - - journal: lancet doi: . /s - ( ) - sha: doc_id: cord_uid: tijcxtwx nan a novel coronavirus outbreak of global health concern by genetic sequencing as a novel coronavirus. risk assessment at that time was guarded but suggested that the outbreak was more like that caused by the middle east respiratory syndrome (mers) coronavirus than the severe acute respiratory syndrome (sars) coronavirus. however, this information was from what now appears to be first-generation cases from a point source, but at the time it seems that a second generation, and perhaps a third generation, of cases was already reported in the incubation period, and this generation appears to have included health workers. health worker infections are an ominous finding in any emerging infection. front-line health workers can be initially at risk and infected when they examine and treat patients who present with a respiratory infection; if handwashing or other infection prevention and control measures are not in place, these health workers are at great risk of infection and become the inadvertent carriers to patients who are in hospital for other diseases and treatments, family members, and the community. early in the sars coronavirus outbreak, frontline health workers became infected, which amplified transmission to patients in hospitals where outbreaks were occurring. early evidence from the initial mers outbreaks suggested that health workers were likewise being infected, but that their infections were less severe than those of patients in hospitals who became infected and had comorbidities such as diabetes or chronic respiratory disease. today, the epidemiology of both sars and mers viruses is mostly understood, and the same will be true for the current outbreak of -ncov if data continue to be freely shared and used to provide realtime guidance. these articles and others being rapidly disseminated and shared will have a major role in assuring that this global collaboration occurs. jan , , a total of cases with laboratoryconfirmed -ncov infection have been detected in china, of whom have died and % remain in hospital (figure). in the lancet, chaolin huang and colleagues report clinical features of the first patients admitted to the designated hospital in wuhan who were confirmed to be infected with -ncov by jan , . the study findings provide first-hand data about severity of the emerging -ncov infection. symptoms resulting from -ncov infection at the prodromal phase, including fever, dry cough, and malaise, are nonspecific. unlike human coronavirus infections, upper respiratory symptoms are notably infrequent. intestinal presentations observed with sars also appear to be uncommon, although two of six cases reported by chan and colleagues had diarrhoea. common laboratory findings on admission to hospital include lymphopenia and bilateral ground-glass opacity or consolidation in chest ct scans. these clinical presentations confounded early detection of infected cases, especially against a background of ongoing influenza and circulation of other respiratory viruses. exposure history to the huanan seafood wholesale market served as an important clue at the early stage, yet its value has decreased as more secondary and tertiary cases have appeared. of the patients in this cohort, ( %) developed severe dyspnoea and ( %) required admission to an intensive care unit, and six died. hence, the case-fatality proportion in this cohort is approximately · %, and the overall case fatality proportion appears to be closer to % (table) . however, both of these estimates should be treated with great caution because not all patients have concluded their illness (ie, recovered or died) and the true number of infections and full disease spectrum are unknown. importantly, in emerging viral infection outbreaks the case-fatality ratio is often overestimated in the early stages because case detection is highly biased towards the more severe cases. as further data on the spectrum of mild or asymptomatic infection becomes available, one case of which was documented by chan and colleagues, the case-fatality ratio is likely to decrease. nevertheless, the influenza pandemic is estimated to have had a case-fatality ratio of less than % but had an enormous impact due to wide spread transmission, so there is no room for complacency. as an rna virus, -ncov still has the inherent feature of a high mutation rate, although like other coronaviruses the mutation rate might be somewhat lower than other rna viruses because of its genomeencoded exonuclease. this aspect provides the possibility for this newly introduced zoonotic viral pathogen to adapt to become more efficiently transmitted from person to person and possibly become more virulent. infecting at least people and causing deaths. the international spread of sars-cov in was attributed to its strong transmission ability under specific circumstances and the insufficient preparedness and implementation of infection control practices. chinese public health and scientific capabilities have been greatly transformed since . an efficient system is ready for monitoring and responding to infectious disease outbreaks and the -ncov pneumonia has been quickly added to the notifiable communicable disease list and given the highest priority by chinese health authorities. the increasing number of cases and widening geographical spread of the disease raise grave concerns about the future trajectory of the outbreak, especially with the chinese lunar new year quickly approaching. under normal circumstances, an estimated billion trips would be made in the spring festival travel rush this year, with million trips happening in wuhan. the virus might further spread to other places during this festival period and cause epidemics, especially if it has acquired the ability to efficiently transmit from person to person. consequently, the -ncov outbreak has led to implementation of extraordinary public health measures to reduce further spread of the virus within china and elsewhere. although who has not recommended any international travelling restrictions so far, the local government in wuhan announced on jan , , the suspension of public transportation, with closure of airports, railway stations, and highways in the city, to prevent further disease transmission. further efforts in travel restriction might follow. active surveillance for new cases and close monitoring of their contacts are being implemented. to improve detection efficiency, front-line clinics, apart from local centres for disease control and prevention, should be armed with validated point-of-care diagnostic kits. rapid information disclosure is a top priority for disease control and prevention. a daily press release system has been established in china to ensure effective and efficient disclosure of epidemic information. education campaigns should be launched to promote precautions for travellers, including frequent hand-washing, cough etiquette, and use of personal protection equipment (eg, masks) when visiting public places. also, the general public should be motivated to report fever and other risk factors for coronavirus infection, including travel history to affected area and close contacts with confirmed or suspected cases. considering that substantial numbers of patients with sars and mers were infected in health-care settings, precautions need to be taken to prevent nosocomial spread of the virus. unfortunately, health-care workers, some of whom were working in the same ward, have been confirmed to be infected with -ncov to date, although the routes of transmission and the possible role of so-called superspreaders remain to be clarified. epidemiological studies need to be done to assess risk factors for infection in health-care personnel and quantify potential subclinical or asymptomatic infections. notably, the transmission of sars-cov was eventually halted by public health measures including elimination of nosocomial infections. we need to be wary of the current outbreak turning into a sustained epidemic or even a pandemic. the availability of the virus' genetic sequence and initial data on the epidemiology and clinical consequences of the -ncov infections are only the first steps to understanding the threat posed by this pathogen. many important questions remain unanswered, including its origin, extent, and duration of transmission in humans, ability to infect other animal hosts, and the spectrum and pathogenesis of human infections. characterising viral isolates from successive generations of human infections will be key to updating diagnostics and assessing viral evolution. beyond supportive care, no specific coronavirus antivirals or vaccines of proven efficacy in humans exist, although clinical trials of both are ongoing for mers-cov and one controlled trial of ritonavir-boosted lopinavir monotherapy has been launched for -ncov (chictr ). future animal model and clinical studies should focus on assessing the effectiveness and safety of promising antiviral drugs, monoclonal and polyclonal neutralising anti body products, and therapeutics directed against immunopathologic host responses. we have to be aware of the challenge and concerns brought by -ncov to our community. every effort should be given to understand and control the disease, and the time to act is now. fgh reports personal fees from university of alabama antiviral drug discovery and development consortium, and is a non-compensated consultant for gilead sciences, regeneron, and sab biotherapeutics, which have investigational therapeutics for coronavirus infections. all other authors declare no competing interests. the novel coronavirus ( -ncov) outbreak is a major challenge for clinicians. the clinical course of patients remains to be fully characterised, little data are available that describe the disease pathogenesis, and no pharmacological therapies of proven efficacy yet exist. corticosteroids were widely used during the outbreaks of severe acute respiratory syndrome (sars)-cov and middle east respiratory syndrome (mers)-cov, and are being used in patients with -ncov in addition to other therapeutics. however, current interim guidance from who on clinical management of severe acute respiratory infection when novel coronavirus ( -ncov) infection is suspected (released jan , ) advises against the use of corticosteroids unless indicated for clinical evidence does not support corticosteroid treatment for -ncov lung injury geneva: world health organization geneva: world health organization beijing: china national health commission geneva: world health organization first travel-related case of novel coronavirus detected in united states a familial cluster of pneumonia associated with the novel coronavirus indicating person-to-person transmission: a study of a family cluster clinical features of patients infected with novel coronavirus in wuhan, china the epidemiology of severe acute respiratory syndrome in the hong kong epidemic: an analysis of all patients geneva: world health organization middle east respiratory syndrome coronavirus (mers-cov). geneva: world health organization epidemiological, demographic, and clinical characteristics of cases of middle east respiratory syndrome coronavirus disease from saudi arabia: a descriptive study who. summary of probable sars cases with onset of illness from age-and sex-specific mortality associated with the - influenza pandemic in kentucky epidemiology and cause of severe acute respiratory syndrome (sars) in guangdong, people's republic of china emergency committee regarding the outbreak of novel coronavirus ( -ncov). geneva, world health organization beijing: china national health commission clinical management of severe acute respiratory infection when novel coronavirus (ncov) infection is suspected. geneva, world health organization key: cord- -k oy avl authors: nan title: department of error date: - - journal: lancet doi: . /s - ( ) - sha: doc_id: cord_uid: k oy avl nan www.thelancet.com vol october , accurate sepsis epidemiology rather than estimates that might greatly misrepresent the truth (in either direction), and to adopt a balanced approach to antibiotic prescribing, media reporting, and public education. most children with infections will not benefit from antibiotics and might be harmed by the effects on microbiota and other unwanted complications, notwithstanding the impact on antimicrobial resistance. in a call to action, arlene king and colleagues emphasise the potential for insolvency at the pan american health organization (paho) and urge member states to pay their outstanding contributions. king and colleagues called on the spirit of solidarity in member states. however, paho, which was established well before who, has always had problems of solidarity. as such, it is apparent that solidarity might not be attainable in the near future to overcome the crisis at paho. king and colleagues also argued that health security will not be possible without a functioning paho; however, it is imperative to note that a functioning paho entails more than securing funding from member states. news reports alleging that paho exploited cuban doctors by retaining a portion of their income (us$ million), which arguably constitutes negligent and criminal behaviour, provide a reminder that additional funds alone are insufficient. ultimately, solidarity and funding, although important, are unlikely to be sufficient or attained in the immediate short term. there needs to be reform and awareness. this reform should require member states to provide sustainable funding that cannot be withdrawn with a change in government, as seen in the usa. awareness should not only emphasise the public health achievements of paho across its more than years of existence but also its effects on the countries that most greatly benefit from paho's work-countries with gross inequities. member states should agree to continued and sustained funding agreements with a focus on the vulnerable communities that paho most greatly affects. financial crisis at paho in the time of covid- : a call for action cuban doctors accuse international agency of profiting from their work coronavirus: trump moves to pull us out of world health organization key: cord- -n xlpqms authors: wang, huali; li, tao; barbarino, paola; gauthier, serge; brodaty, henry; molinuevo, josé luis; xie, hengge; sun, yongan; yu, enyan; tang, yanqing; weidner, wendy; yu, xin title: dementia care during covid- date: - - journal: lancet doi: . /s - ( ) - sha: doc_id: cord_uid: n xlpqms nan those who have died were older adults, most of whom had underlying health problems. globally, more than million people have dementia, and one new case occurs every s. dementia has emerged as a pandemic in an ageing society. the double hit of dementia and covid- pandemics has raised great concerns for people living with dementia. people living with dementia have limited access to accurate infor mation and facts about the covid- pandemic. they might have difficulties in remembering safeguard procedures, such as wearing masks, or in understanding the public health information issued to them. ignoring the warnings and lacking sufficient self-quarantine measures could expose them to higher chance of infection. older people in many countries, unlike in china, tend to live alone or with their spouse, either at home or in nursing homes. as more and more businesses stop non-essential services or initiate telecommuting work in an attempt to maintain social distancing and limit the further spread of sars-cov- , people living with dementia, who have little knowledge of telecommuni cation and depend primarily on in-person support might feel lonely and abandoned, and become withdrawn. to lessen the chance of infection among older people in nursing homes, more local authorities are banning visitors to nursing homes and longterm care facilities. in january, , the chinese ministry of civil affairs implemented similar social-distancing measures. as a result, older residents lost face-to-face contact with their family members. group activities in nursing homes were also prohibited. as a consequence, the residents of nursing homes became more socially isolated. we have observed that under the dual stress of fear of infection and worries about the residents' condition, the level of anxiety among staff in nursing homes increased and they developed signs of exhaustion and burnout after a monthlong full lockdown of the facilities. patients who require imaging. we urge caution and encourage using published guidelines rt-pcr-confirmed covid- from the diamond princess cruise ship. less than two-thirds ( %) of cases had lung opacities on ct; % of symptomatic patients had negative cts. although extremely valuable, these results should not be overstated. the ct findings studied (eg, groundglass opacity, consolidation) are not specific for covid- . similar results would probably be found if ct were used during an influenza epidemic, for example. the positive predictive value of ct will be low unless disease prevalence is high, as we suspect it was in wuhan. their cohort includes "patients suspected of [covid- ]", presumably sick and possibly hospitalised, although details are not provided. rt-pcr to diagnose covid- has some limitations: the test is not universally available, turnaround times can be lengthy, and reported sensitivities vary. nevertheless, it is the accepted standard and only positive in patients who are infected with severe acute respiratory syndrome coronavirus . ct findings in patients with covid- , on the other hand, are seen with numerous pathogens and in many non-infectious aetiologies. we believe ct does not add diagnostic value; positive results can only be believed if the pre-test probability of disease is high. using ct diagnostically is not known to provide clinical benefit and could lead to false security if results are negative. if covid- is suspected, patients should be isolated pending confirmation with (multiple) rt-pcr tests, or until quarantine has lapsed. the results of a ct scan do not change this. we feel that framing ct as pivotal for covid- diagnosis is a distraction during a pandemic, and possibly dangerous. safely using ct to study covid- patients is logistically challenging and can overwhelm available resources. even with proper cleaning protocols, health-care professionals and ct scanners could become vectors of infection to other vulnerable see online for appendix older adults are vulnerable at the onset of natural disasters and crisis, and this has been especially true during the coronavirus disease (covid- ) pandemic. with the aggressive spread of severe acute respiratory syndrome coronavirus (sars-cov- ), the death toll has risen worldwide. according to an interactive online tool that estimates the potential number of deaths from covid- in a population, by age group, in individual countries and regional groupings worldwide under a range of scenarios, most of during the covid- outbreak in china, five organisations, including the chinese society of geriatric psychi atry and alzheimer's disease chinese, promptly released expert recommendations and disseminated key messages on how to provide mental health and psychosocial support. multidisciplinary teams started counselling services free of charge for people living with dementia and their carers. these approaches minimised the complex impact of both covid- outbreak and dementia. as recommended by international dementia experts and alzheimer's disease international, support for people living with dementia and their carers is needed urgently worldwide. in addition to physical protection from virus infection, mental health and psychosocial support should be delivered. for example, mental health professionals, social workers, nursing home administrators, and volunteers should deliver mental health care for people living with dementia collaboratively. within such a team, dementia experts could take the lead and support team members from other disciplines. self-help guidance for reducing stress, such as relaxation or meditation exercise, could be delivered through electronic media. service teams could support behavioural management through telephone hotlines. psychological counsellors could provide online consultation for carers at home and in nursing homes. in addition, we encourage people who have a parent with dementia to have more frequent contact or spend more time with their parent, or to take on some of the caregiving duties so as to give the carer some respite time. china has contained the epidemic, and business is starting to return to normal. we believe that learning lessons from china would empower the world to tackle the covid- pandemic, with little risk of compromising the quality of life of people living with dementia and their carers. bearing the brunt of covid- : older people in low and middle income countries world alzheimer's report : attitudes to dementia the g dementia research summit-a starter for eight? cdc's recommendations for the next days of mitigation strategies for seattle-king, pierce, and snohomish counties based on current situation with widespread covid- transmission and affected health care facilities urgent call for prevention and control of the novel coronavirus pneumonia in nursing homes management of behavioral and psychological symptoms in people with alzheimer's disease: an international delphi consensus delirium in hospitalized older adults alzheimer's disease chinese, psychogeriatric interest group of chinese society of psychiatry, et al. expert recommendations on mental health and psychosocial support for persons with cognitive disorders and their caregivers during the covid- outbreak alzheimer's disease international. adi offers advice and support during covid- a systematic review of internet-based supportive interventions for caregivers of patients with dementia key: cord- - t wpiqy authors: webby, rj; perez, dr; coleman, js; guan, y; knight, jh; govorkova, ea; mcclain-moss, lr; peiris, js; rehg, je; tuomanen, ei; webster, rg title: responsiveness to a pandemic alert: use of reverse genetics for rapid development of influenza vaccines date: - - journal: lancet doi: . /s - ( ) - sha: doc_id: cord_uid: t wpiqy background: in response to the emergence of severe infection capable of rapid global spread, who will issue a pandemic alert. such alerts are rare; however, on feb , , a pandemic alert was issued in response to human infections caused by an avian h n influenza virus, a/hong kong/ / . h n had been noted once before in human beings in and killed a third ( / ) of infected people. , the variant seemed to have been transmitted directly from birds to human beings and caused fatal pneumonia in one of two infected individuals. candidate vaccines were sought, but no avirulent viruses antigenically similar to the pathogen were available, and the isolate killed embryonated chicken eggs. since traditional strategies of vaccine production were not viable, we sought to produce a candidate reference virus using reverse genetics. methods: we removed the polybasic aminoacids that are associated with high virulence from the haemagglutinin cleavage site of a/hong kong/ / using influenza reverse genetics techniques. a reference vaccine virus was then produced on an a/puerto rico/ / (pr ) backbone on who-approved vero cells. we assessed this reference virus for pathogenicity in in-vivo and in-vitro assays. findings: a reference vaccine virus was produced in good manufacturing practice (gmp)-grade facilities in less than weeks from the time of virus isolation. this virus proved to be non-pathogenic in chickens and ferrets and was shown to be stable after multiple passages in embryonated chicken eggs. interpretation: the ability to produce a candidate reference virus in such a short period of time sets a new standard for rapid response to emerging infectious disease threats and clearly shows the usefulness of reverse genetics for influenza vaccine development. the same technologies and procedures are currently being used to create reference vaccine viruses against the h n viruses circulating in asia. in february, , two family members were admitted to intensive care wards in hong kong special administrative region with influenza-like respiratory illness. avian-like h n influenza viruses were isolated from both patients, one of whom succumbed to infection. this was the first time since that h n viruses had been identified in human beings, and who responded by issuing a pandemic alert. candidate vaccines were immediately sought. the recent outbreak of severe acute respiratory syndrome (sars) had been a striking example of the rapid and global spread of an emerging infectious disease. however, even the effects of sars could be dwarfed by those that could arise with the emergence of an influenza pandemic. infection caused by the influenza a virus is a zoonosis, and the animal reservoir of this virus is the aquatic bird populations of the world. the compelling epidemiological link between the presence of the virus in poultry in live-bird markets and the appearance of h n in human beings in suggested that influenza a viruses can be transmitted directly from avian species to man and can cause severe respiratory disease. [ ] [ ] [ ] although control of the outbreak was achieved by culling millions of birds in the hong kong markets, this episode demonstrated that the capability for an effective global response to emerging influenza threats was poor because of technical, legislative, and infrastructural limitations. a disturbing finding that emerged from this event was that the scientific community was unable to produce an effective vaccine even after several years. the inactivated human influenza vaccines in use today are derived from essentially modified viruses. by exploiting the segmented nature of the influenza a genome, vaccine manufacturers and the laboratories of the who influenza network have produced a reassortant virus carrying the circulating virus's gene segments that encode haemagglutinin and neuraminidase, the major targets of neutralising antibodies. the remaining six-gene segments are supplied from pr , a laboratoryadapted avirulent h n strain. the resulting reassortant virus has the antigenic properties of the circulating strain and the safety and high-yield properties of pr . the first batch of inactivated material against the h n virus was not ready for clinical trial until months after the second case of human infection arose, and even today the effectiveness of vaccine against this virus has not been proven. a key reason for this delay in the production of an h n -specific vaccine was the nature of the virus itself. the h n virus is highly pathogenic in human beings and poultry. the agent must be handled only under conditions of at least biosafety level (bsl ), and it can kill fertilised chicken eggs, the standard medium for the reassortment and responsiveness to a pandemic alert: use of reverse genetics for rapid development of influenza vaccines propagation of influenza virus before its inactivation and formulation for use in vaccines. these same traits are present in the h n virus. the pathogenic nature of these h n viruses is linked to the presence of additional basic residues in haemagglutinin at the site of cleavage, a step required for haemagglutinin activation and, thus, for virus entry into cells. [ ] [ ] [ ] to overcome the high pathogenicity of the virus, polybasic aminoacids have to be eliminated. a rapid, reproducible system to achieve these modifications-ie, plasmid-based reverse genetics-has been developed only in the past - years [ ] [ ] [ ] the potential benefits of reverse genetics for the generation and attenuation of vaccine candidates against highly pathogenic and low pathogenic influenza viruses are enormous. [ ] [ ] [ ] however, the host specificity of the rna polymerase i promoter used in the influenza reverse-genetics systems and the required use of an approved cell line limits the practical options for the system's use in the manufacture of human vaccines. the vaccine-candidate reference virus stock described in this report has been produced entirely on a cell substrate licensed for the manufacture of human vaccine, and as such, is-to our knowledge-the first reverse genetically derived influenza vaccine suitable for testing in clinical trials. we describe the construction of a vaccine reference virus in good manufacturing practice (gmp)-grade facilities in less than weeks from the time of virus isolation. our findings highlight the speed with which new technologies can be implemented in response to influenza pandemic alerts. we obtained who-approved vero cells (who-vero, x , p ) from the american type culture collection (manassas, virginia, usa). passage- cells (five passages since their removal from a working cell bank) were used for the rescue of the vaccine-candidate virus. the plasmids containing the genes from pr have been described elsewhere. virus propagation, rna extraction, pcr amplification, and haemagglutinin and neuraminidase gene cloning we obtained a/hong kong/ / (h n ) that had been passaged in eggs from the who influenza network. the virus was isolated and propagated in -day-old embryonated chicken eggs. total rna was extracted from infected allantoic fluid with use of the rneasy kit (qiagen, valencia, ca, usa) in accordance with manufacturer's instructions. reverse transcription was carried out with the uni primer ( Ј-agca aaagcagg- Ј) and amv reverse transcriptase (roche, indiana biochemicals indianapolis, usa). the removal of the connecting peptide of the haemagglutinin was done with use of pcr with the following primer sets: ( ) bm-ha- ( Ј-tattcgtctcagggagcaa aagcagggg- Ј) and ⌬r ( Ј-taatcgtc tcgtttcaatttgagggctatttctgagcc- Ј); and ( ) ⌬f ( Ј-taatcgtctctgaaa ctagaggattatttggagctatagc- Ј) and bm-ns- r ( Ј-atatcgtctcgtattagtag aaacaagggtgtttt- Ј). we amplified the neuraminidase gene of a/hong kong/ / using the primer pair ba-na- ( Ј-tattggtctc agggagcaaaagcaggagt- Ј) and ba-na- r ( Ј-atatggtctcgtattagtagaaacaag gagtttttt- Ј). pcr products were purified and cloned into the vector phw as described previously. the rescue of infectious virus from cloned cdna was done under gmp conditions. vero cells were grown to % confluency in a cm flask, trypsinised (with trypsin-versene), and resuspended in ml of opti-mem i (invitrogen, carlsbad ca, usa). to ml of cell suspension we added ml of fresh opti-mem i; then, we added ml of this diluted suspension to each well of a six-well tissue culture plate (about ϫ cells per well). the plates were incubated at °c overnight. the next day, g of each plasmid and l of transit lt- transfection reagent (panvera, madison, wi, usa) were added to opti-mem i to a final volume of l and the mixture incubated at room temperature for min. after incubation, the medium was removed from one well of the six-well plate, l of opti-mem i added to the transfection mix, and this mixture added dropwise to the cells. h later, the dna-transfection mixture was replaced by opti-mem i. h after transfection, ml of opti-mem i that contained g/ml l-(tosylamido- phenyl) ethyl chloromethyl ketone (tpck)-treated trypsin (worthington biochemicals, lakewood, nj, usa) was added to the cells. about h after the addition of tpck-trypsin, the culture supernatants were harvested and clarified by low-speed centrifugation; we then injected l of the clarified supernatant into the allantoic cavity of individual -day-old pathogen-free embryonated research grade eggs (charles river spafas, north franklin, ct, usa). ten -week-old chickens received intravenous injections of · ml diluted virus (dilution ratio, / ). we monitored chickens for signs of disease for days using the intravenous pathogenicity index, approved by the office of international epizooites (oie). additionally, we took tracheal and cloacal swabs (in ml of media) days and days after infection, and we did assays for the presence of virus by injection of · ml into all of three -day-old embryonated chicken eggs. haemagglutination activity in the allantoic fluid of these eggs was assessed after incubation at °c for days. pathogenicity testing in ferrets we tested pathogenicity of the vaccine in five young adult male ferrets (marshall's farms, north rose, ny, usa) aged - months (weight about · kg) that were shown by haemagglutination inhibition assays to be seronegative for currently circulating human influenza a viruses (h n , h n ) and h n viruses. we anaesthetised the ferrets with inhaled isoflurane, and they were then infected intranasally with % egg infectious dose (eid )/ml of vaccine reassortant virus or wildtype virus. we monitored the ferrets once per day for signs of sneezing, inappetence, and inactivity, and we recorded rectal temperatures and bodyweights. , , and days after infection, the ferrets were anaesthetised with ketamine ( mg/kg), and we collected nasal washes using ml of sterile phosphatebuffered saline (pbs) containing antibiotics. we measured titres of virus in these washes with eid assays. to further assess the pathogenicity of the viruses, we collected tissue samples from lungs, brain, olfactory bulb, spleen, and intestine for virus isolation and histopathological analysis at the time of death or in the case of three ferrets, after euthanasia at day after infection. the tissues were fixed in % neutral buffer formalin, processed and embedded in paraffin, sectioned at g, stained with haematoxylin and eosin and examined by light microscopy in a blinded fashion. to test the stability of the vaccine virus on propagation, we made consecutive passages of the virus in embryonated chicken eggs. a - dilution of the virus was made in pbs, and · ml of the solution was injected into the allantoic cavities of all of four -day-old embryonated chicken eggs. eggs were incubated at ºc for · - days. after incubation, each egg was candled to determine embryo viability before chilling at ºc. we harvested ml of allantoic fluid from each egg harvested, and samples were pooled together, tested for haemagglutination activity, and then reinjected into another four eggs. the sponsor had no role in study design, in the collection, analysis, and interpretation of data, in the writing of the report or decision to submit this manuscript for publication. the first challenge we faced in producing a vaccine against a/hong kong/ / (h n ) was to attenuate the virus in preparation for mass production. previous experiences have shown that removal of the basic aminoacids at the haemagglutinin cleavage site substantially attenuates pathogenic influenza viruses. [ ] [ ] [ ] using a pcr-based mutagenesis approach, we replaced the cleavage site encoded by the haemagglutinin gene of a/hong kong/ / (h n ) with that of the avirulent a/teal/hong kong/w / (h n ) (figure ); this modified haemagglutinin gene and the neuraminidase gene of a/hong kong/ / (h n ) were cloned individually into the vector phw . the two resulting plasmids and the six plasmids encoding the remaining proteins of pr were transfected into whoapproved vero cells under gmp conditions to rescue the vaccine seed virus, ⌬ /pr . - h after transfection, isolated areas of cytopathic effect could be seen on the vero monolayers. although addition of further g aliquots of tpck-treated trypsin every h led to a proportional increase in the cytopathic effect, it was not required for successful virus rescue. the candidate vaccine strain grew to high titres on subsequent amplification in eggs (haemagglutination titres of - ) and did not cause embryo death. the vaccine seed virus was unable to form plaques on madin-darby canine kidney (mdck) cells in the absence of trypsin, a trait consistent with that of influenza viruses that lack the polybasic cleavage site, and was antigenically indistinguishable from the parental h n virus in haemagglutination inhibition assays. the rescued virus was fully sequenced and was identical to the plasmids used in its creation. to assess the pathogenicity of the h n vaccine seed virus, we compared the properties of this virus with those of the wildtype a/hong kong/ / (h n ) in ferrets and in chickens. by stark contrast with the wildtype virus, which was lethal to all chickens within h of infection, intravenous administration of a / dilution of ⌬ /pr did not result in any signs of infection in chickens, and we were unable to detect any virus in swabs of cloacae or tracheae from inoculated birds. compared with a/hong kong/ / (h n ), ⌬ /pr was attenuated in ferrets that had been inoculated intranasally with eid of virus. ferrets infected with a/hong kong/ / had inappetence and weight loss (figure ), with one infected animal dying days after infection and a second killed days after infection because of hind-limb paralysis. infection in these animals was characterised by viral shedding until days after infection and replication of virus in the lower respiratory tract and olfactory bulb (as determined by virus isolation). in the a/hong kong/ / infected animals, there was a mild mononuclear cell infiltrate in the meninges and tracheal submucosal mucous glands and an extensive bronchopneumonia. the pneumatic infiltrate progressed in severity from the bronchi to the pleura. the bronchi and bronchioles contained sloughed necrotic epithelial cells, numerous mononuclear cells, and a few neutrophils. the alveoli were consolidated with inflammatory cells and fibrin (figure ). by contrast, those ferrets infected with ⌬ /pr did not lose weight (figure ) and seemed to remain healthy during the study ( days) ( figure ) . virus was detected in the nasal washes of these animals at days but not days after infection, and virus was recovered from the upper respiratory tract only. by light microscopy, the meninges and trachea of the ⌬ /pr infected ferrets did not have an inflammatory infiltrate and only a few neutrophils were noted occasionally in pulmonary bronchi. our results clearly show that ⌬ /pr was attenuated. in view of our findings, this virus can be safely handled with standard precautions in bsl containment facilities. because the mechanisms and requirements for the accumulation of basic aminoacids at the haemagglutinin cleavage site are not entirely understood, we wanted to confirm that the altered cleavage site remained stable on multiple passages in embryonated chicken eggs. such passaging in eggs would occur in transition and amplification of the reference virus to vaccine stock. the rescued virus was stable on continued serial passage in embryonated eggs, and we did not detect any change in nucleotide sequence of the haemagglutinin cleavage site after passages. there was no evidence of changing pathogenicity of the virus and we noted only one dead embryo at passage . no haemagglutination activity was evident in this egg and no embryo death was seen in passage , which strongly suggests that the death was not related to virus replication. haemagglutination titres at each passage ranged from to with no apparent trend of increasing or decreasing titres in subsequent passages. the rapid response in terms of potential vaccine reference virus production to the h n outbreak differs strikingly from the response to the episode. this difference is attributable to the new scientific technology available in and, just as importantly, to the infrastructure for virus surveillance in hong kong developed since . the first case of h n influenza in hong kong was in may, ; yet several months elapsed before this virus was finally characterised as an h n virus. in , the causative agent was identified only hours after admission of the patients to the hospital. the increased awareness, surveillance, and availability of reagents to identify influenza viruses of all subtypes bode well for the rapid identification of viruses that arise from future interspecies transfer events and for the coordination of international vaccine development by who. the timely distribution of candidate viruses is a very important step in the development of vaccines for pandemic emergencies. despite the heightened security and documentation requirements for shipping and receiving potential bioterrorism agents, the h n and sars outbreaks have shown that in true emergencies, global distribution is feasible. although it is pertinent to prepare for future pandemics by stockpiling potential vaccine strains, the h n situation in -and the ongoing h n outbreaks throughout asia in (http://www.who.int)-have highlighted the fact that some of the focus of pandemic planning must go into the implementation of technology to rapidly produce vaccines from field isolates. although viruses similar to a/hong kong/ / (h n ) had been circulating in bird populations, these viruses were antigenically distinct, despite high genetic similarities (guan y and peiris js, unpublished data). that the aminoacid differences are on the globular head of haemagglutinin and seem to be responsible for much of the antigenic difference means that even a vaccine previously prepared from genetically similar precursor viruses might not provide adequate protection. we may well be faced with potential pandemic situations in the future and the rapid production of a matched vaccine will be needed-a point again highlighted by h n outbreaks in . although the reference virus described in this report was prepared from a virus isolated in a similar geographic region and only a year earlier, it shares only limited antigenic cross-reactivity to the h n viruses. hyperimmune sheep serum samples produced against the purified haemagglutinin of ⌬ /pr has at least a six-fold reduced haemagglutination inhibitory activity against a/vietnam/ / as compared with a/hong kong/ / . as our findings show, we have the technical capabilities to respond rapidly to outbreaks with a safe and stable reference virus, but there is still much to be accomplished before such viruses can be fully used in pandemic and interpandemic influenza vaccine production. the use of reverse genetics introduces a number of new processes into influenza vaccine manufacture that are not encountered with standard reassortment methods. one of the most obvious is the need for cultured cells. although both vero and mdck , cells are in development as substrates for the growth of influenza vaccine, there are additional requirements for the use of cells in reverse genetics. unfortunately, the number of suitable cell lines is very small. in addition to the regulatory requirements, the choice of cell is also limited by the technology. the plasmid based reverse-genetics systems necessitates the use of cells from primate origin. the vero cell line is probably the only option currently able to meet both regulatory and technical demands. we have shown that vero cells can be used to successfully rescue h n , h n , h n , and h n viruses on the pr backbone using the -plasmid system. others have demonstrated the suitability of vero cells for alternative influenza virus reverse-genetics systems. although cultures of vero cells are easily obtained, only cells from fully tested and licensed cell banks are likely to be acceptable for vaccine manufacture. this issue must be acknowledged and access to such cells must be incorporated as part of future pandemic plans. that future threats of influenza pandemics will be addressed by the use of the technology described in this report seems inevitable. despite the presence of low pathogenic surrogate strains, the recent human death from influenza-like illness caused by highly pathogenic h n virus in the netherlands reinforces the fact that future outbreaks will probably occur in which this reversegenetics technology provides the logical-and, possibly, the only-way to respond rapidly and effectively. although our response to the outbreak of h n influenza in has shown that current scientific capabilities are sufficient to respond to the threat, there are still legal and infrastructural barriers to be overcome. these barriers include licensing and intellectual property issues surrounding what is, essentially, a genetically modified organism. yet, these difficulties are not insurmountable and pandemic scares such as the and ongoing h n outbreaks are forcing commercial and regulatory parties to address these issues with some urgency. with the development of the h n vaccine reference virus, and ongoing attempts to create the same for the virus, the challenge in responding to a threat of an influenza pandemic must now be supported by the largescale manufacture of the vaccine and by clinical trials of a new vaccine manipulated by reverse genetics. r j webby, d r perez, j s coleman, j h knight, e i tuomanen, r g webster designed the study; r j webby did much of the construction of the vaccine seed virus; d r perez developed and constructed plasmid templates; y guan and j s peiris characterised and isolated the initial h n virus; j e rehg participated in the design and analysis of animal safety testing of the candidate h n vaccine seed virus; e a govorkova participated in the safety testing of the candidate h n vaccine seed virus; l r mcclain-moss participated in the preparation of gmp documentation of the process and was involved in the reconstitution of the vaccine seed virus. a pandemic warning? characterization of an avian influenza a (h n ) virus isolated from a child with a fatal respiratory illness characterization of avian h n influenza viruses from poultry in hong kong interspecies transmission of influenza viruses: h n virus and a hong kong sar perspective future influenza vaccines and the use of genetic recombinants developing vaccines against pandemic influenza the structure of the hemagglutinin, a determinant for the pathogenicity of influenza viruses proteolytic cleavage of influenza virus hemagglutinins: primary structure of the connecting peptide between ha and ha determines proteolytic cleavability and pathogenicity of avian influenza viruses molecular analyses of the hemagglutinin genes of h influenza viruses: origin of a virulent turkey strain rescue of influenza a virus from recombinant dna a dna transfection system for generation of influenza a virus from eight plasmids generation of influenza a viruses entirely from cloned cdnas eight-plasmid system for rapid generation of influenza virus vaccines plasmid-only rescue of influenza a virus vaccine candidates evaluation of a genetically modified reassortant h n influenza a virus vaccine candidate generated by plasmid-based reverse genetics recombinant influenza a virus vaccines for the pathogenic human a/hong kong/ (h n ) viruses preparation of a standardized, efficacious agricultural h n vaccine by reverse genetics development of a vero cellderived influenza whole virus vaccine influvac: a safe madin darby canine kidney (mdck) cell culturebased influenza vaccine safety and immunogenicity of a trivalent, inactivated, mammalian cell culture-derived influenza vaccine in healthy adults, seniors, and children generation of high-yielding influenza a viruses in african green monkey kidney (vero) cells by reverse genetics avian influenza a virus (h n ) associated with human conjunctivitis and a fatal case of acute respiratory distress syndrome pandemic influenza and the global vaccine supply we thank todd hatchette, katherine sturm-ramirez, and scott krauss for expert advice; ashley baker, christie johnson, yolanda sims, patrick seiler, jennifer humberd, and kelly jones for excellent technical assistance; julia hurwitz for access to the vero-cell banks. editorial assistance was provided by julia cay jones. these studies were supported by grant ai from the national institute of allergy and infectious disease, by cancer center support (core) grant ca from the national institutes of health, and by the american lebanese syrian associated charities (alsac). none declared. the corresponding author has had full access to all the data in the study and has had the final responsibility for the decision to submit this manuscript for publication. key: cord- -mrvk r w authors: li, hui; liu, liang; zhang, dingyu; xu, jiuyang; dai, huaping; tang, nan; su, xiao; cao, bin title: sars-cov- and viral sepsis: observations and hypotheses date: - - journal: lancet doi: . /s - ( ) -x sha: doc_id: cord_uid: mrvk r w since the outbreak of coronavirus disease (covid- ), clinicians have tried every effort to understand the disease, and a brief portrait of its clinical features have been identified. in clinical practice, we noticed that many severe or critically ill covid- patients developed typical clinical manifestations of shock, including cold extremities and weak peripheral pulses, even in the absence of overt hypotension. understanding the mechanism of viral sepsis in covid- is warranted for exploring better clinical care for these patients. with evidence collected from autopsy studies on covid- and basic science research on severe acute respiratory syndrome coronavirus (sars-cov- ) and sars-cov, we have put forward several hypotheses about sars-cov- pathogenesis after multiple rounds of discussion among basic science researchers, pathologists, and clinicians working on covid- . we hypothesise that a process called viral sepsis is crucial to the disease mechanism of covid- . although these ideas might be proven imperfect or even wrong later, we believe they can provide inputs and guide directions for basic research at this moment. the severe acute respiratory syndrome coronavirus (sars-cov- ) outbreak, which was first reported in wuhan, china, in december, , has had an enormous impact on china and the whole world. the disease caused by sars-cov- is named coronavirus disease . by march , , the number of confirmed cases had increased to over . although most patients infected with sars-cov- had a mild illness, about % of patients had severe lung injury or even multiorgan dysfunction, resulting in a · % case fatality ratio. in clinical practice, we noticed that many severe or critically ill covid- patients developed typical clinical manifestations of shock, including cold extremities and weak peripheral pulses, even in the absence of overt hypotension. many of these patients showed severe metabolic acidosis, indicating possible microcirculation dysfunction. moreover, some patients had impaired liver and kidney function in addition to severe lung injury. these patients met the diagnostic criteria for sepsis and septic shock according to the sepsis- international consensus, but sars-cov- infection appeared to be the sole cause in most of them. blood and lower respiratory tract specimen cultures turned out to be negative for bacteria and fungus in % sepsis patients in a covid- cohort. therefore, viral sepsis would be more accurate to describe the clinical manifestations of severe or critically ill covid- patients. understanding the mechanism of viral sepsis in covid- is warranted for exploring better clinical care for these patients. in biopsy or autopsy studies, pulmonary pathology for both early and late phase covid- patients showed diffuse alveolar damage with the formation of hyaline membranes, mononuclear cells, and macrophages infiltrating air spaces, and a diffuse thickening of the alveolar wall. viral particles were observed in the bronchial and type alveolar epithelial cells by electron microscopy. , in addition, spleen atrophy, hilar lymph node necrosis, focal haemorrhage in the kidney, enlarged liver with inflammatory cell infiltration, oedema, and scattered degeneration of the neurons in the brain were present in some patients. , sars-cov- infectious virus particles have been isolated from respiratory samples, as well as from faecal and urine (zhao j, guangzhou medical university, personal communication) specimens from covid- patients, suggesting that multiple organ dysfunction in severe covid- patients is at least partially caused by a direct attack from the virus. however, there are no reports about the post-mortem observations of the broad dissemin ation of the viral particles by autopsy right now. whether sars-cov- can directly target organs other than the lung, especially those organs with high expression of angiotensin-converting enzyme (ace ) , and organs with l-sign as possible alternative cell receptors for sars-cov- , has to be further investigated. in addition, the question of how the sars-cov- spreads to extrapulmonary organs remains an enigma. genomic variation of the circulating sars-cov- has been obser ved, and the difference in the virulence needs further investigation. it has been shown that proinflammatory cytokines and chemokines including tumour necrosis factor (tnf) α, interleukin β (il- β), il- , granulocyte-colony stimulating factor, interferon gamma-induced protein- , monocyte chemo attractant protein- , and macrophage inflam matory proteins -α were signifi cantly elevated in covid- patients. , like in a severe influenza infection, the cytokine storm might play an important role in the immunopathology of covid- . previous studies revealed that lung epithelial cells, macrophages, and dendritic cells all express cytokines to some extent during influenza infection via the activation of pattern recog nition receptors (including the toll-like receptors tlr , tlr , and tlr ), retinoic acid-inducible gene i, and the nod-like receptor family members. however, little is known about the situation in covid- at this moment. it is crucial to identify the primary source of the cytokine storm in response to sars-cov- infection and the virological mechanisms behind the cytokine storm. it would also be relevant to elucidate the kinetics of cytokine activation during sars-cov- infection: when were the first cytokines released and what were they? also, whether direct virus-induced tissue damage, systemic cytokine storm, or the synergistic effects of both, contributes to the multiple organ dysfunction of severe covid- patients remains to be addressed. further more, it is worth keeping track of whether blocking one of these proinflammatory mediators would affect the clinical outcome. the anti-il- r monoclonal antibody or corticosteroids have been proposed to alleviate the inflammatory response. however, il- might play an important role in initiating a preliminary response against virus infection by promoting neutrophilmediated viral clearance, as one study revealed that il- or il- r deficiency led to persistence of influenza infection and ultimately death in mice. and the use of corticosteroids is still controversial. , yet the dysregulated immune response also has an immune suppression stage following the proinflammatory phase. it is characterised by sustained and substantial reduction of the peripheral lymphocyte counts, mainly cd t and cd t cells in covid- patients, and is associated with a high risk of developing secondary bacterial infection. this condition, known as lymphopenia, was also found in severe influenza and other respiratory viral infections. the degree of lymphopenia has been shown to correlate with the severity of covid- . the mechanism underlying lymphopenia remains unknown. previous studies have shown that sars-like viral particles and sars-cov rna were detected in t lymphocytes isolated from peripheral blood sample, spleen, lymph nodes, and lymphoid tissue of various organs, , suggesting that sars-cov might be able to infect t cells directly. the receptor-binding domains of the spike proteins between sars-cov- and sars-cov show a high degree of consistency, , and sars-cov- rna was also detected in blood samples. therefore, it is reasonable to hypothesise that, in addition to the activation-induced cell death induced by fas and fas ligand interaction as well as tnf-related apoptosis-inducing ligand axis, sars-cov- could directly infect lymphocytes, particularly t cells, and initiate or promote the cell death of lymphocytes, which eventually lead to lymphopenia and impaired antiviral responses. however, such a hypothesis needs to be further investigated. it also needs to be identified what types of cell death are happening in the lymphocytes after sars-cov- infection. in addition, it is intriguing that the lymphocytes lack ace expression, suggesting an alternative mechanism by which sars-cov- compromises t lymphocytes. whether or not alveolar macrophages can phagocytise the viral particles and then transfer to lymphocytes is an open question in the field. studies have revealed that · % of non-survivors of covid- matched the grade of overt disseminated intravascular coagulation (≥ points according to the international society on thrombosis and haemostasis criteria) and showed abnormal coagulation results during later stages of the disease; particularly increased concentrations of d-dimer and other fibrin degradation products were significantly associated with poor prognosis. however, the concrete mechanisms for coagulopathy are not identified yet. whether sars-cov- is able to directly attack vascular endothelial cells expressing high levels of ace , and then lead to abnormal coagulation and sepsis, still needs to be explored. meanwhile, ace is also an important regulator of blood pressure. high expression of ace in the circulatory system after infection of sars-cov- might partially contribute to septic hypotension. questions have been raised about using inhibitor therapy with angiotensin ii receptor blockers (arb) and ace inhibitors for covid- patients with hypertension. some researchers suggested that ace inhibitors might benefit these patients by reducing pulmonary inflammation, although others argued that ace inhibitors might enhance viral entry by regulating ace levels. however, there has been little clinical evidence on the risk of treating covid- patients with arb or ace inhi bitors. further research is needed to explore whether these drugs inhibit or aid viral entry. on the basis of observations from covid- patients, we hypothesise that in mild cases, resident macrophages initiating lung inflammatory responses were able to contain the virus after sars-cov- infection; both innate and adaptive immune responses were efficiently established to curb the viral replication so that the patient would recover quickly. however, in severe or critical covid- cases, the integrity of the epithelialendothelial (air-blood) barrier was severely interrupted. in addition to epithelial cells, sars-cov- can also attack lung capillary endothelial cells, which leads to a large amount of plasma component exudate in the alveolar cavity. in response to the infection of sars-cov- , alveolar macrophages or epithelial cells could produce various proinflammatory cytokines and chemokines. upon this change, monocytes and neutrophils were then chemotactic to the infection site to clear these exudates with virus particles and infected cells, resulting in uncontrolled inflammation. in this process, because of the substantial reduction and dysfunction of lymphocytes, the adaptive immune response cannot be effectively initiated. the uncontrolled virus infection leads to more macrophage infiltration and a further worsening of lung injury. meanwhile, the direct attack on other organs by disseminated sars-cov- , the immune pathogenesis caused by the systemic cytokine storm, and the microcirculation dysfunctions together lead to viral sepsis (figure). therefore, effective antiviral therapy and measures to modulate the innate immune response and restore the adaptive immune response are essential for breaking the vicious cycle and improving the outcome of the patients. since the outbreak of covid- , clinicians have tried every effort to understand the disease, and a brief portrait of its clinical features have been identified. however, there are still open questions about the mechanisms of the observations. with evidence collected from autopsy studies on covid- and basic science research on sars-cov- and sars-cov, we have put forward several hypotheses about sars-cov- patho genesis after multiple rounds of discussion among basic science researchers, pathologists, and clinicians working on covid- . we hypothesise that a process called viral sepsis is crucial to the disease mechanism of covid- . although these ideas might be proven imperfect or even wrong later on, we believe that they raise questions for future research. future basic science research is needed to explore whether sars-cov- directly attacks vascular endothelial cells, and to examine the effect of sars-cov- on coagulation and virus dissemination. clinical trials and animal experiments should be done to assess the effect of arb and ace inhibitors on the outcome of sars-cov- infection in vivo. efforts should be made to confirm whether sars-cov- directly infects lymphocytes, and how it influences the adaptive immune response. the kinetics of the cytokine response during sars-cov- infection also need further investigation. the efficacy of immunomodulatory therapies should be assessed in randomised clinical trials. hl did the literature search and drafted the paper. jx helped with the literature search and revised the manuscript. bc put forward the hypothesis and revised the manuscript. ll, dz, jx, hd, nt, and xs provided ideas about the mechanism of viral sepsis and revised the paper. we declare no competing interests. clinical characteristics of coronavirus disease in china liver injury in covid- : management and challenges the third international consensus definitions for sepsis and septic shock (sepsis- ) clinical course and risk factors for mortality of adult inpatients with covid- in wuhan, china: a retrospective cohort study epidemiology and immune pathogenesis of viral sepsis pulmonary pathology of early phase novel coronavirus (covid- ) pneumonia in two patients with lung cancer pathological findings of covid- associated with acute respiratory distress syndrome china national health commision. diagnosis and treatment of novel coronavirus pneumonia in china a pathological report of three covid- cases by minimally invasive autopsies a novel coronavirus from patients with pneumonia in china detection of sars-cov- in different types of clinical specimens a pneumonia outbreak associated with a new coronavirus of probable bat origin tissue distribution of ace protein, the functional receptor for sars coronavirus. a first step in understanding sars pathogenesis cd l (l-sign) is a receptor for severe acute respiratory syndrome coronavirus decoding evolution and transmissions of novel pneumonia coronavirus using the whole genomic data clinical features of patients infected with novel coronavirus in wuhan, china longitudinal characteristics of lymphocyte responses and cytokine profiles in the peripheral blood of sars-cov- infected patients innate immunity to influenza virus infection essential role of il- in protection against h n influenza virus by promoting neutrophil survival in the lung clinical evidence does not support corticosteroid treatment for -ncov lung injury on the use of corticosteroids for -ncov pneumonia the pathology of influenza virus infections multiple organ infection and the pathogenesis of sars evolution of the novel coronavirus from the ongoing wuhan outbreak and modeling of its spike protein for risk of human transmission genomic characterisation and epidemiology of novel coronavirus: implications for virus origins and receptor binding the impact of the interferon/tnf-related apoptosis-inducing ligand signaling axis on disease progression in respiratory viral infection and beyond abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia increasing host cellular receptor-angiotensinconverting enzyme (ace ) expression by coronavirus may facilitate -ncov infection inhibitors of ras might be a good choice for the therapy of covid- pneumonia effect of angiotensin-converting enzyme inhibition and angiotensin ii receptor blockers on cardiac angiotensin-converting enzyme we appreciate the advice and editing of this hypothesis by xuetao cao in nankai university. key: cord- -enfxk ku authors: choo, esther k title: covid- fault lines date: - - journal: lancet doi: . /s - ( ) - sha: doc_id: cord_uid: enfxk ku nan my daughter's art project, a small ceramic bowl, tipped over the edge of the table and broke into pieces. to assuage her tears, i used what i had on hand, a thin wood glue, to patch it together. it was a rushed effort, but i deemed it good enough for the moment. the bowl hung precariously together until she decided, one day, to fill it with water to bathe a toy. under that small challenge, the fragile bonds between the pieces gave way. the water dribbled out, and the bowl cracked open. within any hospital's emergency room, the fault lines of society are barely concealed. the simple act of discharging someone is one of the hardest things we do in medicine. homeless shelters fill quickly, especially in cold weather. domestic violence shelters too. they don't usually have enough resources to handle surges in need. no one would think to provide the luxury of sufficient space and staff to, say, enable the kind of social distancing space between occupants that is recommended in the midst of the coronavirus disease (covid- ) pandemic. the gaps in need are patched over with thin, inadequate solutions. in fact, part of the practice of emergency medicine is constructing the perfect plan and watching it quickly fall apart under social realities. this patient can go home on a course of antibiotics. but what if there's no home, no ability to fill or refrigerate medications? you have no plan. a week or two of rest and immobility is the answer. but what if sick leave means no income, no ability to pay rent or buy food? no plan. admission to hospital would fix it. but what if, in a country like the usa, the cost of that stay, that operation, that transfer would crush the family financially? no plan. covid- has exposed these societal fault lines, baring our vulnerabilities. it has also stimulated a modicum of action, with varying degrees of compassion. the city of las vegas infamously turned a parking lot into a sleeping area after a homeless shelter closed due to a case of covid- , marking squares on the bare ground to enforce social distancing. but in other places, hospitals are admitting stable patients with covid- to avoid discharging them to the street, or hotel rooms and trailers have materialised as extra shelter. the shift to telehealth has meant more accessibility not only for people newly home-bound due to stay-at-home orders but also for those for whom an in-person health visit was never a simple or easy thing, including individuals with disabilities, the elderly, or those without access to transportation. these are successes, and i applaud them. but the imperative to create alternative shelters is driven by the fact that overcrowded shelters and homeless encampments facilitate the spread of disease. the gains to certain populations from virtual visits are an accidental benefit. where were these initiatives before? will they vanish once the pandemic is over? the descriptions of covid- as the "great equaliser" are not quite right, for the illness is hitting some people harder than others. the disease spreads faster in places where social distancing is an impossibility. its collateral damage is hardest on those with low income. covid- seems to be widening, not narrowing, racial and ethnic health disparities caused by longstanding systemic inequities-for example, black and hispanic people in the usa have disproportionately higher rates of hospitalisation and death from covid- . still, the pandemic might make it tougher to pretend that the fate of one corner of society is disconnected from that of another. anyone who wishes to avoid the spread to less densely populated areas must care about what is happening in big cities. anyone in a private home who wishes to address the disease's spread must care about what is happening in group homes, nursing homes, and correctional facilities. it is hard to think forward to a time beyond this immediate moment of crisis. working in the emergency department, the most pressing issues are who has the disease and who doesn't, and what to do with the patient in front of me. but as we scramble to distribute limited resources such as tests and hospital equipment andultimately-therapies and a vaccine, we must be careful to avoid reinforcing existing fault lines going forward. and all of us lucky enough to get a post-pandemic chapter must revisit those fault lines with urgency, holding each other accountable for remembering how intimately our fates are interconnected, even when we don't have a virus to bring the point home. center for policy and research in emergency medicine, oregon health and science university, portland, or , usa chooe@ohsu.edu @choo_ek the penumbra covid- fault lines more on the penumbra see interim guidance for homeless service providers to plan and respond to coronavirus disease (covid- ) what the covid- pandemic means for black americans the challenge of preventing covid- spread in correctional facilities key: cord- -drto xt authors: chen, huijun; guo, juanjuan; wang, chen; luo, fan; yu, xuechen; zhang, wei; li, jiafu; zhao, dongchi; xu, dan; gong, qing; liao, jing; yang, huixia; hou, wei; zhang, yuanzhen title: clinical characteristics and intrauterine vertical transmission potential of covid- infection in nine pregnant women: a retrospective review of medical records date: - - journal: lancet doi: . /s - ( ) - sha: doc_id: cord_uid: drto xt background: previous studies on the pneumonia outbreak caused by the novel coronavirus disease (covid- ) were based on information from the general population. limited data are available for pregnant women with covid- pneumonia. this study aimed to evaluate the clinical characteristics of covid- in pregnancy and the intrauterine vertical transmission potential of covid- infection. methods: clinical records, laboratory results, and chest ct scans were retrospectively reviewed for nine pregnant women with laboratory-confirmed covid- pneumonia (ie, with maternal throat swab samples that were positive for severe acute respiratory syndrome coronavirus [sars-cov- ]) who were admitted to zhongnan hospital of wuhan university, wuhan, china, from jan to jan , . evidence of intrauterine vertical transmission was assessed by testing for the presence of sars-cov- in amniotic fluid, cord blood, and neonatal throat swab samples. breastmilk samples were also collected and tested from patients after the first lactation. findings: all nine patients had a caesarean section in their third trimester. seven patients presented with a fever. other symptoms, including cough (in four of nine patients), myalgia (in three), sore throat (in two), and malaise (in two), were also observed. fetal distress was monitored in two cases. five of nine patients had lymphopenia (< · × ⁹ cells per l). three patients had increased aminotransferase concentrations. none of the patients developed severe covid- pneumonia or died, as of feb , . nine livebirths were recorded. no neonatal asphyxia was observed in newborn babies. all nine livebirths had a -min apgar score of – and a -min apgar score of – . amniotic fluid, cord blood, neonatal throat swab, and breastmilk samples from six patients were tested for sars-cov- , and all samples tested negative for the virus. interpretation: the clinical characteristics of covid- pneumonia in pregnant women were similar to those reported for non-pregnant adult patients who developed covid- pneumonia. findings from this small group of cases suggest that there is currently no evidence for intrauterine infection caused by vertical transmission in women who develop covid- pneumonia in late pregnancy. funding: hubei science and technology plan, wuhan university medical development plan. the type of pneumonia caused by the novel coronavirus disease (covid- ) is a highly infectious disease, and the ongoing outbreak has been declared by who as a global public health emergency. , covid- pneumonia was first reported in wuhan, hubei province, china, in december, , followed by an outbreak across hubei province and other parts of the country. the lancet by huang and colleagues reported the epidemiological, clinical, laboratory, and radiological characteristics, as well as treatment and clinical out comes, of patients with laboratory-confirmed covid- pneumonia. however, huang and colleagues' report mainly focused on non-pregnant adults. the clinical characteristics and vertical transmission potential of covid- pneumonia in pregnant women is unknown. urgent questions that need to be addressed promptly include whether pregnant women with covid- pneumonia will develop distinct symptoms from non-pregnant adults, whether pregnant women who have confirmed covid- pneumonia are more likely to die of the infection or to undergo preterm labour, and whether covid- could spread vertically and pose risks to the fetus and neonate. answers to these questions are essential for formulating the principles of obstetric treatment for pregnant women with covid- infection. therefore, to facilitate efforts, both in china and glo bally, to prevent and control covid- pneumonia in children and pregnant women, we retrospectively collected and analysed detailed clinical data from pregnant women with laboratory-confirmed covid- infection at zhongnan hospital of wuhan university, wuhan, china. in this study we present clinical features of pregnant women with confirmed covid- pneumonia and examine the vertical trans mission potential of covid- . we did a retrospective review of medical records from nine pregnant women with covid- pneumonia admitted to zhongnan hospital of wuhan university from jan to jan , . diagnosis of covid- pneumonia was based on the new coronavirus pneumonia prevention and control program ( th edition) published by the national health commission of china. all nine pregnant women with covid- pneumonia tested positive for severe acute respiratory syndrome coronavirus (sars-cov- ) by use of quantitative rt-pcr (qrt-pcr) on samples from the respiratory tract. this study was reviewed and approved by the medical ethical committee of zhongnan hospital of wuhan university (approval number ). written informed consent was obtained from each enrolled patient. we reviewed clinical records, laboratory findings, and chest ct scans for all nine pregnant women. all information was obtained and curated with a customised data collection form. two study investigators (jg and xy) independently reviewed the data collection forms to verify data accuracy. maternal throat swab samples were collected and tested for sars-cov- with the chinese center for disease control and prevention (cdc) recommended kit (biogerm, shanghai, china), following who guidelines for qrt-pcr. amniotic fluid samples from patients with covid- pneumonia were obtained via direct syringe aspiration at the time of delivery. cord blood and neonatal throat swab samples were collected immediately after delivery in the operating room. additionally, breast milk samples from patients with covid- pneumonia were collected after their first lactation. evidence of vertical transmission was evaluated by testing for the presence of sars-cov- in these clinical samples. sample collection was successful in six cases (patients , - , , and ). among the three patients from whom sample collection was not suc cessful, patient was diagnosed after caesarean section, thus no sample was obtained. patients and underwent caesarean section at night, thus immediate sample collection was not possible. all samples were processed at the state key laboratory of virology/institute of medical virology, school of basic medical sciences, wuhan university, for further testing. sample collection, pro cessing, and laboratory testing complied with who guidance. all samples, as described above, were tested for sars-cov- by use of qrt-pcr with the cdc recommended kit. the test results were confirmed by nested rt-pcr with designed primers. for the nested rt-pcr assay, total rna was extracted from samples by use of the trizol ls reagent (invitrogen, carlsbad, ca, usa), followed by reverse transcription by use of the one-step rt-pcr kit (takara, dalian, china). primers were designed on the basis of evidence before this study we searched pubmed and the china national knowledge infrastructure database for articles published up to feb , , using the keywords "novel coronavirus", " novel coronavirus", " -ncov", "pneumonia", "coronavirus", "wuhan", and "novel" ,"pregnancy", "maternal infection", and "fetal infection" for articles published in both chinese and english. we found two articles: one titled we retrospectively reviewed clinical records, laboratory findings, and chest ct scans for nine pregnant women with laboratoryconfirmed covid- pneumonia. evidence of vertical transmission was assessed by testing for the presence of severe acute respiratory syndrome coronavirus (sars-cov- ) in amniotic fluid, cord blood, breastmilk, and neonatal throat swab samples from six of nine patients. all nine women were in the third trimester. seven presented with fever without chill. other symptoms included cough (in four of nine patients), myalgia (in three), sore throat (in two), and malaise (in two). fetal distress occurred in two cases. five of the nine patients had lymphopenia (< · × ⁹ cells per l). three patients had increased aminotransferase concentrations. none of the patients developed severe covid- pneumonia or died. nine livebirths were recorded. no severe neonatal asphyxia was observed. all nine livebirths had a -min apgar score of - and -min apgar score of - . amniotic fluid, cord blood, neonatal throat swab, and breastmilk samples from six of the nine patients were tested for sars-cov- , and all results were negative. the clinical characteristics of covid- pneumonia in pregnant women were similar to those of non-pregnant adult patients with covid- pneumonia. based on data from this small group of patients, there is currently no evidence of vertical transmission in pregnant women who develop covid- pneumonia in the third trimester. the sequence of wuhan-hu- (mn ). partial s segment sequences (nt - ) were amplified with primers: ′-ctcaggacttgttcttacctt- ′ and ′-caagtgcacagtctac-agc- ′. statistical analysis was done with spss, version . . continuous variables were directly expressed as a range. categorical variables were expressed as number (%). the funding agencies did not participate in study design, data collection, data analysis, or writing of the report. the corresponding authors were responsible for all aspects of the study to ensure that issues related to the accuracy or integrity of any part of the work were properly investigated and resolved. the final version was approved by all authors. the nine pregnant women were all in their third trimester, and all underwent caesarean section. all patients had a history of epidemiological exposure to covid- . the age range of the patients was - years, and the range of gestational weeks at admission was weeks to weeks plus days. none of the patients had underlying diseases such as diabetes, chronic hypertension, or cardiovascular disease. one patient, seven of the nine patients presented with a fever without chills, but none had a high fever (body temperature > °c). patients' body temperatures fluctuated within a range of · - · °c. the two patients with a normal body temperature before caesarean section both had postpartum fever (range · - · °c). other symptoms of an upper respiratory tract infection were also observed: four patients had a cough, three had myalgia, two reported a sore throat, and two indicated malaise. additionally, one patient showed obvious gastrointestinal symptoms. another patient had shortness of breath and preeclampsia. however, none of the nine patients developed severe pneumonia, requiring mechanical ventilation, or died of covid- pneumonia, as of feb , . pregnancy complications that appeared after the onset of covid- infection included fetal distress (in two of nine patients) and premature rupture of the membrane (in two of nine; table ). all patients were given oxygen support (nasal cannula) and empirical antibiotic treatment. six patients were administered antiviral therapy (table ) . data from laboratory tests showed that five of the nine pregnant women with covid- pneumonia had lymphopenia (< · × ⁹ cells per l). six patients had ele vated concentrations of c-reactive protein (> mg/l). three had increased concentrations of alanine aminotransferase (alt) and aspartate aminotransferase (ast), one of whom had alt reaching u/l and ast reaching u/l. additionally, seven patients had a normal white cell count, with none of the patients having a white cell count below the normal range (table ). all nine patients had a chest ct scan. eight patients showed typical findings of chest ct images-multiple patchy ground-glass shadows in lungs (figure). nine livebirths were recorded. no fetal death, neonatal death, or neonatal asphyxia was observed. four patients had preterm labour, but all beyond gestational weeks. two of the four premature neonates at gestational weeks plus days had a birthweight lower than g (table ). neonate had a birthweight of g and the pregnancy was complicated by pre-eclampsia. neonate had a birthweight of g. all nine livebirths had a -min apgar score of - and a -min apgar score of - (table ). neonate had a mild increase in myocardial enzymes on the day of birth (myoglobin · ng/ml and creatine kinase-myocardial band · ng/ml), but without any clinical symptoms. the presence of sars-cov- was tested in amniotic fluid, cord blood, neonatal throat swab, and breastmilk samples collected from six patients. neither the kit recommended by cdc nor our in-house nested rt-pcr assays detected sars-cov- in these samples. we report clinical data from nine pregnant women with laboratory-confirmed covid- pneumonia. the clinical characteristics of these patients with covid- infection during pregnancy were similar to those of non-pregnant adults with covid- infection, as previously reported. none of the nine patients developed severe pneumonia or died, as of feb , . notably, based on our findings in these nine patients, there is currently no evidence to s uggest that development of covid- pneumonia in the third trimester of pregnancy could lead to the occurrence of severe pregnant women are particularly susceptible to respiratory pathogens and severe pneumonia, because they are at an immunosuppressive state, and physiological adaptive changes during pregnancy (eg, diaphragm elevation, increased oxygen consumption, and oedema of respiratory tract mucosa) can render them intolerant to hypoxia. for example, the influenza pandemic caused a mortality rate of · % in the overall population, but % among pregnant women. pregnant women were reported to be at an increased risk of complications from the pandemic h n influenza virus infection, and were more than four times more likely to be admitted to hospital than the general population (relative risk · [ % ci · - · ]). wong and colleagues also reported that around % of pregnant women who developed sars were admitted to the intensive care unit, around % of pregnant women with sars required mechanical ventilation, and the mortality rate was as high as % for these women. in the current study, we treated nine pregnant women with covid- pneumonia in days from jan to jan , . considering that sars-cov- has up to % sequence similarity with sars, [ ] [ ] [ ] [ ] although none of our patients developed severe pneumonia or died of covid- infection, we should be alert to the possibility that the disease course and prognosis of covid- pneumonia could follow the same trend as sars in pregnant women. however, our obser vations are based on a small number of cases and the time between illness onset and delivery was short. according to our study, pregnant women with covid- pneumonia showed a similar pattern of clinical characteristics to non-pregnant adult patients, as recently reported. , common symptoms at the onset of covid- pneumonia for these women included a fever and cough, whereas less common symptoms were myalgia, malaise, sore throat, diarrhoea, and shortness of breath. laboratory tests indicated that lymphopenia is also likely to occur. additionally, increased concentrations however, none of these symptoms was present in every patient, nor were the symptoms specific to pregnant women with covid- pneumonia. by contrast, chest ct might have a high diagnostic value because of its typical images of virus infection, high accuracy with a low false negative rate, and time efficiency. therefore, we recommend that, in addition to using nucleic acid tests as the gold standard for the diagnosis of covid- pneumonia, relevant clinical examinations are done, including blood counts and chest ct and a comprehensive evaluation of a patient's medical history, epidemiological exposure, and symptoms. all nine pregnant women in this study underwent a caesarean section. indications for a caesarean section included severe pre-eclampsia, a history of caesarean sections, and fetal distress. importantly, uncertainty about the risk of intrapartum mother-to-child transmission by vaginal delivery was another reason for carrying out caesarean sections. four of the nine patients had preterm labour. however, the causes of premature birth were not related to covid- pneumonia: one patient had severe pre-eclampsia, one had a history of two stillbirths, one had a history of two caesarean sections and irregular contractions; and one had premature rupture of the membrane for about h and suspected intrauterine infection. moreover, one neonate in our study had a birthweight of g at gestational weeks plus days, and this case was complicated by preeclampsia. furthermore, the time period from onset of covid- pneumonia to admission was only days for this patient; therefore we reasoned that the fetal intrauterine growth restriction was more likely to be a symptom associated with pre-eclampsia. importantly, all nine livebirths had a -min apgar score of - and -min apgar score of - . one infant had a mild increase in myocardial enzymes on the day of birth, but without any clinical symptoms. none of the neonates needed special paediatric treatment. the main focus of this study was to investigate the possibility of intrauterine transmission of covid- infection. we chose to test amniotic fluid, cord blood, and neonatal throat swab samples at birth to ascertain the possibility of intrauterine fetal infection. notably, all the samples tested in our study were collected in the operating room at the time of the caesarean section, thus guaranteeing that the samples were not contaminated and best represented fetal intrauterine conditions. our results show that sars-cov- was negative in all of the above samples, suggesting that no intrauterine fetal infections occurred as a result of covid- infection during a late stage of pregnancy. our findings are in accordance with what was observed in sars, which has a similar sequence to sars-cov- . previous studies have already shown no evidence of perinatal sars infection among infants born to mothers who developed sars infection during pregnancy. , however, our observation of no fetal infection caused by intrauterine vertical transmission could be affected by our small sample size and the stage of pregnancy at the onset of covid- infection. all patients in the study were recruited in their third trimester, so we were unable to ascertain the possibility of intrauterine vertical transmission during the first or second trimester. for example, rubella infection in the first trimester can affect more than % of fetuses via intrauterine infection, whereas by the end of the second trimester the incidence rate is reduced by half. we did not collect samples of vaginal mucosa or shedding in birth canals, which prevented us from analysing whether covid- could be transmitted during vaginal delivery. notably, however, our results showed that breastmilk samples from mothers with covid- infection appeared to be free from sars-cov- . on feb , , a neonate born to a pregnant woman with covid- pneumonia tested positive for sars-cov- infection h after birth. , although many important clinical details of this single case were not available at the time of writing this report, there are reasonable concerns that covid- could be contracted in the womb. reportedly, the pregnant woman had developed fever for h and was suspected to have covid- pneumonia on the basis of her typical chest ct image before admission; an emergency caesarean section was subsequently done, which was followed by confirmation of covid- pneumonia. moreover, the neonate's throat swab sample was collected approximately h after birth, thus providing no direct evidence for intrauterine infection. additionally, no direct testing of intrauterine tissue samples such as amniotic fluid, cord blood, or placenta was done to confirm that the covid- infection in the neonate was due to intrauterine transmission. therefore, we cannot conclude whether or not intrauterine covid- infection occurred in this particular case. nonetheless, this single case of an infected neonate suggests that we should pay special attention to prevent infections in newborn babies born to mothers with covid- pneumonia. this study is limited by the small sample size and retrospective method. several considerations should be taken into account when interpreting the findings. first, all enrolled patients were in the third trimester. the effect of covid- infection on the fetus in the first or second trimester of pregnancy remains to be clarified. second, whether vaginal delivery increases the risk of mother-to-child intrapartum transmission, and whether uterine contraction could increase the possibility of the virus ascending, needs to be further investigated. third, the risk of infection in pregnant women and the effects of the time or mode of delivery on pregnancy outcomes were not evaluated. fourth, whether covid- could damage the placenta, which represents an important link in vertical transmission, also needs to be further investigated. future investigations of these issues and follow-up studies of pregnant women with covid- infection, as well as neonates, will be necessary to ascertain the safety and health of mothers and babies exposed to sars-cov- . in summary, the symptoms of pregnant women with covid- pneumonia were diverse, with the main symptoms being fever and cough. we found no evidence for vertical transmission in late pregnancy. considering the significance of this ongoing global public health emergency, although our conclusions are limited by the small sample size, we believe that the findings reported here are important for understanding the clinical characteristics and vertical transmission potential of covid- infection in pregnant women. yz, wh, and hy made substantial contributions to the study concept and design. hc was in charge of the manuscript draft. jg took responsibility for obtaining written consent from patients, obtaining ethical approval, collecting samples, and confirming data accuracy. cw participated in drafting the manuscript, and revising it on the basis of reviewers' comments. xy made substantial contributions to data acquisition, analysis, and interpretation. dz was the paediatrician in charge of treatment of the newborn babies. dx, qg, jl, and jl were the obstetricians of the pregnant women, and were responsible for data collection and confirmation. wh and fl were in charge of the laboratory tasks, including sample processing and detection. wz made substantial revisions to the manuscript. we declare no competing interests. with the permission of the corresponding authors, we can provide participant data without names and identifiers, but not the study protocol, statistical analysis plan, or informed consent form. data can be provided after the article is published. once the data can be made public, the research team will provide an email address for communication. the corresponding authors have the right to decide whether to share the data or not based on the research objectives and plan provided. a novel coronavirus from patients with pneumonia in china clinical features of patients infected with novel coronavirus in wuhan, china the state council's joint prevention and control mechanism for pneumonia epidemic in response to new coronavirus infection. notice on prevention and control of pneumonia in children and pregnant women with new coronavirus infection new coronavirus pneumonia prevention and control program clinical management of severe acute respiratory infection when novel coronavirus (ncov) infection is suspected. interim guidance -ncov) in suspected human cases. interim guidance detection of novel coronavirus ( -ncov) by real-time rt-pcr the spanish flu in iceland . lessons in medicine and history h n influenza virus infection during pregnancy in the usa pregnancy and perinatal outcomes of women with severe acute respiratory syndrome coronavirus envelope protein: current knowledge novel coronavirus genome sars and mers: recent insights into emerging coronaviruses a pneumonia outbreak associated with a new coronavirus of probable bat origin early transmission dynamics in wuhan, china, of novel coronavirus-infected pneumonia infants born to mothers with severe acute respiratory syndrome vauloup-fellous c. rubella and pregnancy: diagnosis, management and outcomes wuhan tongji hospital diagnoses first case of neonatal infection with new coronavirus neonatal coronavirus expert confirmed at hours of birth: vertical transmission from mother to infant this study was supported by hubei science and technology plan (grant number acb ) and wuhan university medical development plan (grant number tfjc ). apgar score ( min, min) , , , , , , , , , ·· key: cord- - c t an authors: frankish, helen title: new who chief promises greater commitment to hiv/aids date: - - journal: lancet doi: . /s - ( ) -x sha: doc_id: cord_uid: c t an nan w ith a pledge to give greater priority to hiv/aids and achieving results in poor countries, south korea's jong-wook lee took office as the new director-general of who on july . "we must scale up an integrated global hiv/aids strategy linking prevention, care, and treatment, prioritising poor and underserved areas", said lee in his inaugural address to about who staff at the organisation's geneva headquarters. "i am, therefore, constituting an hiv/aids leadership team to ensure that who, working with local, national, and international partners, will be at the forefront of this effort." to promote synergy in combating infectious diseases, the who department in charge of tackling hiv/aids will be brought into one group together with tuberculosis and malaria. taken together, the three diseases are responsible for about % of all deaths worldwide each year. lee named american jack chow, former special representative for hiv/aids to us secretary of state colin powell, as the new head of the hiv/aids, tuberculosis, and malaria cluster. in the long term, lee said, who's goal would be to provide antiretroviral drugs to million people in developing countries by the end of -the so-called "three-by-five" target. "by dec this year, world aids day, who's hiv/aids department, working with partners, will produce a global plan for reaching the three-by-five target", lee said. "together with partners such as unaids, who will use all available tools of advocacy to mobilise the political will and the additional resources needed to put this plan into action." the three-by-five target will guide much of who's work on hiv/aids, he said, but patterns of resistance to antiretroviral drugs would also be closely monitored through a global network in collaboration with who's partners. lee, a communicable diseases expert and former head of who's stop tb programme, also vowed to improve notification and monitoring systems to help tackle contagious diseases such as severe acute respiratory syndrome (sars). "the sars crisis illustrated who's essential role in coordinating the international response to infectious disease outbreaks", he said. but he conceded that the sars epidemic also revealed weaknesses in global disease surveillance. "we will work with our partners in the global outbreak alert and response network, and with bilateral and multilateral donors, to reinforce national and regional surveillance systems." on his first day in office, the new director-general also reinforced who's commitment to achieving the millennium development goals, targets that world leaders agreed on at the millennium summit years ago. "we see the millennium goals as milestones on the road to health for all", he asserted. in his address, lee admitted that in recent years, who's resources have become increasingly concentrated in geneva, and that there has been "a gradual drift" towards programmes driven by headquarters' priorities, rather than towards programmes based on countries' individual needs. to ensure that who's resources are aimed at producing results where they are needed most, lee pledged to increase funds at country level over the coming months and years, adding that the organisation would ensure that country offices have the resources and authority they need to work more effectively in responding to national and local health needs. lee asked the newly appointed assistant directors-general (see panel, p ) to analyse the work of their respective areas and to propose specific steps for moving resources from headquarters to the various regions. "i will begin by deploying additional resources to priority country offices for building up capacity in hiv/aids control and health systems", he said. rights were not granted to include this image in electronic media. please refer to the printed journal. le gales-camus, a former scientific adviser to the director-general of health in france, as head of non-communicable diseases. yach, meanwhile, has been appointed to design a plan to strengthen who's response to non-communicable diseases. david nabarro, from the uk, will be replaced by germany's kerstin leitner, undp's resident representative in china, as head of the sustainable development and healthy environments cluster. nabarro will now lead who's health action in crises programme. and botswana's minister of health, joy phumaphi, will take over from tomris türmen, from turkey, as assistant director-general for family and community health, while türmen will now lead a team charged with developing policy recommendations regarding the health implications of intellectual property rights structures. concluding his address, lee called for the continued commitment of who's staff, the member states, and its national and international partners in order to meet who's goals in the years ahead. "who's founding vision, its achievements, its partners and, above all, its people create a solid foundation. guided by our principles of loyalty, transparency, and commitment to excellence, we will move forward towards the goal of health for all. together, learning from the past, we can change the future of global health." lee also pledged to tackle the shortage of skilled health-care staff worldwide, which will slow progress towards goals such as the three-by-five target and has hindered the millennium development goals. "our cooperation with other countries on this issue must intensify. together, we must build the health workforce using innovative methods of training, development, and supervision of allied and community health workers. community mobilisation is a key to success", he said. lee also outlined ways in which who could directly contribute to strengthening human resources within the health sector. in early , he announced, who would launch the health leadership programme, an initiative to recruit promising young health workers from around the world, and provide them with the opportunity to work within who-at country level, in regional offices, and at who's headquarters in geneva. "mentored by senior who staff, these young professionals will form part of the next generation of international health leaders", he said. notably, lee also marked his takeover from the outgoing director-general, gro harlem brundtland, by replacing many of her most senior staff with a new team of assistant directors-general (see panel). david heymann, executive director of communicable diseases, who led the who's efforts earlier this year to control the sars outbreak, will now take charge of the drive to eradicate polio worldwide. ghanaian anarfi asamoa-baah, a who official who has been working for the agency since , will take over from heymann as assistant director-general of communicable diseases. and south african derek yach, who spearheaded who's framework convention on tobacco control -adopted in may by the world health assembly after a -year negotiation period-will be replaced by catherine gro harlem brundtland hands over to jong-wook lee ap lee's newly appointed team of assistant directors-general uk), formerly chef de cabinet, will become director of the director-general's office anarfi asamoa-baah (ghana), currently executive director for health technology and pharmaceuticals, will lead the communicable diseases cluster director of the eastern mediterranean liaison office, will head the external relations and governing bodies cluster special representative of the us secretary of state for hiv/aids, will take charge of the hiv/aids, tuberculosis, and malaria cluster director of health equity at the rockefeller foundation in new york, will lead the evidence and information for policy cluster catherine le gales-camus (france), most recently scientific adviser to france's director-general of health will take leadership of the non-communicable diseases and mental health cluster un resident coordinator and undp resident representative in china, will be responsible for the sustainable development and healthy environments cluster russia), most recently the head of the department of general and clinical pharmacology at the russian university of people's friendship, will take responsibility for the health technology and pharmaceuticals cluster head of the health division at the swedish international development cooperation agency, will take control of the general management cluster joy phumaphi (botswana), minister of health in botswana and hiv/aids commissioner appointed by the un secretary-general key: cord- -jtv jj z authors: cho, sun young; kang, ji-man; ha, young eun; park, ga eun; lee, ji yeon; ko, jae-hoon; lee, ji yong; kim, jong min; kang, cheol-in; jo, ik joon; ryu, jae geum; choi, jong rim; kim, seonwoo; huh, hee jae; ki, chang-seok; kang, eun-suk; peck, kyong ran; dhong, hun-jong; song, jae-hoon; chung, doo ryeon; kim, yae-jean title: mers-cov outbreak following a single patient exposure in an emergency room in south korea: an epidemiological outbreak study date: - - journal: lancet doi: . /s - ( ) - sha: doc_id: cord_uid: jtv jj z background: in , a large outbreak of middle east respiratory syndrome coronavirus (mers-cov) infection occurred following a single patient exposure in an emergency room at the samsung medical center, a tertiary-care hospital in seoul, south korea. we aimed to investigate the epidemiology of mers-cov outbreak in our hospital. methods: we identified all patients and health-care workers who had been in the emergency room with the index case between may and may , . patients were categorised on the basis of their exposure in the emergency room: in the same zone as the index case (group a), in different zones except for overlap at the registration area or the radiology suite (group b), and in different zones (group c). we documented cases of mers-cov infection, confirmed by real-time pcr testing of sputum samples. we analysed attack rates, incubation periods of the virus, and risk factors for transmission. findings: patients and health-care workers were identified as contacts. mers-cov infection was confirmed in individuals ( patients, eight health-care workers, and visitors). the attack rate was highest in group a ( % [ / ] vs % [ / ] in group b vs % [ / ] in group c; p< · ), and was % ( / ) in health-care workers. after excluding nine cases (because of inability to determine the date of symptom onset in six cases and lack of data from three visitors), the median incubation period was days (range – , iqr – ). the median incubation period was significantly shorter in group a than in group c ( days [iqr – ] vs days [ – ]; p< · ). there were no confirmed cases in patients and visitors who visited the emergency room on may and who were exposed only to potentially contaminated environment without direct contact with the index case. the main risk factor for transmission of mers-cov was the location of exposure. interpretation: our results showed increased transmission potential of mers-cov from a single patient in an overcrowded emergency room and provide compelling evidence that health-care facilities worldwide need to be prepared for emerging infectious diseases. funding: none. since the fi rst identifi cation of middle east respiratory syndrome coronavirus (mers-cov) infection in , most patients infected with the virus have been exposed in the middle east. as of march , , laboratoryconfi rmed cases have been reported to who. on the basis of previous epidemiological fi ndings, the potential of mers-cov to spread to large numbers of people has been considered low, by contrast with severe acute respiratory syndrome coronavirus (sars-cov). the basic reproductive number of mers-cov was estimated to be less than · , suggesting low transmissibility. , however, a outbreak of mers-cov infection in al hasa, saudi arabia, where one patient infected seven other patients in dialysis and intensive care units, raised concerns about potential so-called super-spreaders that were reported during the sars epidemic. , from may to july, , a large outbreak of mers-cov infection occurred in south korea from a traveller returning from the middle east, which led to confi rmed cases (patient to patient ) in the country. patient was diagnosed at our hospital (samsung medical center, seoul, south korea) after transmitting the virus at several health-care facilities before he came to our hospital. patient was exposed to patient outside the hospital and sought additional care at our hospital without knowing he was infected with mers-cov. therefore, we experienced both south korea's fi rst mers-cov case and the case of highest transmission of mers-cov following a single patient exposure in an emergency room. we aimed to investigate the epidemiology of mers-cov infection in a crowded emergency room outside of the middle east and the presence of multiple super-spreaders. in may, , two patients with mers-cov infection (patient and patient ) sought care in our emergency room at the samsung medical center without knowing they were infected with mers-cov. while these patients were in the emergency room, a large number of patients, visitors, and health-care workers were exposed during both events. when mers-cov infection was suspected in patient and patient , contact investigation was immediately initiated. since no one developed mers among contacts who were exposed to patient , only contacts of patient are reported here. we identifi ed, from electronic medical record review and security video footage, all patients who had been in the emergency room with patient as contacts, regardless of the location and duration of exposure. we categorised patient contacts into three groups on the basis of their maximum exposure: patients who were in the same zone in the emergency room (group a; considered close contacts), those who were in diff erent zones but had time overlap with patient in the registration area or radiology suite ( min before and h after; group b), and those who were in diff erent zones (group c). patients who were admitted to hospital for treatment of their primary illness after exposure in the emergency room were quarantined in private rooms for days from the last exposure or discharged home after treatment was fi nished and continued isolation at home. patients and their family members who were already discharged home were reached by telephone, informed about possible mers-cov exposure, and provided with hotline numbers for any inquiries. health-care workers who were exposed were identifi ed through interviews and review of employees' duty schedules, electronic signature on medical records of patient and patient contacts, security video footage, and self-report. health-care workers who provided direct care to patient were initially considered close contacts and were placed into quarantine at home for days from the last day of exposure. other health-care workers who worked in the emergency room during the same time period continued to work with monitoring and were removed immediately from duty if symptoms developed. a confi rmed case was defi ned as a person with laboratory confi rmation of mers-cov infection from sputum samples, initially by real-time rt-pcr testing with amplifi cation targeting the upstream e region (upe) and then confi rmed by subsequent amplifi cation of open reading frame a (orf a) using powerchek mers realtime pcr kits (kogene biotech, seoul, korea). patients' demographic information, underlying disease, dates of emergency room visit, duration of stay with exact arrival and departure times, and location within the emergency room were collected. if radiographic examinations were done, the time of examination was collected. for healthcare workers, age, sex, occupation, history of patient assignments and working or visiting zone, and dates and time of duty or emergency room visits were collected. the attack rate was calculated by dividing the number of confi rmed cases by the total number of exposed individuals in the emergency room in each group. because the total list of visitors was unavailable, we estimated the number of visitors who were in the emergency room by assuming that one patient had at least one visitor during their stay; we also simulated the scenarios of two and four visitors per patient. to avoid underestimation, we chose the assumption of one visitor per patient, which would give the highest attack rate among the scenarios. the incubation period was defi ned as the time of fi rst exposure to the onset of clinical symptoms of mers-cov infections. categorical variables were presented with frequency (percentage) and continuous variables were summarised with median (range, iqr). we calculated overall comparison of attack rates across the groups with χ² test and across zones with fisher's exact test. incubation evidence before this study little information on nosocomial outbreaks caused by middle east respiratory syndrome coronavirus (mers-cov) outside the middle east had been available before the large mers-cov outbreak in south korea in , for which global alert was issued. we searched pubmed for reports published in english from may , , to dec , , using the terms "mers-cov" and "korea". we identifi ed reports, none of which provided detailed description for the contact investigation of massive transmission of mers-cov from a super-spreader in an overcrowded emergency room setting. to our knowledge, this study is the fi rst to categorise exposed patients into groups according to the type of exposure and to document group-specifi c incubation periods and attack rates. furthermore, this study provides detailed epidemiological data, including a fl oor plan of the emergency room, to understand how mers-cov spread by a single super-spreader through several modes of transmission. results from our contact investigation showed increased transmission potential of mers-cov from a single spreader, as has been documented in the severe acute respiratory syndrome epidemic. the potential for similar outbreaks anywhere in the world should be noted, as long as mers-cov transmission continues in the middle east. our study provides evidence that hospitals, laboratories, and governmental agencies should be prepared for mers-cov infection. period and exposure time were compared among groups with kruskal-wallis test, followed by tukey's test using ranks for multiple comparisons. to assess the risk factors for mers-cov infection among all patient contacts, we did a multiple logistic regression analysis based on likelihood ratio, by regressing on age, sex, underlying disease, and groups. in a subgroup analysis of patients in group a, the length of stay in the same zone and location were included. for these analyses, odds ratios and % cis were reported. p values and % cis were adjusted with bonferroni's correction for multiple comparisons if necessary. two-sided p values of less than · were considered signifi cant. we used sas version . and graphpad prism version . for statistical analyses. samsung medical center is a modern -bed university-affi liated tertiary hospital providing referral care in south korea (total population roughly million), with roughly staff , including more than physicians and nurses. the emergency room entrance is located on the ground fl oor near the south gate of the main hospital building. more than patients are seen in the emergency room each day; the average duration of stay in the emergency room was h before the mers-cov outbreak (see appendix p for details on emergency room overcrowding index). the emergency room has seven patient care areas, including zones i to iv for see online for appendix adults, a trauma zone, a resuscitation room, and a paediatric zone (fi gure ). the paediatric zone and zone iv are separated from the rest of the main areas. two negative-pressure rooms are located in the paediatric zone and two are in zone iv. the emergency room has its own radiology suite for emergency room patients only. the sizes of each zone were as follows: zone i · m², zone ii · m², zone iii · m², and zone iv · m². zones i and ii included seating areas ( chairs in zone i and chairs in zone ii), where stable patients received treatment and waited for test results. seriously ill patients, who required close observation and needed a designated bed, were moved to zone iii ( beds) or zone iv ( beds). zone iv was used for patients being admitted. beds in zones iii and iv were spaced roughly · m apart, with curtains in between. nurses were assigned to work in designated zones, whereas physicians and transfer agents took care of patients in several zones. all zones in the emergency room were covered by the same air handling units. there was no funding source for this study. the corresponding author had full access to all the data in the study and had fi nal responsibility for the decision to submit for publication. upon arrival at our emergency room, he denied having travel history to the middle east and any possible exposure to people infected with mers-cov. he was treated for possible bacterial pneumonia on the basis of partial improvement from previous antibiotic treatment and increased c-reactive protein concentration of · mg/dl (normal < · mg/dl; appendix p ). during his stay in the emergency room, he was provided with a mask but frequently could not hold it because of severe respiratory symptoms. he was not isolated in a separate room; a negative-pressure room was not considered at that time. as his dyspnoea aggravated on may , supplemental oxygen was administered at l per min via a nasal cannula (up to l per min). however, no aerosol-producing procedures, including nebuliser treatments, were given. on the night of may , he received a notifi cation call from the health authorities about possible exposure to patient , notifi ed our hospital, and was immediately transferred from the emergency room to isolation in a negativepressure isolation room. mers-cov infection was confi rmed on may , and he was transferred to the nationally designated health-care facility. from may to may , he stayed in three zones in our emergency room: zone ii for roughly h on may , zone iii for h from may to may , and zone iv for h from may to may (fi gure ). additionally, from may to may , he went to the radiology suites four times. on may , he walked around and outside the emergency room and went to the toilet several times because of diarrhoea. between may and may , , the average ventilation rate in the emergency room was maintained at three air changes per h, taking h to remove airborne contaminant with a · % effi ciency. the median temperature was · °c (range · - · ), and the median relative humidity was · % (range · - · ). patients ( in group a, in group b, and in group c), an estimated visitors, and health-care workers were identifi ed as contacts of patient (table ). we assumed that each patient had one visitor and added eight extra visitors (fi ve to group a and three to group c) the epidemic curve of this emergency room-associated outbreak is shown in fi gure . the incubation period was determined from confi rmed mers-cov cases: six cases were excluded because we could not determine the date of symptom onset, and data were not available from three visitors. the median incubation period was days (range - , iqr - ). among patients and visitors in groups a-c (excluding six who were not initially identifi ed as contacts), the median incubation period was signifi cantly shorter in group a than in group c (fi gure ). excluding three patients with confi rmed mers-cov infection who were not identifi ed in the initial patient contact investigation (appendix p ), the overall attack rate for patients in the emergency room was % ( of ). patients in group a had the highest attack rate ( % [ of ]), compared with % (three of ) in group b and % (four of ) in group c (fi gure ). after adjusting for age, sex, underlying disease, and groups, patients in group a had the highest risk for mers-cov infection (table ). in group b, all three patients who had mers-cov infection had time overlap in the radiology suite with patient . the median exposure time for patients in group a to patient was · h in zone ii (range · - · , iqr · - · ), · h in zone iii ( · - · , · - · ), and · h in zone iv ( · - · , · - · ). the attack rates were % ( of ) in zone ii, % (seven of ) in zone iii, and % (three of ) in zone iv (fi gure ). after adjusting for age, sex, underlying disease, and exposure time, staying in zone ii was associated with a signifi cantly higher risk for mers-cov infection than staying in zone iv (table ) . mers-cov transmission occurred in zone iii, despite the fact that the distance from patient 's bed to the beds of other patients were as far as m (fi gure ). in zone iv, patient moved from bed to bed , and six additional cases were documented in patients and visitors occupying beds in the middle of this zone, which were not adjacent to patient 's bed. no mers-cov infection was reported in patients and visitors who had been in the emergency room on may during the time period when they were exposed only to zones ii (n= ) or iii (n= ), while patient was confi ned to zone iv. these patients were exposed to areas that were potentially environmentally contaminated but not to patient himself (fi gure ). under the assumption of one visitor per patient and excluding three visitors with confi rmed mers-cov infection who were not identifi ed in the initial visitor contact investigation (appendix p ), the overall attack rate for visitors was % ( of ). all patient contacts (n= ) any underlying disease · ( · - · ) · error bars represent % ci. mers-cov=middle east respiratory syndrome coronavirus. the attack rates for patients and visitors were % ( of ) in group a, % (six of ) in group b, and % ( of ) in group c. under the assumptions of two visitors per patient and four visitors per patient, the overall attack rates for visitors were % and %, respectively. health-care worker contacts were identifi ed, and fi ve ( %) developed mers-cov infection. three healthcare workers who were not initially identifi ed as contacts (one security guard, one physician, and one patient transfer agent) developed mers-cov infection. although they were not involved in the direct care for patient , they visited the emergency room between may and may . only close contacts were furloughed and other health-care workers were isolated when they developed symptoms. there were no secondary cases from health-care workers among contacts during the their duty hours. we did a contact investigation of the mers outbreak at the samsung medical center by grouping exposed individuals on the basis of the extent of exposure to patients and . to our knowledge, we are the fi rst to document group-specifi c incubation periods and attack rates. our results showed the increased transmission potential of mers-cov from a single patient in an overcrowded emergency room setting. overcrowding is an important issue for this outbreak and is also a common feature of modern medicine. this study is unique because the index exposure occurred in a large emergency room in a tertiary-care centre, with electronic medical record information available to track the location and duration of exposure, thus enabling near-complete tracing of exposed contacts. the classic defi nitions of close contact as being within roughly feet ( · m) or within the same room or care area for a prolonged period of time were diffi cult to apply to an emergency room setting with high patient volumes, ongoing traffi c within the emergency room and to and from the radiology suite, and large numbers of visitors and family members. we considered all patients who visited the emergency room during the stay of patients and as exposed contacts, developed criteria for close contacts by expanding on the defi nitions of the us centers for disease control and prevention (cdc), and categorised patients into diff erent groups. therefore, we could establish group-specifi c viral incubation periods and attack rates during the outbreak. in close contacts who stayed in the same zone, the incubation period was shorter and attack rate was higher than patients who stayed in diff erent zones. additionally, in zones iii and iv, patients were infected even when they were separated by curtains most of the time and were apart as far as m (for beds on either side of the nurse's station; fi gure ). similar to the sars outbreak, we observed so-called superspreaders among patients with mers-cov infection, and these super-spreaders can cause large outbreaks through several modes of transmission similar to those in the sars outbreak. among patients who stayed in various locations, those who overlapped with patient at the radiology suite or registration area had higher attack rates ( %) than the rest of the patients ( %), suggesting that transmission might occur by even brief exposures to recently contaminated objects or encounters with individuals carrying a super-spreader. comparisons of environmental exposure and patient exposure also revealed unique fi ndings. no patient developed mers-cov infection after exposure on may only to the environment that had been potentially contaminated on may (zone ii) and may (zone iii) while patient was confi ned to zone iv on may . it is plausible that even if the environment was heavily contaminated by a super-spreader, the virus might not persist long enough in the environment to be capable of causing any new infection. although patient exposure is clearly the most important factor in the spread of mers-cov, more research is needed to address the potential of environmental spread. increased viral load and larger amounts of respiratory secretions have been suggested as the factors for sars-cov super-spreaders. , in this mers outbreak, frequent ambulation of the index case could be considered as one factor related to high levels of viral transmission, in addition to large amounts of respiratory secretions and high viral load (cycle thresholds · for upe and · for orf a from patient 's sputum, and · for upe and · for orf a from patient 's sputum). of note, patient infected patients in another hospital but caused no confi rmed secondary cases in our hospital, whereas patient caused an additional cases in our hospital. the diff erence of transmissibility between these two individuals could be caused by a combination of factors such as the time from onset of disease, clinical symptoms, duration of contact exposure, pattern of behaviour inside and near the emergency room, and kinetics of viral shedding. we showed that obtaining a travel history from patients is an important element of history taking by all physicians, and not only those specialising in infectious diseases or those working in infection control. suspicion for unusual infections should be maintained if patients do not or cannot report accurate histories. readiness of laboratory support is essential for initial investigation and for control of outbreaks, and overly rigorous requirements for laboratory testing have the potential to delay diagnosis and further spread disease. hospital leadership needs to lead in preparedness for disaster management of high-risk communicable infectious diseases. emergency preparedness at a national level and communication and support from government agencies are imperative to prevent and control any serious outbreak. the results of this study need to be interpreted with caution because the study was not suffi ciently powered to study risk factors for transmission. some of our data were collected retrospectively. analysis on visitors was limited because we did not have detailed data. serological tests were not done simultaneously and attack rates were calculated on the basis of results from real-time rt-pcr of mainly symptomatic individuals. the potential transmission of mers-cov by asymptomatic carriers is under investigation. in conclusion, we report a large nosocomial mers outbreak that occurred outside the middle east. the potential for similar outbreaks anywhere in the world from a single traveller should be noted, as long as mers-cov transmission continues in the middle east. emergency preparedness and vigilance are crucial to the prevention of further large outbreaks in the future. our report serves as an international alarm that preparedness in hospitals, laboratories, and governmental agencies is the key not only for mers-cov infections but also for other new emerging infectious diseases. syc and j-mk designed the study and data collection methods, did the initial data analyses, drafted the manuscript, and approved the fi nal manuscript as submitted. yeh, who suspected and diagnosed the fi rst case of mers-cov infection in south korea, engaged in the management of mers-cov outbreak control at the samsung medical center as an infectious disease specialist and reviewed the manuscript. gep, jyel, j-hk, jyol, jmk, jgr, and jrc coordinated data collection, engaged in the management of mers-cov outbreak control at the samsung medical center, and reviewed the manuscript. sk supervised data collection and analysis, analysed the data, and reviewed the manuscript. hjh, c-sk, and e-sk did laboratory tests for mers-cov detection, coordinated laboratory data collection, and reviewed the manuscript. c-ik, ijj, krp, h-jd, and j-hs supervised data collection and reviewed the manuscript. y-jk and drc conceptualised and designed the study, and critically reviewed and revised the manuscript. all authors approved the fi nal submitted manuscript. we declare no competing interests. isolation of a novel coronavirus from a man with pneumonia in saudi arabia middle east respiratory syndrome coronavirus (mers-cov)-saudi arabia. geneva: world health organization middle east respiratory syndrome coronavirus: quantifi cation of the extent of the epidemic, surveillance biases, and transmissibility interhuman transmissibility of middle east respiratory syndrome coronavirus: estimation of pandemic risk synthesizing data and models for the spread of mers-cov, : key role of index cases and hospital transmission hospital outbreak of middle east respiratory syndrome coronavirus superspreading and the eff ect of individual variation on disease emergence transmission dynamics of the etiological agent of sars in hong kong: impact of public health interventions superspreading sars events middle east respiratory syndrome coronavirus outbreak in the republic of korea guidelines for environmental infection control in health-care facilities. recommendations of cdc and the healthcare infection control practices advisory committee (hicpac) middle east respiratory syndrome coronavirus (mers) evidence of airborne transmission of the severe acute respiratory syndrome virus stability of middle east respiratory syndrome coronavirus (mers-cov) under diff erent environmental conditions severe acute respiratory syndrome-singapore severe acute respiratory syndrome middle east respiratory syndrome in persons, south korea we express our sincere consolation for the patients and their families who had mers-cov infection. we greatly appreciate the eff orts of all the hospital employees and their families at the samsung medical center, who worked tirelessly during this outbreak. we also appreciate the cooperation of all other hospitals in south korea that worked together to overcome the nationwide outbreak. we acknowledge the consultation and support of the korea centers for disease control and prevention, the mers rapid response team of the public-private joint mers task force, who, and the us centers for disease control and prevention. we also sincerely appreciate the discussion and critical feedback from michael t osterholm (university of minnesota, minneapolis, mn, usa) and janet a englund (seattle children's hospital, seattle, wa, usa). key: cord- -upnqi f authors: platt, lucy; elmes, jocelyn; stevenson, luca; holt, victoria; rolles, stephen; stuart, rachel title: sex workers must not be forgotten in the covid- response date: - - journal: lancet doi: . /s - ( ) - sha: doc_id: cord_uid: upnqi f nan as countries maintain or adjust public health measures, emergency legislation, and economic policies in response to the covid- pandemic, there is an urgent need to protect the rights of, and to support, the most vulnerable members of society. sex workers are among the most marginalised groups. globally, most direct sex work has largely ceased as a result of physical distancing and lockdown measures put in place to halt transmission of severe acute respiratory syndrome coronavirus (sars-cov- ), potentially rendering a frequently marginalised and economically precarious population more vulnerable. most sex workers, even those who can move their work online, have been financially compromised and some are unable to stop in-person services. it is imperative that sex workers are afforded access to social protection schemes as equal members of society. as with all aspects of health, the ability of sex workers to protect themselves against covid- depends on their individual and interpersonal behaviours, their work environment, the availability of community support, access to health and social services, and broader aspects of the legal and economic environment. , stigma and criminalisation mean that sex workers might not seek, or be eligible for, government-led social protection or economic initi atives to support small businesses. police arrests, fines, violence, disruption in aid by law enforcement, and compulsory deportation have been reported by sex workers across diverse settings, fuelling concerns that the pandemic is intensifying stigma, discrimination, and repressive policing. , sex workers who are homeless, use drugs, or are migrants with insecure legal or residency status face greater challenges in accessing health services or financial relief, which increases their vulnerability to poor health outcomes and longer-term negative economic impacts. , increased prevalence of underlying health conditions among sex workers might increase risk of covid- progressing to severe illness. demand for shelter and supported housing has increased as sex work venues have been shut down or rental payments default through loss of income. existing mental health problems are likely to be exacerbated by anxiety over income, food, and housing, alongside concerns about infection from continuing to work in the absence of social protection. risk of infection with sars-cov- is heightened for those who share drug paraphernalia for drug use. alternative ways of maintaining or extending treatment and drug substitute prescribing are important to save lives in places where services are closed or restricted or there are staff shortages due to sickness. there is scarce reliable evidence of the risk of infection or complications of covid- among people living with hiv, although the risk could be greater among those who are immunocompromised and not on hiv treatment. review evidence suggests, on average, use of antiretroviral therapies is already low among sex workers who are hiv positive in high-income and low-income settings. it is crucial that disruption to health services does not further reduce access to hiv treatment and prevention or to vital services addressing domestic or other forms of violence. , mathematical models suggest that even with widespread testing and contact tracing, in the absence of a covid- vaccine, physical distancing will be a key intervention to prevent community transmission globally. early modelling that informed physical distancing policies did not account for the needs of all interventions and services must be designed and implemented in collaboration with sex-worker-led organisations. illegal or uncertain residency status • immediate cessation of arrests, raids, and prosecutions for sex work and minor drug-related offences, and long-term reform of policies and laws that have been shown to be harmful to health • provision of emergency housing to those who are homeless, moratorium on evictions, and assistance with rent or mortgage repayments for those in need vulnerable populations, or their access and adherence to official guidance. population-level gains, such as a reduction in hospital admissions and mortality, are likely to be intangible for marginalised populations for whom the immediate negative effects of physical distancing could be substantial. the inability to work, reduced access to health services, and increased isolation are likely to result in poorer health outcomes and increased inequalities, particularly where individuals are largely excluded from formal social protection schemes. sex worker organisations have rapidly responded to covid- by circulating hardship funds; helping with financial relief applications; advocating for governments to include sex workers in the pandemic response; calling for basic labour rights to facilitate safer working conditions; and providing health and safety guidance for those moving online or unable to stop direct services. worldwide, government initiatives have included supplying food packages to sex workers in bangladesh, the provision of emergency housing in england and wales, and the inclusion of sex workers in financial benefits in thailand, the netherlands, and japan. yet these schemes often exclude the most marginalised, including those who are homeless, transgender, or migrants. , there is a critical need for governments and health and social care providers to work with affected communities and front-line service providers to co-produce effective interventions. examples of necessary interventions are described in the panel. existing sex worker organisations provide an essential foundation for community health work and in collaboration with health services they can facilitate, and ensure the appropriateness of, community testing and contact tracing as well as maximising the uptake of potential future covid- vaccines or treatments. achieving healthier communities and controlling covid- requires a collective and inclusive response. resources and support for sex workers need to be prioritised. involvement of communities in social protection schemes, health services, and information will enable sex workers to protect their health during this pandemic as equal citizens, in line with principles of social justice. reforms of social and legal policies, including decriminalisation of sex work, can reduce discrimination and marginalisation of sex workers and enable provision of vital health and social services. this need becomes more acute as existing health and social challenges are exacerbated by the covid- crisis. we declare no competing interests. transform drug policy foundation, bristol, uk (sr); and school of social policy sex workers rights advocacy network. swan statement on covid- and demands of sex workers. sex workers rights advocacy network, . unaids. covid- responses must uphold and protect the human rights of sex workers associations between sex work laws and sex workers' health: a systematic review and meta-analysis of quantitative and qualitative studies hiv infection among female sex workers in concentrated and high prevalence epidemics: why a structural determinants framework is needed refugee and migrant health in the covid- response regional updates covid- migrant sex workers and sex worker responses. the european network for the promotion of rights and health among migrant sex workers testing for latent tuberculosis infection using interferon gamma release assays in commercial sex workers at an outreach clinic in birmingham active or latent tuberculosis increases susceptibility to covid- and disease severity burden and correlates of mental health diagnoses among sex workers in an urban setting emcdda update on the implications of covid- for people who use drugs (pwud) and drug service providers who. q&a on covid- , hiv and antiretrovirals antiretroviral therapy uptake, attrition, adherence and outcomes among hiv-infected female sex workers: a systematic review and meta-analysis covid- strategy update special report: the simulations driving the world's response to covid- individuals and populations: the strategy of preventive medicine transcending the known in public health practice sex-workers' resilience to the covid crisis: a list of initiatives rights in the time of covid - . lessons from hiv for an effective, community-led response project viva: a multilevel communitybased intervention to increase influenza vaccination rates among hard-toreach populations in new york city examining and challenging the everyday power relations affecting sex workers' health key: cord- -qwgmn t authors: livingston, gill; huntley, jonathan; sommerlad, andrew; ames, david; ballard, clive; banerjee, sube; brayne, carol; burns, alistair; cohen-mansfield, jiska; cooper, claudia; costafreda, sergi g; dias, amit; fox, nick; gitlin, laura n; howard, robert; kales, helen c; kivimäki, mika; larson, eric b; ogunniyi, adesola; orgeta, vasiliki; ritchie, karen; rockwood, kenneth; sampson, elizabeth l; samus, quincy; schneider, lon s; selbæk, geir; teri, linda; mukadam, naaheed title: dementia prevention, intervention, and care: report of the lancet commission date: - - journal: lancet doi: . /s - ( ) - sha: doc_id: cord_uid: qwgmn t nan the number of older people, including those living with dementia, is rising, as younger age mortality declines. however, the age-specific incidence of dementia has fallen in many countries, probably because of improvements in education, nutrition, health care, and lifestyle changes. overall, a growing body of evidence supports the nine potentially modifiable risk factors for dementia modelled by the lancet commission on dementia prevention, intervention, and care: less education, hypertension, hearing impairment, smoking, obesity, depression, physical inactivity, diabetes, and low social contact. we now add three more risk factors for dementia with newer, convincing evidence. these factors are excessive alcohol consumption, traumatic brain injury, and air pollution. we have completed new reviews and meta-analyses and incorporated these into an updated risk factor life-course model of dementia prevention. together the modifiable risk factors account for around % of worldwide dementias, which consequently could theo retically be prevented or delayed. the potential for prevention is high and might be higher in low-income and middle-income countries (lmic) where more dementias occur. our new life-course model and evidence synthesis has paramount worldwide policy implications. it is never too early and never too late in the life course for dementia prevention. early-life (younger than years) risks, such as less education, affect cognitive reserve; midlife ( - years) , and later-life (older than years) risk factors influence reserve and triggering of neuropathological developments. culture, poverty, and inequality are key drivers of the need for change. individuals who are most deprived need these changes the most and will derive the highest benefit. policy should prioritise childhood education for all. public health initiatives minimising head injury and decreasing harmful alcohol drinking could potentially reduce young-onset and later-life dementia. midlife systolic blood pressure control should aim for mm hg or lower to delay or prevent dementia. stopping smoking, even in later life, ameliorates this risk. passive smoking is a less considered modifiable risk factor for dementia. many countries have restricted this exposure. policy makers should expedite improvements in air quality, particularly in areas with high air pollution. we recommend keeping cognitively, physically, and socially active in midlife and later life although little evidence exists for any single specific activity protecting against dementia. using hearing aids appears to reduce the excess risk from hearing loss. sustained exercise in midlife, and possibly later life, protects from dementia, perhaps through decreasing obesity, diabetes, and cardio vascular risk. depression might be a risk for dementia, but in later life dementia might cause depression. although behaviour change is difficult and some associations might not be purely causal, individuals have a huge potential to reduce their dementia risk. in lmic, not everyone has access to secondary education; high rates of hypertension, obesity, and hearing loss exist, and the prevalence of diabetes and smoking are growing, thus an even greater proportion of dementia is potentially preventable. amyloid-β and tau biomarkers indicate risk of progression to alzheimer's dementia but most people with normal cognition with only these biomarkers never develop the disease. although accurate diagnosis is important for patients who have impairments and functional concerns and their families, no evidence exists to support pre-symptomatic diagnosis in everyday practice. our understanding of dementia aetiology is shifting, with latest description of new pathological causes. in the oldest adults (older than years), in particular, mixed dementia is more common. blood biomarkers might hold promise for future diagnostic approaches and are more scalable than csf and brain imaging markers. wellbeing is the goal of much of dementia care. people with dementia have complex problems and symptoms in many domains. interventions should be individualised and consider the person as a whole, as well as their family carers. evidence is accumulating for the effectiveness, at least in the short term, of psychosocial interventions tailored to the patient's needs, to manage neuropsychiatric symptoms. evidence-based interventions for carers can reduce depressive and anxiety symptoms over years and be cost-effective. keeping people with dementia physically healthy is important for their cognition. people with dementia have more physical health problems than others of the same age but often receive less community health care and find it particularly difficult to access and organise care. people with dementia have more hospital admissions than other older people, including for illnesses that are potentially manageable at home. they have died disproportionately in the covid- epidemic. hospitalisations are distressing and are associated with poor outcomes and high costs. health-care professionals worldwide around million people live with dementia, and this number is projected to increase to million by , rising particularly in low-income and middleincome countries (lmic) where around two-thirds of people with dementia live. dementia affects individuals, their families, and the economy, with global costs estimated at about us$ trillion annually. we reconvened the lancet commission on dementia prevention, intervention, and care to identify the evidence for advances likely to have the greatest impact since our paper and build on its work. our inter disciplinary, international group of experts presented, debated, and agreed on the best available evidence. we adopted a triangulation framework evaluating the consistency of evidence from different lines of research and used that as the basis to evaluate evidence. we have • three new modifiable risk factors for dementia • new evidence supports adding three modifiable risk factors-excessive alcohol consumption, head injury, and air pollution-to our lancet commission on dementia prevention, intervention, and care life-course model of nine factors (less education, hypertension, hearing impairment, smoking, obesity, depression, physical inactivity, diabetes, and infrequent social contact). • modifying risk factors might prevent or delay up to % of dementias. • be ambitious about prevention • prevention is about policy and individuals. contributions to the risk and mitigation of dementia begin early and continue throughout life, so it is never too early or too late. these actions require both public health programmes and individually tailored interventions. in addition to population strategies, policy should address high-risk groups to increase social, cognitive, and physical activity; and vascular health. • specific actions for risk factors across the life course • aim to maintain systolic bp of mm hg or less in midlife from around age years (antihypertensive treatment for hypertension is the only known effective preventive medication for dementia). • encourage use of hearing aids for hearing loss and reduce hearing loss by protection of ears from excessive noise exposure. • reduce exposure to air pollution and second-hand tobacco smoke. • prevent head injury. • limit alcohol use, as alcohol misuse and drinking more than units weekly increase the risk of dementia. • avoid smoking uptake and support smoking cessation to stop smoking, as this reduces the risk of dementia even in later life. • provide all children with primary and secondary education. • reduce obesity and the linked condition of diabetes. sustain midlife, and possibly later life physical activity. • addressing other putative risk factors for dementia, like sleep, through lifestyle interventions, will improve general health. • tackle inequality and protect people with dementia • many risk factors cluster around inequalities, which occur particularly in black, asian, and minority ethnic groups and in vulnerable populations. tackling these factors will involve not only health promotion but also societal action to improve the circumstances in which people live their lives. examples include creating environments that have physical activity as a norm, reducing the population profile of blood pressure rising with age through better patterns of nutrition, and reducing potential excessive noise exposure. • dementia is rising more in low-income and middleincome countries (lmic) than in high-income countries, because of population ageing and higher frequency of potentially modifiable risk factors. preventative interventions might yield the largest dementia reductions in lmic. summarised best evidence using, where possible, goodquality systematic reviews, meta-analyses, or individual studies, where these add important knowledge to the field. we performed systematic literature reviews and meta-analyses where needed to generate new evidence for our analysis of potentially modifiable risk factors for dementia. within this framework, we present a narrative synthesis of evidence including systematic reviews and meta-analyses and explain its balance, strengths, and limitations. we evaluated new evidence on dementia risk in lmic; risks and protective factors for dementia; detection of alzheimer's disease; multimorbidity in dementia; and interventions for people affected by dementia. nearly all the evidence is from studies in highincome countries (hic), so risks might differ in other countries and interventions might require modification for different cultures and environments. this notion also underpins the critical need to understand the dementias related to life-course disadvantage-whether in hics or lmics. our understanding of dementia aetiology is shifting. a consensus group, for example, has described hippocampal sclerosis associated with tdp- proteinopathy, as limbic-predominant age-related tdp- encephalopathy (late) dementia, usually found in people older than years, progressing more slowly than alzheimer's disease, detectable at post-mortem, often mimicking or comorbid with alzheimer's disease. this situation reflects increasing attention as to how clinical syndromes are and are not related to particular underlying pathologies and how this might change across age. more work is needed, however, before late can be used as a valid clinical diagnosis. the fastest growing demographic group in hic is the oldest adults, those aged over years. thus a unique opportunity exists to focus on both human biology, in this previously rare population, as well as on meeting their needs and promoting their wellbeing. the number of people with dementia is rising. predictions about future trends in dementia prevalence vary depending on the underlying assumptions and geographical region, but generally suggest substantial increases in overall prevalence related to an ageing population. for example, according to the global burden of diseases, injuries, and risk factors study, the global age-standardised prevalence of dementia between and was relatively stable, but with an ageing and bigger population the number of people with dementia has more than doubled since . however, in many hic such as the usa, the uk, and france, age-specific incidence rates are lower in more recent cohorts compared with cohorts from previous decades collected using similar methods and target populations (figure ) and the age-specific incidence of dementia appears to decrease. all-cause dementia incidence is lower in people born more recently, proba bly due to educational, socio-economic, health care, and lifestyle changes. , however, in these countries increasing obesity and diabetes and declining physical activity might reverse this trajectory. , in contrast, age-specific dementia prevalence in japan, south korea, hong kong, and taiwan looks as if it is increasing, as is alzheimer's in lmic, although whether diagnostic methods are always the same in comparison studies is unclear. [ ] [ ] [ ] modelling of the uk change suggests a % increase in the number of people with dementia from to , % of that expected if age-specific incidence rates remained steady, such that by there will be · million uk people with dementia. models also suggest that there will be future increases both in the number of individuals who are independent and those with complex care needs. figure : incidence rate ratio comparing new cohorts to old cohorts from five studies of dementia incidence iidp project in usa and nigeria, bordeaux study in france, and rotterdam study in the netherlands adjusted for age. framingham heart study, usa, adjusted for age and sex. cfas in the uk adjusted for age, sex, area, and deprivation. however, age-specific dementia prevalence is increasing in some other countries. iid=indianapolis-ibadan dementia. cfas=cognitive function and ageing study. adapted from wu et al, by permission of springer nature. hazard ratio incidence ratio ( %ci) in our first report, the commission described a life-course model for potentially modifiable risks for dementia. life course is important when considering risk, for example, obesity and hypertension in midlife predict future dementia, but both weight and blood pressure usually fall in later life in those with or developing dementia, so lower weight and blood pressure in later life might signify illness, not an absence of risk. [ ] [ ] [ ] [ ] we consider evidence on other potential risk factors and incor porate those with good quality evidence in our model. figure summarises possible mechanisms of protection from dementia, some of which involve increasing or maintaining cognitive reserve despite pathology and neuropathological damage. there are different terms describing the observed differential susceptibility to agerelated and disease-related changes and these are not used consistently. , a consensus paper defines reserve as a concept accounting for the difference between an individual's clinical picture and their neuropathology. it, divides the concept further into neurobiological brain reserve (eg, numbers of neurones and synapses at a given timepoint), brain maintenance (as neurobiological capital at any timepoint, based on genetics or lifestyle reducing brain changes and pathology development over time) and cognitive reserve as adaptability enabling preser vation of cognition or everyday functioning in spite of brain pathology. cognitive reserve is changeable and quantifying it uses proxy measures such as education, occupational complexity, leisure activity, residual approaches (the variance of cognition not explained by demographic variables and brain measures), or identification of functional networks that might underlie such reserve. [ ] [ ] [ ] [ ] [ ] [ ] early-life factors, such as less education, affect the resulting cognitive reserve. midlife and old-age risk factors influence age-related cognitive decline and triggering of neuropathological developments. consistent with the hypothesis of cognitive reserve is that older women are more likely to develop dementia than men of the same age, probably partly because on average older women have had less education than older men. cognitive reserve mechanisms might include preserved metabolism or increased connectivity in temporal and frontal brain areas. [ ] [ ] [ ] [ ] [ ] people in otherwise good physical health can sustain a higher burden of neuropathology without cognitive impairment. culture, poverty, and inequality are important obstacles to, and drivers of, the need for change to cognitive reserve. those who are most deprived need these changes the most and will derive the highest benefit from them. smoking increases air particulate matter, and has vascular and toxic effects. similarly air pollution might act via vascular mechanisms. exercise might reduce weight and diabetes risk, improve cardiovascular function, decrease glutamine, or enhance hippocampal neurogenesis. higher hdl cholesterol might protect against vascular risk and inflammation accompanying amyloid-β (aβ) pathology in mild cognitive impairment. numbers of people with dementia in lmic are rising faster than in hic because of increases in life expectancy and greater risk factor burden. we previously calculated that nine potentially modifiable risk factors together are associated with % of the population attributable fraction (pafs) of dementia worldwide: less education, high blood pressure, obesity, hearing loss, depression, diabetes, physical inactivity, smoking, and social isolation, assuming causation. most research data for this calcu lation came from hic and there is a relative absence of specific evidence of the impact of risk factors on dementia risk in lmic, particularly from africa and latin america. calculations considering country-specific prevalence of the nine potentially modifiable risk factors indicate paf of % in china, % in india and % in latin america with the potential for these numbers to be even higher depending on which estimates of risk factor frequency are used. , therefore a higher potential for dementia prevention exists in these countries than in global estimates that use data predominantly from hic. if not currently in place, national policies addressing access to education, causes and management of high blood pressure, causes and treatment of hearing loss, socioeconomic and commercial drivers of obesity, could be implemented to reduce risk in many countries. the higher social contact observed in the three lmic regions provides potential insights for hic on how to influence this risk factor for dementia. we could not consider other risk factors such as poor health in pregnancy of malnourished mothers, difficult births, early life malnutrition, survival with heavy infection burdens alongside malaria and hiv, all of which might add to the risks in lmic. diabetes is very common and cigarette smoking is rising in china while falling in most hic. preventing dementia meta-analysis found variation of the rates of dementia within china, with a higher prevalence in the north and lower prevalence in central china, estimating · million people are living with dementia, whereas a slightly later synthesis estimated a higher prevalence of around million. , these data highlight the need for more focused work in lmic for more accurate estimates of risk and interventions tailored to each setting. risk factors in early life (education), midlife (hypertension, obesity, hearing loss, traumatic brain injury, and alcohol misuse) and later life (smoking, depression, physical inactivity, social isolation, diabetes, and air pollution) can contribute to increased dementia risk (table ) . good evidence exists for all these risk factors although some late-life factors, such as depression, possibly have a bidirectional impact and are also part of the dementia prodrome. , in the next section, we briefly describe relevant newly published and illustrative research studies that add to the commission's evidence base, including risks and, for some, mitigation. we have chosen studies that are large and representative of the populations, or smaller studies in areas where very little evidence exists. we discuss them in life-course order and within the life course in the order of magnitude of population attributable factor. higher childhood education levels and lifelong higher educational attainment reduce dementia risk. , - new work suggests overall cognitive ability increases, with education, before reaching a plateau in late adolescence, when brain reaches greatest plasticity; with relatively few further gains with education after age years. this suggests cognitive stimulation is more important in early life; much of the apparent later effect might be due to people of higher cognitive function seeking out cognitively stimulating activities and education. it is difficult to separate out the specific impact of education from the effect of overall cognitive ability, , and the specific impact of later-life cognitive activity from lifelong cognitive function and activity. , cognitive maintenance one large study in china tried to separate cognitive activity in adulthood from activities for those with more education, by considering activities judged to appeal to people of different levels of education. it found people older than years who read, played games, or bet more frequently had reduced risk of dementia (n= , odds ratio [or]= · , % ci · - · ). the study excluded people developing dementia less than years after baseline to reduce reverse causation. this finding is consistent with small studies of midlife activities which find them associated with better late-life cognition; so for example, in people aged - years, followed up until - years, travel, social outings, playing music, art, physical activity, reading, and speaking a second language, were associated with maintaining cognition, independent of education, occupation, late-life activities, and current structural brain health. similarly, engaging in intellectual activity as adults, particularly problem solving, for people born in , was associated with cognitive ability acquisition, although not the speed of decline. the use it or lose it hypothesis suggests that mental activity, in general, might improve cognitive function. people in more cognitively demanding jobs tend to show less cognitive deterioration before, and sometimes after retirement than those in less demanding jobs. , one systematic review of retirement and cognitive decline found conflicting evidence. subsequently, a -year study of people found older retirement age but not number of years working, was associated with lower dementia risk. those retiring because of ill health had lower verbal memory and fluency scores than those retiring for other reasons. another study found a two-fold increase in episodic memory loss attributable to retirement (n= , mean age years), compared to non-retirees, adjusting for health, age, sex, and wealth. similarly, in a cohort of people retiring at a mean age of years, verbal memory declined % ( % ci - ) faster than before retirement. a cognitive intervention or cognition-orientated treatment comprises strategies or skills to improve general or spe cific areas of cognition. computerised cognitive training programmes have increasingly replaced tasks that were originally paper-and-pencil format with computerbased tasks for practice and training. three systematic reviews in the general population found no evidence of generalised cognition improvement from specific cognitive interventions, including computerised cognitive training, although the domain trained might improve. [ ] [ ] [ ] a meta-analysis of controlled trials of at least hours of computerised cognitive training, (n= , control n= ) for mild cognitive impairment, found a moderate effect on general cognition post-training (hedges' g= · , · - · ); however few high quality studies and no long-term high quality evidence about prevention of dementia currently exists. a meta-analysis of trials of computerised, therapy-based and multimodal interventions for mild cognitive impairment found an effect on activities of daily living (d= · ) and metacognitive outcomes (d= · ) compared to control. a third systematic review identified five high quality studies, four group-delivered and one by computer, and concluded the evidence for the effects of cognitive training in mild cognitive impairment was insufficient to draw conclusions. a comprehensive, high quality, systematic overview of meta-analyses of cognitive training in healthy older people, those with mild cognitive impairment and those with dementia, found that most were of low standard, were positive and most reached statistical significance but it was unclear whether results were of clinical value because of the poor standard of the studies and heterogeneity of results (figure ). in the only randomised controlled trial (rct) of behavioural activation ( people) for cognition in amnestic mild cognitive impairment, behavioural activation versus supportive therapy was associated with a decreased -year incidence of memory decline (relative risk [rr] · , · - · ). hearing loss had the highest paf for dementia in our first report, using a meta-analysis of studies of people with normal baseline cognition and hearing loss present at a threshold of db, which is the who threshold for hearing loss. in the commission, we found an rr of · for dementia in populations followed up over - years, with the long follow-up times making reverse causation bias unlikely. a subsequent meta-analysis using the same three prospective studies measuring hearing using audiometry at baseline, found an increased risk of dementia (or · , % ci · - · ) per db of worsening of hearing loss. a cross-sectional study of individuals designed to be representative of the us population, with a mean age of · years, found a decrease in cognition with every db reduction in hearing, which continued to below the clinical threshold so that subclinical levels of hearing impairment (below db) were significantly related to lower cognition. although the aetiology still needs further clarification, a small us prospective cohort study of adults without baseline cognitive impairment, (baseline mean age · years), and at least two brain mris, with a mean of years follow-up, found that midlife hearing impair ment measured by audiometry, is associated with steeper temporal lobe volume loss, including in the hippocampus and entorhinal cortex. a -year prospective study of people aged years or older found increased dementia incidence in those with self-reported hearing problems except in those using hearing aids. similarly, a cross-sectional study found hearing loss was only associated with worse cognition in those not using hearing aids. a us nationally representative survey of people older than years, tested every two years for years, found immediate and delayed recall deteriorated less after initiation of hearing aid use, adjusting for other risk factors. hearing aid use was the largest factor protecting from decline (regression coefficient β for higher episodic memory · ; p< · ) adjusting for protective and harmful factors. the long follow-up times in these prospective studies suggest hearing aid use is protec tive, rather than the possibility that those developing dementia are less likely to use hearing aids. hearing loss might result in cognitive decline through reduced cognitive stimulation. the international classification of disease (icd) defines mild tbi as concussion and severe tbi as skull fracture, oedema, brain injury or bleed. single, severe tbi is associated in humans, and mouse models, with widespread hyperphosphorylated tau pathology, and mice with apoe ε compared to apoe ε allele have more hippocampal hyper-phosphorylated tau after tbi. , tbi is usually caused by car, motorcycle, and bicycle injuries; military exposures; boxing, horse riding, and other recreational sports; firearms; and falls. a nationwide danish cohort study of nearly million people aged years or older, followed for a mean of years, found an increased dementia (hr · , % ci · - · ) and alzheimer's disease risk ( · , · - · ). dementia risk was highest in the months after tbi ( · , · - · ) and increased with number of injuries in people with tbi (one tbi · , · - · ; ≥ tbis · , · - · ). risk was higher for tbi than fractures in other body areas ( · , · - · ) and remained elevated after excluding cognitive training cognitive stimulation mixed cognition-oriented treatments favours control favours intervention those who developed dementia within years after tbi, to reduce reverse causation bias. similarly, a swedish cohort of over million people aged years or older, found tbi increased -year dementia risk (or · , % ci · - · ); and risk remained elevated, albeit attenuated over years ( · , · - · ). icd defined single mild tbi increased the risk of dementia less than severe tbi and multiple tbis increased the risk further (or · , % ci · - · for single tbi; · , · - · for more severe tbi; and · , · - · for multiple tbi). a nested case control study of early onset clinically diagnosed alzheimer's disease within an established cohort also found tbi was a risk factor, increasing with number and severity. a stronger risk of dementia was found nearer the time of the tbi, leading to some people with earlyonset alzheimer's disease. military veterans have a high risk of occupational tbi, and formal record keeping allows long-term follow-up. a study of veterans with tbi with propensitymatched veterans without tbi found dementia risk was associated with tbi severity (hr · , % ci · - · for mild tbi without loss of consciousness; · , · - · for mild tbi with loss of consciousness; and · , · - · for moderate to severe tbi). similarly women veterans with tbi had increased risk of dementia compared to those without tbi ( · , · - · ). a cohort study of older adults with concussion, found the risk of dementia doubled, with in developing dementia over a mean follow-up of · years, although those taking statins had a % reduced risk of dementia compared to those who were statin-free. they suggest future rcts as statins might mitigate injury-related brain oedema, oxidative stress, amyloid protein aggregation, and neuroinflammation. the term chronic traumatic encephalopathy describes sports head injury, which is not yet fully characterised and covers a broad range of neuropathologies and outcomes, with current views largely conjecture. the evidence has subsequently been strengthened by a study on scottish former soccer players reporting that they are more likely than controls to have alzheimer's disease specified on their death certificates (hr · , % ci · - · ) and to have been prescribed any dementiarelated medications (or · , % ci · - · ) but not on medical records. the study controlled for socioeconomic class based on residential address, which in footballers might be less linked to level of education. persistent midlife hypertension is associated with increased risk of a late life dementia. in the framingham offspring cohort comprising people, elevated systolic blood pressure (≥ mm hg in midlife; mean age years) was associated with an increased risk of developing dementia (hr · , % ci · - · ) over an year follow-up period. in this study risk increased further if hypertension persisted into later life (mean age years; hr · , % ci · - · ). in the same cohort, people in late midlife (mean age years) with ideal cardiovascular parameters (current non-smoker, body mass index [bmi] · - kg/m², regular physical activity, healthy diet, optimum blood pressure < /< mm hg, cholesterol, and normal fasting blood glucose) were compared to people with at least one of these risks. those with ideal cardiovascular parameters had a lower -year risk of all-cause dementia (hr · , % ci · - · ), vascular dementia ( · , · - · ) and clinically diagnosed alzheimer's disease ( · , · - · ). in a uk cohort study of civil servants, a single measure of systolic blood pressure of mm hg or higher at age years but not at age or years was associated with increased risk of dementia ( · , · - · ). in those with persistent systolic blood pressure of mm hg or higher, from mean age to years, dementia risk is increased even if free of cardiovascular disease relative to those without hypertension ( · , · - · ). a further cohort study has provided potential insights into mechanisms, reporting that midlife hypertension, defined as from age years, was associated with reduced brain volumes and increased white matter hyperintensity volume but not amyloid deposition. of note, blood pressure declines in later life and this decline is associated with and, potentially caused by, dementia development (hr · , % ci · - · ). , , antihypertensive drugs, aspirin, and statins the us and puerto rico systolic blood pressure intervention trial (sprint) in hypertensive adults aged years and older, was stopped early because of significantly fewer cardiovascular events and deaths occurring in the intensive treatment arm (aiming for systolic < mm hg, n= ) in comparison with standard treatment (systolic < mm hg, n= ). cognitive assessment continued after stopping the trial intervention in sprint mind. in the intensive compared with the standard treatment group, there were · dementia cases as opposed to · cases/ personyears (hr · ; % ci · - · ) within on average years from the end of the intervention period and years after baseline. pre-specified secondary outcomes were also reduced in the intensive arm for mild cog nitive impairment ( · vs · cases/ person-years; hr · , % ci · - · ), combined mild cognitive impairment or dementia ( · vs · cases/ person-years; hr · , % ci · - · ) making this the first trial to suggest reduction of risk for mild cognitive impairment. those who were lost to follow-up were at greater risk of dementia than those who continued but follow-up rates did not differ according to intervention group. four meta-analyses of blood pressure medications to lower high blood pressure with six studies overlap have provided combined estimates of effects. all metaanalyses suggest reduced dementia in those in the interventions arms for outcomes of any dementia as well as clinically diagnosed alzheimer's disease. the first included randomised controlled trials (rcts) of any drug to lower blood pressure and reported a reduction in risk of around % at marginal significance (rr · , % ci · - · ). meta-regression showed risk lowered more if the achieved systolic pressure differential was larger between the intervention and control group. the second included trials and observational studies of diuretics involving people (median age years) with · years median follow-up (dementia hr · , % ci · - · and alzheimer's disease · , · - · ). the third included used individual participant data from six observational studies; (dementia · , · - · and alzheimer's disease · , · - · ; figure ). the fourth focused on people prescribed calcium channel blocker only, included rcts and observational studies comprising hypertensive older adults (median age years, median follow-up · years) found lowered dementia risk (rr · , % ci · - · ). a metaanalysis addressing which class of anti-hypertensive drug to use to lower risk of either incident dementia or cognitive decline, found over participants in studies and reported no consistent difference in effect according to which class of drug was used. a cochrane review reported good evidence that statins given to older people at risk of vascular disease do not prevent cognitive decline or dementia. one rct found mg aspirin versus placebo in healthy adults older than years did not reduce dementia (hr · , % ci · - · ), death, physical disability, or cardiovascular disease over a period of · years. studies of physical activity are complex. patterns of physical activity change with age, generation, and morbidity and are different across sex, social class, and cultures. the studies suggest a complicated relationship with the potential for both risk reduction and reverse causation. meta-analyses of longitudinal observational studies of - years duration showed exercise to be associated with reduced risk of dementia. a further overview of sys tematic reviews concluded that there is convincing decreased incident dementia evidence for physical activity protecting against clinically diagnosed alzheimer's disease. since the commission, the hunt study of participants aged - years has been published, reinforcing the previous literature in this area. at least weekly midlife moderate-to-vigorous physical activity (breaking into a sweat) was associated with reduced dementia risk over a -year period of follow-up (hr · , % ci · - · ) but the confidence intervals were wide. in contrast the whitehall study reporting on the -year follow-up of people, found that more than · hours of self-reported moderate-to-vigorous physical activity per week, lowered dementia risk over , but not years. very long-term studies are unusual; however, one -year study recruited women (mean age ) purposively to be representative of the swedish population and reported that % of the participants with low baseline peak fitness, % with medium, and % with high fitness developed dementia (high vs medium hr · , % ci · - · , low vs medium · , · - · ). an individual-level meta-analysis of observational studies of relatively younger adults included participants' data (mean baseline age · years; mean follow-up duration · years), reporting an increased incidence of all-cause dementia (hr · , % ci · - · ) and clinically diagnosed alzheimer's disease ( · , · - · ) in those who were physically inactive in the -year period before diagnosis. notably, however, no difference in dementia risk measured - years before time of dementia incidence was found except in those with comorbid cardio-metabolic disease (rr · , % ci · - · ). people might stop exercising due to prodromal dementia so inactivity might be either a consequence or a cause or both in dementia and might be more of a risk in those with cardiovascular morbidity. as with other outcomes, exercise might be required to be sustained and continue nearer the time of risk. since the commission several meta-analyses and systematic reviews have been published with three high quality meta-analyses which we include. the first included rcts with an unclear total number of participants examining moderate or vigorous exercise of any frequency lasting - min per session in cognitively normal adults aged older than years. this analysis reported global cognitive improvements (standard mean difference [smd]= · , % ci · - · ) for moderate or vigorous resistance ( studies) or aerobic exercise ( studies) lasting - min per session with no difference between them but no effect found for yoga. a second meta-analysis of rcts in people with mild cognitive impairment found global cognition improved in the intervention group ( · , · - · ) with aerobic exercise having a higher effect ( · , · - · ). this study did not have dementia as an outcome measure. a third meta-analysis of rcts of longer term exercise found five studies (four lasting months and one months) with participants with normal baseline cognition. the incidence of dementia was · % (n= ) for exercisers and · % (n= ) for controls (random effect rr · , % ci · - · ; fixed effect as no evidence of heterogeneity · , · - · ). the authors concluded that the study showed no significant effect of exercise for reducing dementia, mild cognitive impairment, or clini cally significant cognitive decline but was underpowered. who guidelines have been published since the commission, suggesting specific activity levels drawing on these, and one further systematic review which considered sex differences on the effect of exercise. , it concluded the evidence points towards physical activity having a small, beneficial effect on normal cognition, with a possible effect in mild cognitive impairment, mostly due to aerobic exercise. evidence about the effect of specific types of exercise, such as progressive muscle resistance training, on dementia risk is scarce. in the commission we reported on diabetes as a risk factor for dementia. distinguishing between treated and untreated diabetes as a risk factor for dementia is challenging in observational studies. in a pooled metaanalysis from over · million individuals with type diabetes across cohort studies, including with dementia, diabetes was associated with an increased risk of any dementia (rr · , % ci · - · for women and · , · - · for men). the risk of dementia increased with the duration and severity of diabetes. the effect of different diabetic medications on cognition or dementia outcomes remains unclear as few studies have investigated this area. however, one meta-analysis of cohort studies of diabetes reported that, cross sectionally, people with diabetes taking metformin had lower prevalence of cognitive impairment (three studies or · , % ci · - · ) and, longitudinally, reduced dementia incidence (six studies hr · , % ci · - · ) compared with those taking other medications or no medication. however another analysis did not find a protective effect of metformin for incident dementia (three studies, rr · , % ci · - · ) with possible harm with insulin therapy ( · , · - · ); but this did not account for severity of diabetes of those with type diabetes on insulin. a cochrane review reported intensive compared to standard diabetes control trials with year follow up (n= ), showing no impact on cognitive decline ( · , % ci · - · ) or dementia ( · , · - · ). overall type diabetes is a clear risk factor for development of future dementia; however, whether any particular medication ameliorates this risk is unclear. intensive diabetic control does not decrease the risk of dementia. studies of individual cardiovascular risk factors usually control for other cardiovascular risks, which cluster in individual people. this does not take into account the combinations and contexts in which risk occurs. a uk study of people aged years followed up for years, calculated a cardiovascular health score based on four behaviour-related (smoking, diet, physical activity, bmi) and three biological (fasting glucose, blood cholesterol, blood pressure) metrics each coded on a three-point scale ( , , ). a better score was associated with a lower risk of dementia (hr · , % ci · - · per point scale increment), for both behaviour-related (hr/ point increment in subscales · , % ci · - · ) and biological subscales ( · , · - · ), main tained in people free of cardiovascular disease over the follow-up ( · , % ci · - · ). these authors also reported an association of the score on the scale with hippocampal atrophy and total brain volume but not white matter hyperintensities. this finding underlines the importance of clustering of cardio vascular risk factors in midlife, as studies of individual risk factors in this sample had not shown a significant association, when controlling for other individual risks. heavy drinking is associated with brain changes, cognitive impairment, and dementia, a risk known for centuries. an increasing body of evidence is emerging on alcohol's complex relationship with cognition and dementia outcomes from a variety of sources including detailed cohorts and large-scale record based studies. alcohol is strongly associated with cultural patterns and other sociocultural and health-related factors, making it particularly challenging to understand the evidence base. a french -year longitudinal study of over million people admitted to hospital, found alcohol use disorders (harmful use or dependence as defined in icd) were associated with increased dementia risk, calculated separately for men and women (women hr · , % ci · - · , men · , · - · ). the relationship of dementia with alcohol use disorders was particularly clear in the earlier onset dementias (age less than years) in which · % had an alcohol use disorder noted in their records (n= ; · % all dementias). a systematic review incorporating studies of light to moderate drinking using a variety of definitions reported a reduced risk of dementia compared with not drinking (rr · ; % ci · - · ). risk was not reported separately for men and women. drinking less than units of alcohol per week ( unit of alcohol= ml or g pure alcohol) might be associated with a lower risk of dementia. , a -year follow-up study of men and women volunteers from uk biobank aged - years who drank, included few heavy drinkers and did not analyse abstainers. the study reported that those who drank more than units per week declined slightly more in reaction time in a perceptual matching task than those who drank less (β =− · , % ci − · to − · ). the uk whitehall study with years follow-up, included participants aged - years at baseline. drinking more than units per week and long-term abstinence were both associated with a % ( % ci - and - respectively) increase in dementia compared to drinking less than units. drinking more than units was also associated with right sided hippocampal atrophy on mri. overweight is an emerging concern, given the changing bmi across the world's ageing population. new evidence supports the relationship between increased bmi and dementia from a review of longitudinal studies including people aged to years, followed up for up to years. it reported obesity (bmi ≥ ; rr · , % ci · - · ) but not being overweight (bmi - ; · , · - · ) was associated with late-life dementia. in a further meta-analysis of individual level data from · million adults (aged ≥ years), which included two studies from the meta-analysis cited above, higher body mass measured before probable preclinical and prodromal dementia was associated with increased dementia risk (rr · , · - · / -unit increase in bmi). a meta-analysis of seven rcts ( participants) and longitudinal studies ( participants) of overweight and obese adults without dementia, mean age years, found weight loss of kg or more in people with bmi greater than was associated with a significant improvement in attention and memory. all but one of the studies included participants aged younger than years. the rcts reported memory improvement over - weeks (smd= · , % ci · - · ) and short-term longitudinal studies found improvement over a median of weeks (smd= · , % ci · - · ); however, data about the long-term effects or the effect of weight loss in preventing dementia are absent. smokers are at higher risk of dementia than nonsmokers, and at a higher risk of premature death before the age at which they might have developed dementia, introducing some bias and uncertainty in the association between smoking and risk of dementia. , stopping smoking, even when older, reduces this risk. among men aged older than years, stopping smoking for more than years, compared to continuing, substantially reduced dementia risk over the subsequent years (hr · ; % ci · - · ). worldwide, % of nonsmoking adults and % of children are estimated to be exposed to second-hand smoke; although literature on the impact of this exposure and dementia risk is scarce. one study indicated that in women aged - years, second-hand smoke exposure was associated with more memory deterioration and the risk increased with exposure duration even after controlling for other confounding factors. depression is associated with dementia incidence, with a variety of possible psychological or physiological mechanisms. it is also part of the prodrome and early stages of dementia. reverse causation is possible whereby depressive symptoms result from dementia neuropathology that occurs years before clinical dementia onset. these explanations are not mutually exclusive. as in diabetes, few studies considering depression as a risk factor for dementia have distinguished between treated and untreated depression. in a meta-analysis of studies, with participants, with follow-up from to years, a depressive episode was a risk factor for dementia (pooled effect size · , % ci · - · ). meta-regression analysis revealed a non-significant trend for the association between depression and incident dementia to be weaker when the length of follow-up was longer. the norwegian hunt study, suggested that symptoms of psychological distress predicted dementia years later however with wide bounds of uncertainty (hr · , % ci · - · ). two further studies differentiate between late-life and earlier life depressive symptoms. the uk whitehall study, in a follow-up of people, reports that in late life these symptoms increase dementia risk but not at younger ages (follow-up years hr · ; % ci · - · ; follow-up years · , · - · ). , a -year longitudinal study of initially cognitively healthy men, aged - years, found depression was associated with · ( % ci · - · ) times the incidence of dementia but this association was accounted for by people developing dementia within years of depression. the use of antidepressants did not decrease this risk. a study of people with mild cognitive impairment and with a history of depression from the australian longitudinal alzheimer's disease neuroimaging initiative, considered the effect of selective serotonin-reuptake inhibitor (ssri) treatment, such as citalopram, known to reduce amyloid plaque generation and plaque formation in animal models. the study found that more than years of such treatment was associated with delayed progres sion to clinically diagnosed alzheimer's disease. people treated with antidepressants seem likely to differ from those who are not treated. thus, the question of whether antidepressant treatment mitigates dementia risk remains open. social contact, now an accepted protective factor, enhances cognitive reserve or encourages beneficial behaviours, although isolation might also occur as part of the dementia prodrome. several studies suggest that less social contact increases the risk of dementia. although most people in mid and later life are married, by the time they reach older age, disproportionate numbers of women are widowed as they outlive their husbands, thus reducing their social contact. in these generations, marital status is therefore an important contributor to social engagement. additionally, most marriages are in the relatively young, and married people usually have more interpersonal contact than do single people-this gives a long-term estimate of the effect of social contact. a systematic review and meta-analysis including people worldwide found dementia risk to be elevated in lifelong single (rr · , % ci · - · ) and widowed people ( · , · - · ), compared with married people and the association was consistent in different sociocultural settings. studies adjusted for sex and we do not know if a differential risk between men and women exists. differences persisted in studies that adjusted for education and physical health so might be attributable to married people having more social contact, rather than solely because they tend to have better physical health and more education, although residual confounding is possible. a systematic review and meta-analysis of longitudinal cohort studies of social isolation and cognition included participants aged or more years at baseline, with follow-up of - years. high social contact (measured through either or both of social activity and social network) was associated with better late-life cognitive function (r= · , % ci: · - · ) and no differences according to sex or length of time followed up. a new meta-analysis found that in long-term studies (≥ years), good social engagement was modestly protective (n= , rr= · , % ci · - · ); but loneliness was not associated with dementia risk. no long term (> years) studies of loneliness and dementia outcomes have been done. a uk -year follow-up study of people found that more frequent social contact at age years was associated with lower dementia risk over years of follow-up (hr for one standard deviation social contact frequency · , % ci · - · ). this finding suggests more frequent social contact during late middle age is associated with a modest reduction in dementia risk, independent of socio-economic and other life style factors. a japanese longitudinal cohort study of adults aged older than years with a mean of years follow-up calculated a five-point social contact scale based on: marital status; exchanging support with family members; having contact with friends; participating in community groups; and engaging in paid work. it found the score to be linearly associated with reduced dementia risk; those who scored highest on the five-point scale were % less likely to develop incident dementia compared with those in the lowest category. despite clear cultural variation in the meaning and perception of social isolation, findings of protective effect of more social contact are largely consistent in different settings and for either sex across the studies and metaanalyses. , , little evidence of the effects of social interventions on dementia exists but a systematic review of low quality rcts of adults aged or more years with normal cognition found facilitated meeting and discussion groups were associated with improved global cognition and increased brain volume at follow-up. air pollution and particulate pollutants are associated with poor health outcomes, including those related to non-communicable diseases. attention has turned to their potential effect on the brain. animal models suggest airborne particulate pollutants accelerate neurodegenerative processes through cerebrovascular and cardiovascular disease, aβ deposition, and amyloid precursor protein processing. , although the higher levels of dementia from air pollutants are still subject to the potential for residual confounding, the effects on animal models are evidence of physiological effects over and above those driven by life-course deprivation. high nitrogen dioxide (no ) concentration (> · µg/m³; adjusted hr · , % ci · - · ), fine ambient particulate matter (pm) · from traffic exhaust ( · , · - · ) [ ] [ ] [ ] and pm · from residential wood burning (hr= · , % ci · - · for a μg/m³ increase) are associated with increased dementia incidence. traffic often produces no and pm · and it is hard to separate their effects, although evidence for additive effects of different pollutants exists. [ ] [ ] [ ] a systematic review of studies until including longitudinal studies with - years follow-up of air pollutants exposure and incident dementia, found exposure to pm · , no , and carbon monoxide were all associated with increased dementia risk. the attributable burden of dementia and excess death from pm · in one large -year us study was particularly high in black or african american individuals and socio-economically disadvan taged communities and related to particulate pm · concentrations above the us guidelines. mechanisms by which sleep might affect dementia remain unclear, but sleep disturbance has been linked with β-amyloid (aβ) deposition, , reduced glymphatic clearance pathways activation, low grade inflammation, increased tau, hypoxia , and cardiovascular disease. sleep disturbance is hypothesised to increase inflammation which raises aβ burden, leading to alzheimer's disease and further sleep disturbance. two meta-analyses showed similar findings. the first was a synthesis of longitudinal studies with an average of · years follow-up and the second reported crosssectional and prospective cohort studies of mixed quality with different methods of measuring sleep. sleep disturbances were defined broadly, often self-reported and including short and long sleep duration, poor sleep quality, circadian rhythm abnormality, insomnia, and obstructive sleep apnoea. all these disturbances were associated with a higher risk of all-cause dementia (rr · ; % ci · - · ) and clinically diagnosed alzheimer's disease ( · , · - · ) compared with no sleep disturbance, although not all cohort studies excluded those with cognitive impairment or dementia at baseline from their analyses. a u-shaped association has been reported between sleep duration and risk of mild cognitive impairment or dementia with higher risks of dementia with less than hours (hr= · ; % ci · - · ) compared with more than and less than and more than hours sleep ( · , · - · ) and risks for allcause dementia and clinically diagnosed alzheimer's disease being similar. , [ ] [ ] [ ] the postulated mechanisms of reduced sleep leading to accumulation of alzheimer's type pathology is inconsistent with the evidence that both more sleep and less sleep are associated with increased risk of dementia. new onset late-life sleep disturbance, a few years before clinical dementia, might be part of the natural history of the dementia syndrome, appearing to be a risk factor, or reflect other disorders, for example, mood disturbances or cardiovascular disease. , hypnotic use might increase risks although this is unclear and a study suggests that findings of a connection were related to reverse causality and confounders. when benzodiazepine use was considered, in one study, sleep length was no longer significant but not in all studies. those taking hypnotics were at greater risk of dementia than those who did not regardless of sleep duration. medication for sleep disturbance might be harmful and benzodiazepines are associated with falls, hospital admissions, and possibly dementia. , diet nutrition and dietary components are challenging to research with controversies still raging around the role of many micronutrients and health outcomes in dementia. observational studies have focused on individual components ranging from folate and b vitamins, vitamin c, d, e, and selenium amongst others as potential protective factors. there has been a move towards considering the evidence base for whole diets in the last years, particularly high plant intake such as in the mediterranean diet (high intake of vegetables, legumes, fruits, nuts, cereals, and olive oil; low intake of saturated lipids and meat) or the similar nordic diet, rather than individual nutrients, which might reduce cognitive decline and dementia. one example is a longitudinal cohort study of partici pants, ages - years, in which those reporting the highest intake of green leafy vegetables, equivalent to · servings per day, had less cognitive decline over · years than those reporting the lowest intake (β= · standardised units % ci · - · ). the authors report this difference as being equivalent to being years younger. a further prospective cohort study with three midlife dietary assessments in people, followed up for a mean of nearly years, found neither healthy dietary pattern nor mediterranean diet protected from dementia, except in those with cardiovascular disease, suggesting that diet might influence dementia risk by protecting from the excess risk of cardiovascular risk factors. as well as whole diets, there has been some interest in multi-nutrient interventions. a systematic review and a cochrane review including rcts of supplements (a, b, c, d, and e; calcium, zinc, copper, and multivitamins trials, n- fatty acids, antioxidant vitamins, and herbs) found a lack of evidence for supplement use to preserve cognitive function or prevent dementia in middleaged ( - years) or older people (aged years and older). , cochrane reviews found no evidence for beneficial effects on cognition of those with mild cognitive impairment of supplementation with b vitamins for to months or with vitamin e in preventing progression from mild cognitive impairment to dementia. a -month rct of people of a multi-nutrient drink containing docosahexaenoic acid, vitamins b , b , folic acid, and other nutrients; found no significant effect on preventing cognitive deteriora tion in prodromal alzheimer's dis ease. the authors comment that the control group's cognitive decline was much lower than expected, leading to an inadequately powered trial. meta-analysis of two rcts with participants with normal cognition found the mediterranean diet improved global cognition compared to controls (smd · , % ci · - · ). a further meta-analysis identified five rcts (n= ) with a weak effect on global cognition (smd · , % cl · - · ) but no benefit of mediterranean diet for incident cognitive impairment or dementia. the who guidelines recommend a mediterranean diet to reduce the risk of cognitive decline or dementia, as it might help and does not harm, but conclude vitamins b and e, polyunsaturated fatty acid, and multicomplex supplementation should not be recommended. the finger rct was a -year multidomain intervention to prevent cognitive decline and dementia in people with cardiovascular risk factors aged - years, recruited from a finnish national survey. similar multidomain studies were discussed in the commission. finger found a small group reduction in cognitive decline in the intervention group compared with control (comprehensive neuropsychological test battery z score · , % cl · - · ) regardless of baseline sociodemographic, socio-economic, cognitive, or cardiovascular status. however, in a subgroup analysis, greater beneficial effects were observed on processing speed in individuals with higher baseline cortical thickness in alzheimer's disease areas. the healthy ageing through internet counselling in the elderly (hatice) study recruited older people (≥ years) in the netherlands, finland, and france with two or more cardiovascular risk factors. , it compared an interactive internet platform plus remote support by a coach, aiming to improve self-management of vascular risk factors, with a non-interactive control platform with basic health information. a small improvement in the cardiovascular risk composite primary outcome was observed in the intervention group compared with the control group at months, mainly through weight loss, and the dementia risk score was slightly lower in those who received the intervention (mean difference − · , % ci − · to − · ). a larger effect was observed in the younger age group ( - years) and those with the lowest level of education, who had a higher baseline risk, suggesting that targeting high-risk popula tions might be more effective. several multi domain preventive trials are ongoing-for example, world wide fingers. we incorporated excessive alcohol consumption, tbi, and air pollution into our life-course model of dementia, as well as the original nine risk factors, because of the updated evidence. to calculate new rrs for excessive alcohol consumption, tbi and air pollution, we systematically reviewed the literature and did new metaanalyses for excessive alcohol consumption and tbi. for the other nine factors, we used values for rr and risk factors prevalence from our previous analysis and calculated communality using the same method as in the commission. we used a representative sample of over uk community-dwelling adults, to calculate communality (clustering of risk factors) of risk factors for which data existed, to allow calculation of each factor's unique risk. as we could find no datasets measuring tbi, with the other risk factors of interest, we could not calculate its communality. we therefore used the mean of the other communalities to calculate a weighted paf, so we could include tbi. we used cohabitation as a proxy measure for social contact, and urbanicity for air pollution exposure. our analysis found four principal components, explaining % of the total variance between the eleven risk factors, suggesting substantial overlap. the appendix (p ) shows the paf formula and the steps in calculating communality and we detail our new meta-analyses we searched, from inception to oct , , embase, allied, and complementary medicine, medline, and psycinfo terms "dementia" or "dement*" or "ad" or "vad", "alzheimer*" and "alcohol" or "ethanol" or "alcohol*" or "drink*" or "drunk*" to update an earlier review. we used inclusion criteria: original populationbased cohort studies measuring drinking during midlife, as alcohol intake tends to fall with age; alcohol consumption quantified at baseline by units or number of drinks (one drink, · units) per week; and all-cause dementia ascertained at follow-up using validated clinical measures. we contacted authors for additional data. three studies met our inclusion criteria. , , we converted hrs to rrs and used raw data to calculate rr, for our random effects meta-analysis using generic inverse variance methods. the rr associated with drinking-more than units ( g) of alcohol weeklycompared with lighter drinking was · ( % cl · - · ; figure ). we used health survey england figures for heavier drinking prevalence to calculate paf as we could not find a worldwide estimate. the weighted paf was · . to estimate the rr of tbi of all severities for all cause dementia, we searched embase, medline, and psycinfo from jan , , to oct , , updating an earlier search, using terms ("traumatic brain injury" or "head injury" or "brain injury" or tbi) and (neurodegeneration or "cognitive dysfunction" or dementia or "alzheimer's disease" or "parkinson's disease" or "frontotemporal dementia"). we converted hr figures to rr. , we used inclusion criteria: original population-based cohort studies, baseline tbi of all severities reported, and allcause dementia ascertained at follow-up using validated clinical measures. we combined four new studies meeting inclusion criteria , , , with the four studies meeting criteria from the original review in a random effects metaanalysis. the pooled rr was · ( % ci · - · ) for all cause dementia from all severities of tbi (figure ) although there was heterogeneity in study-specific estimates, possibly because of different popula tions. we used the tbi adult population prevalence of · % from a metaanalysis to calculate paf. the weighted paf was · . chu et al ( ) fann et al ( ) gardner et al ( ) nordström et al ( ) nordström et al ( ) wang et al ( ) total ( % ci) heterogeneity τ = · , χ = · , df= (p< · ); i = % test for overall effects: z= · (p< · ) · · a systematic review synthesised observational studies, finding consistently increased risk of dementia from air pollution, but heterogeneous comparator groups precluded meta-analysis. we updated the search, using the same search terms and searching medline, embase, and psycinfo from sept , , (the end date of the last search) to oct , . we included longitudinal studies with assessment of all cause air pollution exposure; use of formal assessment of cognitive function at baseline; report of incident all-cause dementia, data from adults (age ≥ years); and a minimum follow-up of months. as meta-analysis was not possible, we used data from the only study of allcause air pollution with the outcome of all-cause dementia, with low-moderate risk of bias. this population-based, observational cohort was from canada, where pollutant concentrations are among the lowest in the world and examined people, with a mean baseline age of years. we calculated the rr of dementia for those in the three highest quartiles compared to the lowest was · ( · - · ) . the attributable fraction for exposure to the highest three quartiles versus the lowest quartile of pm · and no was · % ( · - · ). the weighted paf was · . table displays the prevalence, commu nality, relative risk, unweighted and weighted pafs adjusted for communality. figure shows the updated life-course model of potentially modifiable risk factors for dementia, including the three new risk factors. this commission is the most comprehensive ana lysis to date and updates the commission with emerging risk factor evidence convincing enough to calculate paf for potentially reversible risk factors. we reviewed the literature systematically for the chosen risk factors and provided illustrative new literature to update our synthesis and identify data to calculate communality. we find a hopeful picture with an estimate of around % of all cases of dementia being associated with potentially modifiable risk factors. we have made assumptions to calculate this new model. we used global figures for dementia risk although we know the risk factors prevalence varies between countries and most global research is from hic, so lmic are under-represented because of lack of data. we have assumed a causal relationship between risk factors and dementia, although we have been cautious and not included risk factors with less good evidence. no single database exists with all risk factors together, but we found of the factors in a uk database and used the mean figure for communality calculations for tbi. we calculated communality for the other . we do not know how far findings of communality in other geographical populations might differ, or in those with a differing distribution of age groups or sex. we found that social isolation was not explicitly measured and had to use proxies, such as cohabitation when considering prevalence, which are approximate. specifically, evidence for the association of alcohol misuse with dementia comes from hic and future studies from lmic are needed to complete the picture. exposure to air pollution changes over a lifetime and is inextricably linked to poverty and deprivation. however, the effects on animal models suggests specific physiological effects over and above those driven by life-course deprivation. we also considered the overlap with education for this and other risk factors and the correction for education, strongly inversely linked to deprivation, will address at least some of the confounding. however, the results in one study which reported the effect of air pollution on incident dementia showed very little early life difference in estimates before and after adjustment for education and other risk factors, suggesting little residual confounding exists. we were also unable to metaanalyse data on pollution and thus unlike the other relative risks, the figure comes from only one study, from an area of low pollution so is likely to be an underestimate. the longitudinal evidence linking potentially modifiable risk factors to dementia generally fulfils causality criteria in observational data (strength, consistency, biological plausibility, temporality, dose-response, coherence, and quasi-experimental studies, for example, more education or using hearing aids). when measuring a risk nearer to the age of dementia onset, then it is more likely that prodromal change affects, or even causes it. alternatively, a risk factor might act on preclinical pathology or even cause dementia near the time of exposure. thus, excessive alcohol, and tbi are particularly important in young-onset dementia, although many early onset dementias relate to genetic risks. risk factors might also matter more at a time of higher biological vulnerability, which the studies we have drawn on cannot establish. the length of exposure required for risk or protection effect, and their interrelationships as they change across life is unclear-it seems probable that longer or more intense exposure has stronger effects. additionally, as our communality figures show, risk factors overlap. we cannot establish from these data if having multiple risk factors has an additive or synergistic effect. association does not prove causation, however, as already noted, the reductions in prevalence and incidence in several hic suggests that at least some of the risk factors estimated here do have a causal relationship with the clinical expression of dementia. we judge that sufficient new evidence supports adding three additional modifiable risk factors for dementia to our commission model (excessive alcohol, traumatic brain injury, and air pollution). we have been able to add updated evidence on the nine risk factors implicated in the commission (education, hypertension, hearing impairment, smoking, obesity, depression, inactivity, diabetes, and social contact). reduction of these risk factors might be protective for people with or without a genetic risk, although study findings have not been entirely consistent. [ ] [ ] [ ] [ ] as we noted in the commission, others have previously calculated an estimate of the risk associated with apoε at % taking into account some other risk factors and this estimate highlights how relatively important potentially modifiable risk factors are in dementia. , for some risk factors, the pattern of risk and the individual's other health, both physical and mental, might be especially important. currently, the evidence suggests a mediterranean or scandinavian diet might have value in preventing cognitive decline in people with intact cognition, particularly as one component of a healthy lifestyle, although how long the exposure has to be or during which ages is unclear. we do not recommend taking additional vitamins, oils, or mixed dietary supplements as a means of preventing dementia as extensive testing in trials has not led to signals of beneficial effects. data from rcts on interventions to prevent cognitive decline, all-cause dementia, or alzheimer's disease are few. for some key life influences, only observational data, particularly related to natural experiments such as changing the statutory education age, are possible. these influences should be investigated systematically wherever possible. others can theoretically be investigated but the long follow-up required for midlife risk and protective factors and non-random attrition in longer studies are challenging. using intermediate endpoints, such as cognition, and dementia onset in research remains uncertain because no intermediate markers with such a close relationship to dementia outcomes exist that it would be possible to predict with certainty for any given individual, age, and sex. overall, the evidence for treating hypertension is strongest and high blood pressure throughout midlife increases the risk of dementia even without stroke. although a need for more evidence is apparent, recommendations should not wait, as clear indications of ways to reduce the chances of developing dementia without causing harm will also lead to other health and wellbeing benefits. our recommended strategies for dementia risk reduction include both population-wide and targeted interventions (panel). it is important to remember that more socially disadvantaged groups, including black, asian, and minority ethnic groups, are particularly at risk. although we have more to learn about effectiveness, avoiding or delaying even a proportion of potentially modifiable dementias should be a national priority for all. not all dementia will be preventable and we present the latest evidence on intervention and care for dementia. to date the emphasis has been on specific subtypes of dementia, most notably on alzheimer's disease, which has been conceptualised over the years in a variety of changing diagnostic criteria-eg, dsm iv and dsm v. , intense efforts have been put into biomarkers for early preclinical detection of the disease process before it becomes dementia. biomarkers need to show reliability and validity, and for dementias they also need to be very closely and clearly related to clinical syndrome outcomes in the way that, for example, human papillomavirus is for cervical cancer, and hypertension has been for stroke. markers of neurodegeneration linked to clinical dementia include brain volume loss-ie, hippocampal volume loss and entorhinal cortex and medial temporal cortical thinning-seen in structural imaging. the most studied molecular markers are in alzheimer's disease and are amyloid and tau, which pet and csf detect clinically. the prevalence of particular pathologies at different ages is important in interpretation of such studies. so, for example, population derived studies show increases in plaques in the population from less than % at age - years to around % at age - years. amyloid imaging detects amyloid in the brain with high sensitivity and specificity in both cognitively normal and people with alzheimer's disease when the gold-standard comparison is either neuropathology or clinical diag nosis, distinguishing alzheimer's disease from other neurodegenerative conditions. amyloid imaging is not a diagnostic test for dementia. a us study of randomly selected older people from the community recruited people (mean age of years). the prevalence of pet detected amyloid positivity increased from · % ( % ci · - · ) of people without cognitive impairment aged - years to · % ( % ci · - · %) aged - years. in -year follow-up pet positivity was associated with a higher probability of developing alzheimer's disease compared with those who were amyloid negative (hr · , % ci · - · ). in participants with mild cognitive impairment who were amyloid positive the probability (hr · , % ci · - · ) was not very different to those who were amyloid negative ( · , · - · ). similarly, an -year follow-up study of volunteers (average age years) in australia found that cognitively normal pet amyloid-positive people had an elevated risk of developing alzheimer's disease compared with amyloid negative ( · % vs · %; or · , % ci · - · ). over % of the people who were pet amyloid-positive did not go onto develop a cognitive impairment within years, showing positive status does not predict impairment for most people in a timeframe that might be a useful prognostic window. follow-up at years of amyloid-positive participants with normal cognition or mild cognitive impairment versus amyloid negative people found the same pattern of increased risk ( · , · - · ). risk also increases per year of age (hr · , % ci · - · /year), and apoeε status ( · , · - · ). most people who are amyloid positive with no other markers have not developed alzheimer's disease dementia during their lifetime. a model of lifetime risks of people who are amyloid positive without any other biomarkers finds it to be · % for a -year-old woman who is cognitively normal at baseline, · % for a -year-old woman and · % for a -year-old woman. the -year risk is considerably less, so a -year-old woman with only amyloid biomarkers but who is cognitively normal and has no neurodegeneration has a -year alzheimer's disease risk of · % and a man · %, but the risk is higher with accompanying neurodegeneration (table ) . overall, the knowledge of pet-measured amyloid and tau status and mri-derived cortical thickness in a general population derived sample, only adds a small improvement, which might not be clinically important for predicting memory decline over a model with clinical and genetic variables. using amyloid pet in patients with cognitive impairment of uncertain causes, results in changes to the clinical diagnosis of alzheimer's disease and sometimes to medication prescription. we do not know whether pet use improves patient care or decreases care costs. many people have a mixed cause of dementia and a positive result does not indicate only alzheimer's disease. pet imaging is very costly (us$ in the usa) and although used in some clinical settings remains the topic of research to understand its usefulness in broader populations. fluid biomarkers-ie, blood and cerebrospinal fluid tests-have become a more practical focus of interest since it has become possible to measure specific proteins linked to the proteins associated with the neuropathologies of alzheimer's disease. a composite blood biomarker for amyloid tested in a discovery dataset and then a validation cohort of participants aged - years who were already taking part in studies in japan or australia had areas under the receiver operating risks are particularly high in more socially disadvantaged populations including in black, asian, and minority ethnic groups. • prioritise childhood education for all, worldwide • implement social public health policies that reduce hypertension risk in the entire population • develop policies that encourage social, cognitive, and physical activity across the life course for all (with no evidence for any specific activities being more protective) • scrutinise the risks for hearing loss throughout the life course, to reduce the risk of exposure to this risk factor • reduce the risk of serious brain trauma in relevant settings, including occupational and transport • national and international policies to reduce population exposure to air pollution • continue to strengthen national and international efforts to reduce exposure to smoking, both for children and adults, and to reduce uptake and encourage cessation • use hearing aids for hearing loss; we need to help people wear hearing aids as many find them unacceptable, too difficult to use, or ineffective • avoid or discourage drinking or more units of alcohol per week • prevent head trauma where an individual is at high risk • stopping smoking is beneficial regardless of age • reduce obesity and the linked condition of diabetes by healthy food availability and an environment to increase movement • sustain midlife, and possibly late-life physical activity characteristic curves of · % for discovery and · % for validation. the blood biomarker had sensitivity and specificity above % against amyloid pet measurement and correlated with csf concentrations of aβ - . these results are similar to other amyloid blood biomarkers , and harmonisation to a common reference standard is now vital. although csf aβ - / - ratio and amyloid pet are now considered interchangeable, csf tau biomarkers have only correlated weakly with brain tau as currently measured by radioligands. neurofilament light protein is measured in many cohorts; however, it is non-specific. people with huntington's disease, multiple sclerosis, mild cognitive impairment, and alzheimer's disease might have raised blood neurofilament light concentrations, which are a marker of neurodegeneration. [ ] [ ] [ ] to be useful in clinical practice biomarkers must be well understood in the populations to which they are going to be applied, including the effects of age and sex on results. there is now reasonable evidence that amyloid and tau measured by pet or in fluid indicate increased risk for development of cognitive impairment in older adults but at the individual level prognostication is not possible as most cognitively normal people with these markers do not develop dementia within a clinically relevant timeframe. negative amyloid results can be useful for ruling out current alzheimer's pathology in people with cognitive impairment when the cause is uncertain and show an individual is unlikely to develop alzheimer's disease during the next few years. high neurofilament light concentrations indicate a neuro degenerative process but not its cause. the value of biomarkers, in terms of diagnostic value, has not been addressed in different representative populations and particularly not in those from lmic. the potential advantages of blood biomarkers are their low cost and their wider acceptability and applicability in many settings. in many areas of medicine more reliable diagnostic tests have improved research, including epidemiological and public health research and trials, to help distinguish cause from symptom (tuberculosis from a fever) or assess risk factor and disease (hyper cholesterolaemia and ischaemic heart disease). those biomarkers developed for the underlying biology of the dementia syndrome are subject to the same assessment of value. in the commission, we discussed that when concerns are raised by patients or family, an accurate diagnosis is helpful. such a diagnosis provides a gateway to intervention and services where available, for planning for possible futures, and support for family, as well as to research. unfortunately, these services are not always available. national plans for dementia support timely diagnosis and offer help to individuals and their families. we did not address screening of those not presenting with concerns but rigorous systematic reviews by the us task force on prevention have found an absence of evidence of benefit and harm. the first trial of population screening took place in the usa, screening primary care patients aged years or older. no clear benefit or harm in terms of quality of life, mood, or increasing diagnostic rates was found. other strategies might become more valuable in time such as sensitive awareness of risk factors, when routine records suggest an individual might be deteriorating cognitively. people with dementia have complex problems with symptoms in many domains. those providing support and any interventions must consider the person as a whole, as well as their context and their close carers, whether family or friends. individuals' medical, cognitive, psychological, environmental, cultural, and social needs must be given consideration. in the context of under provision of services, this notion is and will continue to be a challenge. dementia, as an illness which affects cognition by definition, affects the ability to organise activities and people with dementia often need help to do what they enjoy-for example, listen to music, or go to gardens and parks. wellbeing is one of the goals of dementia care. data are relative risk ( % ci) or %. reproduced from brookmeyer and abdalla by permission of elsevier. cholinesterase inhibitors have a useful, modest role in improving cognition and activities of daily living in patients with mild-to-moderate alzheimer's disease and memantine can be prescribed in combination or each drug used separately for moderate and severe alzheimer's disease. , , however, although available in most countries these drugs are no longer remunerated in france because it is felt that they offer only a small benefit while shifting clinician's attention from other interventions. whether non-prescribing of this drug will help patients by removing an intervention with known benefit or be detrimental to them is unknown. no advances have been reported in aβ therapeutics, with negative results from phase trials of monoclonal antibodies (eg, solanezumab, crenezumab) and inhibitors of β-secretase, a protease involved in the production of aβ peptides. aducanumab previously abandoned as futile now has further unpublished results. three ht antagonists and the calcium channel blocker nilvadipine , have also been ineffective. these drugs also show substantial impact during treatments at socalled therapeutic concentrations on the leakiness of blood vessels. the long-term impact of such side-effects is unknown. anti-tau, anti-amyloid, and anti-inflammatory drugs continue to be in focus and some argue that pre-symptomatic interventions are necessary, especially if targeting aβ production, but no evidence of efficacy and some evidence of worsening target symp toms currently exists. a meta-analysis of controlled trials of people with mild dementia, completing or more hours of group-based computerised cognitive training (mean age - years, · % female participants), found a small, statistically significant beneficial effect on overall cogni tion, driven by two trials of virtual reality or video games (smd= · , % ci · - · ), one with a low and one with a high risk of bias. a cochrane review found trials of cognitive training, only one of which over lapped with the study above, with around participants with mild-tomoderate dementia, most with a high or uncertain risk of bias. people completing cognitive training, compared with usual treatment or non-specific activities, had small-to-moderate effects on overall cogni tion (smd · , % ci · - · ) and specific cognitive abilities such as verbal fluency and improvements lasted for a few months to year. no direct evidence was observed to suggest that cognitive training was better than cognitive stimulation therapy. the dementia and physical activity rct found moderate-to-high intensity aerobic and strength exercise training did not slow cognitive impairment in people with mild-to-moderate dementia but improved physical fitness. the us reducing disability in dementia study implemented an at-home multicomponent intervention including exercise education, training to increase pleasant events, and activator-behaviour-consequence problemsolving approach over weeks by case managers in community dwelling people with dementia older than years and their family carer and were able to follow up ( · %). the study found increased physical activity; days of taking or more minutes of exercise (effect size · , % ci · - · after the treatment and · , · - · at months) in a before and after intervention comparison. neuropsychiatric symptoms are common and often clus tered in people with dementia. these symptoms might precede dementia and are associated with tau and amyloid neuropathology. this suggests that underlying neurobiological mechanisms might underpin neuropsychiatric symptoms. however, other drivers relating to the personal history and the environment of the person with dementia are also likely to exist. neurodegeneration could lead to increased vulnerability to stressors or triggers. genetics, cognitive reserve, resilience, medical comorbidities, and environment including responses of carers might modify these relationships. needs and responses will also be individual and relate to a person's own social, cultural, and historical context. first-line assessment and management of neuropsychiatric symptoms should focus on basic health: describe and diagnose symptoms; look for causes such as pain (using validated pain assessments might help), illness, discomfort, hunger, loneliness, boredom, lack of intimacy and worry that could cause the behaviours and alleviate these while considering risks of harm. no new evidence of medication effectiveness for these symptoms exists; risperidone in low doses ( · mg daily) and some other antipsychotics are sometimes effective but often ineffective and have adverse effects. specific initiatives have led to a decrease in antipsychotic prescriptions for people with dementia, although often replaced with other psycho tropics (figure ), such as benzodiazepines, antidepres sants, and mood stabilisers. these psychotropics lack evidence of efficacy for neuropsychiatric symptoms but show clear evidence of possible harm; for example, trazodone and benzodiazepines increase fall-related injuries. major policy changes should be assessed carefully, within and across countries for unintended consequences (and perhaps unexpected benefits) and their costs. evidence is slowly accumulating for the effectiveness, at least in the short term, of person-centred evidence-based psychosocial interventions. in germany, a -month cluster rct of nurse-delivered, supervised dementia care management used a computer-assisted nurse assessment to determine personalised intervention modules, then a multi-disci plinary team discussion and agreement with the physician for people (mean age years) with dementia living at home with a primary carer or alone. the mean mini mental state examination (mmse) was , only % had a formal diagnosis of dementia; the majority of participants ( %) had mild dementia but some had moderate and some severe dementia. the intervention consisted of psychosocial management of treatment and care, medi cation management and carer support, and education and discussion with a psychiatrist or neurologist. the intervention, compared with care as usual, was associated with better outcomes for neuropsychiatric symptoms (neuropsychiatric inventory [npi] score − · , % ci − · to − · ), however this effect could be because of deterioration in care as usual (in the care as usual group npi increased from · to · ; in the intervention group npi increased from · to · ). this between-group reduction in neuropsychiatric symptoms was greater than that expected, extrapolating from other study results, with antipsychotic medication. effects on quality of life were only apparent for those people living with a carer. an eight-session home-based tailored activity programme rct, tailored both to the person with dementia living at home and to a family member compared with eight telephone-based education sessions, recruited participants with % follow-up, imputing values for the rest. the study reported a large reduction in overall neuropsychiatric symptoms immediately after the intervention, which were better in the group receiving home-based tailored activity programme on the neuropsychiatric inventory (mean difference in score · , % ci · - · ), and on functional dependence and pain but this was not sustained months later. noncompleters had more severe neuropsychiatric symptoms. since the commission two new systematic reviews of antidepressants to treat depression in dementia reported moderate quality evidence that antidepressant treatment for people with dementia does not lead to better control of symptomatology compared with placebo. , agitation agitation is distressing for people with dementia and those around them, and contributes substantially to the overall costs as the level of agitation increases. the body of evidence on this key behaviour is growing, mostly focused on care-home settings. these findings are valuable as these populations are most affected; however, because many people with dementia reside at home a major gap in knowledge remains. care home residents with agitation often find sitting still difficult and therefore might not be included in activities. , two new cluster rcts of professionals delivering multicomponent, interdisciplinary, interventions in care homes successfully reduced agitation. the wheld study included participants with or without neuropsychiatric symptoms and provided person-centred care, aiming to improve communication with people with dementia. it implemented social, sensory experiences or other activities; educated about antipsychotic review; and addressed physical problems, finding lower cohen mansfield agitation inventory (cmai) at months (md − · points, % ci − · to − · ). the time study for people with moderate-to-high levels of agitation consisted of a manual-based comprehensive assessment of the resident and structured case conference for the staff and doctor, to create a tailored plan, and then implement it. this intervention led to reduced agitation at weeks (npi − · points, % ci − · to − · ; cmai − · points, − · to − · ) and weeks (npi − · , − · to − · ; cmai − · , − · to − · ). these effect sizes are similar to those seen for medications, but without harmful side-effects. , a further rct studied a six-session intervention with staff in groups, teaching staff to understand agitation as related to medical, psychological, or social unmet needs and to implement strategies to meet these needs, using the describe, investigate, create, and evaluate approach. the intervention did not reduce agitation symptoms, although it was cost-effective, improving quality of life. overall, the current evidence for agitation in care homes favours multi-component interventions by clinical staff, including considering if drugs might harm, and not drug interventions. thus a major gap remains in knowledge about people living at home who comprise the majority of those with dementia. people with dementia might be wrongly thought to have delusions when they misremember, and new psychotic symptoms are often due to delirium, thus thorough assessment of symptoms is essential. management of psychosis in dementia should start with non-pharmacological interventions; however, evidence for effectiveness of these interventions for psychosis in dementia is weaker than for agitation. antipsychotics for psychosis in dementia should be prescribed in as low a dose and for the shortest duration possible. however, a cochrane review of antipsychotics withdrawal found two trials with participants with dementia who had responded to antipsychotic treat ment. these reported that stopping antipsychotics was associated with symptomatic relapse suggesting the need for caution in any medication withdrawal in this group. there was lowquality evidence that, in general, discon tinuation might make little or no difference to overall neuropsychiatric symptoms, adverse events, quality of life or cognitive function. apathy apathy might be conceptualised as the opposite of engagement, comprising reduced interest, initiative, and activity. like people without dementia, those with dementia engage more in preferred activities, but require additional support to do so. a study in care homes observed engagement increased during activities in those who attended the groups. a cochrane review of the few people who had been in drug rcts of methylphenidate versus placebo for apathy in dementia found small improvements on the apathy evaluation scale (md − · , % ci − · to− · , n= , three studies, low-quality evidence) but not on the npi apathy subscale (md − · , % ci − · to · , n= , two studies). there is no evidence that medication for sleep in dementia is effective and considerable evidence for harm-ie, earlier death, increased hospitalisation, and falls-exists. , test ing of non-pharmacological interventions is ongoing. carer distress related to neuropsychiatric symptoms rather than the dementia symptoms was associated in one study with increased use and costs of health services, high lighting the need for effectively identifying, educating, and supporting distressed carers. an rct reporting -year follow-up after the eight session strategies for relatives intervention-manual-based coping intervention delivered by supervised psychology graduates-found continuing effectiveness for depressive symptoms in carers (adjusted md − · ; % ci − · to − · ) and risk of case-level depression, with patient-related cost being approximately times lower than those who did not receive the intervention (median £ vs £ in the final year; p= · ). another us study followed up people, mean age years, % women. caregiver depression rather than symptoms of people with dementia predicted emergency department use for people with dementia, with a % (rr · , % ci · - · ) increase. functioning a uk rct of sessions of cognitive rehabilitation focused on individual goal attainment with therapy delivered at home by an occupational therapist or nurse to participants with mild-to-moderate dementia (mmse ≥ for inclusion; mean ) and a family carer. individuals had two or three goals; the most common was engaging in activities ( % of goals). the intervention group reported increased goal attainment over and months compared with usual treatment (effect size · , % ci · - · at both and months). the treatment did not improve participants' quality of life, mood, selfefficacy, cognition, carer stress, or health status and was not cost-effective. a systematic review of rcts without meta-analysis for overall effect size, concluded that all interventions which had improved functioning in people living with dementia in the community have been individual rather than group interventions. these were: in-home physiotherapist delivered aerobic exercise (two studies, larger one positive, people with alzheimer's disease; smaller study negative, people with alzheimer's disease), individualised cogni tive rehabilitation (mild or moderate dementia; two studies; cognitive reserve intervention groups and controls), and in-home activities-focused occupa tional therapy (people with mild to moderate dementia, three studies, intervention, controls) reduced functional decline compared to controls but group-exercise and reminiscence therapies were ineffective. multimorbidity is a huge challenge in dementia, not only because people with dementia have increased rates of other illnesses, but also because they often find it parti cularly difficult to organise care. people with dementia might forget to tell their family or health professionals of symptoms, struggle to understand or follow agreed plans, and are more likely to forget to drink and eat, increasing falling and infection rates. people with dementia consult primary care less often and have fewer dental visits than those without dementia and their family members, if involved, often feel they lack knowledge to assist. health-care professionals need education to be more comfortable, understanding, and positive in communicating with people with dementia. around - % of people diagnosed with dementia in primary care have at least two other chronic illnesses. , people who are physically more frail are more likely to have dementia, but the relationship between pathology and symptoms in these people is comparatively weak suggesting that dementia might be from other causes. compared to the general older population, people with dementia have increased rates of cerebro vascular disease, [ ] [ ] [ ] [ ] stroke, parkinson's disease, , dia betes, , skin ulcers, anxiety and depression, , pneu monia, incontinence, and electrolyte disturbance. multimorbidity in people with dementia is associated with faster functional decline and worse quality of life for people with dementia and their family carers. severe acute respiratory syndrome coronavirus , was first identified in patients with viral pneumonia in hubei province, china. severity and mortality of the associated disease (covid- ) worsen with increasing age and with pre-existing illnesses such as hypertension and diabetes, and thus many people with dementia are at particular risk. death certificates from the uk indicate that dementia and alzheimer's disease were the most common underlying conditions, specified in deaths ( · % of all deaths involving covid- ) in march to may, . many charities, practitioners, and academics supporting people with dementia have issued guidance based on current evidence and best practice, including advance consideration of whether people would wish to be hospitalised if they develop severe covid- . concern has been expressed that the illness and consequent distancing might increase family carer stress, loneliness, neuropsychiatric symptoms and use of psychotropic medication, and lead to complications, including future dementia. interventions delivered remo tely through technology have also been implemented in some places. [ ] [ ] [ ] [ ] people with dementia might struggle to adhere to measures to reduce virus transmission, as they might not understand or remember about required changes to behaviour, such as physical distancing and hygiene, leading to increased risk to themselves and their carers. they might additionally be vulnerable if they depend on others for daily activities or personal care, as this necessitates close personal contact. this situation is particularly concerning in those care homes, where many residents have dementia and where many covid- deaths have occurred in many countries [ ] [ ] [ ] with reports of more than half of residents being admitted to hospital. in us nursing homes, among people with confirmed covid- , residents living with dementia made up % of covid- cases; yet, accounted for % of all deaths (an increased risk of · ). the number of people living together in care homes means that the infection of an individual, either staff or resident, could endanger more people than in traditional or family households. although evidence exists that if staff are sufficiently and rigorously protected they are unlikely to develop covid- , many staff have become unwell and some have died. , illness means that there are fewer people to care for residents at a time when they need particularly high levels of care. this situation is par ticularly relevant in the care of residents with dementia, if they are expected to remain in their own rooms, rather than eating and participating in activities with others. staff or residents might also be moved between care homes and increase risk in other homes. restrictions on visitors to private homes, care homes, and hospitals might cause greater distress for people with dementia and they might not understand why people are wearing masks, recognise who is behind it, or understand speech when lips are covered. lack of restrictions means that the visitors might also be at elevated risk. the impacts of covid- on people with dementia might be particularly severe in lmics, due to smaller health budgets for testing and protective equipment, capacity of health-care systems, quality of care home provision and patterns of workforce mobility. thus, people with dementia are particularly vulnerable to covid- because of their age, multimorbidity, and difficulties in maintaining physical distancing. [ ] [ ] [ ] we recommend rigorous public health measures of protective equipment and hygiene, including not moving staff or residents between care homes or admitting new residents when their covid- status is unknown, should mitigate impacts on people with dementia. it is also imperative that there is frequent and regular testing of staff in care homes for infection, ensuring staff have sick pay so that they do not come in when symptomatic and interim care is being set up for people discharged from hospital so that only those who are covid- free come to live in care homes. resident testing should encompass asymptomatic as well as symptomatic people, when there is exposure within the home to covid- . in the future, many homes might be able to start to provide oxygen therapy so that those who do not want to be admitted to hospital are still able to access oxygen therapy. in addition, it is also important to reduce isolation by providing the necessary equipment and a brief training to relatives on how to protect themselves and others from covid- ; so that they can visit their relatives with dementia in nursing homes safely when it is allowed. further evidence is needed to inform responses to this and future public health emergencies. hospitalisation in people with dementia is associated with adverse, unintended consequences, including distress, func tional and cognitive decline, and high economic costs. [ ] [ ] [ ] people with dementia have · to times more hospital admissions than others with similar illnesses. , [ ] [ ] [ ] a systematic review and meta-analysis including studies of people with dementia found that in the six studies which compared the two groups, people with dementia had increased hospital admissions compared with those without dementia, after adjusting for age, sex, and physical comorbidity (rr · , % ci · - · ; figure ). hospitalisation rates in people with dementia ranged from · to · per person-year in high-quality studies. admissions are often for conditions that might be manageable in the community (potentially preventable hospitalisations). people with dementia experience longer and more frequent admissions and readmissions; health-care expenditure for people with moderate-severe dementia is around double that of people without dementia. , , early detection and management of physical ill-health in people with dementia, particularly of pain, falls, diabetes, incontinence, and sensory impair ment, is important. , , however, no intervention has successfully reduced number of hos pital admissions of community-dwelling people with demen tia, although education, exercise, rehabilitation, and telemedicine have reduced admissions for older people without dementia. high-quality care for people with dementia takes longer than caring for others with the same condition. recognition of dementia in hospital inpatients is necessary for optimum care, but dementia is often undetected or unrecorded. in the uk however, detection rates have increased over the past years. dementia and delirium frequently occur together. in one hospital inpatients' survey nearly % of those older than years experienced delirium; those with prior cognitive impairment had times the risk of devel oping delirium than those without (or · , % ci · - · ). people with delirium without known dementia are more likely to be diagnosed with dementia in the future than others, either because of pre-existing undiagnosed dementia or cognitive impairment, present in · % ( % ci · - · ) and · % ( · - · ) respectively of one cohort, or because delirium has neurotoxic effects and so precipitates dementia. people with similar people diagnosed with alzheimer's disease had mixed causes of dementia. although alzheimer's disease neuropathology was the commonest cause of dementia, alzheimer's disease changes rarely occurred on their own, so only % of people with dementia had pure alzheimer's disease pathology. people who have alzheimer's disease patho logy without developing dementia tend to have fewer age-related health deficits than those who develop it with even low concentrations of plaques and tangles. a moderation analysis showed that the relationship between alzheimer's disease pathology and dementia status differed according to level of frailty (adjusted for age, sex, and education) with increasing frailty weakening the relationship between alzheimer's disease pathology and dementia (figure ). as with delirium, some of this additional health risk might be modifiable. this approach suggests a new type of therapy focus on specific agerelated processes that underpin many diseases of late life might reduce the incidence or severity of dementia. the numbers of people dying with dementia are increasing but the evidence for the best end-of-life care is scarce. trends in age-standardised death rates ( · %) for dementia increased slightly between - , with pronounced increases in the usa and japan and decreases in western europe and central latin america. dementia is more readily being included on death certificates, which accounts for some of the rise. the increase might be related to dementia manifesting at later ages, with higher physical frailty leading to a faster decline. most people with dementia might die while still in the mild-to-moderate stages whereas only about a quarter of those dying with dementia have severe dementia. , the trajectory of dementia is often unpredictable and palliative care initiation should reflect need not prognosis. neuropatho logy show faster cognitive decline if they develop delirium than if they do not. additionally, older people without dementia declined cognitively more than twice as fast after an emergency hospital admission for any cause, compared with those not admitted, suggesting any severe illness is associated with cognitive decline. risk factors for delirium in dementia include sensory impairment, pain, poly pharmacy, dehydration, intercurrent illnesses, such as urinary tract infections or faecal impaction, and an unfamiliar or changing environment. delirium in older people should prompt consideration of underlying dementia. most research on delirium prevention has been in people without dementia. it suggests targeting hydration, stopping medication predisposing to delirium, monitoring the depth of anaesthesia, and sleep promotion. however, no evidence for medication efficacy, including cholinesterase inhibitors, antipsychotic medication, or melatonin exists. [ ] [ ] [ ] the hospital elder life program an intervention to prevent delirium in those admitted to hospital-reduces delirium incidence and includes people who are cognitively impaired. this multidisciplinary treatment consists of daily visits, orientation, therapeutic activities, sleep enhancement, early mobilisation, vision and hearing adaptation, fluid repletion, infection prevention and management of constipation, pain, and hypoxia, and feeding assistance. a network meta-analysis of drugs for prevention and treatment of delirium did not include studies of people with dementia, thus we cannot use this to recommend drugs for people with dementia and delirium as this research might be inapplicable to them. little high-quality research exists on managing delirium in dementia. one rct compared care at a specialist medical and mental health unit to usual care for confused people older than years, acutely admitted to hospital and found no difference in the primary outcome of days spent at home or in hos pital, but increased family satisfaction. a further rct of cognitively stimulating activities for people with delirium in dementia did not improve the delirium. no definitive evidence that any medication improves delirium in people with dementia exists: cholinesterase inhibitors, antipsychotics, and sedating benzodiazepines are ineffective and antipsychotics and benzodiazepines are associated with mortality and morbidity. , , [ ] [ ] [ ] [ ] given the risk of dementia in people who develop delirium, its prevention, and possibly advances in its management, might offer a means for dementia prevention. the fastest growing demographic group in most advanced countries are people aged years and older. one well characterised post-mortem cohort of the oldest old (n= ; mean age years) dying with dementia, found that neuropathological features of alzheimer's disease account for about half of the cognitive decline seen as decision making about end of life is complex and simple rules of thumb, co-designed with staff and carers, provided clarity in some small studies. one rct testing decision-aids about families' and doctors' goals of care for people with advanced dementia led to increased palliative care content in care plans. , in a -month uk prospective study, care home residents with advanced dementia from homes were likely to be living with distressing symptoms, specifically agitation ( %) or pain ( % on movement). capacity to make abstract decisions, including about the future, might be lost early in dementia. therefore, advance care planning, designed to empower people with dementia and improve quality of dying, might theoretically be something everyone should do before developing dementia. however, people might not be able to predict their future wishes. this might explain why family carer proxies show only low-to-moderate agreement with stated end-of-life treatment preferences of people with dementia. advance care planning might, however, reduce carers' uncertainty in decision making and improve perceptions of quality of care. partners of people dying with dementia experience poorer mental health than those facing bereavement from other causes possibly because of long and difficult caring responsibilities. this might be ameliorated through sensitive and timely information, particularly regarding the progression of dementia, individually or through family and staff case-conferencing. , conclusions knowledge about risk factors and potential prevention, detection, and diagnosis of dementia is improving although significant gaps remain. in this commission report, we have specified policy and individual changes to delay the onset of cognitive impairment and dementia and better ways to support and treat people with dementia and their families and to improve their quality of life. interventions, including organisation of the complex physical illness and social needs, to support people affected by dementia can have a huge effect when 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prevention, diagnosis, intervention, and care by we are partnered by university college london (ucl), the alzheimer's society, uk, the economic and social research council, and alzheimer's research uk, and would like to thank them for financial help. these organisations funded the fares, accommodation, and food for the commission meeting but had no role in the writing of the manuscript or the decision to submit it for publication. we would like to thank bernadette courtney, jacques gianino, and nuj monowari, from ucl, london, uk, for their administrative help, including managing finances, booking rooms and food, and setting up a website supported by the university college london hospitals national institute for health research biomedical research centre. we would like thank henrik zetterberg for advice on biomarkers and dementia. key: cord- -qpwvn fi authors: qiao, jie title: what are the risks of covid- infection in pregnant women? date: - - journal: lancet doi: . /s - ( ) - sha: doc_id: cord_uid: qpwvn fi nan since december, , the outbreak of the novel coronavirus disease (covid ) infection has become a major epidemic threat in china. as of feb , , the cumulative number of confirmed cases in mainland china has reached , with ( · %) cured cases and ( · %) deaths; additionally, there have been suspected cases so far. all provinces in mainland china have now adopted the firstlevel response to major public health emergencies. the national health commission of china has published a series of guidelines on the prevention, diagnosis, and treatment of covid pneumonia, based on growing evidence of the pathogens responsible for covid infection, as well as the epidemiological characteristics, clinical features, and the most effective treatments. [ ] [ ] [ ] the central government and some provincial govern ments have provided food and medical supplies and dispatched expert groups and medical teams to manage and control the outbreak response in the hardesthit areas (wuhan and neighbouring cities in hubei province). as the covid outbreak unfolds, prevention and control of covid infection among pregnant women and the potential risk of vertical transmission have become a major concern. more evidence is needed to develop effective preventive and clinical strategies. the latest research by huijun chen and colleagues reported in the lancet provides some insight into the clinical characteristics, pregnancy outcomes, and vertical transmission potential of covid infection in pregnant women. although the study analysed only a small number of cases (nine women with confirmed covid pneumonia), under such emergent circum stances these findings are valuable for preventive and clinical practice in china and elsewhere. although neonatal nasopharyngeal swab samples have been collected in some hospitals across china, this study also collected and tested amniotic fluid, cord blood, and breastmilk samples for the presence of severe acute respiratory syndrome coronavirus (sarscov ), thus allowing a more detailed assessment of the vertical transmission potential of covid infection. sarscov is a new strain of coronaviruses that are pathogenic to humans. another two notable strains are sarscov and the middle east respiratory syndrome (mers) coronavirus (merscov). a study done by roujian lu and colleagues found that although sarscov is genetically closer to two batderived sarslike coronaviruses, batslcovzc and bat slcovzxc (with about % genome sequence identity), than to sarscov (about % identity) and merscov (about % identity), homology modelling has revealed that sarscov has a similar receptor binding domain structure to that of sarscov , which suggests that covid infection might have a similar pathogenesis to sarscov infection. [ ] [ ] [ ] thus, the risk of vertical transmission of covid might be as low as that of sarscov . the present study by chen and what are the risks of covid- infection in pregnant women? data to inform policy in a wider range of countries is clear, while improving lifestyle choices and modifying their social and commercial determinants remain a challenge. we declare no competing interests. stephanie colleagues did not find any evidence of the presence of sarscov viral particles in the products of conception or in neonates, in accordance with the findings of a previous study on sarscov done by wong and colleagues. two neonatal cases of covid infection have been confirmed so far, with one case confirmed at days after birth and having a close contact history with two confirmed cases (the baby's mother and maternity matron) and the other case confirmed at h after birth and for whom the possibility of close contact history cannot be excluded. however, no reliable evidence is as yet available to support the possibility of vertical transmission of covid infection from the mother to the baby. previous studies have shown that sars during pregnancy is associated with a high incidence of adverse maternal and neonatal complications, such as spontaneous miscarriage, preterm delivery, intrauterine growth restriction, application of endotracheal intu bation, admission to the intensive care unit, renal failure, and disseminated intravascular coagulopathy. , however, pregnant women with covid infection in the present study had fewer adverse maternal and neonatal complications and outcomes than would be anticipated for those with sarscov infection. although a small number of cases was analysed and the findings should be interpreted with caution, the findings are mostly consistent with the clinical analysis done by zhu and colleagues of ten neonates born to mothers with covid pneumonia. the clinical characteristics reported in pregnant women with confirmed covid infection are similar to those reported for nonpregnant adults with confirmed covid infection in the general population and are indicative of a relatively optimistic clinical course and outcomes for covid infection compared with sarscov infection. , nonetheless, because of the small number of cases analysed and the short duration of the study period, more followup studies should be done to further evaluate the safety and health of pregnant women and newborn babies who develop covid infection. as discussed in the study, pregnant women are susceptible to respiratory pathogens and to development of severe pneumonia, which possibly makes them more susceptible to covid infection than the general population, especially if they have chronic diseases or maternal complications. therefore, pregnant women and newborn babies should be considered key atrisk populations in strategies focusing on prevention and management of covid infection. based on evidence from the latest studies and expert recommendations, as well as previous experiences from the prevention and control of sars, the national health commission of china launched a new notice on feb , , which proposed strengthening health counselling, screening, and followups for pregnant women, reinforcing visit time and procedures in obstetric clinics and units with specialised infection control preparations and protective clothing, and emphasised that neonates of pregnant women with suspected or confirmed covid infection should be isolated in a designated unit for at least days after birth and should not be breastfed, to avoid close contact with the mother while she has suspected or confirmed covid infection. we need to further strengthen our capacity to deal with emergent infectious disease outbreaks, through laws and regulations to prevent and control the spread of infectious diseases and to avoid outbreak clusters in families, communities, and other public places, and to do so with transparency and solidarity. timely reporting and disclosure of emergent infectious diseases is also important to avoid delayed responses. infection control and management procedures in hospitals and other places with several confirmed cases isolated together should also be maintained, and specialised clothing and equipment provided to protect medical professionals and other health workers from occupational exposure to covid infection. the chinese version of this comment is provided in the appendix. i declare no competing interests. the number of people with novel coronavirus disease (covid ) has risen above globally, over % of whom are in china, with more than cases in other countries as of feb , . , science, however, is stepping up to the challenge. consider the example of africa's efforts to scale up its capacity to detect any cases of infection. on feb , , the only african countries with laboratories that could test for severe acute respiratory syndrome coronavirus (sarscov ) were south africa and senegal. this scarce capacity was a major concern for a continent bracing for possible infections. just a fortnight later, who had sent testing kits to countries on the continent, which are already being used. by the end of this week, the number of countries able to detect covid is expected to have risen to . the africa centres for disease control and prevention has led training for these countries in senegal, with further sessions scheduled for the week of feb , , in south africa. the importance of the ability to test for sarscov in poorer countries cannot be overstated. it gives them the best chance of containment before the virus can spread and devastate weak health systems. reliable diagnostics are crucial in the response to the outbreak. fortunately, scientists around the world are working at breakneck speed to figure out how to detect, treat, and control the new coronavirus. on feb - , , who brought almost scientists together for a research and innovation forum on the new coronavirus. the meeting covered the topics of diagnostics, vaccines, and therapeutics for covid , alongside questions of how to best integrate social science into the response and protection of healthcare workers from infection. the forum generated a research roadmap, due to be published at the end of february, , to develop tools to help control the outbreak, reduce deaths, and minimise damage to economies and the social fabric of communities. the roadmap is intended to enable scientists, researchers, and funders to coordinate and align published online february , https://doi.org/ . / s ( ) national health commission of the people's republic of china. notice of the general office of the national health and health commission on issuing a new coronavirus pneumonia prevention and control plan clinical characteristics and intrauterine vertical transmission potential of covid infection in nine pregnant women: a retrospective review of medical records genomic characterisation and epidemiology of novel coronavirus: implications for virus origins and receptor binding tissue distribution of ace protein, the functional receptor for sars coronavirus. a first step in understanding sars pathogenesis exploring the pathogenesis of severe acute respiratory syndrome (sars): the tissue distribution of the coronavirus (sarscov) and its putative receptor pregnancy and perinatal outcomes of women with severe acute respiratory syndrome national health commission of the people's republic of china a casecontrolled study comparing clinical course and outcomes of pregnant and nonpregnant women with severe acute respiratory syndrome clinical analysis of neonates born to mothers with ncov pneumonia epidemiological and clinical characteristics of cases of novel coronavirus pneumonia in wuhan, china: a descriptive study early transmission dynamics in wuhan, china, of novel coronavirusinfected pneumonia national health commission of the people's republic of china. notice on strengthening maternal disease treatment and safe midwifery during the prevention and control of new coronavirus pneumonia key: cord- -q zdf authors: panchaud, alice; favre, guillaume; pomar, leo; vouga, manon; aebi-popp, karoline; baud, david title: an international registry for emergent pathogens and pregnancy date: - - journal: lancet doi: . /s - ( ) - sha: doc_id: cord_uid: q zdf nan any health-care provider supporting the registry by providing well documented cases will be considered as a collaborator of the registry in any future scientific publications. we declare no competing interests. robust data acquisition on the effect of emergent pathogens on pregnancy is often absent, and often data are available after considerable delay, leaving scientists and clinicians seeking knowledge to depend solely on intuition, extrapolation, and case series as they emerge. the severe acute respiratory syndrome coronavirus (sars-cov- ) pandemic is no exception. , - large cohorts are required to allow for accurate risk estimates, and therefore a global perspective is needed. to scientists and clinicians involved in the care of pregnant patients during a pandemic, this situation feels like déjà vu, given the many similarities to the zika virus epidemic only years ago. to tweak resources, we have adjusted the zika virus international web registry to create covi-preg, a structured data collection tool available to any facility assessing pregnant patients for sars-cov- infection. today, with increased mobility and considerable migration, we have to use the modern tool of worldwide and immediate communication to trigger knowledge sharing and prepare for rapid assessment of existing and future emergent pathogens. this registry and its associated international network will be organised to be rapidly adaptable to any other emerging infectious agent in the future. the feasibility of this global responsive and customisable structure for future emergent pathogens is supported by the strong platform of well established collaborations with antenatal clinics from countries in africa, asia, europe, oceania, and the americas (figure). this structure will allow for the creation of a large dataset capturing global information in an attainable and realistic manner, with affordable costs and an acceptable timeframe. for the ongoing sars-cov- pandemic, we hypothesise that the collected data will allow researchers and health-care professionals to better characterise the disease course and spectrum, quantitatively estimate associated risks, and identify specific risk factors that can be used to define screening strategies in pregnant women and adequate prevention meas ures, and to direct specific and early clinical management of women and fetuses at risk. in the spirit of open science and data sharing, the collected data will be available to any research group provided that clinical analysis of pregnancy in second and third trimesters complicated severe acute respiratory syndrome clinical characteristics and intrauterine vertical transmission potential of covid- infection in nine pregnant women: a retrospective review of medical records lack of vertical transmission of severe acute respiratory syndrome coronavirus clinical analysis of neonates born to mothers with -ncov pneumonia an analysis of pregnant women with covid- , their newborn infants, and maternal-fetal transmission of sars-cov- : maternal coronavirus infections and pregnancy outcomes an international registry for women exposed to zika virus during pregnancy: time for answers sharing research data and findings relevant to the novel coronavirus (covid- ) outbreak key: cord- - sgeraws authors: remuzzi, andrea; remuzzi, giuseppe title: covid- and italy: what next? date: - - journal: lancet doi: . /s - ( ) - sha: doc_id: cord_uid: sgeraws the spread of severe acute respiratory syndrome coronavirus (sars-cov- ) has already taken on pandemic proportions, affecting over countries in a matter of weeks. a global response to prepare health systems worldwide is imperative. although containment measures in china have reduced new cases by more than %, this reduction is not the case elsewhere, and italy has been particularly affected. there is now grave concern regarding the italian national health system's capacity to effectively respond to the needs of patients who are infected and require intensive care for sars-cov- pneumonia. the percentage of patients in intensive care reported daily in italy between march and march , , has consistently been between % and % of patients who are actively infected. the number of patients infected since feb in italy closely follows an exponential trend. if this trend continues for more week, there will be infected patients. intensive care units will then be at maximum capacity; up to hospital beds will be needed by mid-april, . our analysis might help political leaders and health authorities to allocate enough resources, including personnel, beds, and intensive care facilities, to manage the situation in the next few days and weeks. if the italian outbreak follows a similar trend as in hubei province, china, the number of newly infected patients could start to decrease within – days, departing from the exponential trend. however, this cannot currently be predicted because of differences between social distancing measures and the capacity to quickly build dedicated facilities in china. according to nature, the spread of coronavirus disease (covid- ) is becoming unstoppable and has already reached the necessary epidemiological criteria for it to be declared a pandemic, having infected more than people in countries. therefore, a coordinated global response is desperately needed to prepare health systems to meet this unprecedented challenge. countries that have been unfortunate enough to have been exposed to this disease already have, paradoxically, very valuable lessons to pass on. although the containment measures implemented in china have-at least for the momentreduced new cases by more than %, this reduction is not the case in other countries, including italy and iran. italy has had confirmed cases according to the istituto superiore di sanità as of march , and deaths. only china has recorded more deaths due to this covid- outbreak. the mean age of those who died in italy was years and more than two-thirds of these patients had diabetes, cardiovascular diseases, or cancer, or were former smokers. it is therefore true that these patients had underlying health conditions, but it is also worth noting that they had acute respiratory distress syndrome (ards) caused by severe acute respiratory syndrome coronavirus (sars-cov- ) pneumonia, needed respiratory support, and would not have died otherwise. of the patients who died, · % were aged - years, · % were aged - years, · % were aged - years, and · % were aged - years (those aged > years made up · %). the male to female ratio is % to % with an older median age for women ( · years for women vs · years for men). on march , , the italian government imple mented extraordinary measures to limit viral transmission-including restricting movement in the region of lombardythat intended to minimise the likelihood that people who are not infected come into contact with people who are infected. this decision is certainly courageous and important, but it is not enough. at present, our national health system's capacity to effectively respond to the needs of those who are already infected and require admission to an intensive care unit for ards, largely due to sars-cov- pneumonia, is a matter of grave concern. specifically, the percentage of patients admitted to intensive care units reported daily in italy, from march , up until march , was consistently between % and % of patients who were actively infected. in italy, we have approximately beds in intensive care units. of those, as of march , are already devoted to patients with sars-cov- infection, and in the near future this number will progressively increase to the point that thousands of beds will soon be occupied by patients with covid- . given that the mortality of patients who are critically ill with sars-cov- pneumonia is high and that the survival time of non-survivors is - weeks, the number of people infected in italy will probably impose a major strain on critical care facilities in our hospitals, some of which do not have adequate resources or staff to deal with this emergency. in the lombardy region, despite extraordinary efforts to restrict the movement of people at the expense of the italian economy, we are dealing with an even greater fear-that the number of patients who present to the emergency room will become much greater than the system can cope with. the number of intensive care beds necessary to give the maximum number of patients the chance to be treated will reach several thousand, but the exact number is still a matter of discussion among experts. health-care professionals have been working day and night since feb , and in doing so around % (n= ) of them have become infected, and some have died. lombardy is responding to the lack of beds for patients with covid- by sending patients who need intensive care but are not infected with covid- to hospitals outside of the region to contain the virus. we present the following predictions to prepare our political leaders-those who bear the greatest responsibility for national health systems and the government at the regional level, as well as local health authorities-for what is predicted to happen in the days and weeks to come. they can then implement measures regarding staff resources and hospital beds to meet the challenges of this difficult time. official numbers of infected people during the covid- virus outbreak in italy are indicative of the spread of the infection, and of the challenges that will be posed to italian hospitals and, in particular, intensive care facilities. the number of patients who are infected has been published daily since feb , . it is possible to fit the available data for the number of patients who are actively infected into an exponential model, as reported in figure a . the value of the exponent can be computed as r= · ( per day) and is consistent with the number of infected patients reported by the italian health ministry. the consistency between the exponential prediction and the reported data is very close up until day . if the increase in the number of infected patients follows this trend for the next week, there will be more than patients infected by march , as shown in figure b . on the basis of the exponential curve prediction, and the assumption that the duration of infection ranges from to days, it is possible to calculate that the basic reproduction number ranges from · to · . this number is similar to that reported for the initial phase of the infection outbreak in the city of wuhan, china and slightly higher than · , as reported by li and colleagues in a more recent report. the number of patients admitted to intensive care units increased similarly in italy, with an exponential trend up until march . the best fit of the data reported by the italian ministry for health can be obtained using the same exponent that best fits the number of patients figure a . the data available up until march show that the trend in the number of patients who will need admission to intensive care units will increase substan tially and relentlessly in the next few days. we can predict with quite a good degree of accuracy that this number will push the national health system to full capacity in a matter of days. considering that the number of available beds in intensive care units in italy is close to , and assuming that half of these beds can be used for patients with covid- , the system will be at maximum capacity, according to this prediction, by march , . this situation is difficult, given that the number of patients who will need to be admitted to the intensive care unit is predicted to further increase after that date, as shown in figure b . at this point, the most important question is whether the increase in the number of patients who are infected and those requiring intensive care admittance will continue to rise exponentially and for how long. if the change in the slope of the curve does not take place soon, the clinical and social problems will take on unmanageable dimensions, which are expected to have catastrophic results. the only way we can make such predictions is by comparing the trends in the data collected in the hubei region in china for covid- infection with that for the italian population. from the official report of the who-china joint mission on coronavirus disease , it is possible to derive the cumulative curve of the patients who are infected from the start of the data series. these data, as reported in figure , show that the initial phase of the infection outbreak followed the expected exponential trend, with the same exponent previously calculated for the number of italian patients who were infected. starting jan , the cumulative number of patients who were infected started to diverge from the exponential trend days later. if the italian outbreak follows a similar trend to that in china, we can suggest that the number of newly infected patients might start to decrease within - days from march . similarly, we can foresee that the cumulative curve of patients who are infected will peak days later, with the maximum load for clinical facilities for the treatment of these patients foreseen for that period. the most difficult prediction is the maximum number of infected patients that will be reached in italy and, most importantly, the maximum number of patients who will require intensive care unit admission. this prediction is of crucial importance to plan for new facilities in italian hospitals and to calculate the time period in which they need to be available. on the basis that the region of hubei in china has a slightly smaller population than italy (approximately million in hubei and million in italy), we tentatively assumed that the trend for the maximum number of patients who are actively infected would be similar in the two territories. in doing so, we cannot overlook the fact that the effect of travel restric tions on the spread of the covid- outbreak and the extraordinary community measures taken within and outside of wuhan are unlikely to be replicated else where. moreover, the current approach to these patients in lombardy implies non-pharmacological and pharmacological interventions, including antiretroviral medication, which might be different from the wuhan outbreak, and could distort the calculation. we also realise that there is heterogeneity in the transmission dynamics between the city of wuhan and elsewhere in the province, where the number of people who are infected remains lower. therefore, it might not be unrealistic to assume that what is going to happen in italy soon might mirror what happened in hubei. of course, it would have been more appropriate to directly compare greater wuhan ( million people) with the region of lombardy ( million people), the most seriously affected region in italy at the moment, but such data are not available. we do not currently have additional evidence we can take into consideration to make more robust assumptions regarding the exact number of patients who will be infected in the future days or weeks. on the basis of the available data, the number of infected patients reached approximately at the end of february, , in the hubei region, when the number of new cases decreased to almost zero. given that so far the percentage of patients requiring ards treatment is close to % for patients who are actively infected, at least in lombardy, we can assume that we will need approximately beds in intensive care units during the worst period of infection, which is expected to occur in about weeks from march . this is challenging for italy, as there are now just over intensive care beds in total. the aim now is to increase this number to safely meet urgent future needs. according to our prediction, we have only a few weeks to achieve this goal in terms of procuring personnel, technical equipment, and materials. these considerations might also apply to other european countries that could have similar numbers of patients infected and similar needs regarding intensive care admissions. since , italy has had the privilege of having a national health system (servizio sanitario nazionale), which was reshaped from - . its principles and organisation derive from the british national health service model, and it is based on three fundamental principles. the first principle is universality-all citizens have an equal right to access services provided by the national health system. the second is solidarity-every citizen contributes to financing the national health service based on their means, through progressive taxation. the third is uniformity-the quality of the services provided by the national health service to all citizens in all regions must be uniform. all individuals are supposed to pay for it as taxpayers, each person giving a little to receive a lot in return, if they become unwell. in theory, we are in a better position than many other countries to react to the current outbreak. however, an aggressive approach needs to be taken with patients who are critically ill with sars-cov- , often including ventilatory support. the system's capacity to respond to changing circumstances has been under enormous pressure, at least in the lombardy region, where two clusters have already emerged since feb . we predict that if the exponential trend continues for the next few days, more than hospital beds for patients in intensive care units will be needed in only week to treat ards caused by sars-cov- -pneumonia in italy. in the meantime, the government is preparing to pass legislation that will enable the health service to hire more doctors and nurses and to provide more ventilators to italian hospitals. these measures are a step in the right direction, but our model tells us that they need to be implemented urgently, in a matter of days. otherwise, a substantial number of unnecessary deaths will become inevitable. intensive care specialists are already considering denying life-saving care to the sickest and giving priority to those patients most likely to survive when deciding who to provide ventilation to. this attitude has already been criticised by the current president of the italian comitato di bioetica who, in a recent declaration to lay press stated that the constitution recognises the right of every individual to receive all necessary health care. they might not recognise that the reality is that intensive care wards are overflowing with patients and that covid- is not a benign disease. our doctors and nurses are modern heroes in an unexpected war against a difficult enemy. in the near future, they will have no choice. they will have to follow the same rules that health-care workers are left with in conflict and disaster zones. we hope that the present analysis will help political leaders and health authorities to move as quickly as they can to ensure that there are enough resources, including personnel, hospital beds, and intensive care facilities, for what is going to happen in the next few days and weeks. finally, our analysis tends to suggest that measures to reduce transmission should certainly be implemented, as our government did on march , by inhibiting people's movement and social activities, unless strictly required. rather than revising the schengen visa-free zone, the most effective way to contain this viral outbreak in european countries is probably to avoid close contact at the individual level and social meetings in each country. ar was responsible for data analysis and statistics, and writing of the manuscript. gr was responsible for data analysis and writing of the manuscript. we declare no competing interests. time to use the p-word? coronavirus enter dangerous new phase tourism flows and death rates suggest covid- is being under-reported real-time nowcast and forecast on the extent of the wuhan cov outbreak, domestic and international spread early transmission dynamics in wuhan, china, of novel coronavirus-infected pneumonia joint mission coronavirus covid- global cases we thank kerstin mierke for writing assistance. key: cord- -w ne mj authors: leverenz, david l; tarrant, teresa k title: is the hscore useful in covid- ? date: - - journal: lancet doi: . /s - ( ) - sha: doc_id: cord_uid: w ne mj nan in a review of patients with covid- admitted to hospital, the iqr of ferritin concentrations at time of admission in non-survivors was · - · ng/ml, and the median ferritin did not exceed · ng/ml until days after symptom onset, when most patients had experienced acute respiratory distress syndrome requiring intubation. other hscore criteria such as hypertriglyceridaemia, splenomegaly, hepatomegaly, and bone marrow haemophagocytosis are not reported in most cohort studies of covid- . finally, high fevers are weighted heavily in the hscore; however, temperature above · °c does not distinguish between patients with moderate versus severe covid- . in summary, although we agree that the detection and management of hyperinflammatory states in covid- is important, we recommend against using the hscore due to a potential lack of sensitivity. we declare no competing interests. covid- : consider cytokine storm syndromes and immunosuppression development and validation of the hscore, a score for the diagnosis of reactive hemophagocytic syndrome clinical course and risk factors for mortality of adult inpatients with covid- in wuhan, china: a retrospective cohort study clinical and immunologic features in severe and moderate coronavirus disease key: cord- -ozvdz ew authors: altmann, daniel m; douek, daniel c; boyton, rosemary j title: what policy makers need to know about covid- protective immunity date: - - journal: lancet doi: . /s - ( ) - sha: doc_id: cord_uid: ozvdz ew nan about a third of the world is under lockdown as a public health measure to curb the spread of severe acute respiratory syndrome coronavirus (sars-cov- ), the virus that causes coronavirus disease . policy makers are increasingly pressed to articulate their rationales and strategies for moving out of lockdown; the process of re-emergence is already cautiously starting in austria, switzerland, denmark, wuhan, and some us states. as the counterpoise between further disease spread and socioeconomic costs is debated, it is essential that policy makers in all affected countries have the best possible data and understanding to inform any course of action. strategies in various countries that aim to stagger return to work on the basis of disease severity risk and age do not take account of how exposing even lower-risk individuals, such as young people with no comorbidities, to the virus so as to increase herd immunity can still result in pandemic spread. the only selective pressure on sars-cov- is transmission-stop transmission and you stop the virus. the linchpin for a strategy to move out of lockdown seemingly rests on increased testing and contact tracing, possible returnto-work permits based on immune status, repurposed or new therapeutics, and, finally, vaccination. , this approach is broadly sensible, yet immunology is a complex branch of molecular medicine and policy makers need to be alerted to important aspects of immunology in relation to covid- . there is no certainty as to the immunological correlates of antiviral protection or the proportion of the population who must attain them, making it impossible to identify a point when this level of immunity has been reached. current discussion, for example, addresses the notion that scaled up antibody testing will determine who is immune, thus giving an indication of the extent of herd immunity and confirming who could re-enter the workforce. there are questions to be addressed about the accuracy of tests and practicalities of implementation of laboratory-based versus home-use assays. for any country contemplating these issues, another crucial question is how solid is the assumption that antibodies to sars-cov- spike protein equate to functional protection? furthermore, if presence of these antibodies is protective, how can it be decided what proportion of the population requires these antibodies to mitigate subsequent waves of cases of covid- ? any discussions should be informed by consideration of correlates of protection. initially proposed by stanley plotkin, , this concept rests on the notion of empirically defined, quantifiable immune parameters that determine the attainment of protection against a given pathogen. caution is needed because total measurable antibody is not precisely the same as protective, virusneutralising antibody. furthermore, studies in covid- show that - % of symptomatically infected people have little or no detectable antibody. in some cases of covid- , low virus-binding antibody titres might correlate with lethal or near-lethal infection, or with having had a mild infection with little antigenic stimulation. importantly, scientists must not only identify correlates of protection but also have a robust understanding of the correlates of progression to severe covid- , since knowledge of the latter will inform the former. the route to certainty on the degree and nature of the immunity required for protection will require evidence from formal proofs using approaches such as titrated transfers of antibodies and t lymphocytes to define protection in non-human primate models, as used, for example, in studies of ebola virus. a study of survivors of sars showed that about % had functional, virus-neutralising antibodies and around % had strong t-lymphocyte responses. these observations bolster confidence in a simple view that most survivors of severe covid- would be expected to have protective antibodies. a caveat is that most studies, either of sars survivors or of covid- patients, have focused on people who were hospitalised and had severe, symptomatic disease. similar data are urgently needed for individuals with sars-cov- infection who have not been hospitalised. how long is immunity to covid- likely to last? the best estimate comes from the closely related coronaviruses and suggests that, in people who had an antibody response, immunity might wane, but is detectable beyond year after hospitalisation. [ ] [ ] [ ] obviously, longitudinal studies with a duration of just over year are of little reassurance given the possibility that there could be another wave of covid- cases in or years. specific t-lymphocyte immunity against middle east respiratory syndrome coronavirus, however, can be detectable for years, considerably longer than antibody responses. some of the uncertainty about covid- protective immunity could be addressed by monitoring the frequency of reinfection with sars-cov- . anecdotal reports of reinfection from china and south korea should be regarded with caution because some individuals who seemed to have cleared sars-cov- infection and tested negative on pcr might nevertheless have harboured persistent virus. virus sequencing studies will help to resolve this issue and in cases of confirmed reinfection it will be important to understand if reinfection correlates with lower immunity. policy briefings in the uk and other countries have rightly emphasised the imperative to collect seroprevalence data. this approach has sometimes been construed in a narrow sense as testing that would allow people back to work. however, seroprevalence data can show what proportion of a population has been exposed to and is potentially immune to the virus, and is thus wholly distinct from the snapshot of people who accessed pcr testing. how can one determine how much herd immunity is sufficient to mitigate subsequent substantial outbreaks of covid- ? this calculation depends on several variables, including the calculated basic reproduction number (r ), currently believed to be about · for sars-cov- . on the basis of this estimated r , the herd immunity calculation suggests that at least % of the population would need to have protective immunity, either from natural infection or vaccination. this percentage increases if r has been underestimated. most of the available covid- serology data derive from people who have been hospitalised with severe infection. , in this group, around % develop igg antibodies within the first weeks of symptomatic infection and this appearance coincides with disappearance of virus, supporting a causal relationship between these events. however, a key question concerns antibodies in non-hospitalised individuals who either have milder disease or no symptoms. anecdotal results from community samples yield estimates of under % of tested "controls" developing specific igg antibodies. we await larger seroprevalence datasets, but it seems likely that natural exposure during this pandemic might, in the short to medium term, not deliver the required level of herd immunity and there will be a substantial need for mass vaccination programmes. there are more than candidate covid- vaccines in development, with a handful in, or soon to be in, phase trials to assess safety and immunogenicity. candidate vaccines encompass diverse platforms that differ in the potency with which immunity is stimulated, the specific arsenal of immune mediators mobilised, the number of required boosts, durability of protection, and tractability of production and supply chains. , safety evaluation of candidate covid- vaccines will need to be of the highest rigour. some features of the immune response induced by infection, such as high concentrations of tumour necrosis factor and interleukin , which could be elicited by some candidate vaccines, have been identified as biomarkers of severe outcome. researchers should be commended for decades of iterative efforts, bringing us to a point where there are many candidate vaccines in development against a novel virus first sequenced in january, . delivery of efficacious vaccines is not a competitive race to the finish, but a considered evaluation of a safe, potent, global response. few would disagree that science should guide the clinical therapeutic approach to an infected person. science must also guide policy decisions. reliance on comprehensive seroprevalence data and a solid, researchbased grasp of correlates of protection will allow policy to be guided by secure, evidence-based assumptions on herd immunity, rather than optimistic guesses. we declare no competing interests. amanat f, krammer f. sars-cov- vaccines: status report. immunity ; : - . the covid- vaccine development landscape evaluation of antibody testing for sars-cov- using elisa and lateral flow immunoassays vaccination against the major infectious diseases immunologic correlates of protection induced by vaccination viral kinetics and antibody responses in patients with covid- chimpanzee adenovirus vaccine generates acute and durable protective immunity against ebolavirus challenge t cell responses to whole sars coronavirus in humans longitudinally profiling neutralizing antibody response to sars coronavirus with pseudotypes mers-cov antibody responses year after symptom onset, south korea t cell-mediated immune response to respiratory coronaviruses government begins large-scale virus infection and antibody test study vaccination and herd immunity to infectious diseases early transmission dynamics in wuhan, china, of novel coronavirus-infected pneumonia the basic reproduction number (r o ) of measles: a systematic review neutralizing antibody responses to sars-cov- in a covid- recovered patient cohort and their implications trials of anti-tumour necrosis factor therapy for covid- are urgently needed key: cord- -qkvo cji authors: marston, cicely; renedo, alicia; miles, sam title: community participation is crucial in a pandemic date: - - journal: lancet doi: . /s - ( ) - sha: doc_id: cord_uid: qkvo cji nan community participation is essential in the collective response to coronavirus disease (covid- ), from compliance with lockdown, to the steps that need to be taken as countries ease restrictions, to community support through volunteering. communities clearly want to help: in the uk, about million people volunteered to help the pandemic response and highly localised mutual aid groups have sprung up all over the world with citizens helping one another with simple tasks such as checking on wellbeing during lockdowns. global health guidelines already emphasise the importance of community participation. , incorporating insights and ideas from diverse communities is central for the coproduction of health, whereby health professionals work together with communities to plan, research, deliver, and evaluate the best possible health promotion and health-care services. pandemic responses, by contrast, have largely involved governments telling communities what to do, seemingly with minimal community input. yet communities, including vulnerable and marginalised groups, can identify solutions: they know what knowledge and rumours are circulating; they can provide insight into stigma and structural barriers; and they are well placed to work with others from their communities to devise collective responses. such community participation matters because unpopular measures risk low compliance. with communities on side, we are far more likely-together-to come up with innovative, tailored solutions that meet the full range of needs of our diverse populations. in unstable times when societies are undergoing rapid and far-reaching changes, the broadest possible range of knowledge and insights is needed. it is crucial to understand, for instance, the additional needs of particular groups, and the lived experiences of difficulties caused by government restrictions. we know lockdowns increase domestic violence; that rights and access to contraception, abortion, and safe childbirth care risk being undermined; and that some public discourse creates the unpalatable impression that the value of each individual's life is being ranked. identifying and mitigating such harms requires all members of society to work together. past experience should be our guide. grassroots move ments were central in responding to the hiv/aids epidemic by improving uptake of hiv testing and counselling, negotiating access to treatment, helping lower drug prices, and reducing stigma. [ ] [ ] [ ] community engagement was also crucial in the response to ebola virus disease in west africa-eg, in tracking and addressing rumours. coproduction under the pressures of the covid- pandemic is challenging and risks being seen as an added extra rather than as fundamental to a successful, sustainable response. good mechanisms for community participation are hard to establish rapidly. high-quality coproduction of health takes time. , meaningful relationships between communities and providers should be nurtured to ensure sustainable and inclusive participation. managing participatory spaces takes sensitivity and care to recognise and harness the different types of knowledge and experiences brought by diverse communities and individuals, , and to avoid replicating social structures that could create harms such as stigma. so how can we create constructive coproduction in the context of emergency responses to the covid- pandemic where time is short? we summarise the key steps in the panel. first, governments should immediately set up and fund specific community engagement taskforces to ensure that community voice is incorporated into the pandemic response. this requires dedicated staff who can help governments engage in dialogue with citizens, work to integrate the response across health and social care, and coordinate links with other sectors such as policing and education. this engagement will require additional resources to complement existing health services and public health policy. dedicated virtual and physical spaces must be established to co-create the covid- response, with different spaces tailored to the needs of different participants-eg, different formats for discussion, timings, locations, and levels of formality. second, those of us working to address covid- in the health and social care sectors and beyond should look to existing community groups and networks to build coproduction. engagement with such groups is needed to include their voices in local, regional, or national responses to the pandemic. how can we ensure that the most marginalised are represented? how can we ensure front-line providers have a chance to feed into service improvements when they are already working long hours with little respite? third, policy makers working on the covid- response should ensure citizens understand that their voices are being heard. showing how policy responses or local actions address specific concerns will help communities believe that their wellbeing is valued and their needs addressed, which in turn will help increase compliance with restrictions and encourage sharing of creative solutions. examples of responses to citizens' concerns have included introducing income guarantees for the self-employed; implementing road closures and widening to allow safer cycling and walking; and policy changes on home use of abortion medication to reduce risk of infection from attending clinics. institutional cultures that support coproduction must be created in political and health systems. we would argue that mechanisms to ensure citizen participation are essential for high-quality, inclusive disaster response and preparedness, and these can be called upon again in future emergencies. all societies have community groups that can co-create better pandemic response and health services and politicians must be supported to incorporate these voices. such public participation will reveal policy gaps and the potential negative consequences of any response-and identify ways to address these together. community participation holds the promise of reducing immediate damage from the covid- pandemic and, crucially, of building future resilience. we declare no competing interests. a million volunteer to help nhs and others during covid- outbreak. the guardian spaniards find beauty in helping each other amid covid- crisis the global strategy for women's, children's and adolescents' health ( - ). geneva: world health organization rights in the time of covid- . lessons from hiv for an effective, community-led response community participation for transformative action on women's, children's and adolescents' health international planned parenthood federation european network. sexual and reproductive health and rights during the covid- pandemic: a joint report by epf & ippf en grassroots community organizations' contribution to the scale-up of hiv testing and counselling services in zimbabwe adherence as therapeutic citizenship: impact of the history of access to antiretroviral drugs on adherence to treatment global assemblages: technology, politics, and ethics as anthropological problems social mobilization and community engagement central to the ebola response in west africa: lessons for future public health emergencies slow co-production" for deeper patient involvement in health care ten years of negotiating rights around maternal health in uttar pradesh spaces for citizen involvement in healthcare: an ethnographic study participation, health and the development of community resources in southern brazil guidance: claim a grant through the coronavirus (covid- ) self-employment income support scheme milan announces ambitious scheme to reduce car use after lockdown. the guardian rt hon matt hancock mp. decision: temporary approval of home use for both stages of early medical abortion towards a "fourth generation" of approaches to hiv/aids management: creating contexts for effective community mobilisation key: cord- -w dup b authors: so, loletta k-y; lau, arthur cw; yam, loretta yc; cheung, thomas mt; poon, edwin; yung, raymond wh; yuen, ky title: development of a standard treatment protocol for severe acute respiratory syndrome date: - - journal: lancet doi: . /s - ( ) - sha: doc_id: cord_uid: w dup b a series of patients with probable sars, diagnosed from who criteria, were treated according to a treatment protocol consisting of antibacterials and a combination of ribavirin and methylprednisolone. through experience with the first patients, we were able to finalise standard dose regimens, including pulsed methylprednisolone. one patient recovered on antibacterial treatment alone, showed rapid and sustained responses, and achieved improvement with step-up or pulsed methylprednisolone. four patients required short periods of non-invasive ventilation. no patient required intubation or mechanical ventilation. there was no mortality or treatment morbidity in this series. a series of patients with probable sars, diagnosed from who criteria, were treated according to a treatment protocol consisting of antibacterials and a combination of ribavirin and methylprednisolone. through experience with the first patients, we were able to finalise standard dose regimens, including pulsed methylprednisolone. one patient recovered on antibacterial treatment alone, showed rapid and sustained responses, and achieved improvement with step-up or pulsed methylprednisolone. four patients required short periods of non-invasive ventilation. no patient required intubation or mechanical ventilation. there was no mortality or treatment morbidity in this series. severe acute respiratory syndrome (sars) is an emerging infectious disease associated with a novel coronavirus and causing worldwide outbreaks. in two large series, the clinical, laboratory, radiological, and microbiological findings have been analysed. , treatment strategies remain diverse and experimental without uniform effectiveness. we describe, from our continuing prospective study, the development of a standard treatment protocol and its preliminary outcome. between march , and march , , clinically compatible sars patients were admitted to pamela youde nethersole eastern hospital, hong kong, among whom could be traced to an index case admitted on march and who died on march . our case definitions were: fever Њc or higher at presentation or in the previous days, with or without chills or rigor; influenza-like symptoms; new radiological infiltrates compatible with pneumonia; and contact history. exclusions were preexisting infective lung disorders, aspiration, or hospitalacquired bacterial pneumonia. all cases fulfilled the who criteria for probable sars cases current at that time. laboratory investigations included haematological (complete blood counts with differentials and clotting profile), biochemical (electrolytes, liver and renal function, creatine kinase, lactate dehydrogenase), and microbiological tests to exclude other causative pathogens (bacterial cultures of blood, sputum, and urine, serologies by microagglutination for mycoplasma and legionella, serologies by direct immunofluorescence for chlamydia, influenza, parainfluenza, and respiratory syncytial and adenoviruses, nasopharyngeal aspirates for viral cell cultures, and direct sputum smear for pneumocystis carinii by silver stain). all chest radiographs were semiquantified by separating each lung into six sections (upper, middle, and lower zones and medial and lateral divisions) and scoring them on a four-point scale: clear, subtle haziness or mild infiltrates, ground-glass appearance or prominent infiltrates, and confluent or dense opacities. three respirologists scored chest radiographs independently, with consensus decided between themselves in case of discordance. we launched the initial protocol on march , , consisting of combination treatment with a broad-spectrum antiviral and an immunomodulating agent. antibacterials were instituted before exclusion of recognised pathogens. acute viral infection may produce damage to host cells by cytolysis or immunopathological damage. in the early stage, cytolysis is accompanied by viral amplification, such that development of a standard treatment protocol for severe acute respiratory syndrome loletta k-y so, arthur c w lau, loretta y c yam, thomas m t cheung, edwin poon, raymond w h yung, k y yuen standard treatment protocol for sars (suspected and probable) in adult patients antibacterial treatment q start levofloxacin mg once daily intravenously or orally q or clarithromycin mg twice daily orally plus coamoxiclav (amoxicillin and clavulanic acid) mg three times daily orally if patient < years, pregnant, or suspected to have tuberculosis add combination treatment with ribavirin and methylprednisolone when: q extensive or bilateral chest radiographic involvement q or persistent chest radiographic involvement and persistent high fever for days q or clinical, chest radiographic, or laboratory findings suggestive of worsening q or oxygen saturation < % in room air standard corticosteroid regimen for days q methylprednisolone mg/kg every h ( mg/kg daily) intravenously for days q then methylprednisolone mg/kg every h ( mg/kg daily) intravenously for days q then prednisolone · mg/kg twice daily ( mg/kg daily) orally for days q then prednisolone · mg/kg daily orally for days q then prednisolone · mg/kg daily orally for days q then off ribavirin regimen for - days q ribavirin mg every h ( mg daily) intravenously for at least days (or until condition becomes stable) q then ribavirin mg twice daily ( mg daily) orally pulsed methylprednisolone q give pulsed methylprednisolone if clinical condition, chest radiograph, or oxygen saturation worsens (at least two of these), and lymphopenia persists q give as methylprednisolone mg twice daily intravenously for days, then back to standard corticosteroid regimen ventilation q consider non-invasive ventilation or mechanical ventilation if oxygen saturation < % while on > l per min oxygen or if patient complains of increasing shortness of breath conditioning) was increased to - changes per h. two exhaust ventilation fans were installed in each cubicle to achieve negative-pressure airflow. closed-system suction was used for mechanical ventilators, the tubes of which were fitted with high-efficiency particulate air or similar filters. all health-care workers wore surgical or n- masks, protective eye-wear, full-face shields, caps, gowns with full sleeve coverage, surgical gloves, and shoe covers. advanced barriers, such as the air-mate hepa powered air purifying respirator system ( m, mn, usa) or t personal protection system (stryker instruments, mi, usa) were stocked in case high-risk procedures, such as endotracheal intubation, were required. staff washed hands with antiseptic rubs after every contact with patients or contaminated objects and after taking off protective garments. direct contact of eyes, nose, or mouth with hands before sanitisation was discouraged. environmental or equipment surfaces were cleaned daily and immediately after use with domestic bleach ( ppm hypochlorite solution) for non-metallic items and % alcohol for metallic items. we treated chinese residents ( men) with a mean age of · years (sd · ). four ( %) patients were smokers and one had comorbidities (diabetes mellitus, hypertension, coronary artery disease). clinical and laboratory features for were described in earlier reports. , overall, presenting symptoms included pyrexia ( %), chills or rigor ( %), malaise ( %), anorexia ( %), cough ( %), myalgia ( %), headache ( %), dyspnoea ( %), and diarrhoea ( %). mean temperature was · Њc ( · ), pulse · beats per min ( · ), respiratory antivirals may be important in treatment. in the later stage, when adaptive immune response is mounted, viral clearance can be accompanied by severe inflammatory damage, especially with high viral burden. an immunomodulating agent, such as a corticosteroid, could reduce tissue damage. as an antiviral we chose ribavirin for its potency against dna and rna viruses, and methylprednisolone to achieve immunomodulation. dose and weaning schedules of methylprednisolone were modified according to our experiences in treating the first patients and the index case. the index case's fatal outcome suggested that late administration of combination treatment was probably ineffective. patients with heavier bodyweights worsened despite intravenous mg methylprednisolone every h. correction for bodyweight to mg/kg daily resulted in lowering of fever and radiographic improvement in - days, but in most patients fever worsened again thereafter. we therefore increased the initial methylprednisolone dose to mg/kg daily, but several severe cases continued to worsen and required pulsed methylprednisolone. finally, since stepdown of methylprednisolone dose in - days resulted in rebound of sars in some patients, each dose level was continued for days. we finalised our treatment protocol on march , (panel). we also implemented stringent infection control measures to keep to a minimum droplet spread and possible contact with patients' secretions, fluids, or excreta. patients with suspected or probable sars and convalescent cases were put into isolation cubicles, each accommodating four to six patients, and visits were not allowed. a=rapid and sustained response to ribavirin and methylprednisolone mg/kg daily. b=extensive disease requiring early pulsed methylprednisolone to achieve response. c=early step down of methylprednisolone dose resulted in rebound of sars; the patient responded later to pulsed methylprednisolone. rate · breaths per min ( · ), and oxygen saturation · % ( · ). common presenting laboratory findings were lymphopenia ( · ϫ /l [ · ]) in %, thrombocytopenia ( ϫ /l [ ]) in %, and raised lactate dehydrogenase ( iu/l [ ]) in %. all patients had chest-radiograph abnormalities on admission ( % bilateral), with %, %, % in upper, middle, lower zones, respectively, features of subtle haziness in %, ground glass appearance in %, and dense opacities in %. total mean chest radiography scores were · ( · ). we followed up patients for a mean of · days ( · ). of patients required combination treatment at a mean of · ( · ) days after admission and · ( · ) days after symptom onset. one patient, who was seropositive for the novel coronavirus and viral rna in nasopharyngeal aspirates recovered on levofloxacin alone. rapid (within - days) and sustained response to the combination treatment was evident in patients (figure). in the remaining , two required step-up of methylprednisolone dose and received pulsed methylprednisolone for severe disease (figure) or rebound after rapid step-down of methylprednisolone dose (figure). patients required oxygen and four required short periods ( - days) of noninvasive ventilation at - cm h o expiratory pressure. no patient required intubation nor mechanical ventilation, and no death has occurred since we started using the treatment protocol. we attribute the death of our index case to late diagnosis and treatment that did not conform to our subsequent standard protocol. high dose corticosteroids produced no severe complications, although prophylactic antibiotics (piperacillin and tazobactam) had been given to seven patients who had fever and raised white cell counts; all recovered and had negative bacterial cultures. ribavirin led to no complications, despite its known adverse effects of haemolysis and arrhythmia. in this emerging disease that frequently has rapid deterioration, the inclusion of control patients was not possible or ethical. future controlled studies may be able to shed more light on the efficacy of our treatment protocol. l k-y so and a c w lau designed the study. the treatment protocol was developed by a c w lau, l k-y so, t m t cheung, and l y c yam. data collection was done by l k-y so, a c w lau, and e poon, and data analyses by a c w lau and l k-y so. l k-y so and a c w lau wrote the report, which was reviewed by all investigators. k y yuen and r w h yung provided microbiological and infection control advice, and l y c yam coordinated the whole study. transient myeloid disorder is a unique self-regressing neoplasia specific to down's syndrome. the transcription factor gata is needed for normal growth and maturation of erythroid cells and megakaryocytes. mutations in gata have been reported in acute megakaryoblastic leukaemia in down's syndrome. we aimed to investigate changes in gata in patients with down's syndrome and either transient myeloid disorder (n= ) or acute megakaryoblastic leukaemia (n= ). we recorded mutations eliminating exon from gata in all patients with transient myeloid disorder (age - days) and in all with acute megakaryoblastic leukaemia (age - months). the range of mutations did not differ between patients with each disorder. patients with transient myeloid disorder with mutations in gata can regress spontaneously to complete remission, and mutations do not necessarily predict later acute megakaryoblastic leukaemia. lancet ; : - transient myeloid disorder is a self-regressing myeloproliferative disorder that arises mainly in babies with down's syndrome during the first weeks of life, - affecting as many as % of all neonates with down's syndrome. it could therefore provide valuable insights into cellular mechanisms that could be exploited to control proliferation outside conventional therapeutic approaches. , wechsler and colleagues noted acquired mutations in the erythroid/megakaryocyte lineage-specific transcription factor gata in genomic dna samples from six of six patients with down's syndrome and acute megakaryoblastic leukaemia, and in none of controls. all mutations were acquired (dna from remission samples did not have the gata changes) and all resulted in a premature translation termination, eliminating the gata activation domain (encoded by exon ). without examination of patients with transient myeloid disorder, we cannot understand if the gata dysfunction is a primary permissive event or a second hit, important for emergence of fully developed leukaemia. thus, we aimed to investigate gata mutations in tissue samples from patients with down's syndrome and transient myeloid disorder. we analysed exon of gata by reverse transcription pcr (rt-pcr), directly from rna of presentation samples of patients. samples were surplus or archived clinical coronavirus as a possible cause of severe acute respiratory syndrome a major outbreak of severe acute respiratory syndrome in hong kong case definitions for surveillance of severe acute respiratory syndrome (sars) induction of postinflammatory cytokines in human macrophages by influenza a (h n ) viruses: a mechanism for the unusual severity of human disease? a cluster of cases of severe acute respiratory syndrome in hong kong correspondence to: dr loletta kit-ying so we thank s w pang, f m f cheung, and lily ma-tung, department of pathology, for providing diagnostic support for our index case; and frankie choi, department of nuclear medicine, pamela youde nethersole eastern hospital, for his scientific and technical contributions. we thank also all our medical and nursing colleagues who have worked in the sars wards of pamela youde nethersole eastern hospital. none declared. key: cord- -ve lag authors: yang, yichang title: use of herbal drugs to treat covid- should be with caution date: - - journal: lancet doi: . /s - ( ) - sha: doc_id: cord_uid: ve lag nan on april , , a chinese official announced at a press conference that indications of three patent herbal drugs were approved to be expanded to include covid- symptoms. this included lianhuaqingwen capsules and jinhuaqinggan granules for mild conditions, and xuebijing (injectable) for severe conditions. these drugs are widely used to treat covid- in china. the official claimed the patent herbal drugs can effectively relieve symptoms, such as fever, cough, and fatigue, and reduce the probability of patients developing severe conditions, but without giving fur ther details. so far, no high-quality, rigorously peerreviewed clinical trials of herbal drugs have been reported in internationally recognised journals. the approvals, based on in-vitro investigations and an ecdotal clinical data, will probably lead to several worrisome consequences. first, safety is the top priority. advocates argue that herbal drugs are widely used and safe, but the truth is that all drugs carry risks. in the s, vanherweghem and colleagues reported that some women who followed a slimming herbal remedy developed rapidly progressive renal failure and urothelial carcinoma. further investigations highlighted the role of aristolochic acid, a compound found in many traditional herbs. , certain batches of an injectable herbal drug called xiyanping, which is recommended by the chinese diagnosis and treatment protocol of covid- , have already been recalled after reports of adverse effects. although these patent herbal drugs have been used clinically for several years, when we apply them to a novel disease like covid- , especially in combination with other antivirals, antibiotics, and immune suppressants, the safety should be cautiously evaluated. second, more evidence is required through controlled clinical trials to support the efficacy of these herbal drugs. many traditional medicine practitioners believe that herbal remedies cannot be tested because they are tailored to each individual's syndromes. this argument is simply not convincing. because the patent herbal drugs are produced in advance of any treatment and their composition is fixed, clinical endpoints including mortality, time to clinical improvement, and number of days in an intensive care unit can be used to evaluate the efficacy of the herbal drugs for covid- . standardised trials might have methodological challenges, consuming time and effort, but that should not be the reason for lowering safety and efficacy standards. thousands of years of usage and faith cannot be taken as evidence for efficacy of traditional herbs. third, the basic molecular mechanism is obscure. lianhuaqingwen capsules have been shown to have wide-spectrum antiviral effects and anti-inflammatory activities, , but the active ingredients and the underlying mechanism of action are unknown. herbal drugs usually contain many active ingredients, and it is important to better understand which ingredients are functional, and how they work. limited experimental cell cultures and animal studies cannot guarantee safety and efficacy. finally, the public can easily purchase herbal drugs without a doctor's prescription. driven by the claim that some patent herbal drugs can effectively treat covid- , some patients with flu symptoms who fear quarantine measures are likely to selfmedicate with herbal remedies and avoid going to hospital, thus delaying the proper diagnosis and treatment of the disease, and hampering the government's testing, tracing, and quarantining efforts. at the end of january, , rumours circulating on social media suggested that a patent herbal drug called shuanghuanglian, which contains honeysuckle and forsythia and is used routinely in traditional medicine to treat influenza and the common cold, helps ward off or even cure covid- . millions of people nationwide crowded into drug stores to buy the herbal drug as a justin-case remedy. the current covid- pandemic is an unprecedented challenge for the chinese government and the general public. doctors and researchers are desperately seeking a proven cure for it. when the conventional drugs such as lopinavir, ritonavir, chloroquine, and hydroxychloroquine are not as effective as expected, , screening potential active components from traditional herbal medicine is a viable strategy that should not be dismissed. my colleagues and i have previously called for more attention to testing traditional herbal medicine for the treatment of covid- , but a rushed judgment without sufficient scientific evidence should be cautioned against. given the formidable morbidity and mortality of covid- , it is understandable to see emergency use of unproven drugs, but the approval of a new indication for herbal drugs should still build on evidence. in the past decades, the chinese government has invested huge sums of money to promote the modernisation and standardisation of traditional medicine, carrying out sustainable basic and clinical research to get international recognition, but the rushed approval seems to be a backward step. the attempt to develop rigorously tested drugs from traditional herbal medicine should not be given up. it is the only way to protect our vulnerable patients. national health commission. press conference of the joint prevention and control mechanism of the state council on rapidly progressive interstitial renal fibrosis in young women: association with slimming regimen including chinese herbs urothelial malignant disease and chinese herbal nephropathy diagnosis and treatment protocol of covid- traditional chinese medicine needs proper scrutiny the chinese prescription lianhuaqingwen capsule exerts anti-influenza activity through the inhibition of viral propagation and impacts immune function lianhuaqingwen exerts anti-viral and antiinflammatory activity against novel coronavirus (sars-cov- ) a trial of lopinavirritonavir in adults hospitalized with severe covid- chloroquine and hydroxychloroquine in covid- traditional chinese medicine for covid- key: cord- -ttz oszw authors: jordana, jacint; triviño-salazar, juan carlos title: where are the ecdc and the eu-wide responses in the covid- pandemic? date: - - journal: lancet doi: . /s - ( ) - sha: doc_id: cord_uid: ttz oszw nan as the eu continues to face the covid- pandemic, an unprecedented transboundary crisis, its member states resort to measures within the boundaries of the nation state. this situation questions the capacity of the eu to deploy public health instruments to cope with pandemics. one such instrument, the european centre for disease control (ecdc), seems to show a discreet involvement in this crisis, suggesting emerging isolationist behaviours of the member states. the ecdc was established in with a mandate that aimed to "identify, assess and communicate current and emerging threats to human health from communicable diseases". however, such a mandate was not complemented with enough resources to help the ecdc become a european knowledge hub in communicable diseases. to put this into perspective, the us centers for disease control and prevention (cdc) have legal powers and cover a greater range of public health areas through bodies such as the national institute for occupational safety and health or the national center for health statistics. the cdc also has a much larger budget than the ecdc (approximately us$ billion for , whereas the ecdc received € million ) and staff ( employees in , whereas the ecdc employed people that year ). the ecdc was established within a context that involved inconsistent national laws on pandemic planning across the eu member states, which already had their own institutes and agencies of public health. in fact, it has been noted that the protectiveness of member states concerning their national privileges sometimes blocks agreement on practical and collective measures. in our research on the role of eu agencies in crisis episodes, we described how the low cooperation in public health issues within europe severely hampered the involvement of the ecdc in the european response to the ebola outbreak. although the massive dimensions of the current crisis are not comparable to the ebola outbreak, the restrictive political mechanism at play previously shows what might be standing in the way of a coherent response to the covid- pandemic. in january, , the member states did not see the need for the eu to coordinate their responses, as they tended to underestimate the impact of the pandemic and the resources needed. however, the pandemic intensified within a very short period and became a large threat for the entire european population. such a quick escalation became an obstacle to coordination at the eu level-a scenario where the ecdc could have been called to have a more active role, on behalf of the european commission and the member states. the lack of coordination at the eu level became even more evident when national leaders sought to legitimise their decisions by giving voice to national experts, in the absence of multinational meta-analytical infrastructure or supranational coor dination mechanisms, or even coherent systems for sharing procedures and protocols. the european commission advisory panel on covid- was set up by the eu member states as late as march , . from a policy perspective, a european public health response to the covid- pandemic was not possible because emergency structures had not been set up. neither was it perceived to be a public good, not even when it spread across european countries. for instance, the creation of a strategic eu medical stockpile was approved by the commission in march, . however, it was only implemented after who declared the outbreak a global pandemic on march , , and several member states had difficulties in purchasing medical equipment. we have found that only when key actors in the eu polity agree on a common response that is less politically costly than disagreement can european-wide public health mechanisms such as the ecdc adopt a more active role. however, for this situation to occur, institutions need enough time to frame coordinated responses and a political leadership capable of going beyond national responses and confronting such global challenges in a more effective way. we declare no competing interests. regulation (ec) no / of the european parliament and of the council of budget statement of revenue and expenditure of the european centre for disease prevention and control for the financial year ( /c / ) the role of networks in the european union public health experience eu agencies' involvement in transboundary crisis response: supporting efforts or leading coordination? commission decision of . . setting up the commission's advisory panel on covid- commission implementing decision (eu) / of march amending implementing decision (eu) / as regards medical stockpiling resceu capacities covid- : commission creates first ever resceu stockpile of medical equipment key: cord- -ntv e s authors: han, qide; chen, lincoln; evans, tim; horton, richard title: china and global health date: - - journal: lancet doi: . /s - ( ) - sha: doc_id: cord_uid: ntv e s nan china is the world's oldest continuous civilization. during the past years, the country has emerged as a strong and confi dent global partner. at home, china has experienced unprecedented material improve ments, doubling its gross domestic product per capita, for example, between and . what are the major challenges for the health of the chinese people? what are the implications for global health? the authors of the papers in this special issue of the lancet on china's health system were invited to address these questions as china's global engagement continues to expand in the opening decade of the st century. - the reasons for commissioning this report are compelling. despite accounting for over a fi fth of the world's population, the importance of china to global health has been under-recognised by the international health community. this perception is changing rapidly, especially after the august, , olympics. there are at least four reasons, contemporary and historical, for china's growing role in global health. first, the sheer demographic weight of china's popula tion undergoing rapid and profound health transitions is of enormous global importance. china is a substantial part of virtually all global health challenges: the prevalence of chronic cardiovascular diseases and cancers; re-emergence of infectious threats such as avian infl uenza; nutritional transitions due to changing food, diet, and physical activity; and new environmental and behavioural threats. [ ] [ ] [ ] for each of these health challenges, what happens in china is a major driver in the dynamics of global health. second, china is a major source of health innovationwhether based on its rich traditional pharmacopoeia, its modern cadres of engineers and scientists, or as a source of social experimentation. for example, artemesinin, the most eff ective drug against the malaria parasite, comes from traditional chinese medicine. china's universities and modern research laboratories are increasingly attracting outsourced research and development investments. community health workers that were pioneered in the s and subsequently refashioned as barefoot village doctors are an acknowledged chinese innovation for primary health care. china, like many other countries, is struggling to manage the public-private mix in health care; its new eff orts to address various market failures are likely to contribute signifi cantly to global understanding of what does and does not work. , , third, china is a major contributor in the control and spread of global health risks, an inevitable aspect of china's growing international participation in the trade of goods, services, and people. in other words, what happens in china is important for the health of others around the world. emergence of new infectious diseases, such as severe acute respiratory syndrome, and persistence of old pathogens (eg, tuberculosis) illustrate why china's health situation has global importance. the spread of transnational health risks is an inevitable aspect of china's participation in global transactions, as recently illustrated by controversy surrounding pet foods, cough syrup, and toothpaste. moreover, as china's energy consumption grows, industrial pollution and carbon production will assume growing global health importance. finally, china's customary reserved role in international institutions is changing as the country assumes more global responsibilities, especially in peace and social sectors such as health. although china's health sector is overwhelmingly internally focused, its global reach is expanding, as shown by its assistance to sub-saharan africa, to where china has dispatched more than health teams. china's success in securing the election of the fi rst chinese head of a un agency, who, marked a turning point of china's participation in global health governance. to probe the scope and depth of china in the context of global health, a collaboration between chinese and international health scientists-convened by the peking university health sciences centre, the lancet, and the china medical board-commissioned this report, including papers: seven theme papers and commentaries. - written by authors, of whom two-thirds are chinese, the report brings together diverse scientifi c evidence about china's major health problems, its current strategies, and china's health future. like many other developing countries, china has experienced dramatic demographic and epidemiological transitions. with a population that is mainly urbanised and elderly, china's major health threats are chronic diseases, now accounting for more than three-quarters of all deaths. patterns of injury are also changing. although china has been successful in the control of infections and maternity-related conditions, these health problems have by no means been eliminated, as exemplifi ed by continuing infectious outbreaks, reproductive health problems, and persistent schistosomiasis. evidence underscores the fact that china faces a daunting health future. behavioural shifts cast a long and dark shadow of burdens due to such risk factors as smoking and changes to diet and physical activity that will be accompanied by new infections, environmental threats, and behavioural pathologies. an important signal of china's stronger political commitment to health is shown by the expanding role of the state in health-care provision and stewardship, together with the mobilisation of communities and civil society for health improvement. the results of these changes are already measurable. china is now on track to reach millennium development goal (mdg) , reducing child mortality by two-thirds between and . this achievement has been made through antipoverty policies, land reform, investments in agriculture, and economic growth, as well as through improved health services. china has also made important progress on mdg , the reduction of maternal mortality. health care in china, however, is distinctive in several ways. first, the scale is vast. whatever the problem or solution, china's health conditions are gigantic in size-with more than million smokers, million people with hypertension, and an estimated million urban migrants, stretching demand for new forms of health care. , second, the speed of health change in china has been extremely rapid. health transitions that took nearly a century in other richer countries have taken place in a few decades in china. , third, china's unique national history and ecology have resulted in great diversity in health conditions and responses. many aspects of health in china will demonstrate both commonality and exceptionalism within the country and among nation states. an example is medical ethics and human rights, in which china has been moving towards universal norms while at the same time contributing a unique tradition of chinese philosophy and values. and fourth, china increasingly has the economic capacity to make profound advances in health. china's spectacular economic growth enables it to augment its investments in health substantially. like many countries facing complex health and healthcare challenges, it is all too easy to oversimplify the situation in china, where there are many unanswered puzzles. even as china has witnessed increasing numbers of deaths from transport injury, for example, it has had a striking but largely unexplained decline in suicides; sociocultural dynamics that generate high male but low female smoking rates are inadequately understood; and many clinical medicine graduates do not end up working as doctors. understanding these and other health conundrums deserves prioritisation, facilitated by a review of research needs and eff orts to improve the quality of and access to relevant health information. achieving health equity is china's main health challenge, in view of the well documented problems of incomplete coverage, uneven access, mixed quality, escalating cost, and high risk of catastrophic health expenditures. the chinese government recognises these challenges and has announced the healthy china initiative to reform disease prevention and health promotion, health-care services, pharmaceutical policies, and health insurance. these eff orts are the latest and most ambitious round of health reforms that aim to tackle growing health inequities. , drastic reforms of health fi nancing (more public investment, improved prevention, universal insurance, containment of costs, enhancement of quality, and alignment of incentives) and human resource development (improved quality and distribution of a quantitatively large workforce) will be necessary. , china has a unique opportunity to mobilise its resources and to harness global knowledge to achieve advances in health, compressing the time and reducing the scale of the disease burden that many other developed countries have had. [ ] [ ] [ ] [ ] [ ] how china fares is important not only for chinese people but also for the global health community. the global importance of china is assured by its size and scale, its wellspring of innovation, and its role in shared risks and interdependent solutions. in the future, china's global-health interactions will undoubtedly acceleratein areas such as science and technology, research and development, clinical trials, and new procedures such as organ transplantation. china will also be the source of social system innovations, such as its real-time online disease surveillance system. history has shown that china can produce and harness knowledge, create innovative approaches, and implement at large-scale eff ective solutions for both its own people as well as the world community. this report aims to initiate long-term collaboration between the lancet and china, together with the china medical board and who, including critically important partners, such as scientists outside china who have strong interests in working with chinese colleagues. the purpose of this collaboration is to introduce china's health system, achievements, and predicaments to the world and to foster scientifi c and institutional alliances that can strengthen the health-and ameliorate the adverse social and environmental determinants of health-of the chinese people. we are at the beginning of this relationship. our report, we hope, has the potential to catalyse progress towards enhanced human health and wellbeing in china. advances in medicine in the th century, along with an ageing population and changes in lifestyles, have altered the nature of diseases. malnutrition and traditional infectious diseases have been replaced by chronic non-communicable diseases and emerging infectious diseases. in china, more than % of deaths are caused by chronic non-communicable diseases. these increasing worldwide needs have placed biomedicine centre stage. the development of biomedical research in china, a country with · billion people, is a massive and unique challenge. initially when china opened its doors via policy tackling the challenges to health equity in china emergence and control of infectious diseases in china emergence of chronic non-communicable diseases in china injury-related fatalities in china: an under-recognised public-health problem china's human resources for health: quantity, quality, and distribution reform of how health care is paid for in china: challenges and opportunities china's health system performance biomedical science and technology in china evolution of china's health-care system traditional chinese medicine anthropology in china's health promotion and tobacco reproductive health in china: improve the means to the end china's hiv/aids epidemic: continuing challenges schistosomiasis control: experiences and lessons from china china's barefoot doctor: past, present, and future medical research ethics in china government and organ transplantation in china internal migration and health in china countdown to for maternal, newborn, and child survival: the report on tracking coverage of interventions key: cord- - bui ioe authors: jarlais, don c des; arasteh, kamyar; gwadz, marya title: increasing hiv prevention and care for injecting drug users date: - - journal: lancet doi: . /s - ( ) - sha: doc_id: cord_uid: bui ioe nan in the lancet today, bradley mathers and colleagues make a heroic eff ort-in fact, a systematic review-to document the coverage (services provided per individual in need of services) for hiv prevention and care for injecting drug users (idus) throughout the world. whilst the problems in obtaining data and in assessing the quality of data that could be obtained were formidable, two conclusions can be safely drawn. first, there is great variation in coverage of hiv-related services for idus across diff erent countries; and second, in much of the world, coverage is clearly inadequate. there is considerable evidence that hiv-prevention programmes for idus, particularly combined programming, in which multiple programmes are provided, can be very eff ective in reducing injecting-related hiv transmission. , this evidence suggests that the primary global need is not for new interventions to change the behaviour of idus, but for eff ective interventions to change the behaviour of policy makers to make policies and programmes consistent with the evidence base for hiv prevention and care for idus. over the past years, several useful theories have been developed for changing the health behaviour of idus and others at high risk for hiv. it may be time to apply those theories to changing the behaviour of policy makers. the fi rst set of theories are diff usion of innovations and social learning/modelling theories. these theories articulate how new behaviours spread through social systems and how individuals in these systems infl uence each other to either adopt (or resist) new behaviours. , these theories have been applied in idu interventions developed by many diff erent researchers and have the major advantage of often producing self-sustaining behavioural changes in the idu community. applying these theories to changing the behaviour of national policy makers raises interesting questions. is the policy-making system relatively open or relatively closed to innovations? is the policy-making system highly centralised (one decision centre) or decentralised (multiple decision centres)? who might become the early adopters and serve as models or opinion leaders for others in the system? the answers to such questions would provide guidance about initiating system change. the second theory is contingency management. this theory comes from basic behaviourism theory. , if you want to increase the frequency with which an individual performs a specifi c behaviour, provide a reward when syringe-exchange programmes in which a drug user is given a new sterile syringe for bringing in a used and potentially contaminated syringe might be the most common example of contingency management to reduce hiv transmission. within behaviour theory, onefor-one reinforcement is typically not the most eff ective schedule for behavioural change. for syringe exchange, the maximum reductions in risk behaviour seem to occur when drug users are provided with suffi cient numbers of syringes to meet their own needs, and they obtain extra syringes which can then be given to peers, leading to additional social reinforcement. syringeexchange programmes typically have many services in addition to basic exchange, which serve as additional reinforcers. who would provide what sort of reward to political leaders for implementing hiv services for idus? the reward of averting large numbers of hiv infections in idus is certainly important, but is not consistent with a primary principle of contingency management: that rewards should be given immediately after performance of the desired behaviour. international donors, however, could require that evidence-based services for idus be included in national plans to address hiv for a country to receive any hiv prevention and treatment resources. the global fund for aids, tuberculosis and malaria has adopted this approach, although, as shown by mathers and colleagues, there is a need for better follow-through to ensure that appropriate resources are actually provided to idus, particularly for antiretroviral therapy. the third theory is psychological framing of decisions. framing refers to setting the psychological context within which a decision will be made. , the same person might make diff erent decisions depending on how a question is framed. aids reframed the act of sharing syringes for idus. before aids, sharing was an act of assistance and solidarity; after aids, sharing syringes became an act in which a fatal disease could be transmitted. many policy makers frame hiv prevention for idus in terms of what appears to encourage or condone drug use, and then oppose harm-reduction programmes. within this frame, data showing that such programmes do not lead to increased drug use have had little eff ect in reducing opposition. it might be more eff ective to frame hiv prevention for idus in terms of the health of the community as a whole, and that public health is fundamental to the economic wellbeing of a society. for example, the economic costs of the epidemic of severe acute respiratory syndrome in china were instrumental in convincing the government there that it needed to address aids. what are we learning? literally millions of dollars and euros have been spent on collecting data and evaluating interventions to change the hiv-related behaviours of idus. it is time to establish a mechanism for collecting and systematically analysing data on eff orts to change policies to increase implementation of hiv programmes for idus. hiv continues to spread among idus in many diff erent countries, and the need for scaling up prevention and treatment is urgent. although theorybased policy-implementation interventions need to be adapted to local situations, we suggest that contingency management and framing the issue in community health-economic terms might be the most useful for immediate policy change. long-term sustained eff orts to protect the health of individuals who use both licit and illicit drugs might require that policy makers acquire a basic scientifi c understanding of drug use and addiction, and frame policies toward drug users within a public health and human rights perspective. the vaccine was incorporated into the cdc's vaccines for children program at the same time. some public health professionals speculated that the vaccine's rapid fda approval and lightning-fast inclusion in cdc programmes would be followed by a colossal failure in the delivery system. specifi cally, although the vaccine's greatest potential clearly lies in the benefi ts it could confer on girls who face a high risk of cervical cancer, public health experts anticipated that the vaccine would mostly go to girls at low risk of the disease. the groups of girls more and less likely to benefi t from hpv vaccination can be readily distinguished in the usa. those who are poor and have restricted access to regular pap testing (and the follow-up assessments and treatments that it triggers) are at high risk of invasive cervical cancer. those who are more affl uent and have access to regular pap testing are at low risk of the disease because the test, when properly done, is highly eff ective. cervical cancer burden diff ers greatly between these two groups. in the fairly poor state of mississippi (median annual household income us$ ), the ageadjusted cervical cancer mortality rate is · per . in rhode island, which is a wealthy state (median $ ), the cervical cancer mortality rate is % lower ( · per ). were the vaccine to mostly go to girls in states such as rhode island rather than those in mississippi, such a pattern would not only fail to match contingency management and relapse prevention as stimulant abuse treatment interventions syringe exchange, injecting and intranasal drug use choices, values and frames contributions of behavioural decision theory to research in political science community attitudes toward hiv prevention for injection drug users: fi ndings from a cross-border project in southern china and northern vietnam human rights and hiv prevention among drug users key: cord- -lbcxl w authors: anderson, roy m; heesterbeek, hans; klinkenberg, don; hollingsworth, t déirdre title: how will country-based mitigation measures influence the course of the covid- epidemic? date: - - journal: lancet doi: . /s - ( ) - sha: doc_id: cord_uid: lbcxl w nan governments will not be able to minimise both deaths from coronavirus disease (covid ) and the economic impact of viral spread. keeping mortality as low as possible will be the highest priority for individuals; hence governments must put in place measures to ameliorate the inevitable economic downturn. in our view, covid has developed into a pandemic, with small chains of transmission in many countries and large chains resulting in extensive spread in a few countries, such as italy, iran, south korea, and japan. most countries are likely to have spread of covid , at least in the early stages, before any mitigation measures have an impact. what has happened in china shows that quarantine, social distancing, and isolation of infected populations can contain the epidemic. this impact of the covid response in china is encouraging for the many countries where covid is beginning to spread. however, it is unclear whether other countries can implement the stringent measures china eventually adopted. singapore and hong kong, both of which had severe acute respiratory syndrome (sars) epidemics in - , provide hope and many lessons to other countries. in both places, covid has been managed well to date, despite early cases, by early government action and through social distancing measures taken by individuals. the course of an epidemic is defined by a series of key factors, some of which are poorly understood at present for covid . the basic reproduction number (r ), which defines the mean number of secondary cases generated by one primary case when the population is largely susceptible to infection, determines the overall number of people who are likely to be infected, or more precisely the area under the epidemic curve. for an epidemic to take hold, the value of r must be greater than unity in value. a simple calculation gives the fraction likely to be infected without mitigation. this fraction is roughly - /r . with r values for covid in china around · in the early stages of the epidemic, we calculate that approximately % of the population would become infected. this is a very worst case scenario for a number of reasons. we are uncertain about transmission in children, some communities are remote and unlikely to be exposed, voluntary social distancing by individuals and communities will have an impact, and mitigation efforts, such as the measures put in place in china, greatly reduce transmission. as an epidemic progresses, the effective reproduction number (r) declines until it falls below unity in value when the epidemic peaks and then decays, either due to the exhaustion of people susceptible to infection or the impact of control measures. the speed of the initial spread of the epidemic, its doubling time, or the related serial interval (the mean time it takes for an infected person to pass on the infection to others), and the likely duration of the epidemic are determined by factors such as the length of time from infection to when a person is infectious to others and the mean duration of infectiousness. for the influenza a h n pandemic, in most infected people these epidemiological quantities were short with a day or so to infectiousness and a few days of peak infectiousness to others. by contrast, for covid , the serial interval is estimated at · - · days, which is more similar to sars. first among the important unknowns about covid is the case fatality rate (cfr), which requires information on the denominator that defines the number infected. we are unaware of any completed largescale serology surveys to detect specific antibodies to covid . best estimates suggest a cfr for covid of about · - %, which is higher than the order of · % cfr for a moderate influenza a season. the second unknown is the whether infectiousness starts before onset of symptoms. the incubation period for covid is about - days. , combining this time with a similar length serial interval suggests there might be considerable presymptomatic infec tiousness (appendix ). for reference, influenza a has a presymptomatic infectiousness of about - days, whereas sars had little or no presymptomatic infectiousness. there have been few clinical studies to measure covid viraemia and how it changes over time in individuals. in one study of patients with covid , peak viraemia seems to be at the end of the incubation period, pointing to the possibility that viraemia might be high enough to trigger transmission for - days before onset of symptoms. if these patterns are verified by more extensive clinical virological studies, covid would be expected to be more like influenza a than sars. for sars, peak infectiousness took place many days after first symptoms, hence the success of quarantine of patients with sars soon after symptoms started and the lack of success for this measure for influenza a and possibly for covid . the third uncertainty is whether there are a large number of asymptomatic cases of covid . estimates suggest that about % of people with covid have mild or asymptomatic disease, % have severe disease, and % are critically ill, implying that symptombased control is unlikely to be sufficient unless these cases are only lightly infectious. the fourth uncertainty is the duration of the infectious period for covid . the infectious period is typically short for influenza a, but it seems long for covid on the basis of the few available clinical virological studies, perhaps lasting for days or more after the incubation period. the reports of a few superspreading events are a routine feature of all infectious diseases and should not be overinterpreted. what do these comparisons with influenza a and sars imply for the covid epidemic and its control? first, we think that the epidemic in any given country will initially spread more slowly than is typical for a new influenza a strain. covid had a doubling time in china of about - days in the early phases. second, the covid epidemic could be more drawn out than seasonal influenza a, which has relevance for its potential economic impact. third, the effect of seasons on transmission of covid is unknown; however, with an r of - , the warm months of summer in the northern hemisphere might not necessarily reduce transmission below the value of unity as they do for influenza a, which typically has an r of around · - · . closely linked to these factors and their epidemiological determinants is the impact of different mitigation policies on the course of the covid epidemic. a key issue for epidemiologists is helping policy makers decide the main objectives of mitigation-eg, minimising morbidity and associated mortality, avoiding an epidemic peak that overwhelms healthcare services, keeping the effects on the economy within manageable levels, and flattening the epidemic curve to wait for vaccine development and manufacture on scale and antiviral drug therapies. such mitigation objectives are difficult to achieve by the same interventions, so choices must be made about priorities. for covid , the potential economic impact of self-isolation or mandated quar antine could be substantial, as occurred in china . no vaccine or effective antiviral drug is likely to be available soon. vaccine development is underway, but the key issues are not if a vaccine can be developed but where phase trials will be done and who will manufacture vaccine at scale. the number of cases of covid are falling quickly in china, but a site for phase vaccine trials needs to be in a location where there is ongoing transmission of the disease. manufacturing at scale requires one or more of the big vaccine manufacturers to take up the challenge and work closely with the biotechnology companies who are developing vaccine candidates. this process will take time and we are probably a least year to months away from substantial vaccine production. so what is left at present for mitigation is voluntary plus mandated quarantine, stopping mass gatherings, closure of educational institutes or places of work where infection has been identified, and isolation of households, towns, or cities. some of the lessons from analyses of influenza a apply for covid , but there are also differences. social distancing measures reduce the value of the effective reproduction number r. with an early epidemic value of r of · , social distancing would have to reduce transmission by about % or less, if the intrinsic transmission potential declines in the warm summer months in the northern hemisphere. this reduction is a big ask, but it did happen in china. school closure, a major pillar of the response to pandemic influenza a, is unlikely to be effective given the apparent low rate of infection among children, although data are scarce. avoiding large gatherings of people will reduce the number of superspreading events; however, if prolonged contact is required for transmission, this measure might only reduce a small proportion of transmissions. therefore, broaderscale social distancing is likely to be needed, as was put in place in china. this measure prevents transmission from symptomatic and nonsymptomatic cases, hence flattening the epidemic and pushing the peak further into the future. broaderscale social distancing provides time for the health services to treat cases and increase capacity, and, in the longer term, for vaccines and treat ments to be developed. containment could be targeted to particular areas, schools, or mass gatherings. this approach underway in northern italy will provide valuable data on the effectiveness of such measures. the greater the reduction in transmission, the longer and flatter the epidemic curve (figure), with the risk of resurgence when interventions are lifted perhaps to mitigate economic impact. the key epidemiological issues that determine the impact of social distancing measures are what propor tion of infected individuals have mild symptoms and whether these individuals will selfisolate and to what effectiveness; how quickly symptomatic individuals take to isolate themselves after the onset of symptoms; and the duration of any nonsymptomatic infectious period before clear symptoms occur with the linked issue of how transmissible covid is during this phase. individual behaviour will be crucial to control the spread of covid . personal, rather than government action, in western democracies might be the most important issue. early selfisolation, seeking medical advice remotely unless symptoms are severe, and social distancing are key. government actions to ban mass gatherings are important, as are good diagnostic facilities and remotely accessed health advice, together with specialised treatment for people with severe disease. isolating towns or even cities is not yet part of the uk government action plan. this plan is light on detail, given the early stages of the covid epidemic and the many uncertainties, but it outlines four phases of action entitled contain, delay, research, and mitigate. the uk has just moved from contain to delay, which aims to flatten the epidemic and lower peak morbidity and mortality. if measures are relaxed after a few months to avoid severe economic impact, a further peak is likely to occur in the autumn (figure). italy, south korea, japan, and iran are at the mitigate phase and trying to provide the best care possible for a rapidly growing number of people with covid . the known epidemiological characteristics of covid point to urgent priorities. shortening the time from symptom onset to isolation is vital as it will reduce transmission and is likely to slow the epidemic (appendices , ) however, strategies are also needed for reducing household transmission, supporting home treatment and diagnosis, and dealing with the economic consequences of absence from work. peak demand for health services could still be high and the extent and duration of presymptomatic or asymptomatic transmission-if this turns out to be a feature of covid infection-will determine the success of this strategy. contact tracing is of high importance in the early stages to contain spread, and modelbased estimates suggest, with an r value of · , that about % of contacts will have to be successfully traced to control early spread. analysis of individual contact patterns suggests that contact tracing can be a successful strategy in the early stages of an outbreak, but that the logistics of timely tracing on average contacts per case will be challenging. superspreading events are inevitable, and could overwhelm the contact tracing system, leading to the need for broaderscale social distancing interventions. data from china, south korea, italy, and iran suggest that the cfr increases sharply with age and is higher in people with covid and underlying comorbidities. targeted social distancing for these groups could be the most effective way to reduce morbidity and concomitant mortality. during the outbreak of ebola virus disease in west africa in - , deaths from other causes increased because of a saturated healthcare system and deaths of healthcare workers. these events underline the importance of enhanced support for healthcare infrastructure and effective procedures for protecting staff from infection. in northern countries, there is speculation that changing contact patterns and warmer weather might slow the spread of the virus in the summer. a baseline simulation with case isolation only (red); a simulation with social distancing in place throughout the epidemic, flattening the curve (green), and a simulation with more effective social distancing in place for a limited period only, typically followed by a resurgent epidemic when social distancing is halted (blue). these are not quantitative predictions but robust qualitative illustrations for a range of model choices. see online for appendices , r of · or higher, reductions in transmission by social distancing would have to be large; and much of the changes in transmission of pandemic influenza in the summer of within europe were thought to be due to school closures, but children are not thought to be driving transmission of covid . data from the southern hemisphere will assist in evaluating how much seasonality will influence covid transmission. modelbased predictions can help policy makers make the right decisions in a timely way, even with the uncertainties about covid . indicating what level of transmission reduction is required for social distancing interventions to mitigate the epidemic is a key activity (figure). however, it is easy to suggest a % reduction in transmission will do it or quarantining within day from symptom onset will control transmission, but it is unclear what communication strategies or social distancing actions individuals and governments must put in place to achieve these desired outcomes. a degree of pragmatism will be needed for the implementation of social distancing and quarantine measures. ongoing data collection and epidemiological analysis are therefore essential parts of assessing the impacts of mitigation strategies, alongside clinical research on how to best manage seriously ill patients with covid . there are difficult decisions ahead for governments. how individuals respond to advice on how best to prevent transmission will be as important as govern ment actions, if not more important. government communication strategies to keep the public informed of how best to avoid infection are vital, as is extra support to manage the economic downturn. who. coronavirus disease (covid ) situation report- mrc centre for global infectious disease analysis. news / covid -report : transmissibility of ncov. factors that make an infectious disease outbreak controllable coronavirus disease (covid ) situation report- heterogeneity in estimates of the impact of influenza on population mortality: a systematic review early transmission dynamics in wuhan, china, of novel coronavirusinfected pneumonia epidemiology, transmission dynamics and control of sars: the - epidemic sarscov viral load in upper respiratory specimens of infected patients european centre for disease prevention and control. daily risk assessment on covid superspreading and the effect of individual variation on disease emergence will covid go away on its own in warmer weather? center for communicable disease dynamics (ccdd) at the harvard t.h. chan school of public health. transmission parameters of the a/h n ( ) influenza virus pandemic: a review mitigation strategies for pandemic influenza a: balancing conflicting policy objectives closure of schools during an influenza pandemic department of health and social care. coronavirus action plan feasibility of controlling covid outbreaks by isolation of cases and contacts the efficacy of contact tracing for the containment of the novel coronavirus (covid ) the novel coronavirus pneumonia emergency response epidemiology team. the epidemiological characteristics of an outbreak of novel coronavirus disease (covd ) the health impact of the - ebola outbreak rma was a nonexecutive director of glaxosmithkline (gsk) for years up to may, , and had past advisory roles for sars and influenza a for who and the uk government. dk works at the national institute for public health and the environment in the netherlands and is as such involved in advising the dutch government on infectious disease control. hh and tdh declare no competing interests. key: cord- -r eebet authors: kass, david a; duggal, priya; cingolani, oscar title: obesity could shift severe covid- disease to younger ages date: - - journal: lancet doi: . /s - ( ) - sha: doc_id: cord_uid: r eebet nan obesity could shift severe covid- disease to younger ages c o r o n a v i r u s d i s e a s e (covid- ) caused by severe acute respiratory syndrome coronavirus was first reported in china in late december, , and has since evolved into a global pandemic. as of april , , covid- has been confirmed in more than million individuals in countries and regions, with an overall mortality rate of more than %. severe disease involves bilateral interstitial pneumonia requiring intensive care unit (icu) ventilatory support and can evolve into adult respiratory distress syndrome with high mortality. the largest study of icu patients from italy reported a median age of years, with only patients ( %) younger than years. common comorbidities are hypertension, cardiovascular disease, type diabetes, and, more rarely ( [ %] of ), obstructive pulmonary disease. similar data have been reported from china. when the covid- epidemic began in the usa, we anticipated a similar icu population. news reports and communications from the us federal government had emphasised that covid- was a particular problem for older people, and a resistance to social distancing and sheltering in place by younger people might have been informed by this idea. however, as the pandemic hit the johns hopkins hospital in late march, , younger patients began to be admitted to our icu, many of whom were also obese. an informal survey of colleagues directing icus at other hospitals around the country yielded similar findings. at this time, news editorials were noting obesity as an underappreciated risk factor for covid- . this risk is particularly relevant in the usa because the prevalence of obesity is around %, versus a prevalence of · % in china, % in italy, and % in spain. with use of least squares univariate and multivariate linear regression, we examined the correlation between body-mass index (bmi) and age in patients with covid- admitted to icu at university hospitals at johns hopkins, university of cincinnati, new york university, university of washington, florida health, and university of pennsylvania (appendix). acquisition of the de-identified data for this analysis was approved by the johns hopkins university institutional review board. in our dataset of patients ( % male patients), we found a significant inverse correlation between age and bmi, in which younger individuals admitted to hospital were more likely to be obese (figure). there was no difference by sex (p= · ). the median bmi was · kg/m², with only % of individuals having a bmi of less than kg/m², and % exceeding a bmi of · kg/m². obesity can restrict ventilation by impeding diaphragm excursion, impairs immune responses to viral infection, is pro-inflammatory, and induces diabetes and oxidant stress to adversely affect cardiovascular function. we conclude that in populations with a high prevalence of obesity, covid- will affect younger populations more than previously reported. public messaging to younger adults, reducing the threshold for virus testing in obese individuals, and maintaining greater vigilance for this at-risk population should reduce the prevalence of severe covid- disease. baseline characteristics and outcomes of patients infected with sars-cov- admitted to icus of the lombardy region, italy clinical course and risk factors for mortality of adult inpatients with covid- in wuhan, china: a retrospective cohort study americans are already too diseased to go back to work right now global health obsevatory (gho) data: overweight and obesity impact of obesity on influenza a virus pathogenesis, immune response, and evolution key: cord- -m i ss w authors: poortmans, philip m; guarneri, valentina; cardoso, maria-joão title: cancer and covid- : what do we really know? date: - - journal: lancet doi: . /s - ( ) -x sha: doc_id: cord_uid: m i ss w nan the covid- outbreak challenges the medical community, including creating an unprecedented competition for health-care resources. the oncology community has suddenly needed to protect a population assumed to be vulnerable from a potentially fatal infection, without jeopardising cancer treatments. dealing with shortages and lockdowns, the immediate reaction was ruled by the general principle of risk-to-benefit ratios. [ ] [ ] [ ] [ ] in the lancet, lennard lee and colleagues patients were followed up from the date of hospital admission until the patient outcomes were met (death or discharge), and ( %) patients died. although risk of death was significantly associated with age, male sex, and comorbidities, no interaction between anticancer treatments within weeks before testing positive for severe acute respiratory syndrome coronavirus (sars-cov- ) and covid- morbidity or mortality was found. the primary endpoint was all-cause mortality within days of covid- diagnosis. after a median follow-up of days, ( %) patients died and ( %) were severely ill. increased -day mortality was associated with age, male sex, smoking, comorbidities, eastern cooperative oncology group performance status, active cancer, region of residence, and receipt of azithromycin plus hydroxychloroquine, but not with anticancer therapy. the urgency with which data were obtained meant short follow-up times and high proportions of missing data. the mortality rate observed by the ukccmp was probably due to the selection of patients who were admitted to hospital, underlying the need for data from patients without cancer from a matched population. moreover, ending the observation after discharge does not capture the full disease trajectory. similarly, for ccc , by limiting observation to days, and with follow-up data missing for ( %) of patients admitted to the intensive care unit (icu), mortality rates are likely to increase. subsequently, both studies are missing important data, without concise definitions of viral and cancer stage and status. the main lesson that we might deduce from both studies is that standard oncological care should be offered if feasible, including chemotherapy administration. we strongly encourage the continuation of these and other projects that will add pieces to the complex covid- puzzle and the disease's interactions with cancer and cancer treatments. will covid- negatively affect active oncological treatments or, on the contrary, might anticancer therapy be protective against the cytokine storm caused by sars-cov- ? - are disease stage and status important for these interactions? after counting the number of sars-cov- infections, hospital, and icu admissions, and measuring mortality and acquirement of immunity, we will start measuring excess mortality, and comparing expected mortality country-wise with that during the pandemic. however, this measurement is not so simple, as data show that the lockdown influences other types of mortality. whether the shortages of non-covid- -related health-care provisions will affect oncological and cardiovascular mortality is too early to predict. , finally, we must focus on improving future research, prospectively collecting all relevant data considering the specific local background, encouraging international collaboration, and setting a clear goal to stop, contain, control, delay, and reduce the effects of this virus at every opportunity, never forgetting that we will keep fighting together on behalf of our patients with cancer. pmp reports working as a medical adviser for sordina iort technologies, outside of the area of work commented on here. vg reports personal fees from eli lilly, novartis, and roche, outside of the area of work commented on here. m-jc declares no competing interests. international guidelines on radiation therapy for breast cancer during the covid- pandemic recommendations for triage, prioritization and treatment of breast cancer patients during the covid- pandemic cancer care during the spread of coronavirus disease (covid- ) in italy: young oncologists' perspective cancer patient management during the covid- pandemic covid- mortality in patients with cancer on chemotherapy or other anticancer treatments: a prospective cohort study clinical impact of covid- on patients with cancer (ccc ): a cohort study do patients with cancer have a poorer prognosis of covid- ? an experience in snapshot: covid- is low dose radiation therapy a potential treatment for covid- pneumonia? cancer and covid- -potentially deleterious effects of delaying radiotherapy cancer patients in sars-cov- infection: a nationwide analysis in china key: cord- -y o e k authors: elachola, habida; gozzer, ernesto; zhuo, jiatong; memish, ziad a title: a crucial time for public health preparedness: zika virus and the olympics, umrah, and hajj date: - - journal: lancet doi: . /s - ( ) - sha: doc_id: cord_uid: y o e k nan groups. furthermore, the long-term adherence to a daily injection therapy for patients with non-alcoholic steatohepatitis remains to be determined. most importantly, short-term histological outcomes are used to assess the effi cacy of treatment. unlike in viral hepatitis, histological outcomes are not known to be valid surrogate outcomes in the assessment of non-alcoholic steatohepatitis. after all, the ultimate aim is not to change histology but to prevent the development of cirrhosis and hepatocellular carcinoma. in this respect, results of recent longitudinal studies , showed that fi brosis, but not other histological features of non-alcoholic steatohepatitis, correlated with overall and disease-specifi c mortality. fibrosis progression can also occur in patients with nafld who do not have steatohepatitis, albeit at a slower rate. , these outcomes highlight the urgent need to defi ne reliable surrogate outcomes for the disorder. until the time comes when there are robust surrogate outcomes for the treatment of non-alcoholic steatohepatitis, the follow-up of treated patients for long-term clinical outcomes will be very important. the lean study has introduced liraglutide as a new potential treatment option for patients with non-alcoholic steatohepatitis. the drug should be tested further in large studies with a long duration of follow-up. this study has also raised issues pertinent to drug development in this area. in the meantime, keeping lean remains the most important aspect of management of non-alcoholic steatohepatitis. department of medicine and therapeutics, the chinese university of hong kong, hong kong; and state key laboratory of digestive disease, the chinese university of hong kong, hong kong wongv@cuhk.edu.hk vw-sw has served as an advisory board member for gilead and janssen, as a consultant for abbvie, merck, and novomedica, and has received paid lecture fees from abbvie, echosens, gilead, and roche. gl-hw has served as an advisory board member for gilead and has received paid lecture fees from abbvie, bristol-myers squibb, echosens, gilead, janssen, and roche. the spread of the arbovirus to more than countries, zika virus could be following the geographical spread of dengue and chikungunya, all of which are transmitted by the aedes aegypti mosquito. , the potential role of scheduled international mass gatherings in could exacerbate the spread of zika virus beyond the americas. in brazil, the rio carnival on feb - attracts more than visitors, and on aug - more than million visitors are expected to go to the summer olympics followed by paralympic games on sep - . meanwhile, saudi arabia expects to host more than million pilgrims from over countries for the umrah, between june and september, and the hajj pilgrimage on sept - . , saudi arabia receives about pilgrims from latin america annually. since the rio carnival participants are largely domestic, and the spread of zika virus is already extensive, it will be challenging to assess if there was excess transmission related to the carnival. although winter temperatures mean that mosquito density is expected to be low in brazil at the time of the olympics, given the summer time mosquito density in the northern hemisphere, including in saudi arabia, the introduction of a few infections to the mosquito population might be suffi cient to cause outbreaks of zika virus in other countries. , in brazil, cases of dengue are more frequent from february to may. in the regions of saudi arabia frequented by pilgrims (jeddah, mecca, medina), aedes aegypti larvae are present throughout the year, nearly two thirds in indoor habitats. larvae density is, however, variable and decreases in the months before october. in these regions, where rainfall is rare and unpredictable, reports have suggested all year risk for dengue fever, with dengue seroprevalence ranging from % to % among general patients seeking medical consultations. , although the olympics and the hajj are very diff erent events, each of them might favour transmission of zika virus. the olympics attracts mostly young healthy adults from middle and upper-middle income groups who live in developed countries. such visitors are less likely to have been exposed to arbovirus infections and less familiar with mosquito bite prevention than hajj pilgrims. sexual transmission of zika virus from commercial sex workers with asymptomatic infection might also be a possibility for those who attend the olympics. by contrast, the hajj and umrah participants are more likely to be older adults, many of whom have pre-existing health problems, and about two thirds of them originate from low-income countries and the tropics where personal habits of mosquito bite prevention can be suboptimum. also, umrah and hajj pilgrims' immersion in religious rituals could reduce personal uptake of mosquito avoidance measures. for saudi arabian authorities, it is now a standard procedure to convene international public health consul tations each year before the pilgrimage season to develop disease-specifi c recommendations. brazilian authorities in collaboration with the organizing committee for the olympic and paralympic games have already outlined vector control measures in the olympics vicinity. although both countries may have robust vector control eff orts, no single approach is adequate to prevent mosquito bites and non-vector modes of zika virus transmission; a combination of measures is needed at personal, community, and policy levels. with the emergence of chikungunya and dengue, hajj authorities have been proactive in vector control measures. given that pilgrim fl ow to saudi arabia is continuous, these eff orts will help minimise current transmission of zika virus as well. one important issue is the targeted promotion of options for personal mosquito bite protection-eg, the use of insect repellents, protective clothing, including long-sleeved shirts and trousers, insecticide-treated mosquito nets, and air conditioning in residences. despite the uncertainty about sexual transmission of zika virus, , the promotion of safe sex and provision of condoms is benefi cial from a broader health perspective. health-care providers can be encouraged to use travel health visits as an opportunity to emphasise the need for personal protection against mosquito bites and sexual transmission. health advice for individuals can be provided during predeparture health visits that are usually routine for pilgrims travelling to saudi arabia. additionally, by training athletic coaches on prevention of zika virus transmission, their frequent contacts with athletes can be used to remind athletes about the need for compliance with public health advisories. public health agencies in the home countries of travellers to brazil and saudi arabia can partner with travel agencies and transport services, including airlines, to engage in communication about risks of disease transmission. advice on personal protection can be reinforced at points of departure and arrival in home and host countries. increasing the availability and distribution points of methods to prevent mosquito bites is also crucial. similar approaches were part of prevention eff orts for pandemic infl uenza a h n in and middle east respiratory syndrome (mers) in during the hajj. , , methods for prevention of mosquito bites can be provided to each traveller at the arrival port before immigration control. given that brazil is facing a shortage of supply of insect repellents, global eff orts will be needed to procure and distribute them in adequate quantity. in the absence of commercially available rapid test kits and the asymptomatic nature of most zika virus infections, it is premature to consider mandatory entry or exit screening and restrictions. although there are confl icting reports on the value of exit and entry temperature screening, it can help the detection of a few individuals with symptoms and might persuade some people with febrile illness to avoid travel and can help reinforce health advisories. these mass gatherings provide an additional opportunity to undertake research on the transmission and prevention of zika virus. preparedness has been the key to success of recent hajj mass gatherings held amid known risks, such as pandemic infl uenza a h n , mers, and ebola outbreaks. , lessons from saudi arabia's success with hosting hajj during declared pandemics can be helpful to brazil and the olympics organisers. the next months will be a crucial period for both brazilian and saudi authorities to review emerging research fi ndings on the natural history of zika virus through expert consultations. international stakeholders can facilitate the needed advocacy and support. with proactive planning and preparedness, the eff ect of zika virus infection on mass gatherings participants and their home and host countries can be minimised and the events can be held with a sense of confi dence among organisers, participants, and the global community. by doing so, available global and country resources can be used to address the unanticipated course of the zika virus threat. habida elachola, ernesto gozzer, jiatong zhuo, *ziad a memish incidence of non-alcoholic fatty liver disease in hong kong: a population study with paired proton-magnetic resonance spectroscopy the natural history of nonalcoholic fatty liver disease with advanced fi brosis or cirrhosis: an international collaborative study nonalcoholic fatty liver disease: a feature of the metabolic syndrome liraglutide safety and effi cacy in patients with non-alcoholic steatohepatitis (lean): a multicentre, double-blind, randomised, placebo-controlled phase study liraglutide versus glimepiride monotherapy for type diabetes (lead- mono): a randomised, -week, phase iii, double-blind, parallel-treatment trial liraglutide once a day versus exenatide twice a day for type diabetes: a -week randomised, parallel-group, multinational, open-label trial (lead- ) weight loss through lifestyle modifi cation signifi cantly reduces features of nonalcoholic steatohepatitis orlistat for overweight subjects with nonalcoholic steatohepatitis: a randomized, prospective trial vitamin e, or placebo for nonalcoholic steatohepatitis farnesoid x nuclear receptor ligand obeticholic acid for non-cirrhotic, non-alcoholic steatohepatitis (flint): a multicentre, randomised, placebo-controlled trial surrogate end points and long-term outcome in patients with chronic hepatitis b liver fi brosis, but no other histologic features, is associated with long-term outcomes of patients with nonalcoholic fatty liver disease fibrosis stage is the strongest predictor for disease-specifi c mortality in nafld after up to years of follow-up disease progression of non-alcoholic fatty liver disease: a prospective study with paired liver biopsies at years fibrosis progression in nonalcoholic fatty liver vs nonalcoholic steatohepatitis: a systematic review and meta-analysis of paired-biopsy studies guangxi centers for disease control and prevention eg is director of peru's instituto nacional de salud. jz is deputy director for guangxi centers for disease control and prevention. we declare no competing interests executive board on zika situation interim guidelines for pregnant women during a zika virus outbreak-united states ihr ) emergency committee on zika virus and observed increase in neurological disorders and neonatal malformations mass gathering medicine: hajj and umra preparation as a leading example kingdom of saudi arabia. hajj -health regulations zika virus transmission from french polynesia to brazil household survey of container-breeding mosquitoes and climatic factors infl uencing the prevalence of aedes aegypti (diptera: culicidae) in makkah city, saudi arabia monitoramento dos casos de dengue, febre de chikungunya e febre pelo vírus zika até a semana epidemiológica the epidemiology of dengue fever in saudi arabia: a systematic review potential sexual transmission of zika virus olympics will inspect for water to help prevent zika pandemic h n and the hajj pandemic h n infl uenza at the hajj: understanding the unexpectedly low h n burden international travels and fever screening during epidemics: a literature review on the eff ectiveness and potential use of non-contact infrared thermometers key: cord- -xu h ac authors: berlinguer, giovanni title: bioethics, health, and inequality date: - - journal: lancet doi: . /s - ( ) - sha: doc_id: cord_uid: xu h ac nan first, the technique of preimplantation genetic diagnosis (pgd), which was introduced after in-vitro fertilisation (ivf), allows recognition and elimination of an embryo with a genetic disorder or malformation and permits selection of sex. the international bioethics committee (ibc) of unesco (united nations educational, scientific, and cultural organization) recommended that "pgd be limited to medical indications. therefore sex selection for non-medical reasons is considered to be unethical." nevertheless pgd is also practised, and sometimes morally and legally justified, in developed countries. the debate in frontier bioethics concerns mainly the right of parents to decide the characteristics of their children. sex selection, however, is widely put into practice not only through elaborate technologies but also in daily life through infanticide, discrimination in nutrition and health care, and other barbarous methods. in , amartya sen showed the existence-on the basis of changes in the ratio of women to men in the total population of asia and africa-of hundreds of millions of missing women caused by similar actions. worldwide indignation and appropriate cultural and legal measures have been taken in several countries to reduce this situation. did anything change? sen revisited the data in , and reported that the reduction in female overmortality has been counterbalanced by the spread of sexselective abortion against the female fetus, and as a result the number of missing women is now greater. embryos, fetuses, or babies can be selected by many methods from different cultures, which manifest a unique and crude tendency-this selection is a sharp and visible aspect of gender inequality. in developed countries, acceptance of sex selection through biotechnological methods can hinder any effort to reduce any kind of sex selection in any part of the world. second, the question of whether the human body be bought and sold has a history as long as the existence of slavery, and has been a very embarrassing problem for philosophers, from aristotle to locke, and for theologians. the antislavery movements finally imposed its abolitionone of the most impressive cases of a turn in history by effect of moral principles. it led to the geneva convention (sept , ) , which called on all nations to pursue the suppression of slavery in all its forms, as soon as possible. but in many places, old and new forms of slavery still exist, including bonded labour, in which a worker or labourer is bound to a company or a landlord for life by inextinguishable debts. a type of such bonded slavery existed in the villages of sultanpur mela, kot momin, and mateela in pakistan. in this case, peasants-almost one in every family-sold one of their kidneys for less than us$ . specialised hospitals transplanted their organs into rich patients coming from different cities and other countries. the peasants were obliged to become rewarded donors for the hope or the illusion to free themselves from debts. in this way, slavery met the biotechnological market of spare parts of human bodies. such rewarded donation is the dark side of the enormous advantages coming from the possibility to transfer, from a person to another, organs, corneas, tissues, cells, gametes, stem cells, and other commodities. the moral question "is there a freedom to sell his own body?" was answered, to a certain extent, long ago by immanuel kant (man cannot be at the same time a person and an object; therefore we cannot sell any part of our body) and by john stuart mill (man has all the liberties, except that of choosing to be a slave). now the debate has been reopened. the june, , edition of the journal of medical ethics was dedicated to supply of organs for transplantation, and particularly to the moral legitimisation of the biotechnological market. in my opinion, the question would be most clear if raised the other way round: has a person the right to buy (or to rent) parts of the body of another human being? robert evans, a uk labour member of the european parliament, answered no, and proposed to declare illegal and punishable such practice, according to which wealthy people "are able to exploit desperate people with no fear of penalties". if the answer to this question is yes, the risk is to legitimise a society in which everything could be bought; ourselves, too, who would be regarded as the final commodity. third, prevailing opinion on human cloning is mainly in favour of the cloning of cells and tissues for therapeutic reasons but is against reproductive cloning because this technique denies the casual combination of genes, restricts individual freedom, and implies genetic predetermination. the few people who are in favour of reproductive cloning affirm that human beings are almost always largely predetermined insofar that they are born in a particular country, time, class, and family. if a person's destiny is to become social, cultural, and moral clones, why should genetic cloning not be permitted? perhaps human liberty and self-determination should prevail over all limits and obstacles, either due to social and gender injustice or manipulation of minds; use of science in favour of genetic arrogance would deny or discourage the daily efforts of any person to build autonomously his or her own future. can we develop universal principles in bioethics? these and similar cases could stimulate the debate and (i hope) growth, by consensus, of common universal values in bioethics and of moral norms, accompanied (sometimes) by legal international regulations. this action becomes necessary for two additional reasons. first, many scientific practices have extended beyond national borders, such as the legal (and sometimes illegal) importation and exportation of stem cells, tissue collections, organs, dna samples, and genetic data. moreover, human experiments are done in several countries, and we should avoid putting unnecessary burdens on poor people and communities or creating new forms of exploitation. the bioethical issues that are generated need fair solutions, in accordance with the plurality of values and with the common interests of the world community. second, positive actions for health are essential on a world and local scale. the idea that the combination of scientific progress and free market would spontaneously extend its benefits worldwide, which was dominant in the past two decades, has failed, and a paradoxical situation about science has arisen. new, impressive advances in biomedical knowledge, which at some times in the past were largely accessible-eg, in the s and s, use of antibiotics against microbial diseases and vaccines against smallpox and poliomyelitis-are now becoming more and more selective. many individuals affected by aids or other serious infectious diseases can benefit from new drugs and survive; however, most people cannot afford to pay for the drugs and could die. in africa and other areas of the world, aids could lead to catastrophic effects similar to those the black death caused in europe in - . according to roy porter, "plague killed a quarter of europe's population-and far more in some towns; the largest number of fatalities caused by a single epidemic disaster in the history of europe. this provoked a lasting demographic crisis." the differences are in the progress of the aids pandemic, which is slower than that of the black death but equally cruel, and in the fact that now we know the causes and possible remedies for aids, malaria, tuberculosis, and other scourges. the eradication of smallpox, the substantial reduction of childhood diarrhoeal deaths, and the elimination of poliomyelitis in countries show that www.thelancet.com vol september , wellcome library, london rights were not granted to include this image in electronic media. please refer to the printed journal. many goals have already been achieved through knowledge and common action. unfortunately, the undesired but foreseeable result of medical progress tends to increase inequalities, because it is oriented by vested interests and directed towards the rich instead of general goals. annette flanagin and margaret a winker wrote: "the contemporary era of globalization, which was anticipated to capitalize on advances in technology, science, communication, and cross-national interdependence, has been accompanied by gaps . . . and wide disparities in societal resources . . . moreover, only a small fraction of funds for biomedical research is dedicated to research that affects most the poor or supports research conducted by resource-poor scientists and for the benefit of resource-poor populations." the / gap refers to the fact that only % of the us$ billion spent on health research and development by the private and public sector is used for research into % of the world's health problems. a similar (or greater) imbalance exists for expenditures on prevention and health care. benefit-sharing and equal access to advances in biomedical science are now urgent and universal issues. this moral change in values and priorities should guide public policies on health at all levels. if we think of universal principles in bioethics, the fundamental ones should probably be equal dignity of every individual and equity of life, disease, and death. a step towards universal principles-on a european level-is the convention for the protection of human rights and dignity of the human being with regard to the application of biology and medicine, adopted by the council of europe in oviedo on april , , and opened to the signature of other nations. two fundamental articles state that the convention "shall protect the dignity and identity of all human beings and guarantee everyone, without discrimination, respect for their integrity and other rights and fundamental freedom" (article ), and that "the interests and welfare of human beings shall prevail over the sole interest of society or science" (article ). the convention includes articles on the rights of the patient, on equitable access to health care, on respect for private life, on non-discrimination on genetic grounds, on transplants, and on prohibition of financial gains "from the human body and his parts as such" (article ). at its st session in , the general council of unesco-after an explicit invitation of the round table of ministers of science-invited its director general to submit the technical and legal studies undertaken regarding the possibility of elaborating universal norms on bioethics. during and , the ibc of unesco worked on a feasibility study, and concluded in june, , with a report on the possibility of elaborating a universal instrument on bioethics, a declaration that is less binding than a convention. the nd session of unesco in october, , judged setting of universal standards in this area to be imperative and desirable, and invited the director general "to continue preparatory work on a declaration, and to submit a draft declaration at its rd session in , involving from the very beginning states, the united nations and the other specialized agencies of the un system, other inter-governmental and non-governmental organizations and appropriate national bodies and specialists". i know by personal experience in the ibc (in which i was a rapporteur) that to proceed from a feasibility study to a universal declaration on bioethics is almost impossible, but trying is worthwhile. the process of elaboration can be itself a contribution to the ethics debate, to knowledge and participation, as long as the existence of many different ethics, and bioethics in particular, is considered-not as an obstacle-but as an expression of richness and freedom. since the text of the preliminary report of the ibc is now publicly accessible, i will not discuss it in detail. i would only underline that, after the preliminary remarks, its first substantial section deals with health and health care (points , , and ) . it begins with this paragraph: "health has a dual moral value: it is essential for the quality of life and life itself, and is instrumental as a precondition for freedom. when disease prevails, the destiny of a person (and even of a nation) is left to external www.thelancet.com vol september , during the summer of , more than elderly people died in france ap rights were not granted to include this image in electronic media. please refer to the printed journal. factors and powers and may enter into an irreversible vicious circle of regression. the inequality between the rich and the poor-at the level of individuals, communities and nations-is becoming increasingly deeply felt in the area of health and healthcare, thereby contributing to the desperation and injustice that prevail and continue to increase in other health-related fields such as food, income and education." the main difficulty in practising moral principles concerning human dignity and equity in health is that in the past years a singular ethics (and a singular policy) prevailed in the world, which resulted in overturning the health paradigms that had successfully guided public health and health services for one century. the principle that health is a value and an objective of economic development has been replaced by the opposite idea: that systems of universal care represent one of the main obstacles to economic growth. the leadership of national health policies has been transferred from health ministers to economics ministers, and internationally (particularly in developing and under-developed countries) was influenced more by the international monetary fund (imf), the world bank, and the world trade organization (wto) than by who. even when the negative results of their policies in relation to equity became clear, and the action of who (whose president at the time was gro harlem brundtland) succeeded in bringing health back on the world political agenda, the model of the commission appointed by who on macroeconomic and health continues to be that of the influential report of the world bank, investing in health. the model does not include any critical analysis "of currently dominant macroeconomic policies or of the structure and mechanisms that entrench developing countries disadvantage, ill health, and deteriorating services". in this framework, the debate refers mainly to healthcare systems, putting aside the concepts of healthy societies and systems. the idea of the priority of primary health care and of the prevention accessible to everybody has been supplanted by high technologies, even in countries where the resources are minimal. discussions on resources for health have been restricted to monetary aspects, ignoring the many possibilities of human resources, of changes in environment and workplace, and of improvements in nutrition and education. the need to identify priorities and to distribute fairly the resources for health care is replaced by the idea of rationing them: not through priorities and universal inclusion, but through selective exclusion. the analysis of diseases' causes has been concentrated mainly on individual factors, such as genes and behaviours, whereas the role of social factors, so important for disadvantaged people, has been neglected. the role of social factors is sometimes even concealed. one example is in the world health report ( ). another example comes from the death, during the summer of , of more than elderly men and women in france, many of them poor or socially marginalised; of more than in germany and italy; and of others in many other european countries. it is true that in august the temperature in these countries was unusually high, but this risk had been widely described in epidemiological research, and preventive measures for elderly people in such conditions are available in almost all gerontology textbooks. the almost unanimous comment of the media was that they were killed by the heat. commentators forgot the isolation, loneliness, lack of attention by many family doctors and local health services, absence of any warning or information being broadcast on television (which is often the only communication between non-self-sufficient elderly individuals and the rest of the community), and insufficient funding for active assistance and care at home. the ministers of health were surprised by the events, and local health authorities tried to underestimate and even to conceal numbers (almost like the epidemic of severe acute respiratory syndrome in china). very few raised two general questions: what else can we expect for world health from potential climate change, and what should we do about present and future risks? at the end of the s, new political and moral trends began to emerge in the world, and new emphasis was given to health and equity in health. these trends became very influential culturally, although they were politically contradicted by the orientations of the dominant powers. health was reintroduced to the international political agenda. in many countries, researchers have shown a growing interest in health equity, inspired either by their moral and scientific sensitivity, or by evidence. the main efforts were inspired by the attempt to integrate altruism and self-interest, to reconsider health as an indivisible good, and by the refusal of simple charitable transfers of benefits among countries or groups. this is an old idea, now defined as compassionate conservatism, which may include the virtue of ethics but has two faults: ( ) those who are helped are placed in a compromising, dependent position, treated as victims not agents; and ( ) societal rules and structures that generate such social consequences are not addressed. public opinion, nevertheless, became more critical towards inequities in health, probably for two reasons. one is that the inequity in health, which often means life or death, raises higher indignation than other inequities concerning income or material goods. the other is an increased knowledge of reality through public inquiries, books, medical journals, and campaigns. a few years ago, amartya sen, closing in dhaka the bangladesh session of the global equity in health initiative in , said: "information concerning discrimination, torture, poverty, illness, and abandonment helps coalesce the forces opposing these events by extending the opposition to the general public. this is because the people have the capacity and willingness of reacting to other people's difficulties." evidence confirms the willingness of people to help others. millions, mainly young people, are working in voluntary services at home or abroad. often, they combine in their activities two aspects that in the past have been separated and even conflicting: to struggle for collective interests, and at the same time to work daily to help individuals. on the political and cultural scene, the role of civil society and of community organisations has increased almost everywhere. a new generation has emerged that criticises the effects of one-sided globalisation on environment, health, justice, and relations between science and society, which underlines that a better world is possible and demands peace. there are some analogies with the youth movements of the late s, but also three differences that can make this new movement more lasting and more effective: their extension beyond schools and far beyond the usa and western europe; their will to integrate criticism with proposals; and their growing influence on national policies and on international agencies, as we can see from two examples. one example is the victory obtained against the bill of indictment, requested by the multinational pharmaceutical industries to the south african court against nelson mandela and his government, for the crime of producing and importing antiretrovirals by ignoring or violating patents. mandela made the decision to ignore the patent to make therapies accessible for the poor population, in a country where one in nine people is hivpositive. after global criticism from governments, nongovernmental organisations, hiv/aids specialists, and a globalised movement mainly organised through the internet, the pharmaceutical companies decided not to pursue the case. after a bitter struggle between the companies and who, new rules were adopted. it is now possible to suspend or limit the royalties for "intellectual property" in case of widespread epidemics: a partial victory in what could be called, perhaps improperly, conflict between patents and patients. later, in october, , the south african competition commission concluded that the companies "had overcharged for the drugs and had limited their licensing to competitors to try to suppress competition"; and finally, in december of that year, glaxosmithkline and boehringer ingelheim, while still rejecting the accusation, agreed to reduce the price for therapy by as much as %. a door has been opened for new international rules on everyday bioethics. the second example is the wto meeting in cancun, mexico, sept - , , where no agreement was reached on trade in agricultural and industrial products, and the attempt to push decisions on fundamental issues, such as the privatisation of water resources and of health and educational services, completely failed. the consequences of this failure may be contradictory, but surely a new factor emerged: the formation of an alliance between more than developing countries who represent more than half of the world's population, and antiglobalisation movements. developing countries have been deeply divided in the past - years, and have had almost no voice in the international arena. cultural and political antiglobalisation groups had already gained publicity in seattle years ago, and now had common goals with many governments. so far, the main result is the defeat of the proposal to extend rules governing the trade of commodities to the services for persons, such as health and education, and to natural resources. the argument has been that such services affect human rights, are essential for human life and growth, and that nations should decide how to guarantee them to all citizens. the two cases show how far other international agencies such as the wto, the imf, and the world bank, are involved in decisions about people's health, which often is not considered as a value but a variable and uncomfortable element of the economic system. as far as ethics is concerned, the difference is that who does have a moral obligation towards people's health, whereas the wto, the imf, and the world bank do not. during and after the recent change in the who leadership, there was much discussion about its future, such as the stimulating debate in the lancet. at the same time, the connections between health and human security became more evident. the un appointed an ad hoc commission that stated: "in addition to the persistent problems and vulnerabilities with which the world has long been familiar, there is a new wave of dramatic crises at the turn of the millennium related to terrorist attacks, ethnic violence, epidemics and sudden economic downturns. there is also a fear that existing institutions and policies are not able to cope with weakening multilateralism, failing respect for human rights, eroding commitments to eradicate poverty and deprivation, outdated sectarian perspectives in educations systems and the tendency to neglect global responsibilities in an increasingly interrelated world. at the same time, the opportunities for working towards removing insecurity across the world are also larger than ever before." two deep contradictions are now arising. one is the move back to the idea of security, which was historically intended (with mixed intentions and results) to counter the threat of aggression across borders or violence against people. in the th century this concept was deepened and expanded through the experience of the welfare state and through the emergence of new personal and collective rights. the questions are now: what security, and for whom? not only against the threat of attacks and crimes against nations and persons, but also for individuals and their dignity; for human welfare, health, and nutrition; for water and clean air; for the biosphere; and for the interests of future generations. the other contradiction is the policy of governments like the usa that, in the struggle against the threat ofinternational terrorism, choose to use their military and repressive power, without addressing the social, cultural, and political causes that cannot ever justify but might explain the growth of terrorism. from a practical point of view, the results of this policy are dubious at the very least. from an ethical point of view, it restricts the range of individuals who could contribute to society; it might demobilise popular, intellectual, and political energies; it introduces a rigid separation between those who are considered good and those who are branded evil; and it weakens the duties of public authorities and international institutions to face other individual and collective needs. the future of health, health policies, and health equity is strictly connected to the resolution of these contradictions. everyday bioethics: reflections on bioethical choices in daily life letters from prison report of the ibc on preimplantation genetic diagnosis and germ-line intervention: shs-est/ /cib- / . geneva: united nations educational, scientific, and cultural organization missing women missing women: revisited il villaggio dei disperati: qui tutti si vendono i reni (the village of the desperates: here all sell their kidneys) il corriere della sera oct la merce finale: saggio sulla compravendita di parti del corpo umano (the final commodity: an essay on the sale and purchase of parts of the human body). milan: baldini and castoldi attack on organ trade begins with transplant tourists. the times the greatest benefit to mankind: a medical history of mankind global health: targeting problems and achieving solutions convention for the protection of human rights and dignity of the human being with regard to the application of biology and medicine (convention on human rights and biomedicine) report of the ibc on the possiblility of elaborating a universal statement on bioethics investing in health: world development indicators the report of the commission on macroeconomics and health: a summary critical appraisal: geneva: who the world health report : reducing risks, promoting healthy life. geneva: world health organization morti da canicola: epidemiologia per non dimenticare challenging inequities in health: from equity to action agreement expands generic drugs in south africa to fight aids who director-general elections-join the lancet debate united commission on human security (ogata s, sen a, co-chairs) what is security? key: cord- - fcyjw l authors: lu, cheng-wei; liu, xiu-fen; jia, zhi-fang title: -ncov transmission through the ocular surface must not be ignored date: - - journal: lancet doi: . /s - ( ) - sha: doc_id: cord_uid: fcyjw l nan on jan , guangfa wang, a member of the national expert panel on pneumonia, reported that he was infected by ncov during the inspection in wuhan. he wore an n mask but did not wear anything to protect his eyes. several days before the onset of pneumonia, wang complained of redness of the eyes. unprotected exposure of the eyes to ncov in the wuhan fever clinic might have allowed the virus to infect the body. infectious droplets and body fluids can easily contaminate the human conjunctival epithelium. respiratory viruses are capable of inducing ocular complications in infected patients, which then leads to respiratory infection. severe acute respiratory syndrome coronavirus (sarscov) is predominantly transmitted through direct or indirect contact with mucous membranes in the eyes, mouth, or nose. the fact that exposed mucous membranes and unprotected eyes increased the risk of sarscov transmission suggests that exposure of unprotected eyes to ncov could cause acute respiratory infection. thus, huang and colleagues should have analysed conjunctival scrapings from both confirmed and suspected ncov cases during the onset of symptoms. the respiratory tract is probably not the only transmission route for ncov, and all ophthalmologists examining suspected cases should wear protective eyewear. we declare no competing interests. *cheng-wei lu, xiu-fen liu, zhi-fang jia clinical features of patients infected with novel coronavirus in wuhan, china peking university hospital wang guangfa disclosed treatment status on weibo and suspected infection without wearing goggles avian influenza and sialic acid receptors: more than meets the eye? ocular tropism of respiratory viruses the severe acute respiratory syndrome key: cord- - e akcjf authors: liu, peilong; guo, yan; qian, xu; tang, shenglan; li, zhihui; chen, lincoln title: china's distinctive engagement in global health date: - - journal: lancet doi: . /s - ( ) -x sha: doc_id: cord_uid: e akcjf china has made rapid progress in four key domains of global health. china's health aid deploys medical teams, constructs facilities, donates drugs and equipment, trains personnel, and supports malaria control mainly in africa and asia. prompted by the severe acute respiratory syndrome (sars) outbreak in , china has prioritised the control of cross-border transmission of infectious diseases and other health-related risks. in governance, china has joined un and related international bodies and has begun to contribute to pooled multilateral funds. china is both a knowledge producer and sharer, offering lessons based on its health accomplishments, traditional chinese medicine, and research and development investment in drug discovery. global health capacity is being developed in medical universities in china, which also train foreign medical students. china's approach to global health is distinctive; different from other countries; and based on its unique history, comparative strength, and policies driven by several governmental ministries. the scope and depth of china's global engagement are likely to grow and reshape the contours of global health. in only three decades, china's global engagement has accelerated from closed autarky to open engagement; from relative isolation to integration into the world system; from a low-income to a middle-income country; and from an aid recipient to an aid donor. as a global demographic and economic giant, china's prominence in global health should not be surprising. with % of the world's population, china weighs heavily in all global health metrics, such as life expectancy, disease burden, and health systems. as the world's largest trading nation, its movement of goods and services is associated with transfer of health technologies, diseases, and risk factors. in health knowledge and strategies, china has a rich history of traditional medicine and has pioneered many health-care innovations. china's ascendency has generated many questions and some concerns. a common assumption is that china uses foreign aid to secure energy and natural resources and to expand export markets. , china's claim of aid with "no strings attached", is considered by some to encourage corruption, weaken accountability, or ignore human rights. the international press has reported delayed and muddled notifi cation of infectious outbreaks, and much news of exported contaminated chinese manufactured products. china is sometimes perceived as working alone and insuffi ciently cooperating with other countries. in this review, we attempt to address the following questions: what is china's role in global health? is china's engagement distinctive or similar to other countries? what does the evidence illuminate of china's global health engagement? china, similar to most countries, has no single offi cial source of data for global health because of the multiplicity of governmental stakeholders, the absence of a national strategy on global health, and the unclear borderline between aid and trade investments. a study by nyu's wagner school has estimated china's foreign aid to africa, latin america, and southeast asia from to . strange and coauthors estimated all previous estimates of chinese development fi nance to africa. the state council of the chinese government, the highest body of state administration, published white papers summ arising china's overall foreign aid in and . none of the above estimations disaggregated or separately reported health aid. , we thus have resorted to an extensive search of data from multiple chinese sources-the state council, the ministries of health, commerce, education, foreign aff airs, and science and technology. reports from provincial governments, chinese embassies abroad, and the press were searched. altogether, we obtained data from sources- from various websites, from statistical yearbooks, from regular reports, and from newspapers. data sourced came from groups of organisations, including sources from the ministry of commerce, from the health ministry (national health and family planning commission), and from ministry of education. the overwhelming proportion of these data sources are in chinese ( %), with less than % in english. all data sources are shown in the appendix. interviews were done with dozens of former offi cials, medical team members, and key provincial authorities to collect fi rst-hand information. not surprisingly, the data quality is mixed, often incomplete, and the fragments need to be matched and fi tted together. the chinese government is essentially the only source of information, without other sources of independent verifi cation. reports of classifi cation and nomenclature often do not follow international standards. a common limitation is the mixing of stock data versus fl ow data. our compiled data, nevertheless, generate what we believe to be the most robust estimation possible. matching and piecing together the fragments allows inconsistencies to be double checked for consistency. most inconsistencies relate to exact numbers, but estimation of the general order of magnitude is believed to be reasonably robust. all data sources for this review are shown in the appendix in both original chinese and translated english. after introducing a framework, we present sections on china's work in health aid, health security, health governance, and knowledge exchange. china's participation in global health has deep historical roots, not only just in recent years. in the fi rst millennium, knowledge of medical cures were transmitted by the silk road that facilitated exchange between china, india, the middle east, and europe. in the th century, some chinese health crises such as the manchurian plague epidemic captured the attention of neighbouring countries of the international community. china has historically been the origin of many infectious epidemics and a source of key health innovations of breakthroughs such as the barefoot doctor (a term that emerged in the s and s, which refers to farmers who received minimal basic medical and paramedical training and worked in rural china to promote basic hygiene, preventive health care, family planning, and treat common illnesses. the name comes from southern farmers, who would often work barefoot in the rice paddies), and artemisinin, an eff ective antimalaria drug developed from plant-based chinese traditional medicine. , because there is no universal consensus for the defi nition of global health, some approaches focus on transnational health risks, which lie beyond the reach of national governments, whereas other approaches stress the global commitment and responsibility to address health inequities and to support health. we have adopted a framework of global health as characterised by health and related transnational fl ows of diseases, people, money, knowledge, technologies, and ethical values. [ ] [ ] [ ] four domains capture these globalisation processes (fi gure ). first, health aid aims to advance global health equity. it is the traditional area of offi cial development assistance (oda) coordinated by organisation for economic cooperation and development (oecd) countries. second, global health security should be ensured by management of interdependence in global health and mutual protection against shared and transferred risks, such as epidemic diseases. third, health governance is needed for global stewardship to set ground rules as mediated by health diplomacy. fourth, knowledge exchange is needed, which includes the sharing of lessons and knowledge production, ownership, and application worldwide. knowledge centrally aff ects all four pillars of global health, and global health governance is recognised to be central to all four domains (fi gure ). on the basis of this framework, china's modern timeline might be demarcated by fi ve landmarks. first, in , china sent its fi rst overseas medical team to algeria, followed years later by the donation of its fi rst hospital in tanzania. the explicitly articulated purpose of china's health aid was to further political solidarity as part of china's foreign policy. second was china's economic openings after , which launched the dramatic transformation of china from a low-income to a middle-income country, leading to china qualifying as an aid recipient followed by increasingly becoming an aid donor. third, starting from , china has hosted a series of forums on china-africa cooperation, with each forum announcing yet another major aid pledge-eg, hospital construction, malaria control, and high education scholarships ( - ); training of health workers and artemisinin drug donation ( - ); and brightness action (eye care) campaign ( - ). , fourth, global engagement greatly accelerated after when china entered the world trade organization (wto), an event that marked china's joining almost all international bodies. finally, and perhaps most dramatically, the severe acute repiratory syndrome (sars) epidemic underscored both china's neglect of its health sector and the reality that china's global trade cannot be done without mutual health protection. in recent years, the state council has published two white papers in april, , and july, , summarising china's foreign aid by volume and type. the white paper reports foreign aid of us$ · billion accumulated up to and including in three categories: grants of $ · billion; concessional loans of $ · billion; and interest-free loans of $ · billion. this amount is fairly close to another estimate of china's foreign aid at $ · billion cumulative from to , reaching $ · billion annually by . , the aid increased signifi cantly during the period of - , reaching an average of $ · billion per year, of which the grants accounted for · %. figure shows that african countries received % of all aid, with asia receiving about a third ( %) and latin america receiving around %, before the end of . the share for african countries increased to · % during the past years, whereas latin america received relatively less. another estimate computed china aid to africa in , at $ · billion in comparison with japan at $ · billion and usa at $ · billion. chinese aid in health is provided in fi ve categories: medical teams, construction of hospitals, donation of drugs and equipment, training of health personnel, and malaria control. the largest share of health aid is spent on medical teams and donated facilities. the fi nancial value of chinese in-kind health aid is diffi cult to estimate. crudely, from to , we estimated the value of chinese medical teams in africa to be about $ million annually, with donated facilities at a similar amount. total health aid to africa annually has been estimated at about $ million. understanding of the type of health support off ered rather than the precise volume of funding might be more important. diff erent from most oecd donors, china does not off er general sectoral support, albeit small cash grants given to several countries in recent years. its health aid uses a project approach. the in-kind provision in the fi ve categories is based on chinese competencies. health seems to constitute only a small proportion of the total chinese aid. health aid is mainly in donation form, whereas most of china's overall foreign aid is off ered as either concessional or interest-free loans. since , under the protocol on the dispatch of medical teams signed between the government of china and the recipient countries, about chinese medical workers have been sent to about countries to provide services to an estimated million people. at the end of , chinese medical workers were working in medical centres in countries. of the countries are in africa, and the remaining seven are mainly small countries-four in asia, one in europe, one in south america, and one in oceania. the table shows african countries in according to medical teams, aided facilities, and malaria control programmes, along with the chinese provinces twinned to each country. figure shows china health aid to africa with countries shaded according to density of medical team coverage and demarcated by aided facilities and malaria control. the distribution shows wide coverage of nearly all african countries with a higher density of medical teams in western and eastern africa regions. the largest and most powerful african countries such as south africa, nigeria, and kenya do not have chinese medical teams. chinese selection of hosting countries is based on country request and the joint decision by china's ministries of health, foreign aff airs, and fi nance. the medical teams are overseen by the chinese embassy economic and commercial counsellor's offi ces. medical teams are fi nanced by the health aid budget in the health ministry (except the basic salaries), which is responsible for dispatching medical teams. selected countries are twinned to specifi c chinese provinces with public hospitals and local medical schools responsible for staffi ng, supervising, and partially funding the medical teams. some practical criteria such as willingness and workload are used to match chinese provinces and recipient countries in the twinning arrangement. the number of members in medical teams ranges from a half dozen people to nearly , usually working out of chinese donated hospitals and clinics. most workers are clinicians, and most teams include a leader and a translator. public health skills are usually not included. medical teams mainly provide clinical services, especially for specialties in short supply-eg, surgery, gynaecology, and obstetrics. the average duration of an overseas assignment is years, with team members receiving housing and food plus enhanced salaries. over the period of - , these medical teams working in countries had provided about million medical consultations and treatments. panel describes some of these medical teams in southern sudan and the democratic republic of the congo. since , china has constructed more than a hundred health facilities overseas with its health aid. china accelerated its assistance in the construction of hospitals and clinics-from to , china has supported about construction projects of health facilities. most of these facilities are donated, and only a few are built as part of large infrastructure projects funded by chinese loans. african countries were the recipients of more than three-quarters of the donated facilities. although most countries have received at least one facility, some have received up to . these facilities are mostly so-called turnkey operations, for which chinese construction fi rms build the facility for transfer to local authorities. malaria control has recently been prioritised. control programmes are undertaken through anti-malaria centres, featuring artemisinin based on chinese traditional medicine. panel describes an ambitious chinese programme of malaria eradication with mass drug administration with artemisinin on the comoros islands. the question of whether health aid is mainly driven by china's commercial interest is not easy to investigate. much depends upon interpretation of underlying motivation. for example, chinese aid to africa might be viewed as either helping the world's poorest countries or building friendship with the origin of much of the world's energy and natural resources and potential export markets. a comprehensive analysis of this question would need access to data not currently available. as a preliminary fi rst step, we attempted to examine correlations between health aid and commercial economic indicators. regression analysis of african countries with variables of health aid (medical teams, donated facilities, malaria control) and economic interests (petroleum imports, china's foreign investment, and china's imports and exports) yielded no signifi cant pattern. figure shows four scatter-plots of china health aid and african trade. in the four diagrams, individual african countries are plotted according to health and commercial indicators. the scatter-plots did not show any association between medical aid and economic interests. spearman's rank correlation and t test analysis for the period of - showed no signifi cant fi ndings of correlations. these preliminary analyses should not be interpreted as conclusive. a core component of global health is mutual health protection against international transfer of health risks, which shows health interdependence. transborder movement of infectious diseases, contaminated goods and products, air pollution, and globally pooled co are prime examples. for china, the sars epidemic was a crisis with serious economic and political consequences. both disease control and international cooperation were delayed. chinese errors made in the early stage of sars have been acknowledged and have generated strong corrective measures, both domestically and internationally. domestic measures include major re-investment in the public health system via the chinese center for disease control and prevention (cdc), including development of the world's largest real-time electronic surveillance system. international eff orts include active participation and leadership in many international forums that foster cooperation in compliance of disease reporting and control, as shown by the initiation of the un resolution on enhancement of capacity-building in global public health in , and the joint international pledging conference on avian and human pandemic infl uenza with china, the european commission, and the world bank held in beijing in . [ ] [ ] [ ] subsequent management of infectious outbreaks such as avian infl uenza a h n virus shows that china recognises the importance of strict adherence to the international health regulations. in the sars outbreak, china needed days between fi rst case detection and report to who and another days for joint teams to investigate the outbreak. for h n one decade later, less than half the days lapsed between fi rst case and report to who and the initiation of joint investigations. [ ] [ ] [ ] infections can move in several directions. china has been the destination of cross-border infectious transmissions. in , a polio epidemic was imported from pakistan into china's xinjiang province. after making arduous eff orts and expending large resources. similarly, china has been threatened by the import of dengue fever, malaria, and several other transmissible diseases. , cross-border risks can also accompany the import and export of commodities. as the world's largest exporter of manufactured products, china, of course, transfers health risk overseas. news reports have been plentiful of contamination in chinese exports of toothpaste, lead paint, milk products, and heparin. [ ] [ ] [ ] [ ] these safety concerns are not limited to exporters. china has also been a destination in the dumping of contaminated chemicals from richer to poorer countries; these safety hazards are of equal concern to the chinese public. these concerns might be why china has upgraded its state food and drug administration (sfda) to the status of a ministry with larger budget, increased staff , and stronger regulatory powers. environmental pollution also moves across national boundaries. air pollutants in china have been cited as causing acid rain damage to forests in korea and japan. , china is today the world's largest emitter of carbon dioxide, contributing substantially to global climate change. to tackle air pollution, china's state council released an action plan setting a -year road map for air pollution control. its implementation deserves tracking for monitoring and evaluation of control eff ect. health governance sets ground rules for global stewardship of diverse activities. across the board, china has become an active member of the world system, opening with china's economic reform and accelerating after its entry into the wto in every aspect-eg, political (un), fi nancial (world bank, international monetary fund), economic (wto), and military (arm control and data underscore the participation of china in global governance. china's receipt of net offi cial development assistance and offi cial aid peaked at about $ million in , had steadily decreased to a third of that amount by , and is already disappearing as china increasingly becomes an aid donor rather than an aid recipient. from to , china's receipt and contribution to who were equal at about $ million. by - , china's assessed contribution to who had increased to $ million, while who funding to china had remained at baseline. in parallel with this increase in funding, the number of chinese staff members in who has expanded. whereas in , there were only chinese offi cials working in who, that number had tripled to by , although chinese staff in who are still under-represented. additionally, based on the newly released white paper, china allocated $ million to support the global fund and other international organisations in - . global health participation by china has been mainly governmental. in non-governmental stakeholders, growth in the international participation of some academic universities, business, and industry has occurred. china has very few non-governmental organisations (ngos) and thus the chinese are mostly absent from global civil society forums. a few international ngos work in china, but few have achieved offi cial registration from the chinese government. it will take substantial time, if ever, before china's civil society becomes active in global health. knowledge is both local and global, and its production, ownership, exchange, and application have global dimensions. china has much to share with and much to learn from the rest of the world. in medicine, strategy, and implementation, china has had some spectacular accomplishments, worthy contributions to the world's knowledge pool. chinese traditional medicine off ers many health-enhancing technologies-ranging from ephedrine to acu puncture. [ ] [ ] [ ] in the s, village health workers were fi eld tested, and later re-engineered as the barefoot doctor. china's three-tier rural health system was established soon after the founding of the people's republic. the alma ata movement for primary health care took great encouragement from china in showing what barefoot doctors could do at the community level. the three decades after the founding of the people's republic in witnessed some of the steepest advances of mortality control in human history. china's management of common infectious diseases, maternal-child health, tropical disease control, malaria and schistosomiasis containment, mass social hygiene campaigns, and recent achievement of near-universal health coverage are worthy of documentation as valuable lessons. physicians, two nurses, two chefs, two translators, and one medical engineer from shaanxi province constituted china's th medical team to sudan in - . the th chinese team from hebei province to the democratic republic of the congo arrived in , consisting of a team leader, physicians (including one in chinese traditional medicine), two nurses, one french translator, and one chef. for both teams, their primary role was to provide clinical care to patients. an ancillary function was to mentor, train, and improve the skill of local health workers. medical teams were self-suffi cient, bringing all their own supplies, equipment, and medicines. in response to questionnaires, team members commented positively on their experiences. higher salaries, fi nancial subsidies, and allowances from both central government and employers (about a six-fold increase) operated as important incentives. reported constraints included language barriers, unaccustomed disease profi les, poor facilities and equipment, unstable water and electricity supply, and homesickness. if the opportunity were off ered, nearly all would be willing to serve again. , panel : traditional chinese medicine to eradicate malaria? malaria eradication in some countries had been successful with dichlorodiphenyltrichloroethane, and hopes have focused on new vaccines. but a professor of chinese traditional medicine from guangzhou university of chinese medicine is leading an unprecedented eff ort to eradicate malaria on the comoros islands with traditional chinese medicine. starting in on moheli island where % of the residents were carriers of plasmodium falciparum, disease prevalence has dropped to · % in months with mass administration of artemisinin and piperaquine, donated by china's ministry of commerce. years later, the chinese team extended this programme to anjouan, an island of , reducing the prevalence of p falciparum carriers from % to · %. last year, the eff orts were expanded to the residents of grande comore, the country's largest island. the project goal is malaria eradication in the people of the comoros by . panel describes an innovative grant by uk government's department for international develop ment (dfid) to foster research by, and capacity building for chinese universities and other institutions to disseminate and share chinese lessons with other countries. for the future, china aspires to be a worldwide knowledge leader and it has fast growing research and development investments in biomedicine. chakma reported china's biomedical research and development at $ · billion in , in comparison with usa ($ billion), europe ($ billion), and japan ($ billion). the absolute size of these fi gures might undervalue chinese investments because the lower salaries, cost of infrastructure, and cost of operations in china might not be captured fully by purchasing power parity-adjusted values. strikingly, china's investments since have increased annually at % in comparison, for example, to − % for the usa. china, moreover, houses laboratories for most of the major pharmaceutical companies. it has advanced genetic research capacity as shown by its genetic sequencing of the h n virus within days of isolation and identifi cation. china is also a growing producer and exporter of generic products. china aspires to be a powerhouse in the discovery and production of new drugs and vaccines in global health. china's medical universities are increasingly undertaking research and education in global health. in the past year, several new multidisciplinary centres of china supports government offi cials, technical professionals, and young people from developing countries to participate in training and education programmes in china. in - , the government provided scholarships for such programmes, of which many were health related. china's medical universities also train foreign medical students. according to the data from the china education yearbook, in - , china trained foreign medical students, who constitute % of all foreign students in . for that year, the ministry of education reported almost foreign medical students studying modern medicine and studying traditional chinese medicine. , by , china had extended authorisation to medical schools to admit foreign students who will study medicine in english. figure shows the rapid increase of foreign medical students and scholarships in china in - . although foreign interest in traditional medicine is high, most foreign students register for modern medicine. about % of the foreign medical students receive chinese government scholarships that might be regarded as part of china's foreign health aid. chinese medical schools charge foreign students higher than chinese tuition fees, and the schools acknowledge foreign students as a source of school revenue. in , many of the students came from neighbouring asian countries, such as india, japan, pakistan, south korea, and southeast asia. our most salient fi nding is china's distinctive mode of engagement in global health. china's health aid volume is small, but the mode is distinctive, driven by china's health capabilities and national experiences. unlike many other traditional donors, china's in-kind aid focuses more on some important aspects of the health system. china's overall global engagement follows a very diff erent path from developed countries partly because it has no colonial experience nor did it participate in shaping the american-led post-world war world order. china was inward-looking until it expanded into the global economy in . over the ensuing three decades, china has had large shifts from a low-income to a middle-income country, and from aid recipient increasingly to aid donor. the spread of its foreign aid throughout the breadth of africa presumably refl ects both eff orts to solidify friendship politically, promote mutually benefi cial economic gains, and compete with taiwan for political friendship. china's health aid is embedded in the dynamic shifting of foreign and economic policies. the opening in marked a shift from economic development serving foreign policy to foreign policy serving economic development because china's association, for example, with africa, has developed from a political one in the s to a broader economic-based and trade-based engagement. , these are all defi ning characteristics of china's engagement in global health. china's global health work, unfortunately, does not seem to rank highly in government agencies. health has been assigned a lower position than political and commercial aff airs. taking advantage of both domestic and international resources and accessing both domestic and international markets is china's explicit national development strategy. these powerful economic motives drive much of china's global engagement, including its engagement in africa, to the point where the dividing line between trade and aid become blurred and hard to demarcate. health aid is only a very small adjunct to these much larger and more powerful forces. china's overseas forces include several government agencies. as a result, improved interministerial coordination is a necessary development for the evolution of a coherent overall engagement in global health. formulation of a china global health strategy could help bring coherent policy and harmonised action, because it would compel the articulation of specifi c health and humanitarian objectives in chinese governmental policies. an explicit china global health strategy would provide a stronger context for ngos and private sector overseas participation. china's bilateral approach diff ers substantially from its multilateral approach. although china's bilateralism takes an independent approach, china's multilateral strategy is full participation, joining as a regular member and complying with its responsibilities and privileges in un bodies such as who. the records show that china respects and complies with rules governing multilateral institutions in all aff airs-health, trade, migration, environment, and other aspects of global governance. china has increased its contribution to multilateral funding pools, such as the global fund from $ million per year in , to $ million per year in . how important china will become as a major donor to these pooled funds is uncertain. some see the early actions as symbolic gestures of cofunding, whereas others hope that the size of the chinese economy will propel it to become a fi nancial leader of multilateral funds. the new development bank being established by brics countries aims to compete with the world bank and international monetary fund, which is one example of how china has debatably played a leadership role. most important is the avoidance of over-simplifi cation. no country's international engagement is free from political or economic motives-eg, europe colonialism, us millennium development accounts, or sweden-vietnam partnership during the american war. and no single modality of foreign aid has proven to be more eff ective or more sustainable. , although china's health aid is generally appreciated by recipient offi cial statements, there are indeed complaints about the scale of china's intrusion, access to natural resources, and the trade market in africa. but energy resource-based trade structure with africa does not occur only in china; it occurs with all major african trading partners. the most fundamental improvement is to increase the capacity for independent development, to which all partners in africa should contribute. china's global health engagement is diffi cult to attribute to one motivation factor. chinese driving forces are undoubtedly several and complex-political, economic, social, and humanitarian. china's approach has been characterised as pragmatic that "combines the utilitarian logic of reaping material benefi t, the realist objective of expanding its global power and infl uence, the neo-liberalist interest in pursuing absolute gains from international cooperation, and the constructivist attempt to become a responsible stakeholder in the system". china's global health engagement will probably grow substantially with expanding budgets, more projects, and more staff sent abroad. china will pursue its own distinctive approach, not copying the developed world model; chinese government policy and indigenous professional capacity will be key. the fi rst generation of chinese professionals with experience and foreign language fl uency is emerging along with stronger global health institutions. given this trajectory, one should assume global health will likely be re-shaped by china's participation, with its structures and processes increasingly accommodating chinese characteristics. pl led and coordinated the authors' group. all authors participated in study design, data collection, analysis, interpretation, and paper writing and editing. lc and zl produced the fi rst draft. we declare no competing interests. emory global health institute. case study: can global sanitation contribute to china's prosperity? atlanta, e-mory global health institute china's global hunt for energy council on foreign relations will china change international development as we know it? china's foreign aid activities in africa, latin america, and southeast asia china's development fi nance to africa: a media-based approach to data collection information offi ce of the state council white paper on china's foreign aid, the people's republic of china passage to china the great manchurian plague of - : the geopolitics of an epidemic disease the barefoot doctors of the people's republic of china artemisinin (qinghaosu): a new type of antimalarial drug making sense of global health governance: a policy perspective towards a common defi nition of global health health professionals for a new century global health governance at a crossroads chinese medical cooperation in africa aid within the wider china-africa partnership: a view from the beijing summit the fi fth ministerial conference of the forum on china-africa cooperation beijing action plan china's engagement with global health diplomacy: was sars a watershed? shifting paradigm: how the brics are reshaping global health and development chinese development aid in africa: what, where, why, and how much? china to strengthen cooperation with africa on health key players in global health: how brazil, russia, india, china, and south africa are infl uencing the game characteristics of china-africa health collaboration: the case of democratic republic of congo the experience of chinese physicians in the national health diplomacy programme deployed to sudan fighting malaria china engages global health governance: processes and dilemmas china information system for disease control and prevention (cisdcp) permanent mission of the people's republic of china to the un. statement by chinese permanent representative wang guangya at the th session of the un introducing a draft resolution entitled "enhancing capacity building in global public health who. international pledging conference on avian and human pandemic infl uenza china's health diplomacy: sharing experience and expertise infl uenza a virus subtype h n joint mission on human infection with avian infl uenza a (h n ) virus timeline: sars virus controlling the polio outbreak in china xinjiang remains polio-free china tightens quarantine for malaria, dengue china regions on alert for malaria, dengue fever elements of a sustainable trade strategy for china made in china melamine in milk products in china: examining the factors that led to deliberate use of the contaminant contaminated heparin seized by fda toxic exports: the transfer of hazardous wastes from rich to poor countries china upgrades drug safety agency-people's congress: move aims to raise quality of food and drug supply trend of acid rain and neutralization by yellow sand in east asia-a numerical study air pollution from china reaches japan, other parts of asia world carbon dioxide emissions data by country: china speeds ahead of the rest ministry of environmental protection, the people's republic of china. the state council issues action plan on prevention and control of air pollution introducing ten measures to improve air quality data: net offi cial development assistance and offi cial aid received (current us$) who. financial and auditing reports from world health assembly, from wha to wha who. human resources: annual report chinese materia medica: chemistry, pharmacology and applications chinese acupuncture and moxibustion asian medicine. the new face of traditional chinese medicine health service delivery in china: a literature review mortality in china global health support programme supports shared international development objectives uk global health support programme (ghsp) asia's ascent-global trends in biomedical r&d expenditures duke kunshan university, and the leading chinese universities launch new global health consortium liberal education meets chinese tradition china consortium of universities for global health established in beijing ministry of education of people's republic of china. china education yearbook . beijing: people's education press ministry of education of people's republic of china. brief statistics of international students in china new list of chinese medical institutions admitting international students for academic year ministry of education of people's republic of china. interim provisions to control the quality of foreign students' undergraduate education (english class) in china beyond borders: potential gaps in the international system of public health surveillance china: foreign policy serves domestic development china's priorities in africa: enhancing engagements collection of important documents since third plenary session emerging economics to launch development five metaphors about global-health policy development assistance for health: critiques and proposals for change the great escape: health, wealth, and the origins of inequality china and global health governance we thank haomin yang, yang li, and jing bai for their work on data collection, data analysis, and research assistance. key: cord- -djclli n authors: ruan, yijun; wei, chia lin; ling, ai ee; vega, vinsensius b; thoreau, herve; se thoe, su yun; chia, jer-ming; ng, patrick; chiu, kuo ping; lim, landri; zhang, tao; chan, kwai peng; lin ean, lynette oon; ng, mah lee; leo, sin yee; ng, lisa fp; ren, ee chee; stanton, lawrence w; long, philip m; liu, edison t title: comparative full-length genome sequence analysis of sars coronavirus isolates and common mutations associated with putative origins of infection date: - - journal: lancet doi: . /s - ( ) - sha: doc_id: cord_uid: djclli n background: the cause of severe acute respiratory syndrome (sars) has been identified as a new coronavirus. whole genome sequence analysis of various isolates might provide an indication of potential strain differences of this new virus. moreover, mutation analysis will help to develop effective vaccines. methods: we sequenced the entire sars viral genome of cultured isolates from the index case (sin ) presenting in singapore, from three primary contacts (sin , sin , and sin ), and one secondary contact (sin ). these sequences were compared with the isolates from canada (tor ), hong kong (cuhk-w and hku ), hanoi (urbani), guangzhou (gz ), and beijing (bj , bj , bj , bj ). findings: we identified sequence variations among the isolates, with recurrent variant sequences. common variant sequences at four loci define two distinct genotypes of the sars virus. one genotype was linked with infections originating in hotel m in hong kong, the second contained isolates from hong kong, guangzhou, and beijing with no association with hotel m (p< . ). moreover, other common sequence variants further distinguished the geographical origins of the isolates, especially between singapore and beijing. interpretation: despite the recent onset of the sars epidemic, genetic signatures are emerging that partition the worldwide sars viral isolates into groups on the basis of contact source history and geography. these signatures can be used to trace sources of infection. in addition, a common variant associated with a non-conservative aminoacid change in the s region of the spike protein, suggests that immunological pressures might be starting to influence the evolution of the sars virus in human populations. published online may , http://image.thelancet.com/extras/ art web.pdf the first cases of severe acute respiratory syndrome (sars) were identified in november, , in guangdong province, china. by april, , the epidemic had spread worldwide, affecting individuals resulting in deaths. in march, , the putative cause of sars was identified as a new coronavirus. , oropharyngeal specimens from patients with sars induced a cytopathic effect on vero e tissue culture cells and revealed the presence of coronavirus-like particles. reverse transcriptase-pcr analysis with random or broadly-specific coronavirus primers amplified a dna fragment that resembled, but was distinct from, known coronavirus genomes. when tested, these diagnostic pcr methods detected the sars virus in many clinical samples taken from affected patients. in addition, serological evidence has shown the presence of antibodies specific to the new coronavirus in the serum of patients with sars. collectively, these data strongly implicate the new coronavirus as the cause of sars, which we designate as sars-cov. sars-cov is a member of the coronoviridae family of enveloped, positive-stranded rna viruses, which have a broad host range. some coronavirus infections in people, cattle, and birds cause respiratory disease, whereas other coronavirus infections in rodents, cats, pigs, and cattle lead to enteric disease. the - kb genomes of coronaviruses, the largest of rna viruses, encode putative proteins, including four major structural proteins; nucleocapsid (n), spike (s), membrane (m), and small envelope (e). the spike protein, a glycoprotein projection on the viral surface, is crucial for viral attachment and entry into the host cell. in addition, variations of s protein among strains of coronavirus are responsible for host range and tissue tropism. differences in virulence of mice coronaviruses have also been linked to genetic variance in the s protein. , and the serological response in the host is typically raised against the s protein. however, the s, m, and n mature proteins all contribute to generating the host immune response as seen in transmissible gastroenteritis coronavirus, infectious bronchitis virus, , pig respiratory coronavirus, and mouse hepatitis virus. a characteristic of rna viruses is the high rate of genetic mutation, which leads to evolution of new viral strains and is a mechanism by which viruses escape host defenses. therefore, from a public-health perspective, understanding the mutation rate of the sars virus as it spreads through the population is important. moreover, the genetic mutability of sars-cov, especially in the segments encoding the major antigenic proteins, would also have an effect on development of broadly effective vaccines. we aimed to determine the complete genome sequence for five sars-cov related isolates from a single sars index case, three associated primary contact cases, and one secondary contact and compare them with nine other sars-cov isolates available in public-domain databases. we obtained five positive isolates for coronavirus from the index patient of the outbreak (sin ), three primary contacts of this patient (sin , sin , sin ), and one secondary contact (sin ) who was related to the index patient, but contracted sars from another primary contact not included in this study. all patients fitted the who case definition for probable sars fever of ºc or higher, respiratory symptoms (eg, cough, shortness of breath, difficulty in breathing), hypoxia and chest radiograph changes suggestive of pneumonia, and history of close contact with another patient with sars or travel to a region with documented community transmission of sars within days of onset of symptoms. the index patient had a history of travel to hong kong and had stayed in hotel m. the viral sources were all from respiratory samples: two endotracheal tube aspirates, two nasopharyngeal aspirates, and one throat swab obtained from the patients between and days after of onset of symptoms. the virus-containing samples were inoculated into various cell lines including vero cells, which showed a cytopathic effect characterised by generalised rounding against a granular background seen - days after inoculation. we maintained the cells at ºc and repassaged them after days of incubation. we spotted washed cell pellets from harvested cells showing cytopathic effects onto glass slides and overlaid them with acute and convalescent serum samples from the patients from whom we obtained the respiratory samples. all five cell lines showed reactivity by immunofluorescence (methods available from authors) with convalescent serum samples from the respective patients. we confirmed the presence of the sars coronavirus by pcr on the cell supernatants using sarsspecific primers. , when tested, two of the infected vero cell lines also had coronavirus-like particles on electron microscopy. we isolated the viral rna template from the supernatants of vero cells that showed cytopathic effects by centrifugation at relative centrifugal force for · h to pellet the viral particles and extracted rna with the qiamp viral rna mini kit (qiagen, valencia, ca, usa). to sequence the viral genome we used both shot-gun and specific priming approaches. from the rna templates, we synthesised double strand cdna with the superscript cdna system (invitrogen, carlsbad, ca, usa). the cdna were pcr amplified ( cycles) with random -mer by platinum taq polymerase. the amplicons were then cloned into pcr . -topo vector (invitrogen). we selected random clones for single pass sequencing analysis on abi sequencers (applied biosystems, foster city, ca, usa). we compared sequence data generated from the library with human, mouse, and viral genome databases managed at the us national center for biotechnology the basic local alignment search tool is a system for searching similar sequences against all available sequence databases irrespective of whether the query is dna or protein sequences. the blast programs consist of blastn, blastp, tblast, tblastn, tblastx, psi-blast, megablast, and so on. the most improved point of this software is its high searching speed clustalw clustalw is a multiple sequence alignment tool that is commonly used in the bioinformatics community. it produces global multiple sequence alignments through three major phases: pairwise alignment, guide tree construction, and multiple alignment. the guide tree generated by clustalw is an estimate of relations between sequences much like a phylogenetic tree paup* the phylogenetic analysis using parsimony (paup*) is a well established package for phylogenetic tree construction. it uses various methods, including parsimony, maximum likelihood, and distance methods to estimate phylogenetic relations. bioinformatics tools to assemble shotgun sequences, which are available from university of washington, phred=base-calling program; phrap=assembly program for shotgun sequences; consed=unix-based graphic editor for phrap sequence assemblies positive-stranded rna viruses some viruses, such as coronaviruses, carry their genetic material as rna rather than the more typical dna-based genomes. positivestranded rna (also called plus-stranded) indicates that the single stranded rna genome is of the same sense as coding messenger rna accession number we designed sequence-specific primers on the basis of cdna sequence data to fill the gaps of - kb distance. after we completed the first rough genome sequence for the sample sin , we designed primer pairs incorporating sequence information from the newly available tor sars virus to cover the whole viral genome with each primer pair amplifying about base pairs. we then used this sequence-specific priming approach to generate reverse transcriptase-pcr fragments for the five whole viral genomes. each pcr fragment was directly sequenced from both directions inward and outward, in duplicate. therefore, for any region of the genome there was six to eight-fold coverage. we used the phred/phrap/consed package (university of washington, seattle, wa, usa; http://www.phred.org) to process all the raw sequence reads for base calling, assembly, and editing. nucleotide differences in the assembled genome sequences were also checked manually for accuracy. sequence regions that were poor quality were resequenced either from purified pcr fragments or cloned plasmid. all genetic variations of singapore isolates identified when compared with available sars-cov genome sequences were further confirmed by primer extension genotyping technology (sequenom, san diego, ca, usa). the panel shows the sars-cov isolates we accessed from genbank. we determined the locations of point mutations by aligning the sars sequences with clustalw. we calculated putative coding sequences by completing the multialignment of the sars sequences with the tor nucleotide sequence annotation as the reference. the annotations of the proteins are taken from the corresponding entries in the ncbi entrez site. associations between the members of the coronaviridae family to the sars virus were assessed by comparing overlapping fragments of the sin genomic sequence against a database of coronavirus sequences. to calculate regional homologies with sister coronaviruses we used sequences within sliding base pair windows sampled in a tiled fashion every base pairs across the viral genomes using the blast blastn program from wu-blast (washington university, st louis, mo, usa). in the heat map that was generated, the sars genomic fragments are plotted along the horizontal axis in the order they appear in the sponsor of the study had no role in study design, data collection, data analysis, data interpretation, or in the writing of the report. we have sequenced the complete genomes of sars-cov from five singapore isolates derived from one index case (sin ), three primary cases (sin , sin , and sin ), and one secondary case (sin ). these sequences showed that the genomes of sars-cov isolated in singapore are comprised of bases, with the exception of a five-nucleotide deletion in strain sin and a six-nucleotide deletion in sin . initial blast analysis suggested that the singapore sars virus is similar to, but distinct from, the group coronaviruses in the coronaviridae family of enveloped and positive-stranded rna viruses. as in the recently sequenced sars-cov (hku , cuhk-w , tor , and urbani), the singapore sars virus contains predicted open reading frames that encode putative mature proteins with known and unknown functions. most of the non-structural proteins seem to be encoded in the first half of the genome including nsp and nsp , with putative proteinase function and nsp rna-dependent rna polymerase, whereas most of the structural proteins such as spike, membrane, envelop, and nucleocapsid are located in the second half of the genome (figure , webfigure: http://image.thelancet. com/extras/ art webfigure.pdf). the haemagglutinin esterase, which is common in the group coronavirus, is missing in the sars-cov genome, suggesting that some of the non-structural genes are dispensable in coronaviruses. although the genome organisation of sars-cov is similar to that of other coronaviruses, sars-cov is only distantly related to any coronavirus member, irrespective of species specificity, at both nucleotide and aminoacid levels (figure ). in assessing the homology with coronaviridae genomes from other species with the sars-cov, sequence the genome, and the corresponding fragments from other coronaviruses are placed vertically. the brightness of a pixel corresponds to the strength of the match between a sars fragment and a coronavirus genome; the smaller the p value, the brighter the pixel. at p= it is black, and the brightness is proportional to log ( ÷p) until p is less than - , when it is white. the panel shows the accession numbers of the coronavirus sequences used. in the analysis of the common sequence variations, the probability of co-occurrence of multiple polymorphisms or mutations in an isolate was used as a measure of significance. we used of the samples (we excluded sample bj because of substantial missing sequence information) and restricted our attention to loci at which nucleotides were determined in all samples. the null hypothesis was that the nucleotides at these loci were obtained by mutating a single consensus sequence independently at random at each position of each sequence. the mutation rate was estimated from the data by the fraction of positions in the various genomes that differed from the consensus sequence obtained by taking the most frequent nucleotide at each position. we also tested a weaker null hypothesis, in which the mutations taking place at any given locus in different samples are independent, but arbitrary dependence between the loci is possible subject to this constraint. details of the analytical approach are described in webappendix (http://image.thelancet.com/extras/ art webappendix .pdf) and on our website (http://www. gis.astar.edu.sg/ homepage/toolssup.jsp). phylogenetic analysis of the sars viral genomes was done with paup* with the maximum probability criterion. we used the default variable settings, with one exception: the substitution rates were estimated from the data. a separate phylogenetic analysis done with clustalw gave the same structure. conservation seems to be restricted to the middle part of the genome, between bases and , where the rna-dependent polymerase and several uncharacterised proteins (eg, orf ab:nsp - ) are located. the remainder of the genome, especially at the Ј and Ј regions, diverges from other strains at the nucleotide and aminoacid level. we aligned the five complete genome sequences of singapore sars-cov isolates and the nine sars-cov genomes from outside of singapore, which were sequenced by others, and investigated the genetic variations between these genomes (webappendix ). in total, there were single nucleotide sequence variations, one deletion of six nucleotides (nt - ) in strain sin , and one deletion of five nucleotides (nt - ) in strain sin (webappendix , http://image.thelancet.com/extras/ art webappendix .pdf). both these deletion sites were in the noncoding sequences between an uncharacterised open reading frame and the nucleocapsid protein. of the base substitutions, changed the aminoacid sequence (webappendix ). the mutations were in the following open reading frames: orf a polyprotein, orf a rna-polymerase, orf ab: nsp to nsp , spike glycoprotein, membrane nucleocapsid, and several uncharacterised putative proteins. to eliminate mutational noise induced in culture from real strain differences, we reanalysed the data using a probabilistic approach. mutations that might have been artifacts of cell culture would occur only once in our survey, whereas sequence variants associated with common ancestry should be seen in multiple isolates. of the sequence variations in the isolates, variant loci were identified in two or more isolates, and eight were seen in three or more isolates ( figure ). with the more stringent criterion, four loci recurred five or more times in the sars-covs analysed: c/t polymorphisms at position resulting in a valine to alanine change in orf a (nsp ); position leading to an isoleucine to threonine change in orf ab (nsp ); position changing an isoleucine residue to threonine in the s portion of the spike protein, and position which is in a non-coding region ( figure ). in addition, a t/g polymorphism is noted at position changing orf ab (nsp , helicase domain) from an aspartic acid to a glutamic acid. sequence variants at these four loci segregate together as a specific genotype. assuming that all base substitutions were random events propagated in the vero cells, the probability of four specific nucleotide changes occurring concurrently is very low. the significance is at p< - when the null hypothesis is that each locus in each sample mutates independently, and p< - when dependence is allowed among the loci. the c:g:c:c and t:t:t:t genotypes are, therefore, very unlikely to have emerged by chance, and might be evidence for the first genetic signature of strain differences in the sars virus. all isolates with the t:t:t:t genotype were linked to infection acquired at the hotel m in hong kong, whereas none of the c:g:c:c genotype isolates had this association ( figure ). phylogenetic analysis based on the common variant sequences (defined as present in two or more isolates) confirmed that the cases associated with exposure in the hotel m formed a cluster that was distinct from the other isolates ( figure ) . on the basis of the molecular and contact history, we have reconstructed a probable lineage map of the sars-cov infections investigated here ( figure ). in addition to this four-locus genotype, four other common variant sequences (all occurring three to four times in the isolates) seem to further define subgroups geographically (figure ). the variant sequences at position seem to distinguish the singaporean isolates from all others. although all nine isolates from outside singapore showed a c at this position, four of the five isolates from singapore had a t. the only reversion from t to a c in sin (a secondary contact case) might be the result of a backmutational event potentially occurring during the passage of the virus. taking into account missing data, the polymorphisms at nucleotide positions , , and all segregate with isolates identified specifically in beijing. thus, these common sequence polymorphisms might be useful in identifying the differential source of a sars viral infection. although the genome organisation of sars-cov is similar to that of other coronaviruses, the sars-cov sequence is only distantly related to any coronavirus member. results of earlier reports suggested that sars-cov more closely resembled the cow coronavirus and the mouse hepatitis virus by comparing a conserved aminoacid segment of the polymerase protein product. however, when taking into account the entire genomic sequence, the strength of the associations was reduced, confirming the reports of others that the sars coronavirus is a completely new pathogenic strain that does not arise from a simple recombination of known existing strains. , since the s subunit of the spike protein is the major antigenic moiety for coronaviruses and is not an essential structural protein, it is prone to high mutation rates as the virus evolves in host populations. that the s region did not seem to have excessive numbers of base substitutions suggests that the viral isolates have not been subject to immunological selection. , however, because all samples were from viral cultures propagated in vero cells, some, if not most, of these mutations might have occurred during in-vitro expansion and not because of host pressures. in addition, some of the available nucleotide substitutions might have been the result of sequencing errors since several of the sequences were submitted in draft form. to reduce the effects of these technical artifacts, we restricted our analysis to the loci with recurrent mutations among the isolates. these loci are the sequence variants most likely to have been resident in human populations. of special interest are the nucleotide changes in four of these loci (positions , , , and ) that recurred five or more times. the base substitutions at these locations are highly restricted and segregate together as specific genotypes (c:g:c:c vs t:t:t:t). thus, it is highly unlikely that the c:g:c:c and t:t:t:t genotypes emerged by chance. rather, we believe this to be evidence for the first genetic signature of strain differences in the sars virus. all isolates with the t:t:t:t genotype were linked to infection acquired at the hotel m in hong kong, whereas none of the c:g:c:c genotype isolates had this association. the index case from singapore (from which the singaporean infections described herein were derived) acquired the sars-cov infection while staying at hotel m. the tor virus, cultured in canada, and the hku isolate from hong kong, were from patients who became infected through contact at hotel m, although perhaps not directly. the urbani sars-cov isolate was from a physician infected by a patient who contracted sars while staying at hotel m. isolates cuhkw , gzd , bj , bj . bj , bj , however, came from patients with no known linkage with hotel m and, on the whole, were derived later than the hotel m linked set. our results showed that the cases associated with exposure in the hotel m formed a cluster that was distinct from the other isolates. in addition to this four locus genotype, the variant sequences at position distinguished the singaporean isolates from all others. there also seems to be a signature for the north china isolates at positions , , and . thus, the common sequence polymorphisms might be useful in identifying the differential source of a sars viral infection. whether any of these common polymorphisms will result in biological and clinical differences remains to be determined. however, the common mutation in position changing an isoleucine residue to threonine in the important antigenic region of the spike protein might be relevant. mutations in this region of the sars-cov genome can arise because of selective pressure from host immune responses. that an isoleucine is present in all hotel m linked isolates whereas a threonine at the same position in the major antigenic protein is found in all other geographically distinct isolates suggests that such non-conservative aminoacid changes have occurred to evade immunological pressures. the sars viral epidemic has placed a substantial strain on the health and economic status of nations. understanding the nature of this virus and deriving methods to control the epidemic are very important. our results show several molecular facets of the sars coronavirus pertinent to public-health management of this epidemic. its novelty as a human pathogen suggests that most populations might be immunologically naive to its infection. the discovery of genotypes linked to geographic and temporal clusters of infectious contacts suggests that molecular signatures can be used to refine contact histories. a e ling organised and directed the in-vitro investigations of the biology of the sars virus. k p chan provided viral cultures, and l l oon and s y sethoe did the molecular diagnostic analysis and extraction of the viral nucleic acids. n m lee did the electron microscopy of the initial viral samples. y s leo was the chief infectious disease clinician caring for the patients. sequence determination and analysis was done by y ruan, c wei, h thoreau, p ng, k chiu, l lim, t zhang, e e c ren, l stanton, p long, and e t liu. cumulative number of reported probable cases of severe acute respiratory syndrome (sars) identification of a novel coronavirus in patients with severe acute respiratory syndrome a novel coronavirus associated with severe acute respiratory syndrome coronavirus as a possible cause of severe acute respiratory syndrome retargeting of coronavirus by substitution of the spike glycoprotein ectodomain: crossing the host cell species barrier targeted recombination demonstrates that the spike gene of transmissible gastroenteritis coronavirus is a determinant of its enteric tropism and virulence pathogenesis of chimeric mhv /mhv-a recombinant viruses: the murine coronavirus spike protein is a major determinant of neurovirulence the jhm strain of mouse hepatitis virus induces a spike protein-specific db-restricted cytotoxic t cell response expression of immunogenic glycoprotein s polypeptides from transmissible gastroenteritis coronavirus in transgenic plants production and immunogenicity of multiple antigenic peptide (map) constructs derived from the s glycoprotein of infectious bronchitis virus (ibv) recombinant nucleocapsid protein is potentially an inexpensive, effective serodiagnostic reagent for ibv an adenovirus recombinant expression the spike glycoprotein of porcine respiratory coronavirus is immunogenic in swine nucleotide sequence comparison of the membrane protein genes of three enterotropic strains of mouse hepatitis virus severe acute respiratory syndrome (sars) update: outbreak of severe acute respiratory syndrome, worldwide clustal-w-improving the sensitivity of progressive multiple sequence alignment through sequence weighting, position-specific gap penalties and weight matrix choice phylogenetic analysis using parsimony (and other methods). version the genome sequence of the sars-associated coronavirus generation of coronavirus spike deletion variants by highfrequency recombination at regions of predicted rna secondary structure origin and evolution of georgia (ga ), a new serotype of avian infectious bronchitis virus effects of passage history and sampling bias on phylogenetic reconstruction of human influenza a evolution we thank prasanna kolatkar, marie wong, liu jianjun, and joshy george for their help in this project. the authors are members of the gis and are therefore funded by the agency for science technology and research of singapore. none declared. key: cord- -slkqu pt authors: carrabba, giorgio; tariciotti, leonardo; guez, sophie; calderini, edoardo; locatelli, marco title: neurosurgery in an infant with covid- date: - - journal: lancet doi: . /s - ( ) - sha: doc_id: cord_uid: slkqu pt nan administering general aneasthesia to infants with respiratory infections is a challenge because aneasthetic drugs suppress immunity and can thus contribute to intubation-related mechanical stress and inflammation. neurosurgery in infants with coronavirus disease (covid- ) therefore poses a dilemma because the infection is associated with relative immune suppression and a dysregulated inflammatory response, which act as drivers of the disease. from milan, italy, we report the case of an -month-old male patient with a complex hydrocephalus who had a shunt malfunction during the covid- pandemic. the infant presented with a mild temperature, a dry cough, and an occipital cerebrospinal fluid collection, suggestive for shunt malfunctioning. neurological examination was negative, but the infant deteriorated and vomited repeatedly. the head ct scan indicated a shunt disconnection. a chest x-ray was negative for overt interstitial pneumonia (appendix) and the nasopharyngeal swab tested positive for severe acute respiratory syndrome coronavirus . while the baby showed upper respiratory symptoms due to covid- , concerns emerged regarding the need for general anaesthesia for shunt revision. to our knowledge, no reports exist regarding the risk of general anaesthesia in infants with covid- . nevertheless, considering the certainty of progressive neurological deterioration if no intervention was taken, the neurosurgical intervention was arranged. according to the available protocols for patients with covid- , a negative pressure operating room was set up. the staff were provided with full-head hoods, eye protection, filtering facepiece masks, fluidresistant gowns, double long-sleeved gloves, and impermeable disposable shoe covers. surgeons and scrubbing nurses had additional sterile surgical suits and an additional pair of longsleeved gloves. the patient was transferred from a ward dedicated to patients with covid- to the surgical theatre through an isolated and restricted area by trained personnel wearing protective gear. surgery lasted approximately h, and the infant recovered from general anaesthesia promptly. days after surgery, vomiting had worsened and a second neurosurgical revision of the shunt was done. again, the baby underwent surgery under general anaesthesia without respiratory complications. the baby was promptly extubated, and the neurosurgical course was favourable. to the best of our knowledge, this is the first reported case of an infant with covid- undergoing neurosurgical operations under general anaesthesia. this case might reflect a general observation of relative resistance of babies and children to suggesting the possibility that paucisymptomatic infants with covid- can undergo major surgical procedures without additional morbidity. this early case report needs confirmation and extension and might have broader implications for other surgical procedures addressing potentially lifethreatening conditions in infants. sars-cov- infection in children practical recommendations for critical care and anesthesiology teams caring for novel coronavirus ( -ncov) patients see online for appendix we declare no competing interests. key: cord- - pxdeva authors: nicholson, karl g; wood, john m; zambon, maria title: influenza date: - - journal: lancet doi: . /s - ( ) - sha: doc_id: cord_uid: pxdeva although most influenza infections are self-limited, few other diseases exert such a huge toll of suffering and economic loss. despite the importance of influenza, there had been, until recently, little advance in its control since amantadine was licensed almost years ago. during the past decade, evidence has accrued on the protection afforded by inactivated vaccines and the safety and efficacy in children of live influenza-virus vaccines. there have been many new developments in vaccine technology. moreover, work on viral neuraminidase has led to the licensing of potent selective antiviral drugs, and economic decision modelling provides further justification for annual vaccination and a framework for the use of neuraminidase inhibitors. progress has also been made on developing near-patient testing for influenza that may assist individual diagnosis or the recognition of widespread virus circulation, and so optimise clinical management. despite these advances, the occurrence of avian h n , h n , and h n influenza in human beings and the rapid global spread of severe acute respiratory syndrome are reminders of our vulnerability to an emerging pandemic. the contrast between recent cases of h n infection, associated with high mortality, and the typically mild, self-limiting nature of human infections with avian h n and h n influenza shows the gaps in our understanding of molecular correlates of pathogenicity and underlines the need for continuing international research into pandemic influenza. improvements in animal and human surveillance, new approaches to vaccination, and increasing use of vaccines and antiviral drugs to combat annual influenza outbreaks are essential to reduce the global toll of pandemic and interpandemic influenza. influenza viruses have segmented genomes and show great antigenic diversity. of the three types of influenza viruses-a, b, and c-only types a and b cause widespread outbreaks. influenza a viruses are classified into subtypes based on antigenic differences between their two surface glycoproteins, haemagglutinin and neuraminidase. haemagglutinin subtypes (h -h ) and nine neuraminidase subtypes (n -n ) have been identified for influenza a viruses (figure ). viruses of all haemagglutinin and neuraminidase subtypes have been recovered from aquatic birds, but only three haemagglutinin subtypes (h , h , and h ) and two neuraminidase subtypes (n and n ) have established stable lineages in the human population since . only one subtype of haemagglutinin and one of neuraminidase are recognised for influenza b viruses. although most influenza infections are self-limited, few other diseases exert such a huge toll of suffering and economic loss. despite the importance of influenza, there had been, until recently, little advance in its control since amantadine was licensed almost years ago. during the past decade, evidence has accrued on the protection afforded by inactivated vaccines and the safety and efficacy in children of live influenza-virus vaccines. there have been many new developments in vaccine technology. moreover, work on viral neuraminidase has led to the licensing of potent selective antiviral drugs, and economic decision modelling provides further justification for annual vaccination and a framework for the use of neuraminidase inhibitors. progress has also been made on developing near-patient testing for influenza that may assist individual diagnosis or the recognition of widespread virus circulation, and so optimise clinical management. despite these advances, the occurrence of avian h n , h n , and h n influenza in human beings and the rapid global spread of severe acute respiratory syndrome are reminders of our vulnerability to an emerging pandemic. the contrast between recent cases of h n infection, associated with high mortality, and the typically mild, self-limiting nature of human infections with avian h n and h n influenza shows the gaps in our understanding of molecular correlates of pathogenicity and underlines the need for continuing international research into pandemic influenza. improvements in animal and human surveillance, new approaches to vaccination, and increasing use of vaccines and antiviral drugs to combat annual influenza outbreaks are essential to reduce the global toll of pandemic and interpandemic influenza. we reviewed international reports published in english before december, . the data for this non-systematic review of articles were identified by searches of medline, embase, integrated science citation index, pubmed, and the cochrane library electronic databases with relevant keywords. we also searched cited references in retrieved articles, reviewed articles we have collected over many years, referred to the textbook of influenza, and used knowledge of new data presented at international scientific meetings. because of the large number of articles that are published every year and limitations on the number of citations, we gave emphasis to clinically relevant issues, particularly disease burden, the emergence of new subtypes, vaccines, and antivirals, and diagnosis. we gave priority to randomised controlled trials when available, to larger studies, articles published in high-impact journals that have a wide readership, and the systematic review and economic decision modelling, for the prevention and treatment of influenza, commissioned by the health technology assessment programme on behalf of the national institute of clinical excellence. we also drew on our own knowledge when it seemed appropriate to fill in the gaps in the published work and included several recent pertinent articles. haemagglutinin facilitates entry of the virus into host cells through its attachment to sialic-acid receptors. it is the major antigenic determinant of type a and b viruses to which neutralising antibodies are directed and the crucial component of current influenza vaccines. an important function of neuraminidase, the second major antigenic determinant, is to catalyse the cleavage of glycosidic linkages to sialic acid, thereby assisting in the release of progeny virions from infected cells. accordingly, neuraminidase has become an important target for antiviral activity. the m ion channel of influenza a, which is blocked by the antiviral drug amantadine, regulates the internal ph of the virus, which is crucial during early viral replication. the epidemiological behaviour of influenza in people is related to the two types of antigenic variation of its envelope glycoproteins-antigenic drift and antigenic shift. during antigenic drift, new strains of virus evolve by accumulation of point mutations in the surface glycoproteins. the new strains are antigenic variants but are related to those circulating during preceding epidemics. this feature enables the virus to evade immune recognition, leading to repeated outbreaks during interpandemic years. antigenic shift occurs with the emergence of a "new", potentially pandemic, influenza a virus that possesses a novel haemagglutinin alone or with a novel neuraminidase. the new virus is antigenically distinct from earlier human viruses and could not have arisen from them by mutation (figure ). four or five pandemics of influenza occurred during the th century with intervals of - years. the h n pandemic of - was the most devastating, with - million deaths; an estimated · million excess deaths, representing % of the population, occurred in india alone. however, the cumulative mortality from influenza during the intervening years is generally many times greater than that associated with pandemics. although influenza a or b viruses circulate virtually every winter in temperate zones of the northern and southern hemispheres, quantification of the burden of influenza on consultations, emergency-department examinations, hospital admissions, and mortality has been difficult because influenza lacks pathognomonic features, it cocirculates with other respiratory pathogens, and it causes a range of nonspecific complications, such as exacerbations of chronic cardiopulmonary disease. nevertheless, there is much evidence that the h n subtype of influenza a virus causes more severe illness than h n or influenza b, - more hospital admissions for pneumonia and influenza, and higher numbers of excess deaths. during outbreaks, sentinel schemes, such as the royal college of general practitioners' network in england, report increased consultation rates for influenza-like illness and other respiratory syndromes that are strongly associated with excess mortality. in england and wales, an estimated - people died during each of the epidemics between - and - . these estimates are about ten times the number of death certifications for influenza, because the disease is the cause of many "hidden deaths". in the usa, during the about % of these influenzaassociated excess deaths are among people aged years and older. although there are age-related increases in deaths from influenzal illness in both at-risk and low-risk groups, most deaths and hospital admissions occur in elderly people with chronic cardiopulmonary disorders. among toddlers, rates of influenza-associated hospital admission in the usa have ranged from about per population for those with high-risk conditions to per for those without high-risk conditions. [ ] [ ] [ ] [ ] admission rates are highest among children younger than year and are similar to rates found among people aged years and older. , among children in hong kong, china, the numbers of excess hospital admissions attributed to influenza are very high in children younger than months ( and per in and , respectively) and decrease with age ( and per children aged - months; and per children aged - years; and per children aged - years; and and per children aged - years). in the tropics and subtropics, influenza occurs either throughout the year with no distinct seasonality or visible excess mortality, or twice a year, with the more intense activity during the rainy season. consequently, the morbidity and mortality from influenza are probably greatly underestimated in these regions. during summer, , an epidemic of respiratory illness with cases and % case-mortality affected madagascar; it was attributable to influenza a/panama/ / -like (h n ) virus. the loss of life was greatest in young children and was ascribed to malnutrition and poor access to health care. another outbreak attributable to influenza a/panama/ / -like (h n ) virus occurred during november and december, , in the district of bosobolo, democratic republic of congo. the casefatality rate was · % in children younger than years and · % in people over . these rates illustrate the seriousness of such outbreaks and are one of the reasons why improved linkage of morbidity and mortality analysis with virological surveillance is one of the key objectives of the who global agenda on influenza, formulated in . in southern china, influenza viruses circulate throughout the year. there is evidence for the origin in china of the viruses that caused the pandemics of h n influenza in , h n influenza in , and the re-emergence of h n influenza in . recent outbreaks of avian influenza a h n and h n in people in hong kong show the importance of virological surveillance in this region for the early detection of potentially pandemic viruses. there is also evidence that some drift variants circulate in china for up to years before causing epidemics in europe and north america. , this region is thought to provide an appropriate ecological niche for the emergence of new influenza viruses with pandemic potential, owing to the proximity of dense populations of people, pigs, and wild and domestic birds, thereby facilitating genetic reassortment of viruses from different species (figure ), or for the emergence of drift variants, given the high human population density and year-round virus circulation. these observations provided the impetus for improving the who global influenza surveillance programme in china that has provided many of the vaccine strains recommended by who in the past decade. the examples cited below indicate the unpredictability of influenza-virus variation and the great capacity for evolution, but they also show that novelty alone is insufficient for the emergence of pandemic influenza. adaptation to replication in human beings, the ability to spread from person to person, and a susceptible population are also prerequisites. thus, the emergence of new influenza-virus variants in the human population does not necessarily herald pandemic influenza. influenza a/hong kong/ (h n ) in may and november-december, , cases of influenza h n infection were identified in people in hong kong. this outbreak, which followed serious outbreaks of avian h n influenza in chicken farms, signalled the possibility of an incipient pandemic. the human influenza isolates were of avian origin and were not derived by reassortment. the high mortality (six of patients died from acute respiratory distress syndrome or multiple organ failure, most previously healthy young adults ) suggested an unusually aggressive clinical course. deterioration was rapid, with pneumonia necessitating ventilatory support developing within a few days of illness onset. striking features of severe cases were the early onset of lymphopenia and high concentrations of serum transaminases. fortunately, there were few if any secondary infections, and the h n outbreak ceased when all chickens in hong kong (about · million) were slaughtered. the territory's poultry stocks were again depopulated when highly pathogenic a/hong kong/ (h n ) virus reemerged in flocks in may, , and february and april, . however, no further human cases of h n influenza were identified until february, , when two cases were confirmed in a family of hong kong residents. the first patient, a -year-old boy who was admitted to hospital in hong kong and recovered, became unwell during travel to fujian province, mainland china. the boy's -year-old father died in a hong kong hospital and his -year-old sister died in a hospital while the family was in china; the cause of her death is not known. genetic analysis of the two h n isolates showed that the virus genes were purely avian in origin, but differed from the strains that infected human beings. after the h n outbreak in hong kong, heightened surveillance in the adjoining guandong province led to recovery of nine human isolates of h n virus during july-september, . in march, , influenza h n viruses were isolated from two children in hong kong. the illness in both was mild and self-limited. no serological evidence of h n infection was found in family members or health-care workers who had close contact with the children; thus, h n viruses, like h n viruses, seem not to be easily transmitted from person to person. three lineages of h virus have been defined, with the prototype viruses being g , g , and y . the g "avian" h n viruses isolated from human beings have some receptor properties similar to those of other human viruses-ie, binding to ␣ , sialic acid linkages, in contrast to the binding preference to the ␣ , linkages normally found with avian influenza viruses. in hong kong, antibody to h viruses was found in about % of blood donors, which suggests that human infection with h n may occur in this locality. surveillance of pigs in southern china has shown that h n viruses are cocirculating with human a/sydney/ -like h n viruses and other porcine h n and h n viruses. together, these observations indicate that all the precursors of potentially pandemic h human-avian reassortants are in place. during february, , a new influenza h n virus was isolated from patients with influenza-like illness in england and the middle east. in the uk it affected mainly young children. these h n viruses arose after reassortment of the segments of the currently circulating influenza a (h n ) and a (h n ) subtypes. although influenza a (h n ) viruses have been identified previously, during - , when influenza a (h n ) viruses were isolated in six cities in china, the virus did not spread further. , the limited effect of h n in and during the - and - seasons is attributable to the good pre-existing immunity in the population. in , four people contracted purulent conjunctivitis within days of post-mortem examination of harbour seals that died during an outbreak of influenza a/seal/mass/ / (h n ), an a/fowl plague/dutch (h n )-like virus, in cape cod, ma, usa. subsequently, a/seal/mass/ / (h n ) was recovered from the conjunctiva of an investigator who developed conjunctivitis when an infected animal sneezed into his face. in , avian h n virus was isolated in the uk from a woman with conjunctivitis who kept ducks. although none of these six patients had respiratory symptoms, an outbreak of highly pathogenic avian h n influenza in poultry farms in the netherlands, which began at the end of february, , was associated with fatal respiratory illness in one of human cases by april . the person who died was a previously healthy -year old veterinary surgeon who developed severe headache, renal impairment, interstitial pneumonia, and acute respiratory distress after visiting an affected poultry farm. most patients presented with conjunctivitis (n= ), and only seven (< %) had respiratory illness. transmission of h n influenza from poultry workers to family members was found on three occasions. most virus isolates obtained from human beings had not accumulated significant genetic changes, including those from cases of human-to-human transmission. however, the virus isolated from the person who died had aminoacid substitutions, which suggests a role in pathogenicity. rapid, near-patient tests for influenza can aid clinical management, but the usefulness of existing tests for decisions on whether to start antiviral drug treatment is limited because they are complex or have low sensitivities (table ) . [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] however, rapid influenza tests can show whether virus is circulating in specific populations or localities, and they may become a useful adjunct to surveillance programmes. thus, treatment with anti-influenza drugs commonly depends on patients' symptoms. although influenza has no pathognomonic features, it was diagnosed correctly in clinical trials in about two-thirds of adults when the clinical entry criteria were met. cough and fever (temperature · °c or above) are the most predictive symptoms of influenza, but fever may not be present in elderly people. in primary care, about - % of patients with influenza-like illness have the disease during outbreaks. [ ] [ ] [ ] thus, optimum implementation of guidelines for antiviral treatment depends on continuous community-based clinical and virological surveillance and awareness by general practitioners that influenza is circulating. most of what we know about highly pathogenic influenza viruses derives from studies with avian influenza viruses in birds. this situation is potentially relevant to disease in human beings because some mechanisms of pathogenicity in birds may operate in mammals and new human influenza a strains may come ultimately from the avian reservoir. tissue tropism and the capacity for systemic spread are the most important determinants of pathogenicity in birds. the molecular correlates of these pathogenic properties reside in the viral haemagglutinin and have been well studied. [ ] [ ] [ ] however, in mammals, factors other than viral haemagglutinin are involved in determining pathogenicity, including viral non-structural protein , pb , and neuraminidase. recovery of nucleic acid of the pandemic virus from post-mortem tissue or preserved human remains has shown that this highly pathogenic virus did not have the molecular motifs in haemagglutinin associated with virulence in avian strains. , the use of reverse genetics techniques has allowed the direct manipulation of influenza-virus gene products and creation of new recombinant viruses. selective testing of specific mutations engineered into recombinant viruses in a mouse model has shown that greater virulence is obtained by specific molecular properties of haemagglutinin, but these do not fully explain pathogenicity. the balance between viral replication and host immune response determines the outcome of viral infection. highly virulent viruses, such as h n , have a remarkable capacity to resist the antiviral effects of host cytokines. infection of human macrophages also results in induction of high cytokine expression, suggesting that severe outcome of infection is due both to lack of inhibition of viral replication by cytokines and to excess induction of cytokines leading to tissue damage in the infected host. the key genetic component determining replication of highly pathogenic virus may be the nonstructural protein of the virus, which has been identified as the major immune modulator. factors contributing to the pathogenesis of influenza in people are incompletely understood. these include understanding of the nature of tissue restriction of proteases, differences in reactivity of the innate immune system at different stages of life, and varying susceptibilities in different human populations, leading to different ranges of disease in certain populations; for example, encephalopathy is well recognised in japan, but less so in other populations. , study of mechanisms of virulence should provide more than simply elucidation of pathogenesis, notably development of alternative means of attenuating influenza viruses (eg, by deletion of non-structural protein or m [matrix protein ] genes) to make safer vaccine strains. current vaccines are produced from virus grown in fertile hens' eggs and inactivated by either formaldehyde or ␤-propiolactone. they consist of whole virus, detergent-treated split product, or purified haemagglutinin and neuraminidase surface antigen formulations of the three virus strains currently recommended by who. about countries have government-funded national immunisation programmes, and influenza vaccine is available in many others. about million of the world's population of billion were vaccinated during . specific vaccine recommendations vary, but most involve annual vaccination of elderly people and those with certain chronic medical disorders. these recommendations were founded on proven morbidity and mortality in the at-risk groups, consistent demonstrations of vaccine efficacy in military recruits, recognition of the relation between antibody and protection, and proof of vaccine antigenicity. whole-virus vaccines are not widely available because they cause adverse reactions in young children, whereas split-product formulations and those containing purified surface antigen are well tolerated and extremely safe. the virtual absence of published reports suggests that hypersensitivity reactions are rare. recent randomised controlled trials efficacy and effectiveness of current vaccines studies on the efficacy and effectiveness of inactivated influenza vaccines reveal substantial benefits. in children, meta-analysis of double-blind - and singleblind , randomised controlled trials estimated the efficacy of vaccine in preventing symptomatic laboratory-confirmed influenza at % (table ) . other benefits include reductions in school absenteeism, otitis media, asthma exacerbations, and febrile respiratory illness in unvaccinated household contacts. , [ ] [ ] [ ] [ ] [ ] in adults of working age, meta-analysis of two randomised controlled trials of split influenza vaccines , estimated the efficacy in preventing laboratory-confirmed influenza at % (table ) . associated benefits include reductions in absenteeism, consultations, antibiotic use, and use of over-thecounter medication. [ ] [ ] [ ] the frequency of laboratory-confirmed influenza fell by % in vaccinees in a randomised controlled trial (table ) and by % in a prospective cohort study of elderly people living in the community. many cohort and case-control studies have shown lower rates of hospital admissions for pneumonia and influenza, - all respiratory disorders, , respiratory disorders and heart failure, deaths from pneumonia and influenza, , and all-cause mortality , , in vaccinees than in controls (table ) . a meta-analysis of reports published before showed that vaccination reduces numbers of cases of influenza-like illness by %, hospital admissions for pneumonia and influenza by %, and all-cause mortality by %. a prospective observational study of nursinghome residents in japan showed a % reduction in laboratory-confirmed influenzal illness among vaccinees. vaccination also reduced numbers of hospital admissions among vaccine failures and thus appears to ameliorate illness severity. gross and colleagues did a meta-analysis of cohort studies. the odds ratios for development of respiratory illness ( · ) or pneumonia ( · ), hospital admission ( · ), and mortality ( · ) indicate substantial protection. vaccination of elderly patients with chronic lung disease reduces hospital admissions for pneumonia and influenza by %, all-cause mortality by %, and complications (death, exacerbations of lung disease, pneumonia, heart failure, angina, and myocardial infarction) by %. influenza vaccination also prevents heart failure, brain infarction, recurrent myocardial infarction, and primary cardiac arrest, indicating important benefits in patients with cardiovascular disease. vaccination of patients with diabetes mellitus is associated with an estimated % reduction in hospital admissions, mostly ( %) for reasons of diabetic control. thus, influenza vaccine protects against several potentially fatal events that explain the many hidden deaths that accompany epidemics. staff have been implicated as the source of influenza in several outbreaks in nursing homes. accumulating that influenza vaccination of staff caring for elderly people in long-stay facilities provides benefits to residents. [ ] [ ] [ ] one study showed substantial herd immunity ( - % protection) among patients exposed to staff with high vaccine coverage. during the past decade, there have been many new developments in vaccine technology that have aided vaccine production or aimed to improve vaccine immunogenicity and acceptability. subunit influenza vaccine with adjuvant mf , an emulsion of squalene in water for parenteral use, is licensed in some european countries but not the uk. mf significantly increases haemagglutinationinhibition antibody responses to interpandemic influenza a h n and influenza b antigens, particularly in older people with chronic diseases, and is well tolerated despite slightly higher rates of transient mild local reactions than with other vaccines. virosomes consist of bilayers of phospholipids (liposomes) containing virus surface proteins embedded in the bilayer. virosomes have been extensively evaluated in various human populations. typically, virosomes induce higher concentrations of antibody after vaccination, higher rates of seroconversion, and a greater proportion of individuals with "protective" antibody titres than conventional inactivated vaccines. virosomal influenza vaccine for parenteral use became available in the uk during the - season. cell-culture vaccines offer the potential of being able to respond quickly to epidemics or a pandemic at any time of the year and avoid the risk of contaminated eggs, which could affect the bioburden and endotoxin content of vaccines. moreover, influenza viruses grown in mammalian cells more closely resemble those present in clinical samples than viruses isolated and grown in eggs, hence offering the potential for more effective vaccine. influenza vaccines prepared with madin darby canine kidney (mdck) and african green monkey (vero) cells as substrate have been licensed in the netherlands but are not yet available commercially. live attenuated influenza vaccines intranasal delivery of live influenza vaccines offers the advantage of mimicking natural infection, thereby providing a broader immunological response and more durable protection than with inactivated vaccines. strategies for use of live influenza vaccines based on the transfer of genes coding for cold adaptation (ca) and temperature sensitivity from an attenuated parental virus donor have been used in russia for many years and were approved in june, , by the us food and drug administration for use in healthy children and adolescents aged - years, and in healthy adults aged - years after three decades of clinical evaluation. vaccines based on ca replicate well at the temperatures found in the nasopharynx but not at temperatures in the lower airways. in young children, a recent study of us ca vaccine showed very high protection with benefits in terms of both influenzal illness and otitis media. during the second year of this study, ca vaccine afforded a high degree of protection against a variant not closely matched to the vaccine antigen. studies in nursing-home residents have suggested that a combination of live and inactivated influenza vaccines may improve protection in these communities. immunostimulating complexes are cage-like structures that were originally formed as a complex between cholesterol and saponin derived from the tree quillaia saponaria. vaccines containing a defined saponin called iscoprep stimulated an accelerated serum antibody response in human beings compared with conventional inactivated vaccines, an improved proliferative t-cell response, and a cytotoxic t-cell response. although nasally delivered influenza vaccine could greatly increase vaccine coverage and provide mucosal immunity, intranasal administration of conventional inactivated influenza vaccines has typically been unsuccessful. in animals, incorporation of a mucosal adjuvant derived from bacteria has been necessary to improve immunogenicity, and several such vaccines administered intranasally have been evaluated clinically, with promising results. an intranasal spray formulation containing trivalent subunit influenza vaccine prepared from virosomes and wild-type escherichia coli enterotoxin was licensed briefly in switzerland. although it met the immunogenicity criteria set for yearly relicensing of conventional influenza vaccines, it was withdrawn after a possible association with bell's palsy could not be discounted. various microparticles are being investigated as adjuvants and delivery systems, for parenteral delivery of influenza-virus antigens or delivery to mucosal sites including the gut. subunit influenza vaccines have been prepared from recombinant haemagglutinin and neuraminidase proteins expressed in insect cells by baculoviruses. the recombinant haemagglutinins are well tolerated by young adults and elderly people, and there are significant doseresponse effects for both h and h haemagglutinin vaccines. phase i and virus-challenge studies of baculovirus-expressed recombinant neuraminidase in healthy volunteers have had promising results. the development of reverse-genetics techniques for negative-sense rna viruses has allowed the direct manipulation of influenza-virus gene products and creation of new recombinant viruses. this approach offers enormous potential for preparing interpandemic vaccines. nucleic-acid vaccines dna vaccines present a promising new approach to vaccination, evoking a full range of immune responses, including antibody, cytotoxic, and helper-t-cell responses. dna vaccines with constructs encoding the nucleoprotein (np), haemagglutinin, neuraminidase, matrix protein (m ), and non-structural protein of influenza virus have been studied extensively, either singly, in combination with one another, or together with dna encoding various cytokines. currently, two drug classes are available to manage influenza: the inhibitors of m , amantadine and rimantadine, and the neuraminidase inhibitors, zanamivir seminar the lancet • vol • november , • www.thelancet.com and oseltamivir. rimantadine causes less neurotoxicity than amantadine but is not available in most parts of the world and is not discussed further. amantadine inhibits the m membrane protein ionchannel activity of the influenza a virus but has no effect on influenza b. amantadine has three important limitations: its range of activity excludes influenza b; it has adverse side-effects, including insomnia, lightheadedness, hallucinations, dizziness, headache, and falls, which are particularly troublesome in elderly people; and drug resistance emerges rapidly during treatment. the genetic basis of resistance is a single nucleotide change, resulting in an aminoacid substitution at position , , , , or in the membrane-spanning region of m . estimates of amantadine's therapeutic effectiveness are uncertain owing to the clinical and methodological heterogeneity of clinical trials, a paucity of data by dose, the small number of trials in children and elderly people, and low trial-quality scores. treatment of healthy adults with - mg daily of amantadine cuts the duration of fever compared with placebo by day. there are few data on use of the currently licensed dose in the uk, mg daily. at this dose, amantadine reduced the duration of fever compared with placebo by day, but in a meta-analysis of data from six trials involving a total of patients the effect did not attain statistical significance. there is no high-quality evidence from randomised controlled trials of the effectiveness of amantadine mg daily for the treatment of influenza in at-risk individuals, and illness was significantly shortened with treatment by · days in only one of two small randomised controlled trials in children. , no randomised trial has tested amantadine during outbreaks in nursing homes. moreover, its use in this setting is complicated by toxicity, treatment failures, and frequent recovery of drug-resistant virus (about %). amantadine prophylaxis of other populations during interpandemic outbreaks is precluded by the lack of high-quality evidence from randomised controlled trials at the licensed dose and the high incremental cost per quality-adjusted life-year gained. this second-generation neuraminidase inhibitor is a potent and specific inhibitor of a wide range of influenza virus types a and b. it has poor oral bioavailability and is delivered through an inhaler. zanamivir is licensed for the treatment of influenza a and b in people aged years and over. it is well tolerated; the number, type, and severity of adverse events in healthy adults or people with stable chronic underlying medical disorders differ little from those with placebo. the main safety concern is that inhaled zanamivir may cause bronchospasm. however, respiratory viruses including influenza regularly exacerbate asthma and chronic obstructive pulmonary disease, so the role of zanamivir in bronchospasm is unclear. zanamivir was administered with apparent safety in two studies involving patients with asthma or chronic obstructive pulmonary disease. , difficulty in using the inhaler may limit use of zanamivir. in one study, half of a very elderly group were unable to use the inhaler after training, and two-thirds zanamivir healthy individuals, aged - years · ( · to · ) · ( · to - · ) · (- · to · ) · ( · to · ) at-risk individuals, including older than years · (- · to · ) · ( · to · ) · (- · to · ) · (- · to · ) healthy children · ( · to · ) · ( · to · ) · (- · to · ) · (- · to · ) "all" individuals · ( · to · ) · ( · to · ) · ( · to · ) · ( · to · ) healthy individuals, aged - years · ( · to · ) · ( · to · ) · ( · to · ) · ( · to · ) at-risk individuals, including older than years Ϫ · (- · to · ) · (- · to · ) · ( · to · ) · ( · to · ) healthy children · ( · to · ) · ( · to · ) · ( · to · ) · ( · to · ) "all" individuals · ( · to · ) · ( · to · ) · ( · to · ) · ( · to · ) itt=intention-to-treat. were unable to use it the next day. however, in three other studies, it was used successfully by about % of more than elderly people. summary results, which draw from published [ ] [ ] [ ] [ ] [ ] [ ] and unpublished treatment studies with zanamivir, are shown in table . overall, symptoms were alleviated sooner with zanamivir than with placebo-a median of · days on an intention-to-treat basis and · days for the influenzapositive subgroup. with zanamivir, the median time to return to normal activities was · days shorter for the treatment group, for both the intention-to-treat and influenza-positive populations. in a pooled analysis of intention-to-treat data from trials including both otherwise healthy and at-risk individuals, antibiotics were given to a smaller proportion of patients receiving zanamivir than of those assigned placebo (table ). similar, but nonsignificant, reductions in need for antibiotics in high-risk individuals and in pneumonia were seen with treatment in published and unpublished marginal analyses. seasonal prophylaxis with zanamivir mg daily of mostly unvaccinated healthy adults provided an estimated % reduction in the incidence of laboratory-confirmed clinical influenza compared with placebo, and metaanalysis of two randomised controlled trials of postexposure prophylaxis, with treatment given for days or days, suggested % protection against symptomatic laboratory-confirmed influenza. oseltamivir this third-generation neuraminidase inhibitor is an orally active prodrug of oseltamivir carboxylate. it is licensed for the treatment of influenza a and b in people aged year or older and for the prophylaxis of influenza a and b in people aged years or older. the frequency of nausea is - % higher and of vomiting up to % higher than with placebo; , these gastrointestinal side-effects can be ameliorated if the drug is taken shortly after food. summary results, which draw from published [ ] [ ] [ ] and unpublished treatment studies with oseltamivir (table ) show that for all treatment groups combined, symptoms were alleviated sooner with oseltamivir than with placebo, by · days on the basis of intention to treat and · days for the influenza-positive subgroup. similarly, normal activities were resumed · days and · days sooner with oseltamivir for the intention-to-treat and influenzainfected group, respectively. treatment with oseltamivir reduces the frequencies of otitis media, antibiotic use, pneumonia, and hospital admissions. in children with influenza, the frequency of otitis media was % with placebo and % with oseltamivir. the rate of antibiotic use in the intention-totreat population in one study was · % (eight of ) with placebo and · % (one of ) with treatment. pooled marginal analyses showed lower rates of antibiotic use for lower-respiratory-tract complications in "healthy" and "high-risk" people with influenza with oseltamivir than with placebo; a lower frequency of pneumonia in the influenza-positive group of ten studies ( % among placebo recipients vs < % with oseltamivir; table ); and a significant reduction in the occurrence of hospital admissions in influenza-positive populations of ten trials ( · % vs · %). three different strategies in preventing laboratoryconfirmed symptomatic influenza with oseltamivir have been investigated in randomised controlled trials. metaanalysis of data from two trials of seasonal prophylaxis in non-vaccinated healthy adults with oseltamivir, mg once daily, gave an estimate of % protection. in households, postexposure prophylaxis with oseltamivir, mg once daily for days, gave % protection. similarly, seasonal prophylaxis of mostly vaccinated elderly people receiving residential care with oseltamivir, mg daily for weeks, provided % protection. resistance to neuraminidase inhibitors influenza viruses with low susceptibility to the neuraminidase inhibitors have been isolated in vitro and in vivo. resistance involves either a mutation in the active site of the neuraminidase, altering its sensitivity to inhibition, or a mutation in the haemagglutinin. mutations in haemagglutinin that confer drug resistance decrease the affinity of the protein for the cellular receptor, thus enabling virus to escape from infected cells without the need for viral neuraminidase. to date, few viruses with altered susceptibility to neuraminidase inhibitors have been recovered from patients. the first report of emergence of neuraminidaseinhibitor resistance (r k) during treatment with zanamivir involved a recipient of a bone-marrow transplant. during clinical trials with oseltamivir, · % (four of ) of post-treatment isolates from adults and adolescents and · % (nine of ) from children had low neuraminidase-inhibitor susceptibility, indicating that such viruses are likely to emerge in clinical practice. three resistant variants with neuraminidase mutations (e v, h y, and r k) that have emerged in clinical trials show low infectivity and virulence in animal models, thus the relevance of these mutations in clinical practice remains uncertain. in , an international neuraminidase susceptibility network was established to oversee global surveillance of neuraminidase-inhibitor resistance. the uk national institute for clinical excellence (nice) has recently issued new guidance on the interpandemic use of antivirals for the treatment of influenza. amantadine is not recommended. neither zanamivir nor oseltamivir is recommended for the treatment of influenza in children or adults unless they are at risk. within their licensed indications, zanamivir and oseltamivir are both recommended for the treatment of atrisk adults, and oseltamivir for the treatment of at-risk children, who present with influenza-like illness and can start therapy within h of the onset of symptoms, when it is known that influenza a or b is circulating in the community. nice guidance on the use of antiviral drugs for the prevention of influenza was also issued lately. oseltamivir is recommended for postexposure prophylaxis of influenza in at-risk people aged years and older, who can begin prophylaxis within h, if they live in a residential care establishment, whether or not they have been vaccinated, and a resident or staff member has influenza-like illness; or if they are not effectively protected by vaccination and can begin prophylaxis within h of exposure. oseltamivir is not recommended for postexposure prophylaxis of healthy people up to age years or for seasonal prophylaxis. amantadine is not recommended for either postexposure or seasonal prophylaxis. this guidance does not cover the circumstances of a pandemic. the hong kong "chicken flu" situation in and the rapid global spread of severe acute respiratory syndrome highlighted how ill prepared we are to introduce preventive measures for pandemic influenza. the problems encountered in were due mainly to the dangers of working with the chicken h n virus and the need to produce a safe vaccine strain. conventional technology was unable to produce a safe productive vaccine strain. however li and colleagues were able to modify the haemagglutinin gene of the a/hong kong/ virus. they deleted the series of basic aminoacid residues at the cleavage site associated with virulence, then by use of reverse genetics rescued the modified haemagglutinin gene and the neuraminidase gene from the wild-type a/hong kong/ virus into ca a/ann arbor/ / virus. the resultant ca virus was non-pathogenic in animal models of infection, grew well in eggs, and protected chickens from challenge with lethal virus; it could be a suitable candidate vaccine strain. these experiments show the potential for using reverse genetics technology to develop live and inactivated vaccines for both pandemic and interpandemic use. a second strategy for pandemic vaccine development is the use of recombinant haemagglutinin. however, the disappointing results from clinical trials of baculovirusexpressed haemagglutinin from the a/hong kong h n virus, even after two doses of up to µg, question the role of this strategy alone. clinical trials of conventional inactivated-surface-antigen vaccine produced from an h n virus showed that extremely poor antibody responses were stimulated, even after two doses, whereas an h n subunit vaccine with mf adjuvant was much more immunogenic. the benefit of adjuvants for use in naïve populations has also been shown with a whole-virus h n vaccine with aluminium salts adjuvant. thus, like mf , aluminium salts have promise in increasing vaccine coverage in response to pandemic influenza by allowing scarce antigen to be used more efficiently. from the limited information available, conventional influenza vaccines seem not to be sufficiently immunogenic in a pandemic situation and two doses in conjunction with an adjuvant may be needed. different dosing strategies with various influenza-virus subtypes should be investigated so a robust strategy can be developed. vaccines will be in very short supply during the first stages of a pandemic, and antiviral drugs could have an important role in prevention. who has recently prepared draft guidelines for use of both vaccines and antiviral drugs during a pandemic; they emphasise the need to stockpile drugs and to develop plans for their distribution and use. as with vaccines, there are gaps in our knowledge as to how antiviral drugs should be used. research is urgently required to ensure effective use of both vaccines and drugs in response to an emerging pandemic. kgn has received fees or honoraria from roche pharmaceuticals, wyeth, and berna biotech for speaking at meetings on influenza; research has been supported by chiron vaccines, aventis pasteur, wyeth, and berna biotech. solvay and berna biotech have provided h avian influenza viruses free of charge for a project on candidate pandemic vaccines. mz has received honoraria from berna biotech to speak at pharmaceutical-industry conferences on influenza and has been supported in attendance at an international who workshop on virus neutralisation sponsored by glaxosmithkline. the health protection agency has received funding from chiron vaccines, wyeth vaccines, aventis pasteur, roche, and glaxosmithkline, to carry out analytical work on a contractual basis in mz's laboratory. jmw has no conflicts of interest to declare in relation to this paper. none of these sources of funding had any role in the writing of this seminar. we received no funding in relation to this seminar other than a small payment from the lancet. learning from experience? uses of error reflecting on my medical errors over years of clinical experience, i was disturbed to note that most errors that came to my mind were from the early part of my career. is this a sign that i really did become a better doctor or is it a symptom of ageing? were my early errors more influential on my subsequent practice or are my current errors not recognised or not made known to me by sympathetic colleagues? during my first house job, a middle-aged man was under my care for several months with an infected pleural cavity following a plombage operation for tuberculosis some years previously. he was memorable not only because of his sickness, but also because he was the first patient to give me a present, which i have to this day. months later, i was a casualty officer at a teaching hospital. an intern showed me the chest radiograph of a man with a febrile illness and an opaque hemithorax. i lectured the intern on my patient with the infected plombage, not thinking for a moment that this story was directly relevant to the radiograph i was shown. the patient died of a cardiac arrest in the casualty department. the autopsy showed an infected plombage site and death from untreated septicaemia. years after qualifying, while a locum physician in the northern parts of canada, i was required to do a coroner's post-mortem on a middle-aged man found dead in his cabin. fortunately, the policeman knew what to do and this overcame my anxiety. hours later, i had no doubt that the man was dead, but knew neither why nor how. i dissected the heart and coronary vessels and decided they were atheromatous and that death was from natural causes, probably from myocardial ischaemia. in the coroner's court, i presented my conclusions and the case was closed. i received the pathologist's report as i was due to finish the locum . . . normal heart! being on-call for a unit and not just one's own patients can be an onerous task, particularly as the staff become more numerous and anonymous. in the past years, i have been required to be on-call for a unit of ten consultants at two hospitals, one of which i visit only when on call. i was telephoned in the middle of the night about a patient who had had a cardiac arrest. i did not recognise the patient's name. i was told the arrest team wanted me to advise on their "enthusiasm" for resuscitation. i said that if she was not readily resuscitated, they should not resort to extreme measures, presuming she was a cancer patient admitted under the care of one of my oncology colleagues. on visiting the ward the next morning, i learnt that the patient who had died was a young woman under my care. 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n candidate vaccines key: cord- -xr h c q authors: nan title: million women study most wanted in date: - - journal: lancet doi: . /s - ( ) - sha: doc_id: cord_uid: xr h c q nan the year hormone-replacement therapy in the million women study heart protection study collaborative group. mrc/bhf heart protection study of cholesterol lowering with simvastatin in high-risk individuals: a randomised placebo-controlled trial poulter nr for the ascot investigators. prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower-than-average cholesterol concentrations, in the anglo-scandinavian cardiac outcomes trial--lipid lowering arm (ascot-lla): a multicentre randomised controlled trial coronavirus as a possible cause of severe acute respiratory syndrome comparison of carvedilol and metoprolol on clinical outcomes in patients with chronic heart failure in the carvedilol or metoprolol european trial (comet): randomised controlled trial advances in cystic fibrosis cystic fibrosis elusive schizophrenia genes genes for schizophrenia? recent findings and their pathophysiological implications detecting ovarian cancer use of proteomic patterns in serum to identify ovarian cancer heart protection study collaborative group. mrc/bhf heart protection study of cholesterol-lowering with simvastatin in people with diabetes: a randomised placebo-controlled trial cooperation combination treatment of angiotensin-ii receptor blocker and angiotensin-converting-enzyme inhibitor in non-diabetic renal disease (cooperate): a randomised controlled trial key: cord- -s gdbsfx authors: hon, kle; leung, cw; cheng, wtf; chan, pks; chu, wcw; kwan, yw; li, am; fong, nc; ng, pc; chiu, mc; li, ck; tam, js; fok, tf title: clinical presentations and outcome of severe acute respiratory syndrome in children date: - - journal: lancet doi: . /s - ( ) - sha: doc_id: cord_uid: s gdbsfx hong kong has been severely affected by severe acute respiratory syndrome (sars). contact in households and healthcare settings is thought to be important for transmission, putting children at particular risk. most data so far, however, have been for adults. we prospectively followed up the first ten children with sars managed during the early phase of the epidemic in hong kong. all the children had been in close contact with infected adults. persistent fever, cough, progressive radiographic changes of chest and lymphopenia were noted in all patients. the children were treated with high-dose ribavirin, oral prednisolone, or intravenous methylprednisolone, with no short-term adverse effects. four teenagers required oxygen therapy and two needed assisted ventilation. none of the younger children required oxygen supplementation. compared with adults and teenagers, sars seems to have a less aggressive clinical course in younger children. hong kong has been severely affected by severe acute respiratory syndrome (sars). contact in households and healthcare settings is thought to be important for transmission, putting children at particular risk. most data so far, however, have been for adults. we prospectively followed up the first ten children with sars managed during the early phase of the epidemic in hong kong. all the children had been in close contact with infected adults. persistent fever, cough, progressive radiographic changes of chest and lymphopenia were noted in all patients. the children were treated with high-dose ribavirin, oral prednisolone, or intravenous methylprednisolone, with no short-term adverse effects. four teenagers required oxygen therapy and two needed assisted ventilation. none of the younger children required oxygen supplementation. compared with adults and teenagers, sars seems to have a less aggressive clinical course in younger children. since late february, , who has received reports of outbreaks of a severe form of atypical pneumonia in vietnam, hong kong, and singapore. hong kong is the most severely affected city. who has referred to this unusual form of severe pneumonia as severe acute respiratory syndrome (sars). the surveillance case definition of sars is: history of high fever (> Њc); one or more respiratory symptoms, including cough, shortness of breath, and difficulty breathing; and close contact within days before onset of symptoms with a person who has been diagnosed with sars, history of travel within days before onset before symptoms to an area with reported foci of sars transmission, or both. household contact and contacts in health-care settings are believed to be important routes of transmission. , this transmission route could put children at particular risk, but most data available so far have been in adults. we therefore decided to report our experience in treating children with sars. between march and , , ten children with suspected sars were admitted to and managed at the prince of wales and princess margaret hospitals, hong kong. we prospectively followed up the clinical, laboratory, and radiological profiles and treatment outcomes of these children. microbiological investigations were done to detect common bacterial and viral pathogens associated with communityacquired pneumonia. we treated all patients with combined corticosteroids, antivirals, and antibacterial agents. intravenous cefotaxime, oral clarithromycin, and oral ribavirin ( mg/kg daily, given in two or three doses) were started if a diagnosis of sars was suspected on admission. oral prednisolone ( · mg/kg daily at prince of wales hospital, and · mg/kg daily at princess margaret hospital) was added if fever persisted after h. in addition, we treated patients who had moderate symptoms of high fluctuating fever and notable malaise with intravenous ribavirin ( mg/kg daily, given in three doses) and hydrocortisone ( mg/kg every h) immediately after admission. for patients who had persistent fever and progressive worsening clinically or radiologically, we used pulse intravenous methylprednisolone ( - mg/kg). ribavirin was administered for - weeks and corticosteroid dose was tapered over - weeks. all children satisfied the who case definition for sars and all had been in close contact with infected adults. the demographic, clinical, and laboratory data are shown in the table. fever was a consistent symptom in all children, and lasted for a median duration of days (range - ). there was no clinically significant drop in haemoglobin concentrations during treatment with ribavirin. in eight patients, corticosteroid was added to the regimen when fever did not subside. pulse methylprednisolone was given to one young child (patient ) and four teenagers (patients - ). within days of corticosteroid administration, all but one patient (patient ) became afebrile. the same four teenagers developed respiratory distress and oxygen desaturation on day , , and , respectively, after the onset of fever. these children were placed under strict isolation for days and became asymptomatic before discharge. nine children had abnormal chest radiographs on presentation. the primary abnormality was air-space opacification. of the five children aged years or younger (patients - ), four presented with focal segmental consolidation. patient had ill-defined patchy consolidation, but ct of the thorax showed multifocal air-space consolidation. all these patients had mild progressive consolidative change on serial chest radiographs but complete resolution was achieved within days. the typical radiographic changes in one patient are shown in the figure. three of the five teenagers (patients - ) presented with bilateral lower-lobe opacification at presentation, which progressed rapidly within days. despite clinical improvement, these consolidative changes persisted into the nd week of the illness. patient showed no abnormality on chest radiography at presentation, but high-resolution ct confirmed focal consolidation in the right lower lobe. in ct of the thorax in patients and , the characteristic features of peripheral and alveolar opacities simulated the radiological appearances of bronchiolitis obliterans organising pneumonia. four teenagers required supplemental oxygen, one required bi-level positive airway pressure and intermittent positive-pressure ventilation. respiratory distress developed - days after presentation. lymphopenia ( · - · ϫ /l) was reported in all patients, but the teenagers were generally more severely affected than the younger children. lymphopenia mostly occurred between days and , after the onset of fever. no bacteria, fungi, mycoplasma, chlamydia, or common respiratory viruses were detected by the laboratory investigations. coronavirus was isolated by viral culture from the nasopharyngeal aspirates of patients and . reverse-transcriptase pcr targeting the novel coronavirus present in the nasopharyngeal aspirate samples was positive in four of six children tested (patients , , , and ). clinical presentations and outcome of severe acute respiratory syndrome in children it was more severe among the teenage children. however, since young children normally have higher lymphocyte counts than adults, the interpretation of results must take into account the patients' ages. furthermore, lymphopenia frequently resolves when the disease is improving. we adopted a treatment regimen of ribavirin and steroids similar to that used in adult sars patients. , ribavirin is a broad-spectrum antiviral agent and has been used for treatment of severe respiratory syncytial virus infection in we noted two distinct patterns of clinical presentation among the children we studied. teenage patients presented with symptoms of malaise, myalgia, chill, and rigor similar to those of adults, , whereas the younger children presented mainly with cough and runny nose, and none had chills, rigor, or myalgia. the clinical course was much milder and shorter among younger patients, and radiological changes were milder and generally resolved more quickly than in the teenagers. all paediatric patients had clinically important lymphopenia, clinical features and treatment outcomes among sars children children. among our patients, short-term use of high-dose ribavirin was well tolerated and had no major short-term adverse effects such as severe haemolytic anaemia. in addition, high-dose corticosteroid was used in combination with the antiviral agent because severe immune-mediated damage of lung tissue was reported in postmortem examination of sars patients. eight of the ten children had been attending school at the time of presentation. there was no evidence that they had spread the infection to their classmates. this finding is in sharp contrast to the experience reported among adults that sars carries a very high infectivity rate. , at the time of our study, adults had died in hong kong. during the study period, around children were suspected as having sars in hong kong. so far, no child has died. our preliminary findings suggest that young children develop a milder form of the disease with a less-aggressive clinical course than do teenagers and adults. serial chest radiographs of patient , who presented with fever and cough a=ill-defined air-space consolidation in periphery of right upper lobe and abutting horizontal fissure. b=increased consolidation in right upper zone on day . in an anecdotal report, complete resolution of chemotherapyinduced nausea was seen in a patient with breast cancer, after she was placed on the anticonvulsant gabapentin. on this basis, we did an open-label study in which oral gabapentin mg thrice daily was given for every other chemotherapy treatment in nine patients with breast cancer. six of the nine reported at least a three-point improvement in peak delayed nausea (on an eight-point nausea scale), and three patients had complete resolution of nausea when taking gabapentin. this preliminary evidence shows that gabapentin might have a role in treatment of chemotherapy-induced nausea. delayed onset of nausea induced by chemotherapy remains a problem for about half of patients receiving moderately emetogenic chemotherapy, despite preventive treatment with a serotonin antagonist and dexamethasone. we describe an open-label study of therapy with the anticonvulsant gabapentin for acute (within h) and delayed onset (days - ) nausea induced by chemotherapy. the initial report came from a -year-old woman who began to have hot flushes soon after stopping oral oestrogen therapy because of newly diagnosed breast cancer. chemotherapy consisting of doxorubicin mg/m and cyclophosphamide mg/m was given four times, the treatments separated by weeks. ondansetron mg and dexamethasone mg were given before each treatment. the patient reported severe nausea after the first two chemotherapy treatments. prochlorperazine mg taken thrice daily as required was ineffective. midway between the second and third chemotherapy treatments, oral gabapentin mg thrice daily was started for treatment of the patient's hot flushes. within days, all such symptoms had resolved. unexpectedly, she had no nausea after either the third or the fourth chemotherapy treatments. no other medication changes had been made. we did an open-label study examining the effects of oral gabapentin mg thrice daily on chemotherapy-induced nausea in breast-cancer patients who had not previously and members of the sars study group. coronavirus as a possible cause of severe acute respiratory syndrome a major outbreak of severe acute respiratory syndrome in hong kong blood and blood-forming tissues a controlled trial of aerosolized ribavirin in infants receiving mechanical ventilation for severe respiratory syncytial virus infection special adminstrative region, china; and department of paediatrics and adolescent medicine 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- -laerx n authors: bedford, juliet; enria, delia; giesecke, johan; heymann, david l; ihekweazu, chikwe; kobinger, gary; lane, h clifford; memish, ziad a; oh, myoung-don; sall, amadou alpha; ungchusak, kumnuan; wieler, lothar h title: living with the covid- pandemic: act now with the tools we have date: - - journal: lancet doi: . /s - ( ) - sha: doc_id: cord_uid: laerx n nan the responses of countries to the covid- pandemic have been disparate. , many countries are reopening workplaces, schools, and social gatherings and striving to adapt their economies and resume international travel. other countries are attempting to suppress transmission of severe acute respiratory syndrome coronavirus (sars-cov- ) by again restricting businesses, industries, and schools while hoping for future covid- vaccines or treatments. the strategic and technical advisory group for infectious hazards (stag-ih), the independent advisory group to the who health emergencies programme, has reviewed information from countries around the world and has concluded that the most sound approach on the basis of current understanding is to deploy long-term strategies with a focus on preventing amplification of transmission, protecting those most at risk of severe illness, and supporting research to better understand the virus, the disease, and people's responses to them. evidence suggests that children shed sars-cov- as do adults, mostly with non-severe clinical presentations. but many characteristics of sars-cov- are not yet fully understood, such as the levels of immunity and the immune response, the full spectrum of disease and long-term sequelae, the possibility of re-infection, , and the potential of the virus to become endemic. until more is known about the immune response to sars-cov- , it is not possible to make sound predictions. sars-cov- does not seem to behave epidemiologically like influenza virus and continues to resurge in clusters or outbreaks, not always in waves with rapid widespread community transmission. with a more precise and epidemiologically based public health response involving active case finding, contact tracing, and strategic testing strategies, outbreaks caused by sars-cov- can be contained and community spread decreased to a more manageable level. some countries in asia and europe (eg, south korea, japan, hong kong, singapore, vietnam, and germany) , have shown that this approach keeps transmission at sustainably lower and safer levels than in countries not following this approach, thus preventing surges of patients in health facilities and decreasing overall mortality. this approach is based on three principles: understanding, trust, and participation by all population groups; decreased transmission of sars-cov- using basic epidemiological and public health interventions; and acknowledging that any potential covid- vaccines and treatments will only be part of the solution and that they will best perform in conjunction with a longterm overall public health strategy. the components of this epidemiologically based public health response to the covid- pandemic (panel) are familiar to public health specialists, but have been neglected or are inappropriately understood in some countries, both by leaders and the general public. alongside this comprehensive response, continued assessment is needed of how best to resume international travel. most countries have focused on international travel as a risk for the (re)introduction of sars-cov- and use various risk-mitigation strategies (eg, pcr testing of international travellers and voluntary or mandatory isolation after arrival). yet there is no optimum way to prevent importation of sars-cov- , no matter how rigorously quarantine and testing are applied, because of the range in the sars-cov- incubation period ( - days), the spectrum of disease (with subclinical and mild illness in many infected individuals), the fact that many travellers return to households with others who are not quarantined, and the number of days after infection to the time when pcr testing becomes positive. other measures that could be equally or more effective include urging travellers to monitor their health and recommending they do not travel when ill; questioning travellers about their health status immediately before they travel; adhering to personal hygiene measures, physical distancing, and wearing masks in public when physical distancing is not possible; reporting illnesses to the destination country; and ensuring implementation of measures to provide safe travel environments. introduction of digital smart tools might complement these measures and their evaluation should be continued. many countries consider that travel is safer from locations with low circulation of sars-cov- and strong capacities for outbreak containment, and they are keen to obtain credible information about the infection and transmission status of other countries. available who case reports are, however, based on laboratoryconfirmed sars-cov- infections and since testing strategies vary by country they are not an accurate indication of true transmission rates. identification and use of more meaningful indicators of infection and transmission status are urgently required. covid- vaccines, therapeutics, and diagnostics are important for the pandemic response, and if any of the covid- vaccine candidates are shown to be safe and effective, they will probably be deployed before full approval through emergency use authorisations or other strategies. strategies must be developed to ensure equitable access through the covax pillar of the access to covid- tools (act) accelerator and other mechanisms. in terms of treatments, use of glucocorticoids for critically ill patients is now best practice on the basis of evidence from clinical trials. other therapeutics, including antivirals (nucleoside analogues and antibody preparations) and immunomodulators, continue to be investigated. multiple diagnostic tests for nucleic acid, antigen, and antibody are being evaluated, including by a partnership between who and the foundation for innovative new diagnostics (find). as results of this research become available, countries will be able to make decisions about which tests meet their own standards and fit with their testing strategies. one example is the announcement by who, find, and the global fund to fight aids, tuberculosis and malaria on the provision of externally validated, point-of-care rapid antigen detection diagnostic tests for sars-cov- . as other diagnostic tests are externally validated, they must be made widely available through the act accelerator and other access mechanisms. despite the urgency of identifying effective therapeutics and vaccines for covid- , the rules of science and the ethics of clinical research do not change in the setting of a pandemic. the most effective way to develop vaccines and therapeutics is through trials with robust safety and efficacy endpoints. with current knowledge, even in the absence of covid- vaccines or treatments and comprehensive knowledge of the immune response to sars-cov- , countries can navigate pathways to reduced transmission, decreased severe illness and mortality, and less economic disruption in the short and longer term. despite geopolitical tensions, information contributing to greater understanding of covid- continues to be shared within the scientific community and with who. international travel is increasing, economic panel: checklist of the basic components of an epidemiologically sound public health response to covid- pandemic  rapidly detect people with infection, outbreaks, and sites of increased transmission strengthen surveillance of influenza-like illness and acute respiratory tract infections and/or establish detection systems in health and other sectors, including schools, the homes of schoolchildren, and workplaces  isolate and manage people infected with sars-cov- individuals who test positive for sars-cov- need to be isolated and managed at an appropriate level of care with best practices that incorporate evolving evidence  investigate outbreaks retrospective contact tracing and diagnostic testing, and/or serological surveys are needed to investigate outbreaks and understand where transmission is occurring  decrease community transmission prospective contact tracing and self-quarantine of contacts must be undertaken, with the use of testing in a way that ensures that those contacts who develop signs and symptoms of covid- can be properly managed  strengthen control measures ensure individuals, communities, and organisations are fully engaged in control activities (eg, physical distancing, wearing masks, and handwashing and cough and sneeze etiquette)  ensure that testing is strategic use highly sensitive and specific nucleic acid, antigen, and antibody tests linked to surveillance and contact tracing, patient diagnosis, and management  protect the health and social care system ensure that health facilities can accommodate the current disease burden and any disease occurring from future resurgence by protecting health workers and strengthening infection prevention and control practices; understanding the characteristics of high-risk groups and increasing their protection, especially in institutions such as care homes where they may live; and monitoring the health-care system to plan for and secure additional capacity if needs arise  continue mitigation of general risks prevent or de-risk large public gatherings and events  involve the business and private sectors engage with private sector in innovative ways to ensure a safe and productive workforce  apply short-term preventive and mitigation measures use these short-term measures, such as time-limited closures and restrictions where transmission is occurring, until transmission has been reduced or eliminated  conduct, fund, and support research research is crucial to better understand the characteristics of sars-cov- , including the course of infection and the immune response; establish cohort studies to understand the extent of sequelae; and conduct qualitative studies to better understand and strengthen people's response to covid- ; at the same time, continued clinical research on vaccines, therapeutics, and diagnostics is also required who. who coronavirus disease (covid- ) dashboard. covid- ) weekly epidemiological update and weekly operational update summary: what is the evidence for transmission of covid- by children covid- re-infection by a phylogenetically distinct sars-coronavirus- strain confirmed by whole genome sequencing genomic evidence for a case of reinfection with sars-cov- clusters of coronavirus disease in communities covid- strategic preparedness and response plan country and technical guidance-coronavirus disease (covid- ) operational considerations for covid- surveillance using gisrs: interim guidance who. coronavirus disease (covid- ) technical guidance: the unity studies: early investigation protocols. incubation period of covid- : a rapid systematic review and meta-analysis of observational research covax, the act-accelerator vaccine pillar who. corticosteroids for covid- international clinical trials registry platform covid- ) pandemic-emergency use listing procedure (eul) open for in vitro diagnostics global partnership to make available million affordable, quality covid- rapid tests for low-and middle-income countries key: cord- -hhsa k authors: wu, yuntao; ho, wenzhe; huang, yaowei; jin, dong-yan; li, shiyue; liu, shan-lu; liu, xuefeng; qiu, jianming; sang, yongming; wang, qiuhong; yuen, kwok-yung; zheng, zhi-ming title: sars-cov- is an appropriate name for the new coronavirus date: - - journal: lancet doi: . /s - ( ) - sha: doc_id: cord_uid: hhsa k nan be significantly attenuated to the point of becoming a new low-pathogenic or non-patho genic virus, such attenuated viral isolates could be named as lowpathogenic human coronaviruses, such as lph-cov. we believe that the naming of sars-cov- by the coronavirus study group is aligned with the goals of the international committee on taxonomy of viruses to facilitate good practice and scientific exchange. given that sars-cov- is already being used in the scientific literature, a name change at this stage would cause confusion in the scientific community. with all the uncertainties about this newly emerged pathogenic virus, we suggest keeping sars-cov- as its name. we declare no competing interests. the opinions expressed in this correspondence are the personal opinions of the authors. we have read with great interest the correspondence by shibo jiang and colleagues, in which they propose a name change for the newly emerged coronavirus, which was recently designated severe acute respiratory syndrome coronavirus (sars-cov- ) by the coronavirus study group of the international committee on taxonomy of viruses. the authors argued that the use of sars in the virus name could confuse the public about the disease that it causes; in addition, they noted that the name sars-cov- is not consistent with the disease name chosen by who, coronavirus disease . the authors also indicated that scientifically, sars-cov- is naturally occurring and different from other sars-like or sars-related coronaviruses that are mainly characterised by their genome sequences. furthermore, given the probability of future attenuation of this virus to a low-pathogenic form, the authors predict that the use of the name sars-cov- might have adverse effects, both socially and economically. on these grounds, the authors suggest that the name of the new virus is changed to human coronavirus (hcov- ). although these concerns and suggestions are appreciated, we feel that the adoption of sars-cov- by the coronavirus study group was appropriate. to facilitate good practice and scientific exchange, the international committee on taxonomy of viruses has established standardised formats for classifying viruses. under these rules, a newly emerged virus is normally assigned to a species based on phylogeny and taxonomy. through diversity partitioning by hierarchical clustering-based analyses, the newly emerged coronavirus was deemed not sufficiently novel but is a sister virus to sars-cov, the primary viral isolate defining the species. the sars-cov species includes viruses such as sars-cov, sars-cov_pc - , and sarsr-cov-btky . sars-cov- is the newest member of this viral species. the use of sars in naming sars-cov- does not derive from the name of the sars disease but is a natural extension of the taxonomic practice for viruses in the sars species. the use of sars for viruses in this species mainly refers to their taxonomic relationship to the founding virus of this species, sars-cov. in other words, viruses in this species can be named sars regardless of whether or not they cause sars-like diseases. the relationship between the name of a viral pathogen and its associated diseases is complex. although the inter national committee on taxonomy of viruses is responsible for naming viral species, who is responsible for naming the diseases caused by newly emer ging viruses. for various reasons, the name of a disease and its causative viral patho gen can be different, as exemplified by acquired immunodeficiency syndrome (aids) and human immunodeficiency virus (hiv). we also believe that the use of the name sars-cov- will not affect social stability and economic development in the affected countries, as the authors envision. given that the cross-species transmission of sars-cov- is currently not well understood, and no effec t ive approach to stop such zoonotic transmission has been established, sars-related coronaviruses, such as sars-cov- (or even sars-cov- in the future), might continue to emerge and reemerge. this has been exemplified in the transmission of middle east respiratory syndrome-related coronavirus, in which multiple spillover events occurred from camels to humans, resulting in human infec tions. thus, keeping sars in the names of viruses of that species would be beneficial to keep the general public vigilant and prepared to respond quickly in the event of a new viral emergence. should sars-cov- a distinct name is needed for the new coronavirus a novel coronavirus from patients with pneumonia in china severe acute respiratory syndrome-related coronavirus: the species and its virusesa statement of the coronavirus study group consensus statement: virus taxonomy in the age of metagenomics partitioning the genetic diversity of a virus family: approach and evaluation through a case study of picornaviruses emergence of mers-cov in the middle east: origins, transmission, treatment, and perspectives key: cord- - sldbte authors: nkengasong, john n; onyebujoh, philip title: response to the ebola virus disease outbreak in the democratic republic of the congo date: - - journal: lancet doi: . /s - ( ) - sha: doc_id: cord_uid: sldbte nan the unfolding outbreak of ebola virus disease in the democratic republic of the congo (drc) dominated discussions at last month's world health assembly (wha) in geneva, switzerland. several funding pledges were made and who estimated that us$ million will be required to control the outbreak. on may , , the drc government declared an outbreak of ebola virus disease, initially in a remote area of the equateur province (figure). as of june , , the government of drc reported cases of ebola virus disease and deaths (case fatality rate · %). of the cases, were laboratory confirmed, were probable where it was not possible to collect laboratory specimens for testing, and were suspected. of the confirmed and probable cases, ( %) are from iboko, ( %) from bikoro, and four ( %) from wangata health zones. a total of five health-care workers have been affected, with four confirmed cases and two deaths. although this is the ninth outbreak of ebola virus disease in drc since , certain features of the current epidemic have caused serious concerns in the international community. first, four cases have been identified in wangata, a district of mbandaka, the capital of the equateur province with an estimated population of · million inhabitants. thus, this is the first time the drc government and partners are response to the ebola virus disease outbreak in the democratic republic of the congo aaa screening. routine management includes a ct angiography of the whole aorta for large screeningdetected aaa and an ultrasound of the popliteal arteries for all screening-detected aaas to detect concomitant popliteal artery aneurysms. sometimes, another aneurysm in the thoracic aorta or a more complex aortic aneurysm can be detected, which needs more careful planning and advanced interventional techniques. according to a recent report of screening-detected aaa, % of individuals who had surgery did not have a straightforward and simple evar. instead, they had a complex procedure associated with increased operative morbidity and mortality. an increasing proportion of popliteal artery aneurysms are found and operated because of screening for aaa. these scenarios have not been taken into account in the debate about the benefits and harms of aaa screening. smoking is eight times more common in individuals with aaa than in healthy controls and is implicated in % of aaa cases. the decreasing prevalence of smoking in sweden (from % of the population in , to % of the population in ) should be viewed as the main cause of the decreasing incidence and mortality of aaa. every percentage drop in the prevalence of smoking will have a huge effect on smoking-related diseases such as cancer and aaa. primary prevention programmes to reduce the prevalence of tobacco smoking is a top priority, whereas screening for aaa is not. department of clinical sciences, lund university, malmö , sweden stefan.acosta@med.lu.se i declare no competing interests. tackling an outbreak of ebola virus disease in an urban city. second, the other epicentres of the ebola virus disease outbreak are in rural remote areas: bikoro and iboko are located close to the river congo, which serves the two neighbouring countries of the central africa republic and the republic of the congo, creating an increased risk of the disease spreading to these countries if the outbreak is not rapidly controlled in drc. the - outbreak of ebola virus disease in west africa, which resulted in deaths, showed how rapidly the disease could spread into neighbouring countries. although the outbreak of ebola virus disease in drc is ongoing, two features of the response are noteworthy: the swiftness of the response time and the introduction of ring vaccinations, an innovative, pre-emptive strategy to vaccinate those most at risk of infection. the global health community learned from the - west africa ebola virus disease outbreak that a speedy response was vital to control the outbreak. the response to the current outbreak in drc has been rapid at the national, continental, and international levels. the drc health minister, oly ilunga kalenga, has led his country's response with pragmatism and expediency, both in kinshasa and at the provincial levels, by developing a comprehensive response plan and establishing appropriate technical committees and mobilising the requisite political, financial, and technical support. at the continental level, within days of declaration of the outbreak the africa centres for disease control and prevention (africa cdc), which one of us (jnn) leads, had activated its emergency operation center in addis ababa, ethiopia; deployed an advance team of epidemiologists to kinshasa to assist the ministry of heath; and briefed an extraordinary session of the permanent representative committee of the african union member states. in addition, the director of the africa cdc (jnn) led a delegation to kinshasa, bikoro, and mbandaka for an assessment of the gaps in the responses requiring support from africa cdc. the africa cdc team worked with the staff from who to assist the ministry of health to develop three strategies: surveillance and contact tracing; focal health-care zones to ensure adequate control measures; and laboratory testing. africa cdc is also deploying more than health-care workers, including epidemiologists, infection control and laboratory experts, and anthropologists. globally, who has had a crucial role by rallying appropriate attention to the outbreak and mobilising essential international partners to action. who has augmented the drc health ministry's response plan by deploying many health-care workers in the field and is supporting a ring vaccination programme with a merck-produced ebola vaccine. the vaccination programme is led by drc's ministry of health and supported by who and partners. this is the first time such a vaccine has been used outside of the west africa - epidemic. importantly, the vaccine is being deployed as the outbreak unfolds as part of a new international approach for rapid mitigation of outbreaks through multiple interventions. anthropological and sociological determinants of the uptake of the vaccination programme will be crucial as the intervention is scaled up. moreover, issues of access, equity, and ethical considerations in deploying the vaccine will need to be considered. containment centres at the affected sites to minimise transmission and improve clinical outcomes for detected patients. several other partners are assisting with the response, including the us centers for disease control and prevention, the international federation of red cross and red crescent societies, and others. however, six important gaps in outbreak governance and logistics management must be addressed to ensure a more comprehensive response to the ebola virus disease outbreak in drc. the first is leadership of the response. much has been learned from dealing with past outbreaks of ebola virus disease in west africa but each new outbreak has unique challenges. it is the responsibility of each country to ensure the health security of its citizens. however, effective leadership of the government of drc may be challenged given the weak health system of the country due to its long history of conflict and resulting economic and political difficulties. all efforts should be made to strengthen their leadership. as such, financial, human, and material assistance from the global community to drc's leadership will be central to ensure an effective response. second, coordination-but not controlof contributing partners' effort is essential to create efficiencies to control the outbreak. third, translating global material and financial commitment into countrylevel disbursements must be accelerated. fourth, commitments made to support the response in drc must be fulfilled. there have been huge logistical challenges with airlifting supplies and health-care workers from kinshasa to mbandaka, iboko, and bikoro, because no commercial flights exist from kinshasa to mbandaka and motorable roads from mbandaka to the other affected areas are non-existent. although financial and material support was expressed at the wha, ensuring that these commitments reach drc in a timely way is not yet evident. fifth, there has been inadequate support of the focal health-care zones (bikoro, iboko, mbandaka, and equateur province) to establish appropriate control measures and minimise transmission. finally, laboratory testing has been challenged by insufficient supplies and a shortage of experienced staff. the outbreak of ebola virus disease in drc is far from over and may take several months to bring under control. the steps taken in the next few weeks will be crucial to the trajectory of the outbreak and it is vital that effective coordination of partners' efforts and rapid provision of requisite and well tested interventions are put in place. in this context, fiscal and infrastructural support to drc will be important for rapid containment of the outbreak. as more partners join the fight to control this outbreak, standard operating procedures for engaging with the government, coordinating with other partners, allocating financial resources, and deployment in the field should be established quickly to ensure effective coordination, but not control, of partners' efforts. such standard operating procedures for outbreak governance will ensure that aid is not a burden to drc but an asset in the response. any successful public health response is based on trust between practitioners, patients, government, and communities. trust is essential for effective outbreak control and must be underpinned by active case finding, contact tracing and follow-up, and engagement with communities. in addition, health-care infrastructure needs to be strengthened and supported to provide health care for non-ebola patients. strengthened health-care systems are needed to address existing endemic health challenges and respond to future ebola outbreaks and other emerging infections in drc. alongside the response to the outbreak, post-ebola recovery plans for drc must include supporting the country to develop a functional national public health institute. in future, the response to a potential tenth outbreak of ebola virus disease in drc must be led by the country's national public health institute. in november, , an outbreak of the severe acute respiratory syndrome caught china unprepared. in response to that outbreak, the government of china established the chinese center for disease control and prevention (china cdc). today, if faced with a similar disease threat, china cdc, and not the international community, would lead the response in china. this is what should be done in drc and all african countries. this is a vision africa cdc and the african union are promoting as a new public health order for africa's health and economic security. to ensure that this vision is achieved, the african union commission and africa cdc will be convening an international conference on ebola in drc: response in july, , to raise funding and advocate for sustained support for the drc's response efforts. cardiac troponin assays were introduced into clinical practice in for the diagnosis of acute myocardial infarction. originally, this assay could not help to reliably rule out myocardial infarction until about h after symptom onset. consequently, there has been a drive to develop more sensitive and reliable troponin assays that would facilitate an earlier exclusion of myocardial infarction, ideally in the emergency department. [ ] [ ] [ ] the new high-sensitivity cardiac troponin (hstrop) assays are able to detect troponin at much lower concentrations than those detected previously. this is in keeping with the universal definition of myocardial infarction, which recommends that a troponin assay used to diagnose myocardial infarction should have a coefficient of variation of % or less at the threshold concentration representing the th percentile upper limit of a so-called normal reference population. modern hstrop assays can detect troponin in more than % of the general population, with some assays able to detect some troponin in nearly everyone. however, there are important implications of this increased detection sensitivity on the interpretation of positive hstrop results by front-line clinicians, particularly in the context of the well established subclassification of myocardial infarction, the most clinically relevant being type and type myocardial infarction. type myocardial infarction is a classic heart attack, in which erosion or fissuring of the surface of an atherosclerotic plaque attracts a plateletmediated thrombus, thus reducing the coronary artery flow. by contrast, type myocardial infarction is due to a myocardial oxygen supply-demand mismatch, which occurs in conditions such as tachyarrhythmias, anaemia, and sepsis. evidence unequivocally supports the use of hstrop as a rule-out test for type myocardial infarction, allowing for early discharge of patients with a low subsequent clinical event rate. as a rule-in test for type myocardial infarction, however, the hstrop test is subject to considerable troponin cardiac protein molecule swedish national board of health and welfare. screening for abdominal aortic aneurysm-recommendation and assessment bases benefits and harms of screening men for abdominal aortic aneurysm in sweden: a registry-based cohort study outcome of the swedish nationwide abdominal aortic aneurysm screening program psychosocial consequences in men taking part in a national screening program for abdominal aortic aneurysm cost-effectiveness of screening for abdominal aortic aneurysm in combination with medical intervention in patients with small aneurysms population screening and intervention for vascular disease in danish men (viva): a randomised controlled trial clinical practice guidelines of the european society for vascular surgery on the complexity of screening detected abdominal aortic aneurysms: a retrospective observational multicenter cohort study increasing the elective endovascular to open repair ratio of popliteal artery aneurysm the aneurysm detection and management study screening program: validation cohort and final results tackling the tobacco epidemic in the nordic countries and lower cancer incidence by / in a -year periodthe effect of envisaged scenarios changing smoking prevalence as aid workers move to the heart of congo's ebola outbreak, "everything gets more complicated ebola outbreak in the dr congo: lessons learned la situation épidémiologique de la maladie à virus ebola ebola outbreak in west africa democratic republic of the congo. strategic response plan for the ebola virus disease outbreak democratic republic of efficacy and effectiveness of an rvsv-vectored vaccine in preventing ebola virus disease: final results from the guinea ring vaccination, open-label, cluster-randomised trial (ebola Ça suffit!) infectious disease trends in china since the sars outbreak africa centres for disease control and prevention, african union headquarters, po box , w k addis ababa, ethiopia nkengasongj@africa-union.org jnn is director of africa centres for disease control and prevention and po is senior adviser for policy and strategy in the office of the director at africa centres for disease control and prevention. we declare no other competing interests. key: cord- -y s iv authors: logunov, denis y; dolzhikova, inna v; zubkova, olga v; tukhvatullin, amir i; shcheblyakov, dmitry v; dzharullaeva, alina s; grousova, daria m; erokhova, alina s; kovyrshina, anna v; botikov, andrei g; izhaeva, fatima m; popova, olga; ozharovskaya, tatiana a; esmagambetov, ilias b; favorskaya, irina a; zrelkin, denis i; voronina, daria v; shcherbinin, dmitry n; semikhin, alexander s; simakova, yana v; tokarskaya, elizaveta a; lubenets, nadezhda l; egorova, daria a; shmarov, maksim m; nikitenko, natalia a; morozova, lola f; smolyarchuk, elena a; kryukov, evgeny v; babira, vladimir f; borisevich, sergei v; naroditsky, boris s; gintsburg, alexander l title: safety and immunogenicity of an rad and rad vector-based heterologous prime-boost covid- vaccine in two formulations: two open, non-randomised phase / studies from russia date: - - journal: lancet doi: . /s - ( ) - sha: doc_id: cord_uid: y s iv background: we developed a heterologous covid- vaccine consisting of two components, a recombinant adenovirus type (rad ) vector and a recombinant adenovirus type (rad ) vector, both carrying the gene for severe acute respiratory syndrome coronavirus (sars-cov- ) spike glycoprotein (rad -s and rad -s). we aimed to assess the safety and immunogenicity of two formulations (frozen and lyophilised) of this vaccine. methods: we did two open, non-randomised phase / studies at two hospitals in russia. we enrolled healthy adult volunteers (men and women) aged – years to both studies. in phase of each study, we administered intramuscularly on day either one dose of rad -s or one dose of rad -s and assessed the safety of the two components for days. in phase of the study, which began no earlier than days after phase vaccination, we administered intramuscularly a prime-boost vaccination, with rad -s given on day and rad -s on day . primary outcome measures were antigen-specific humoral immunity (sars-cov- -specific antibodies measured by elisa on days , , , , and ) and safety (number of participants with adverse events monitored throughout the study). secondary outcome measures were antigen-specific cellular immunity (t-cell responses and interferon-γ concentration) and change in neutralising antibodies (detected with a sars-cov- neutralisation assay). these trials are registered with clinicaltrials.gov, nct and nct . findings: between june and aug , , we enrolled participants to the two studies ( in each study). in each study, nine volunteers received rad -s in phase , nine received rad -s in phase , and received rad -s and rad -s in phase . both vaccine formulations were safe and well tolerated. the most common adverse events were pain at injection site ( [ %]), hyperthermia ( [ %]), headache ( [ %]), asthenia ( [ %]), and muscle and joint pain ( [ %]). most adverse events were mild and no serious adverse events were detected. all participants produced antibodies to sars-cov- glycoprotein. at day , receptor binding domain-specific igg titres were with the frozen formulation and with the lyophilised formulation, and neutralising antibodies were · with the frozen formulation and · with the lyophilised formulation, with a seroconversion rate of %. cell-mediated responses were detected in all participants at day , with median cell proliferation of · % cd (+) and · % cd (+) with the frozen formulation, and a median cell proliferation of · % cd (+) and · % cd (+) with the lyophilised formulation. interpretation: the heterologous rad and rad vector-based covid- vaccine has a good safety profile and induced strong humoral and cellular immune responses in participants. further investigation is needed of the effectiveness of this vaccine for prevention of covid- . funding: ministry of health of the russian federation. covid- was first reported in wuhan, china, at the end of december, . the disease is an acute respiratory illness ranging in severity from mild to severe, with death in some cases; many infected people are asymptomatic. since the end of january, , cases of covid- have been reported in more than coun tries around the world. on march , , who described the spread of covid- as a pandemic. the causative agent of covid- is the betacoronavirus severe acute respiratory syndrome coronavirus (sars-cov- ). sars-cov- can be transmitted in many ways, with the main route of transmission via contact with infected people (eg, by secretions, particularly droplets). as of aug , , there have been more than million laboratory-confirmed cases of sars-cov- infection, and more than deaths. because of the rapid global spread of sars-cov- infection and the high mortality rate, development of a vaccine is an urgent task. vaccination will restrict the spread of covid- and reduce mortality. intensive research and development of vaccines is currently underway in china, russia, the uk, the usa, and other countries. according to who, on aug , , candidate covid- vaccines based on different platforms (vectored, dna, mrna, inactivated, etc) were being tested in clinical trials. prevention of sars-cov- infection might be achieved by targeting the spike protein (glycoprotein s), which interacts with the ace receptor and enables entry of sars-cov- into the cell. blocking this interaction decreases viral internalis ation and replication. [ ] [ ] [ ] most vaccines that are currently in development target glycoprotein s as the main antigen. the structure and function of the sars-cov- glycoprotein s is similar to that of other highly pathogenic betacoronaviruses, such as middle east respiratory syndrome coronavirus (mers-cov) and severe acute respiratory syndrome coronavirus (sars-cov). glycoprotein s consists of two subunits: s contains a receptor-binding domain (rbd), which interacts with the ace receptor on the cell surface; s mediates the fusion of viral and cell membranes via formation of a six-helix bundle fusion core. , to protect against sars-cov- infection, it is important to form neutralising antibodies targeting s rbd, s n-terminal domain, or the s region; these antibodies block binding of the rbd to the ace receptor and prevent s -mediated membrane fusion or entry into the host cell, thus inhibiting viral infection. , when developing a vaccine (particularly during a pandemic), it is important to consider that a protective response must develop in a short time (eg, up to month). moreover, previous work on vaccines for mers-cov and sars-cov showed that both humoral and cellular (cytotoxic) immune responses are important to induce a protective immune response. to achieve these goals, one of the most attractive options is for vaccines to be based on recombinant viral vectors, which can induce humoral and cellular immune responses and form protective immunity after one or two doses. , recombinant adenovirus vectors have been used for a long time, with safety confirmed in many clinical studies of various preventive and therapeutic drugs. [ ] [ ] [ ] [ ] [ ] [ ] [ ] moreover, the long-term effects of vectors based on adenoviruses have been investigated, by contrast with newer methods that remain to be studied long term. for evidence before this study we searched clinicaltrials.gov and pubmed up to aug , , with the terms "covid- " or "sars-cov- " and "vaccine" and "clinical trial", with no date or language restrictions, to find information about adenovirus-based covid- vaccine candidates in active clinical trials. according to who, on aug , , candidate vaccines based on different platforms (vectored, dna, mrna, inactivated, etc) were being tested in clinical trials against severe acute respiratory syndrome coronavirus (sars-cov- ) proteins. recombinant viral vector-based vaccines are promising candidates for covid- prevention because they induce humoral and cellular immune responses and can provide protective immunity after one or two doses. several candidate covid- vaccines have been tested in clinical trials, including an adenovirus type (ad ) vector-based vaccine (cansino biological/beijing institute of biotechnology, china), an ad vector-based vaccine (johnson & johnson, usa), and a vaccine containing a simian adenoviral vector (astrazeneca/university of oxford, uk). since boosting vaccination is necessary for formation of a more powerful immune response, the effectiveness of such vaccination can be reduced when using a homologous vector (because of formation of an immune response not only to the target antigen but also to the vector components after priming vaccination). we designed a covid- vaccine with two different adenoviral vectors (recombinant ad [rad ] and recombinant ad [rad ]), both carrying the gene for sars-cov- spike glycoprotein (rad -s and rad -s), and we implemented a prime-boost regimen. we did two open, phase / non-randomised trials of two formulations (frozen and lyophilised) of the vaccine in healthy adult volunteers. safety of the two individual vaccine components (rad -s and rad -s) was confirmed in phase . both components were then administered as a prime-boost vaccination in phase , with testing for safety and immunogenicity. the vaccine was well tolerated and produced humoral and cellular immune responses in healthy adults. igg responses were elicited in all participants, with geometric mean titres significantly higher than those reported in people who have recovered from covid- . antibodies to sars-cov- glycoprotein and neutralising antibodies increased significantly at day and continued to increase throughout the observation period. specific t-cell responses peaked at day after vaccination. our findings indicate that a heterologous rad and rad vector-based covid- vaccine is safe and immunogenic in healthy adults. further investigation is needed of the effectiveness of this vaccine for prevention of covid- . formation of a robust long-lasting immune response, a prime-boost vaccination is advisable, which is widely used with registered vaccines for diseases including hepatitis b and ebola virus disease. when using vector-based vaccines, immune responses are formed not only to the target antigen but also to the vector component. as a result, the best vaccination scheme is heterologous vaccination, when different viral vectors are used to overcome any negative effects of immune response to vector components. [ ] [ ] [ ] such an approach was successfully used with an ebola virus disease vaccine developed in russia and licensed in . we designed a novel, heterologous adenoviral vectorbased vaccine against sars-cov- suitable for primeboost vaccination. the vaccine was designed with two recombinant adenovirus vectors and was developed as two formulations (frozen [gam-covid-vac] and lyophilised [gam-covid-vac-lyo]). we aimed to assess safety and immunogenicity of both vaccine formulations and to compare the humoral immune response with that recorded in people who have recovered from covid- . we did two open, phase / non-randomised studies at hospitals in russia (burdenko hospital and sechenov university, moscow, russia). for each study, healthy adult volunteers (aged - years) were preselected to be included in the volunteer register; all adults provided signed informed consent to be included in this database for study participation. volunteers were screened by demographic data, had a physical examination and bodyweight mea sured, were assessed for vital functions (eg, blood pressure, pulse, and temperature), had a blood test for clinical and biochemical testing, were screened for infections such as hiv, hepatitis, and syphilis, underwent pcr for sars-cov- and had a test for antibodies to sars-cov- , and had a urine test for drugs, alcohol, and pregnancy (in women). we included adult volunteers of both sexes with a body-mass index of · - · kg/m², who had a negative pcr and negative igg and igm to sars-cov- , and who had no history of covid- or contact with patients with covid- . volunteers had no infectious diseases at the time of vaccination and for days before vaccination, and they did not receive any other vaccinations within days of participation in the study. based on the results of the preliminary screening, volunteers were selected ( for each clinical trial) for inclusion in the register of volunteers planning to take part in the study of vaccines against covid- . as soon as the volunteers were included in the register they began self-isolation. all participants provided written informed consent. the two studies were reviewed and approved by appropriate national and local competent authorities, including the regulator (department of state regulation for medicine distribution, approval nos and ) and the ethics committee of the ministry of health of the russian federation. the vaccine comprises two vector components, recombinant adenovirus type (rad ) and recombinant adenovirus type (rad ), both of which carry the gene for sars-cov- full-length glycoprotein s (rad -s and rad -s). both components were developed, manufactured, and stored by n f gamaleya national research centre for epidemio logy and microbiology (moscow, russia) according to good manufacturing practices. a full dose of the vaccine was ¹¹ viral particles per dose for both recombinant adenoviruses and all participants received full doses. the dose was set based on findings of preclinical studies (unpublished data). the vaccine was manufactured as two formulations, frozen (gam-covid-vac) and lyophilised (gam-covid-vac-lyo). the frozen vaccine has a volume of · ml (per dose) and the lyophilised vaccine needs to be reconstituted in · ml of sterile water for injection (per dose). the study of gam-covid-vac was done at a branch of burdenko hospital, an agency of the ministry of defence. both civilian and military volunteers took part in that study. military personnel were contract employees (who received a salary for their work) and not individuals conscripted for compulsory military service. the study of gam-covid-vac-lyo took place at sechenov university and all volunteers in that study were civilians. in all cases, vaccines were administered intramuscularly into the deltoid muscle. during phase of both studies, participants received one dose intramus cularly of either rad -s or rad -s and were assessed for safety over days. phase of both studies began no earlier than days after phase vaccination, after an interim safety assessment had been done. during phase , participants received prime-boost vaccination, with one dose of rad -s administered intramuscularly on day and one dose of rad -s administered intramuscularly on day . injection-site reactions, systemic reactogenicity, and medication use to alleviate such symptoms were monitored for days after the first injection (in phases and ) and at day (phase only). no randomisation or special selection was done for phases and . participants were included as soon as informed consent was signed. participants underwent clinical and laboratory assessments on days , , and in phase and on days , , , and in phase . laboratory analyses included complete blood and urine counts, alanine aminotransferase, aspartate amino transferase, protein, bilirubin, total cho lesterol, lactate dehydro g enase, alkaline phosphatase, prothrombin index, glucose, urea, and creatinine. immune status was analysed on days and in phase and on days , , and in phase . volunteers were in hospital for days from the start of vaccination. information on adverse events was recorded daily. determination of immunogenicity is described in detail in the appendix (pp - ). in brief, antigen-specific humoral immune responses were analysed on days , , , and in phase and on days , , , , and in phase . the titre of glycoprotein-specific antibodies in serum was ascertained by elisa. to test anti-sars-cov- igg, we used an elisa that was developed at n f gamaleya national research centre for epidemiology and micro biology and registered for clinical use in russia (p h / - - ). the elisa measures iggs specific to the rbd of sars-cov- glycoprotein s. the titre of neutralising antibodies was measured on days , , and in phase and on days , , , and in phase and was ascertained by microneutralisation assay using sars-cov- (hcov- /russia/ moscow_pmvl- / ) in a -well plate and a % tissue culture infective dose (tcid ) of . cellmediated immune responses were measured on days , , and after the first injection by determination of antigen-specific proliferating cd + and cd + cells by flow cytometry and by quantification of interferon-γ release. to compare post-vaccination immunity with natural immunity that forms during infection with sars-cov- , we obtained convalescent plasma from blood samples of people from moscow who had recovered after covid- (between march and aug , ). convalescent plasma was obtained from people who had had a laboratory-confirmed covid- diagnosis, who had been recovered for at least weeks, and who had tested negative by pcr twice. the average time from recovery to convalescent plasma collection was about month. convalescent plasma was collected from people who had had mild (fever ≤ °c without pneumonia) and moderate (fever > °c with pneumonia) disease severity. humoral immune responses were ascertained as men tioned above. primary outcome measures were safety and immunogenicity of the covid- vaccine. the primary outcome measure for safety was the number of participants with adverse events from day to day after vaccination in phase and from day to day after vaccination in phase . the primary outcome measure for immunogenicity was change from baseline in antigen-specific antibody levels at days (from day to day ), measured by elisa. secondary immuno genicity outcome measures were virus neutra lising antibody titres (on days , , and after vaccination in phase and on days , , , and after vaccination in phase ) and determination of antigen-specific cellular immunity (specific t-cell immunity and interferon-γ production or lymphoproliferation) on days , , and after vaccination. the sample size for both studies was calculated from previous clinical trials of a mers vaccine based on the same recombinant viral vectors as used in our vaccine but carrying the mers-cov glycoprotein s gene. preliminary results of a study of a mers vaccine in which more than people participated showed a seroconversion rate of %. when calculating the sample size for our study, we expected % efficiency, which required inclusion of participants in each study. considering the possibility of early dropout of volunteers, we decided that volunteers should be recruited into the immunogenicity assessment group in phase of each study. a total sample size of ( in each study) was expected to produce reliable data on adverse events. all statistical calculations were done in graphpad prism . normality of the data distribution was assessed with the d'agostino-pearson test. paired samples were compared with the wilcoxon test and unpaired samples with the mann-whitney u test. correlation analysis was done with spearman's test; the correlation coefficient r shows interactions between two datasets and takes values either from to (in the case of a positive correlation) or from - to (in the case of a negative correlation). we used the mann-whitney u test to compare at various timepoints antibody titres, the level of proliferating cd and cd cells, and increases in concentrations of interferon-γ between volunteers receiving the two vaccines, and when comparing antibody titres in volunteers on days and after vaccination with antibody titres in convalescent plasma. we used the wilcoxon test to compare data within the same group of volunteers at different timepoints (eg, when comparing day to day ). these trials are registered with clinicaltrials.gov, nct and nct . the funder had no role in study design, data collection, data analysis, data interpretation, or writing of the report. all authors had full access to all data in the studies and had final responsibility for the decision to submit for publication. between june and aug , , healthy adults were enrolled to the two studies from the volunteer register (figure ). adults were selected at the beginning of each study from the volunteer registry; participants were included in each study and five people were kept as backup volunteers in case of dropouts (two for phase and three for phase ). nine participants in each study received rad -s in phase , nine received rad -s in phase , and received sequential injections of rad -s (on day ) and rad -s (on day ) in phase . all volunteers in the main group were analysed and additional volunteers from the backup groups were not needed. thus, in each study, volunteers were vaccinated. more men than women took part in the study (table ) . in both studies, systemic and local reactions (table ) (combined data for both the lyophilised and frozen vaccine formulations). comparing data for antibody responses to sars-cov- at days and with data for antibody responses in convalescent plasma showed that postvaccination elisa titres were signifi cantly higher than were titres after covid- (for both days and , p< · ), whereas significant differences in neutralising antibodies were not seen (p= · ; figure ). we also analysed the correlation between sars-cov- rbd elisa titres and neutralising antibody titres and noted a strong correlation between these variables (r= · , % ci · - · ; p< · ; appendix p ). when analysing antigen-specific iggs, the seroconversion rate was % for both vaccine formulations on days and of the study, and when analysing neutralising antibody responses, serocon version was % on day of the study for both vaccine formulations. seroconversion rates on days , , , and (in phase ) are presented in the appendix (pp - ). descriptive statistics for humoral immune responses are presented in the appendix (pp [ ] [ ] [ ] [ ] . cellular immune responses showed formation of antigen-specific cells of both t-helper (cd + ) and t-killer (cd + ) cells, and an increase in the concentration of interferon-γ secretion in peripheral blood mononuclear cells, in % of volunteers (figure ). cells from vaccinated participants proliferated significantly in response to glycoprotein s, particularly on day . the number of participants with cd + and cd + proliferative responses to antigen are shown in the appendix (p ). cell-mediated responses were detected in all participants at day , with median cell proliferation of · % cd + to investigate the effect of the pre-existing immune response to adenoviral vectors, neutralising antibodies to recombinant vectors were measured in all participants on days and in both studies (figure ). after one injection of vaccine components, not only is an immune response to target antigen formed but also an immune response is seen to components of the vaccine vector. further, a correlation analysis was done to compare the level of neutralising antibodies to recombinant vectors with the level of antigen-specific antibodies (appendix p ). no significant correlation was noted between the titre of neutralising antibodies to recombinant viral vectors on day and the titre of rbd-specific iggs in serum samples of participants on days , , and from the start of vaccination in participants in phase of each study and on days , , , and from the start of vaccination in participants in phase of each study. moreover, formation of cross-reactive neutralising antibodies to vectors rad and rad was analysed. administration of rad did not increase the titre of neutralising antibodies to rad on day , and vice versa, which indicates the absence of cross-reactivity with respect to vaccine components ( figure ) . thus, the presence of a pre-existing immune response to the components of vaccine vectors rad and rad does not affect the titre of rbd-specific antibodies in the serum of participants. these findings of two open, phase / non-randomised studies of a heterologous prime-boost covid- vaccine based on recombinant adenoviral vectors rad -s and rad -s show that the vaccine is safe, well tolerated, and induces strong humoral and cellular immune responses in % of healthy participants. all reported adverse events were mostly mild. the most common systemic and local reactions were pain at the injection site, hyperthermia (body temperature - °c), headache, asthenia, and muscle and joint pain, which are typical for vaccines based on recombinant viral vectors. no serious adverse events were reported during the study. in general, the adverse event profile did not differ from those reported in pub lished work for other vector-based vaccines. , [ ] [ ] [ ] the incidence of adverse events in our studies was slightly lower than in other work; a comparative clinical study with other vaccines is needed to confirm these findings. in preclinical studies of the vaccine (unpublished data), robust humoral and cellular immune responses were elicited in non-human primates, providing protection from sars-cov- infection. the vaccine showed % protectivity in a lethal model of sars-cov- challenge in immunosuppressed hamsters. no antibody-dependent enhancement of infection was seen in vaccinated and sars-cov- -challenged animals. in general, titres of neutralising antibodies to sars-cov- were lower than those reported in studies of vaccines based on mrna and chadox . , in our study, we used a high dose of virus ( tcid ) and a small amount of serum ( µl serum and µl of virus), whereas in studies of other vaccines, doses of - tcid and a larger amount of serum were used for analyses. , despite the fact that research results cannot be compared with each other in this case, we can make a comparison between titres of neutralising antibodies in vaccinated volunteers and in convalescent plasma. we showed that volunteers who received the heterologous rad and rad vaccine elicited the same titre of sars-cov- neutralising antibodies as did people who had recovered from covid- . according to our study protocols (nct and nct ), the t-cell response in healthy adult volunteers after vaccination was to be assessed using two methods. first, by measuring percentages of proliferating cd and cd t (cd + ) cells in response to antigenic re-stimulation in culture. second, by measuring interferon-γ in culture medium produced by peripheral blood mononuclear cells. interferon-γ is a marker cytokine of t-helper- biased cellular response towards vaccination, and high rates of antigen-specific cd + t cells generally correspond to potentiation of t-helper- polarisation. we understand that results obtained from both assays could indirectly characterise the t-helper- response. in the phase clinical trial, we will supplement our research methods with more focus on t-helper- and t-helper- polarisation. the main issue that can limit use of vectors based on recombinant adenoviruses is widespread pre-existing immunity in the human population. after vaccination with an adenoviral vector, immune responses form not only to the target antigen but also to the vector proteins (particularly in case of pre-existing immunity). in our study, despite formation of neutralising antibodies to recombinant adenoviruses after vaccination with rad and rad , formation of a humoral immune response to target antigen (sars-cov- glycoprotein s) in vaccinated volunteers was not affected. moreover, neutralising antibodies to rad did not neutralise rad when serum samples from vaccinated volunteers were obtained and analysed days after immunisation (and vice versa). thus, use of a heterologous prime-boost immunisation, when rad -s is used for priming and rad -s is used for boosting, is an effective approach to elicit a robust immune response and to overcome the immune response that is formed to the components of a viral vector. for more accurate estimation of the effect of preexisting immunity on vaccination, the number of observations should be increased and analysed during future research. limitations of our studies include the short duration of follow-up ( days), inclusion of only male volunteers in some parts of phase , the low number of participants (n= ), and no placebo or control vaccine. despite planning to recruit healthy volunteers aged - years, in general, our study included fairly young volunteers. further research is needed to evaluate the vaccine in different populations, including older age groups, individuals with underlying medical conditions, and people in at-risk groups. participants in these phase / trials will be followed up to days after initial immunisation. we designed the vaccine in two formulations, frozen (storage at - °c) and lyophilised (storage at - °c). the lyophilised form was developed for vaccine delivery to hard-to-reach regions of russia, and the frozen form was developed for large-scale use. production volumes in a pandemic will be strongly biased towards the frozen vaccine, since production of a lyophilised form takes much more time and resources. in conclusion, these data collectively show that the heterologous vaccine based on rad -s and rad -s is safe, well tolerated, and does not cause serious adverse events in healthy adult volunteers. the vaccine is highly immunogenic and induces strong humoral and cellular immune responses in % of healthy adult volunteers, with antibody titres in vaccinated participants higher than those in convalescent plasma. unprecedented measures have been taken to develop a covid- vaccine in russia. based on our own experience in developing vaccines against ebola virus disease and mers, the covid- vaccine has been developed in a short time. preclinical and clinical studies have been done, which has made it possible to provisionally approve the vaccine under the current decree of the government of the russian federation of april , , no on aug , (registration no lp- [gam-covid-vac]) and on aug , (registration no lp- [gam-covid-vac-lyo]). provisional licens ure requires a large-scale study, allows vaccination in a consented general population in the context of a phase trial, allows the vaccine to be brought into use in a population under strict pharmacovigilance, and to provide vaccination of risk groups. the phase clinical trial was approved by the appropriate national and local competent authorities, including the regulator (department of state regulation for medicine distribution) and the ethics committee of the ministry of health of the russian federation, on aug , (approval ). the phase clinical trial is planned with involvement of volunteers from different age and risk groups. the phase clinical trial will be undertaken with constant monitoring of the condition of volunteers through an online application, and each dose of vaccine will have its own qr code, which will be assigned to the volunteer. dyl is the principal investigator, did research, and coordinated the study. ivd and dvs wrote the draft report. ivd, nll, yvs, and eat coordinated the study. ivd, ovz, ait, asd, dmg, ase, avk, agb, fmi, op, tao, ibe, iaf, diz, dvv, dns, and ass collected data. ivd, ovz, ait, yvs, eat, nll, dae, nan, and mms contributed to data analysis and data interpretation. dyl, dvs, bsn, and alg edited the report. lfm, eas, evk, vfb, and svb did research. alg organised the research and had final responsibility for the decision to submit for publication. all authors critically reviewed the report and approved the final version. alg and dyl report funding from the ministry of health of the russian federation. ovz, tao, ivd, op, dvs, dmg, asd, ait, dns, ibe, eat, agb, ase, ass, svb, dyl, bsn, and alg report patent pending (patent for the use of vector constructs for the induction of immunity to sars-cov- ). all other authors declare no competing interests. individual participant data will be made available on request, directed to the corresponding author (dyl). after approval of a proposal, data can be shared through a secure online platform. covid- ) pandemic director-general's opening remarks at the media briefing on covid- transmission of sars-cov- : implications for infection prevention precautions: scientific brief draft landscape of covid- candidate vaccines structure analysis of the receptor binding of -ncov angiotensin-converting enzyme (ace ) as a sars-cov- receptor: molecular mechanisms and potential therapeutic target sars-cov- pandemic and research gaps: understanding sars-cov- interaction with the ace receptor and implications for therapy severe acute respiratory syndrome coronavirus (sars-cov- ): an overview of viral structure and host response inhibition of sars-cov- (previously -ncov) infection by a highly potent pan-coronavirus fusion inhibitor targeting its spike protein that harbors a high capacity to mediate membrane fusion interaction of the spike protein rbd from sars-cov- with ace : similarity with sars-cov, hot-spot analysis and effect of the receptor polymorphism neutralizing antibodies against sars-cov- and other human coronaviruses immunoinformatic analysis of t-and b-cell epitopes for sars-cov- vaccine design middle east respiratory syndrome coronavirus (mers-cov): infection, immunological response, and vaccine development immunological responses against sars-coronavirus infection in humans new vaccine technologies to combat outbreak situations virus-vectored ebola vaccines adenovirus vectors for gene therapy, vaccination and cancer gene therapy adenoviral vectors for gene transfer and therapy adenoviruses as vaccine vectors gene therapy finds its niche methods and clinical development of adenovirus-vectored vaccines against mucosal pathogens adenoviral vector-based strategies against infectious disease and cancer the first approved gene therapy product for cancer ad-p (gendicine): years in the clinic us centers for disease control and prevention. hepatitis b vis safety and immunogenicity of gamevac-combi, a heterologous vsv-and ad -vectored ebola vaccine: an open phase i/ii trial in healthy adults in russia heterologous prime-boost vaccination a heterologous vectored vaccine for prevention of middle east respiratory syndrome induces long protective immune response against mers-cov an mrna vaccine against sars-cov- : preliminary report immunogenicity and safety of a recombinant adenovirus type- -vectored covid- vaccine in healthy adults aged years or older: a randomised, double-blind, placebo-controlled, phase trial safety, tolerability, and immunogenicity of a recombinant adenovirus type- vectored covid- vaccine: a dose-escalation, open-label, non-randomised, first-in-human trial safety and immunogenicity of the chadox ncov- vaccine against sars-cov- : a preliminary report of a phase / , single-blind, randomised controlled trial th /th cytokine responses following hiv- immunization in seronegative volunteers memories that last forever: strategies for optimizing vaccine t-cell memory this research was supported by the ministry of health of the russian federation (state assignment no - - - , to alg and dyl). we thank the study participants, site research staff, and members of the trial management groups, trial steering committee, and independent data monitoring committee. key: cord- - ulnpdm authors: shalhoub, sarah title: interferon beta- b for covid- date: - - journal: lancet doi: . /s - ( ) - sha: doc_id: cord_uid: ulnpdm nan severe acute respiratory syndrome coronavirus (sars-cov- ) has led to a global epidemic with more than million confirmed cases and deaths worldwide thus far. several drugs with antiviral activity against sars-cov- have been tested in vitro as well as in ongoing human studies. existing literature on the efficacy of different treatments for sars-cov and middle east respiratory syndrome coronavirus (mers-cov) provides some insight into options for potential repurposing of these drugs for sars-cov- treatment. clinical studies on the efficacy of type i interferons, including interferon alfa and interferon beta, in the treatment of sars-cov had variable results. , additionally, studies on the effects of these treatments on survival of patients with mers-cov have not shown significant benefits. , sars-cov- triggered lower type i interferon responses than sars-cov in an ex-vivo study in human lung tissue and was found to be more susceptible to type i interferons than sars-cov. in the lancet, ivan fan-ngai hung and colleagues present the results of an open-label, randomised, phase trial that examined the effect of a triple combination regimen of interferon beta- b million international units ( · mg) on alternate days, lopinavir mg plus ritonavir mg every h, and ribavirin mg every h, compared with lopinavir mg plus ritonavir mg every h alone. the investigators enrolled patients with covid- admitted to six hospitals in hong kong. median age of patients was years (iqr - ) and [ %] were men; were assigned to the combination group and to the control group. treatment duration was days. interferon beta- b was given in the combination group only to patients who were enrolled less than days after onset of symptoms, for a maximum of three doses by the end of the first week of symptoms. the primary endpoint was time to negative nasopharyngeal swab for sars-cov- rt-pcr and secondary end points were time to symptom resolution by achieving a national early warning score (news ) of , a sequential organ failure assessment (sofa) score of , -day mortality, and duration of hospital stay. triple therapy was associated with a significant reduction in the duration of viral shedding (time to negative nasopharyngeal swab days [iqr [ ] [ ] [ ] [ ] [ ] [ ] [ ] in the combination group vs days [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] . this significant difference was sustained in a subgroup analysis of patients who were enrolled within less than days of symptom onset ( patients in the combination group, who received interferon beta- b, vs in the control group) but not in the subgroup of patients enrolled later than days from symptom onset ( patients in the combination group, who only received lopinavirritonavir and ribavirin, vs in the control group). most published studies so far have been retrospective or observational. therefore, this prospective, randomised controlled design adds notable value to the growing evidence on treatments, eliminating a number of limitations inherent to retrospective studies. additionally, despite the relatively small number of patients in the interferon beta- b subgroup, significant differences in outcomes were demonstrated. therefore, this study provides much needed data on a potential therapeutic regimen for sars-cov- . it is important to note that the studied population had mild or moderate disease at the time of enrolment, evidenced by a median news of and sofa score of , and there was no mortality in either group. whether similar results are reproducible in populations with severe covd- is unknown and should be explored in future studies. although lopinavir-ritonavir was not efficacious in treating sars-cov- in a recent trial, it is unknown whether this might be partly related to delayed enrolment (median days from symptom onset). the use of placebo as a control in the absence of proven effective therapy is therefore ideal. additionally, earlier enrolment to standardise the number of interferon beta- b doses is important but might be impractical, particularly because patients might not present to hospitals earlier than days, when symptoms typically worsen. this study presents a step towards finding a muchneeded therapy for sars-cov- . however, as the authors acknowledge, future studies to examine the efficacy of interferon beta- b alone or in combination with other drugs to treat severe or critically ill patients with confirmed covid- compared with placebo are warranted. i declare no competing interests. schulich school of medicine and dentistry, western university, london, on n a c , canada situation report . geneva: world health organization evaluation of antiviral therapies for coronavirus disease (covid- ) pneumonia in shanghai role of lopinavir/ritonavir in the treatment of sars: initial virological and clinical findings description and clinical treatment of an early outbreak of severe acute respiratory syndrome (sars) in guangzhou, pr china ribavirin and interferon therapy for critically ill patients with middle east respiratory syndrome: a multicenter observational study ribavirin and interferon alfa- a for severe middle east respiratory syndrome coronavirus infection: a retrospective cohort study weak induction of interferon expression by sars-cov- supports clinical trials of interferon lambda sars-cov- sensitive to type i interferon pretreatment triple combination of interferon beta- b, lopinavir-ritonavir, and ribavirin in the treatment of patients admitted to hospital with covid- : an open-label, randomised, phase trial a trial of lopinavir-ritonavir in adults hospitalized with severe covid- clinical course and risk factors for mortality of adult inpatients with covid- in wuhan, china: a retrospective cohort study key: cord- -nu typ j authors: acuin, cecilia s; khor, geok lin; liabsuetrakul, tippawan; achadi, endang l; htay, thein thein; firestone, rebecca; bhutta, zulfiqar a title: maternal, neonatal, and child health in southeast asia: towards greater regional collaboration date: - - journal: lancet doi: . /s - ( ) - sha: doc_id: cord_uid: nu typ j although maternal and child mortality are on the decline in southeast asia, there are still major disparities, and greater equity is key to achieve the millennium development goals. we used comparable cross-national data sources to document mortality trends from to and to assess major causes of maternal and child deaths. we present inequalities in intervention coverage by two common measures of wealth quintiles and rural or urban status. case studies of reduction in mortality in thailand and indonesia indicate the varying extents of success and point to some factors that accelerate progress. we developed a lives saved tool analysis for the region and for country subgroups to estimate deaths averted by cause and intervention. we identified three major patterns of maternal and child mortality reduction: early, rapid downward trends (brunei, singapore, malaysia, and thailand); initially high declines (sustained by vietnam but faltering in the philippines and indonesia); and high initial rates with a downward trend (laos, cambodia, and myanmar). economic development seems to provide an important context that should be coupled with broader health-system interventions. increasing coverage and consideration of the health-system context is needed, and regional support from the association of southeast asian nations can provide increased policy support to achieve maternal, neonatal, and child health goals. southeast asia has achieved substantial reductions in child and maternal mortality over the past two decades, but these achievements are unevenly distributed among and within the countries in the region. of the ten countries in the association of southeast asian nations (asean), only three have infant and child mortality rates below ten per livebirths-brunei, singapore, and malaysia. infant and under- mortality in thailand and vietnam have declined substantially to below per livebirths within the past two decades, but the philippines and indonesia have seen a levelling off in rates to between and per livebirths. myanmar, cambodia, and laos still have mortality levels of - per livebirths in , which are similar to the rates of their neighbours from more than two decades ago, and rank among the highest for asia. the un estimates that every year about women die as a result of pregnancy or childbirth, as do nearly million children younger than years. worldwide, in , about maternal and child deaths were in southeast asia. laos and cambodia are among seven countries with the highest maternal mortality ratios outside of sub-saharan africa, and indonesia is one of countries that account for % of all maternal deaths worldwide. although southeast asia as a region might achieve the reductions in child mortality set by the un millennium development goal (mdg ), cambodia and myanmar have been rated as having insuffi cient progress. declines in mortality rates in indonesia, laos, and the philippines are also faltering. similarly, although all countries in the region are reporting declines in maternal deaths (towards mdg ), the rates of decline for indonesia, the philippines, and myanmar have notably slowed. • southeast asia has sustained substantial reductions in maternal, neonatal, and child mortality since , but this progress has been uneven. mortality reductions in some countries have been the result of trajectories of rapid decline that started long before the millennium development goals (mdgs) were developed in . others have succeeded in improving progress since the s, but some countries continue to struggle. • causes of death suggest a mortality transition in maternal deaths in the region. child deaths are mainly attributable to the persistence of neonatal causes along with key preventable factors in the postneonatal period. • disparities in intervention coverage are most acute in countries with the lowest intervention coverage overall. • despite the variations in achievements, some countries are notable success stories. suggested key factors include the ability to link maternal, neonatal, and child health interventions to broader health-system investments and to target access to rural and disadvantaged populations. • increasing coverage to % will have a substantial eff ect on maternal deaths caused by unsafe abortion, hypertensive diseases, and postpartum haemorrhage and on neonatal deaths caused by pneumonia, sepsis, and birth asphyxia. although there might not be quick solutions for maternal, neonatal, and child health in the region, coordinated expansion of proven eff ective interventions can contribute to improved reductions in mortality. • there is a need for stronger regional cooperation through the association of southeast asian nations to provide support to countries that need to accelerate progress to meet the mdgs. southeast asia as a region has received little attention in recent eff orts to revitalise and strengthen the policy agenda of the partnership for maternal, newborn and child health, despite the complexity of national trends, including the substantial burden of morbidity and mortality in several countries and the existence of documented successes. as the economies of southeast asia become more integrated with each other, there is an increasing need to assess and resolve the defi ciencies in this agenda and to identify policy options for sustaining, if not accelerating, the pace of reduction in mortality. eff ective and aff ordable technology to reduce most maternal, neonatal, and child deaths is available, - so why has progress been so uneven? we focus on a region, collectively the ninth largest economy in the world, whose performance and achievements are often hidden by larger countries such as india or china, as well as by the un agency groupings of the region that do not take into account historical and geopolitical ties within southeast asia. in this paper, we critically review the region's achievements in reducing maternal and child mortality and highlight key factors that explain the successes and challenges in reaching these goals during competing worldwide, regional, and national health problems. we fi rst report on patterns of mortality reduction within southeast asia and major causes of maternal and child deaths in the context of mdg and mdg . we investigate two country cases to highlight the notable variations in mortality reduction. finally, we use an analysis of the deaths that could be averted through expanded coverage to identify more eff ective approaches for improving maternal, neonatal, and child health in southeast asia. for the ten countries discussed in this paper, we reviewed estimates from national data sources and country ministries of health, as well as from the demographic and health surveys and multiple indicator cluster surveys. we also reviewed estimates from international data sources from unicef, who, and the institute for health metrics and evaluation (webappendix pp - ). we present country-specifi c estimates on maternal, neonatal, and under- mortality rates from recent un mdg reports, , as these estimates enable cross-country comparisons on trends in mortality using replicable estimation methods that reduce sources of non-sampling error. these estimates tend to be more conservative in the rate of decline than estimates from the institute for health metrics and evaluation. on the basis of increasing awareness of the burden of neonatal mortality, we sought comparable estimates of trends that separated neonatal (death within the fi rst days after birth) and postneonatal (death between days and year after birth) mortality. as un models do not have neonatal time trends for all countries in the region, we report estimates from the institute for health metrics and evaluation. we report estimates on causes of neonatal and child deaths on the basis of standardised methods for estimating the distribution of causes of child deaths. we compiled estimates of causes of maternal deaths from countdown country reports and who. we evaluated data from the demographic and health surveys and multiple indicator cluster surveys , to assess existing intervention coverage within the region, with these data sources providing the ability to disaggregate coverage estimates by wealth quintile and rural or urban status [ ] [ ] [ ] [ ] to establish the country average of coverage and to assess the programme coverage in disadvantaged populations by economic status and geography. we calculated regional estimates using country-level data from the specifi c source cited, unless otherwise indicated. to test the contribution of health-sector inputs to mortality reductions, we selected thailand and indonesia as case studies, as high (thailand) and lower (indonesia) achievers, and we focused on maternal and neonatal mortality as outcomes sensitive to healthsystem development. we used national data for these case studies to extend the analysis to the period before see online for webappendix we searched the demographic and health surveys (cambodia and indonesia indonesia , indonesia , indonesia , indonesia - , and philippines philippines , philippines , philippines , and and vietnam and ) , multiple indicators cluster surveys, , data banks of regional and global fi nance institutions such as the asian development bank and the world bank, [ ] [ ] [ ] [ ] the millennium development goals surveillance data sources and publications of the un agencies, mainly unicef, , and who , , from to october, . we used the following search terms: "asia", "asia and pacifi c", "southeast asia", "sea", "association of southeast asian nations", and "asean" (for geographic location); "cambodia", "indonesia", "lao pdr", "laos", "malaysia", "myanmar", "philippines", "thailand", and "vietnam" (our countries of interest); "(maternal or child or neonatal) and (health or health care)", "(health or mortality) and (pregnancy or pregnant)", and "(health or mortality) and (maternal or neonatal or infant or child or under years" (for health conditions); "health systems", "health fi nancing", "leadership", "governance", "information systems", "delivery and organization of services", "regulation of health products", "human resources" (for health systems); "maternal mortality ratio", "infant mortality rate", "neonatal mortality rate", "under mortality rate", "skilled birth attendance", "antenatal care", "prenatal care", "immunization", "maternal and child nutrition", and "causes of maternal, infant and child mortality" (for mortality and health programme indicators); and "gross domestic product", "gdp", "gdp per capita", "national health accounts", "nha", "public and private health expenditures", and "(out-of-pocket or oop) health expenditures" (for fi nance). these data are complemented by nationally representative data and international journal publications. specifi c country data were further verifi ed and updated by members of the writing team. we also searched pubmed from to october, , for peer-reviewed journals for pertinent articles on maternal and child health and the region, and cross-referenced who, unicef, the world bank, and the asian development bank. no initial language exclusion was applied in searching; for full-text papers, english and the languages of the authors (thai, bahasa, malay, chinese, filipino, and burmese) were used. the mdg baseline year ( ). , we fi tted data to a quadratic equation: log mmr or log nmr=intercept+linear eff ect of year +quadratic eff ect of year and to a linear equation: log mmr or log nmr=intercept+linear eff ect of year to establish whether declines in maternal mortality could be attributed to programme changes or temporal trends, where mmr is the maternal mortality ratio and nmr is the neonatal mortality rate. using the lives saved tool (list), we calculated potential deaths that could be averted through increasing population coverage of the interventions proven to be eff ective in reducing maternal, neonatal, and child mortality. , list operates within the spectrum modelling platform, by the futures group, initially developed to project demographic change and complemented by modules to model the eff ect of family planning and hiv/aids interventions. the model yields estimates of deaths averted by cause and intervention for user-specifi ed intervention coverage levels, based on inputs of demographic projections, numbers of maternal and child deaths, data on the distribution of deaths by cause, intervention eff ectiveness, and data on local health status. , - the platform has been used previously for analysis of eff ect of intervention packages on maternal and child survival in south africa and sub-saharan africa, but this is one of the fi rst uses in southeast asia. for this analysis, we assessed all the maternal, neonatal, and child health interventions included in list. the interventions and the estimates of their eff ectiveness are provided in webappendix pp - . values for the eff ectiveness of interventions were developed through a standardised review process using established criteria to identify which interventions to include on the basis of levels of evidence. the analysis was done for all ten countries and then for three subgroups of countries on the basis of observed patterns of mortality reduction: subgroup (brunei, singapore, malaysia, thailand); subgroup (the philippines, indonesia, vietnam); and subgroup (laos, cambodia, myanmar). we assessed potential lives saved at three hypothetical coverage levels: %, %, and %. reductions in maternal, infant, and child mortality in southeast asia are indicative of the diversity of this region, presenting three divergent patterns (fi gure , data not shown for brunei and singapore as these countries are considered to be more developed and where mdg goals might not be as relevant). , the fi rst pattern refl ects countries achieving low rates of mortality between (the mdg baseline year) and in brunei, singapore, malaysia, and thailand. in , maternal mortality ratios in these countries were well below per livebirths, and infant and under- mortality rates were already at or below per livebirths. these countries, the most economically advanced in the region, have also invested in their health systems over time. a second, less distinct, pattern, seen in the philippines, indonesia, and vietnam, starts with relatively high mortality rates and ratios in , fairly large initial reductions (except for the maternal mortality ratio in indonesia) that somewhat faltered after in indonesia and the philippines. by contrast, there were accelerated reductions in mortality in vietnam during this period, with mortality rates and ratios beginning to come close to those of thailand. the third pattern, observed in laos, cambodia, and myanmar has very high levels at the beginning of , followed by sustained reductions from to , with the exception of cambodia's maternal mortality ratio. these three countries, which are on the un list of least developed countries, continue to report high rates of maternal, infant, and child mortality. plotting maternal mortality reductions against gross national income per capita (webappendix p ) indicates that, although countries with high maternal mortality achieved reductions in mortality as their gross national income per capita increased, some of the most notable declines in mortality took place earlier than the rapid rise in gross national income. the rapid reductions in maternal mortality in thailand occurred before . as maternal mortality declined to levels around , smaller reductions take place even as gross national income continues to improve. similar patterns are evident for infant and under- mortality versus gross national income per capita plots (webappendix pp - ). separating infant mortality reduction between and into neonatal and postneonatal (webappendix p ) indicates that the largest declines in infant mortality over time were mainly attributable to substantial postneonatal mortality reductions, as seen in malaysia, thailand, and vietnam. the philippines and indonesia had reductions in neonatal and postneonatal mortality similar to that in laos, cambodia, and myanmar. although starting with comparably lower baseline mortality levels in , rates of decline in the philippines and indonesia were not suffi ciently accelerated since the development of the mdgs. reductions in infant mortality in brunei and singapore stem from larger proportions of decline in neonatal deaths, a pattern similar to other high-income countries. other than brunei and singapore, the slower rates of decline for neonatal mortality for the other eight of the ten asean countries is a cause for concern. interventions for reducing neonatal mortality are more closely linked to maternal interventions in terms of policy and programme implementation and might not be as noticeably tracked towards their eff ect on under- mortality. the philippines, which is deemed to be on target for mdg in achieving reductions in child mortality, has the lowest reduction in neonatal mortality in the region-lower than that for cambodia or myanmar, which have been identifi ed as having insuffi cient progress towards achieving mdg . the distribution of maternal mortality causes (fi gure a) is indicative of the substantial variations in health status and health-system development seen within the region. haemorrhage is a leading cause of death, probably indicative of delays in attaining emergency obstetric care. hypertensive disorders contribute to about one in every six maternal deaths in southeast asia and suggest a diff erent causal pathway more similar to that in developed country settings. the proportion of other indirect causes might indicate the still-substantial burden of infectious disease within the region and the eff ect of malaria and hiv on maternal health. unsafe abortion is a factor in almost % of maternal deaths. these patterns refl ect a causal transition in maternal mortality as the overall risk of maternal death declines and these causes will aff ect the extent to which interventions, both as single modalities or included in a package, can be predicted to avert deaths. diff erent rates of reduction in child mortality can be attributed partly to variations in causes of death (fi gure b). neonatal problems, such as preterm complications, contributed to about % of child mortality, accounting for the single largest proportion of preventable deaths, even as several asean countries are successfully reducing their postneonatal and child mortality burdens. infectious diseases, including pneumonia and diarrhoea, still account for almost half of the deaths in children, indicating substantial scope for continued reductions in child mortality. inequalities are substantial across countries in the region, but also within countries, as indicated by the current variation in intervention coverage by income and by rural or urban subgroups (webappendix pp [ ] [ ] [ ] . disparities exist in antenatal care coverage, use of skilled birth attendance, and diphtheria, polio, tetanus, and measles vaccination together with use of oral rehydration therapy, which are all key to the development of a continuum of care. , with regard to overall programme coverage, laos has a substantially lower coverage than that of other countries in the region and is far from a % coverage level, even for the wealthier groups. antenatal care coverage is the most widespread, being close to or above %, in countries other than laos and cambodia, for the wealthier and urban areas. this disparity suggests that there is scope to eff ectively increase prenatal interventions that can avert maternal deaths. vaccination coverage varies widely between and within countries, although several countries in the region are eligible for funds from the global alliance for vaccines and immunisation and have received substantial fi nancial and policy support that is likely to lead to increases in vaccination coverage over time. laos and cambodia have the greatest disparities in programme coverage. in cambodia, vaccination levels for the wealthiest quintile are similar to those of the other southeast asia countries, matching those of indonesia's highest quintile. however, the coverage in the poorest households in cambodia is almost % lower than that for the wealthiest households, resulting in a large equity gap in immunisation levels. the countries shown in the fi gures in webappendix pp - indicate relatively low coverage of skilled birth attendance (except thailand and vietnam) with inequality particularly acute in the philippines, laos, and cambodia. diff erences in skilled birth attendance between urban and rural laotian populations are the largest among the six countries included in this comparison. skilled birth attendance could be viewed as one indicator of broader health-system development, and the generally low coverage coupled with a high extent of inequality highlights the need for more comprehensive and coordinated health system improvements in the region overall. these patterns also point to the necessity of targeting the most vulnerable populations and maintaining attention to equity while increasing programme coverage. to understand potential determinants of mortality reduction, we look in more depth at two countries with diff erent experiences of lowering mortality. the reduction in the maternal mortality in thailand began in the s (webappendix p ) at a time when skilled birth attendants, mostly midwives, were systematically trained and deployed to community hospitals. [ ] [ ] [ ] at the time of alma-ata in , thailand's maternal mortality ratio was already below and continued to drop even further in the s as the economy improved and a health-care insurance programme for low-income populations was introduced along with specifi c safe motherhood interventions. another round of health-system reforms and maternal, neonatal, and child health interventions were introduced in the early s, including universal health coverage. coordinated health policy support through successive national plans provided a context and investments to stimulate structural, fi nancial, and social capacities to deliver services, particularly in the district health system. , , mandatory rural service for medical graduates provided a stable human resource base within community hospitals. using a log linear model, no single programme could explain the decline in maternal mortality between and , suggesting that the accelerated decline might be attributable to several developments. however, model fi t after the economic crisis was not as good compared with earlier time periods. there was an data for maternal deaths are from un mdg southeast asia, , including from ten asean countries and timor leste (data not broken down to country level). data for child deaths are from black et al. increase in maternal mortality from to , followed by a steady decline. this decline was in parallel with economic recovery and the introduction of universal health insurance coverage, the provincial maternal and child health board groups, the healthy thailand programme, and the saiyairak programme. , , for this short period, assessment of the eff ect of any intervention programmes is diffi cult. the systematic deployment of community-based health personnel took place in indonesia about a decade later than in thailand in the s. major, targeted, safe motherhood initiatives were introduced in the late s, but by that time the maternal mortality ratio of indonesia was about nine times higher than that of thailand (webappendix pp - ). , a village midwife programme was implemented between and , but the comparatively rapid training and deployment of village midwives might have compromised quality of care. access to care in indonesia varies by rural or urban geography, income, and level of education. unlike in thailand, where the provision of skilled birth attendants was followed by increased facility and referral level capacities, in indonesia not all health centres can provide basic obstetric care. about % of district hospitals do not have an obstetrician, indicating limited provision of the -h continuum of care necessary for dealing with emergency situations. a fragmented and devolved health system has challenged the capacity to sustain a comprehensive and concerted focus on maternal and child health. reductions in neonatal mortality (webappendix p ) for the two countries mirror reductions in maternal mortality. interventions to reduce neonatal mortality need more from health systems than either a maternal or child programme alone. in thailand, neonatal interventions have been linked with maternal programmes, , , but this association has not been documented in indonesia. maternal and neonatal mortality reductions in thailand and indonesia occurred in the context of rapid economic growth in both settings along with widespread increases in education levels and in sex equity. although these factors might have aff ected levels of success, other determinants of mortality have been involved. policy implementation in thailand has been multi-sectoral, involving royalty and diff erent ministries, including the national health security offi ce, which is responsible for health fi nancing, especially universal coverage of health insurance. investments in primary health care in the s have led to benefi ts in the long term. however, geographic and demographic context also probably have a role. at the time of its rapid maternal mortality reduction in the s, thailand had a smaller, more circumscribed population compared with the larger and more dispersed indonesian population, and this diff erence might have been an important factor in establishing physical access-a basic requirement for programme coverage. we investigated the potential eff ects of expanding programme coverage through a list analysis of the asean region as a whole, and for subgroups on the basis of the mortality reduction patterns described earlier. we provide percentages rather than absolute numbers, as these estimates should be interpreted with caution in the context of local data. the list analysis is under development as a measure for assessing and evaluating the benefi ts and limitations of interventions. several of the interventions cited and used have been recently reviewed in depth , and used for regional estimates. , these estimates are the best point estimates for the eff ect of interventions, and, although these have been validated against actual observed mortality eff ects in the neonatal period, they still need prospective validation for programme-based eff ectiveness. asean regional averages are closer to those of subgroups and (as defi ned earlier), which consist of the bulk of the population and the higher mortality rates (fi gure a). although diff erences in maternal deaths averted across the groups are substantial, common trends across the region highlight crucial gaps. expanding coverage of interventions for hypertensive disease in pregnancy and safe management of abortions, for example, will reduce maternal deaths substantially throughout the region, and addressing postpartum haemorrhage causes will largely reduce deaths for subgroups and but not subgroup . counterpart calculations were made for neonatal and child mortality (fi gure b and c). interventions for birth asphyxia are more likely to avert deaths in subgroups and than in subgroup . the high proportion of neonatal and child deaths averted through interventions for infectious diseases in all subgroups is indicative that infectious disease remains a challenge for the region as a whole. , to focus on universal coverage, which is receiving greater attention in other health-policy settings, we report the deaths that could be averted at % programme coverage. at the regional level, universal basic obstetric care coverage will save about one in fi ve mothers (table) , but with universal comprehensive obstetric care coverage, more than half of maternal deaths would be averted. almost all these lives saved would be in subgroups and for which current levels of coverage for these services are low (webappendix pp [ ] [ ] [ ] . because there is already good access to basic and comprehensive obstetric care for subgroup , the deaths averted from these interventions are minimal. by contrast, basic postabortion case management will save a higher proportion of mothers in subgroup but more deaths will actually be averted in subgroups and . the fewer lives saved in subgroup with comprehensive abortion versus basic abortion care might be because the access to comprehensive obstetric care that could be used for abortion management in this group is already high. universal basic obstetric care will avert about one in fi ve neonatal deaths in subgroup , whereas comprehensive obstetric care will save almost twice as many lives as basic care will for the region as a whole, but particularly for subgroups and . however, even at % coverage the maximum proportion of neonates that could be saved with either of these interventions does not go beyond a third of deaths, indicating the need for other interventions such as those that take into account prematurity through antenatal steroids and providing kangaroo care. interventions directed towards infectious diseases such as diarrhoea and pneumonia will, likewise, aff ect postneonatal and child deaths mostly in subgroups and . a small but noticeable eff ect on death in subgroup might also be apparent when coverage increases to %. preventive measures such as improving access to safe water can contribute substantially to mortality reduction, averting more deaths than would pneumococcal vaccination in all the subgroups. despite substantial improvements in maternal, neonatal, and child health since , most notably in malaysia, thailand, and vietnam, high mortality, poor coverage, and high inequity continue to challenge other countries in the region, such as laos, cambodia, and myanmar. improvements in the fi rst three countries seem to be attributable to socioeconomic progress and a consistent policy focus on maternal and child health programmes and coordinated health-system components, [ ] [ ] [ ] notably a stable and strategically deployed health workforce coupled with supportive fi nance mechanisms in malaysia and thailand. the importance of favourable health systems is highlighted by the case study in thailand, which indicates that mortality reductions have taken place at modest levels of economic growth and that no single factor or intervention could account for these reductions. the case study in indonesia indicates how similar interventions used in a setting with diff erent system capacities and geopolitical features can result in diff erent outcomes. thus, although the list analysis can estimate the potential eff ect of interventions given with maximum levels of coverage, the case studies caution us that improving health outcomes is not just about increasing the amount of money spent on health. instead, targeted and sustained interventions to reduce the barriers that prevent the most vulnerable population groups from accessing the interventions they crucially need should be ensured in the long term. for example, the list analysis indicates that providing basic and comprehensive emergency obstetric care has the potential to avert half of all maternal deaths and about one in six neonatal deaths in laos, cambodia, and myanmar. however, prevention of these deaths might be possible only if care coverage is rapidly expanded in low-income and rural populations, possibly through sustained donor investments, given the low levels of domestic health spending. in the philippines and indonesia, the two most populous countries in the region, regaining momentum in mortality reduction alongside substantial geographic and cultural access challenges might mean improving access to services through more equitable fi nancing schemes. despite the varying agendas that countries of the region might need to adopt to complete the unfi nished maternal, neonatal, and child health agenda, our fi ndings indicate important areas of common ground. many key interventions to reduce child deaths have been implemented at the community level throughout southeast asia, but necessary health-service investments that will enable the countries of the region to reduce maternal and neonatal deaths have yet to be fully considered. access to safe abortion services and management of hypertensive disorders during pregnancy will prevent maternal deaths from these causes from brunei to myanmar. similarly, all countries in the region recognise space for expanding coverage of crucial neonatal interventions to prevent preterm births and neonatal deaths from infection. our study has several limitations. we have used estimates of mortality reduction from un agencies that might not match national estimates and that use diff erent methods; however, these estimates are preferred for cross-country analysis. these estimates for southeast asia are still mainly derived from household surveys and subject to potential error from under-reporting and misclassifi cation of deaths. only fi ve of the ten countries discussed have vital registration systems, and not all these systems have valid registration of causes of death. there is an acute need for better data in laos and myanmar, particularly on maternal mortality, but the pioneering work in maternal death audits in malaysia provides a potential model for the region. the selection of data sources was mainly aff ected by the availability of comparable, reliable data across all the asean countries. for example, although we used the more inclusive gross national income per capita for webappendix pp - , this measurement was not consistently available for the case studies, hence the use of gross domestic product for thailand and indonesia. we were not able to disaggregate list estimates into relevant national subgroups by wealth or by rural or urban status. this non-separation is important because the poor populations are likely to have higher mortality rates and lower levels of intervention coverage than the wealthier groups, which could aff ect estimates. data limitations restricted our ability to develop this analysis, even as a test case. we have also not analysed the costs involved in extending coverage, which we hope to develop in a future study. since its formation in , asean has positioned itself as an important hub for economic and sociocultural cooperation. infectious diseases have thus far commanded much of asean's attention in health matters. recently, regional focus has begun to shift to other health issues. the asean strategic framework on health development - , which focuses on access to health-care services in addition to communicable diseases and pandemic preparedness, has also gained regional support. given the economic vigour of asean, regional cooperation in health might be key to motivating lessdeveloped members to focus on maternal, neonatal, and child health. the pivotal role of asean in stimulating and channelling international fi nancial aid to tsunami-devastated indonesia in and cyclonestricken myanmar in testifi es to the power of this promise-the goodwill and experience of working with each other in disaster situations can be harnessed for the health and wellbeing of mothers and children in the region. , but how should this aid be used? the experience of the asean, as discussed in this paper, suggests that eff ective interventions to curb maternal and child mortality need to be deployed to actively target the disadvantaged populations who are most aff ected by unsafe abortion, hypertensive diseases, postpartum haemorrhage, pneumonia, sepsis, and birth asphyxia. far from expecting coverage of these programmes to passively diff use to the very poor, governments must innovatively combine health interventions with non-health programmes such as micro-fi nance schemes and conditional cash transfer mechanisms that have proven successful in other settings. , achievement of the mdgs worldwide will not happen without individual country eff orts. as the donor community focuses its attention on the burdens of africa and south asia, asean countries must provide support to each other. examples of such support mechanisms already in place include fi nancial cooperation through the asean surveillance process, which is an early warning system to keep track of macroeconomic trends and to provide early detection of any adverse development. for public health, the asean sars containment information network exemplifi es how member countries share essential information, best practices, and new fi ndings for severe acute respiratory syndrome. however, asean has yet to develop initiatives for maternal, neonatal, and child health, which could be developed through sharing information and best practices (possibly starting by resolving the absence of comparable data across countries); fi nancial cooperation eff orts could be linked to outcomes, and the attainment of mdgs for member countries behind target could be made an asean priority. csa, rf, glk, tth, tl, and ea contributed to the conception, design, and acquisition of data for the fi rst draft. tl, ea, and glk contributed to the acquisition, analysis, and interpretation of data for the case studies. zb, rf, and csa contributed to the acquisition, analysis, and interpretation of data for the list analysis. csa and rf were responsible for the overall analysis and interpretation of data. all authors contributed to the drafting and critical review of the paper. csa is employed by the university of the philippines, national institutes of health and has received consultancy fees from projects with the philippine government, unicef, united states agency for international development, and who regional offi ce for the western pacifi c. glk has received consultancy fees from the institute of gerontology, universiti putra malaysia, international life sciences institute sea, seameo tropmed regional centre for community nutrition, and is employed by the international medical university, malaysia. all other authors have no confl icts of interest. geneva: world health organization trends in maternal mortality: - . geneva: world health organization estimates developed by the un inter-agency group for child mortality estimation countdown to . maternal, newborn and child health. country profi les years after alma-ata: has primary health care worked in countries? strategies for reducing maternal mortality: getting on with what works lancet neonatal survival steering team. evidencebased, cost-eff ective interventions: how many newborn babies can we save? continuum of care for maternal, newborn, and child health: from slogan to service delivery interventions to address maternal, newborn, and child survival: what diff erence can integrated primary health care strategies make? health and health-care systems in southeast asia: diversity and transitions neonatal, postnatal, childhood, and under- -mortality for countries, - : a systematic analysis of progress towards millennium development goal global, regional, and national causes of child mortality in : a systematic analysis van look pfa. who analysis of causes of maternal death: a systematic review demographic and health surveys multiple indicator cluster surveys monitoring the situation of children and women. thailand 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and survival the child health epidemiology reference group reviews of the eff ectiveness of interventions to reduce maternal, neonatal and child mortality saving the lives of south africa's mothers, babies, and children: can the health system deliver? sub-saharan africa's mothers, newborns, and children: how many lives could be saved with targeted health interventions cherg review groups on intervention eff ects. standards for cherg reviews of intervention eff ects on child survival world development indicators database a systematic analysis of progress towards millennium development goal lancet neonatal survival steering team. million neonatal deaths: when? where? why? mind the gap: equity and trends in coverage of maternal, newborn and child health services in countdown countries community fi nancing: thailand experience of blind alleys and things that have worked: history's lessons on reducing maternal mortality bureau of policy and strategy, ministry of public health. health policy in thailand. nonthaburi: ministry of public health health insurance systems in thailand. nonthaburi: health system research institute improving maternal, newborn and child health in the south-east asia region. data source: basic indicators: health situation in south-east asia, world health organization evolution of safe-motherhood policies in indonesia. initiative for maternal mortality programme assessment (immpact) increased educational attainment and its eff ects on child mortality in countries between and : a systematic analysis commentary: list: using epidemiology to guide child survival policymaking and programming list as a catalyst in program planning: experiences from burkina faso, ghana and malawi comparing modelled to measured mortality reductions: applying the lives saved tool to evaluation data from the accelerated child survival programme in west africa emerging infectious diseases in southeast asia: regional challenges to control health-fi nancing reforms in southeast asia: challenges in achieving universal coverage global report on preterm birth and stillbirth equity in maternal and child health in thailand united nations development programme measuring health systems performance in vietnam: results from eight provincial health systems assessments strategy for reducing maternal mortality association of southeast asian nations. joint statement of the th asean health ministers meeting singapore asean regional programme for disaster management. a regional strategy for disaster reduction tripartite core group; the government of the union of myanmar, the united nations, and the association of southeast asian nations. post-nargis joint assessment (ponja) health microinsurance: a comparative study of three examples in bangladesh. good and bad practices conditional cash transfers: reducing present and future poverty this paper is part of a series funded by the china medical board, rockefeller foundation, and atlantic philanthropies. the authors thank the following individuals for their assistance: virasakdi key: cord- - kh tks authors: divala, titus; burke, rachael m; ndeketa, latif; corbett, elizabeth l; macpherson, peter title: africa faces difficult choices in responding to covid- date: - - journal: lancet doi: . /s - ( ) - sha: doc_id: cord_uid: kh tks nan to flatten the curve, some african governments have imposed stringent public health measures (lockdown) based on physical distancing to reduce transmission. however, the safety of this approach in poor communities has not been evaluated, and it is plausible that lives lost to lockdown could exceed those saved from covid- . potentially fatal unintended consequences include widespread economic disruption and hunger, worsening food insecurity if harvesting is disrupted, and increased domestic and state actor violence. large numbers of african patients with hiv and tuberculosis depend on functional health services, with substantial individual and public health consequences if treatment access is disrupted. although anticipated by national programmes, some treatment interruptions are inevitable during prolonged lockdown. with clear understanding of risk, governments can make informed decisions about harms and benefits. we used spiegelhalter's approach to compare age-group specific infection fatality ratios from covid- to background (non-covid- ) mortality risk in malawi, south africa, the uk, and india. - this assumes covid- infection fatality ratios similar to china, but true age-specific casefatality rates might be higher with fragile health systems. for context, malawi has not yet triggered lockdown, whereas the uk, south africa, and india have. we estimate that in the uk, having covid- confers risk of death equivalent to approximately months of background mortality risk, averaged across all age groups. by contrast, in malawi this risk is equivalent to months of background mortality (appendix). this reflects higher background mortality rates in malawi, underscoring the fragility of health under normal circumstances. malawi (median age years) also has relatively few older citizens, with • % of the population older than years. this makes alternative strategies potentially safer and more feasible than lockdowneg, community-led approaches to support older people to self-isolate with provision of food, medicine, and wellbeing support. although we fully agree that macroeconomic arguments against lockdown cannot justify widespread loss of life in europe and asia, the considerations are very different in africa, where lockdown could cost many lives. we urge african governments to carefully contextualise safe physical distancing policies that maximise likely benefits. without a context-specific, ethical approach to physical distancing, unintended harms from stringent lockdown could pose more harm than the direct effects of covid- itself. we declare no competing interests. how much 'normal' risk does covid represent? estimates of the severity of coronavirus disease : a model-based analysis report : impact of non-pharmaceutical interventions (npis) to reduce covid- mortality and healthcare demand covid- control in low-income settings and displaced populations: what can realistically be done see online for appendix key: cord- -l za w authors: anand, sudhir title: human security and universal health insurance date: - - journal: lancet doi: . /s - ( ) - sha: doc_id: cord_uid: l za w nan human security is a multidimensional concept that has been a cornerstone of japanese development cooperation for more than a decade. at the heart of security is the idea of protection or insurance against downside risk. , three distinct questions arise from the concept of human security. first, protection of what? second, insurance against what? and, third, security for whom? the fi rst question relates to the specifi cation of what is to be protected. the defi nition of human security off ered by the commission on human security is: "to protect the vital core of all human lives in ways that enhance human freedoms and human fulfi lment". the core of a person's life is closely concerned with the person's wellbeing and agency, which is best viewed in terms of his or her "capability" to achieve alternative "beings and doings". in this context, health assumes central importance for two reasons: it is directly constitutive of a person's wellbeing; and it enables a person to function as an agent-that is, to pursue the various goals and projects in life that he or she has reason to value. this view deploys the notion of well-functioning, but it is not grounded in notions of economic welfare that are based on utility or income. it is, rather, an agency-centred view of a person, for whom ill health restricts the scope of human agency. since our ability to do things typically depends on our being alive, the capability to lead a long and healthy life must itself be regarded as a basic capability. the second question related to human security is insurance against what. here the concern is to insure against falling below an adequate threshold of human capabilities-in the case of a person's health, a minimum acceptable level. the probability of falling below a minimum threshold depends on both how vulnerable a person is-the degree of downside risk the person facesand how much above the threshold he or she is in the relevant dimension. the extreme case of insecurity is certainty of being below a specifi ed threshold, and the absence of any chance of avoiding that fate. threats to human security can arise, for example, from natural disasters and environmental catastrophessuch as the earthquake and tsunami in japan, and the consequent leakage of radioactive material from the fukushima daiichi nuclear plant. they can arise from disease outbreaks such as hiv/aids, severe acute respiratory syndrome and drug-resistant tuberculosis; from personal accidents and illness; from economic downturns as in the asian fi nancial crisis of - ; and from various other hazards that people face. , , the vulnerability of a person to such risks will depend on his or her individual circumstances-including location, epidemiological environment, health status, and economic position. a person's health is aff ected by health care and various other determinants-eg, socioeconomic, behavioural, continuing commitment. otherwise, we risk alienating patients and damaging the therapeutic alliance. as part of the eradication eff ort, who requested that countries and laboratories either destroy the remainder of their stocks of variola, the causative agent of occupational, and dietary. but access to appropriate health care is also a vital factor in protecting a person from the risk of ill health, and especially of catastrophic ill health. comprehensive health care is thus important both in promotion of health and in response to health crises. without health insurance, a severe medical crisis that threatens survival, for example, can have disastrous fi nancial implications-that can aff ect human security in many other dimensions. the third question concerns security for whom-the entire population or a subset of it? universalism can be defended through a variety of diff erent approaches, which all invoke equity, fairness, or impartiality in some form or other. for instance, we can appeal to impartiality through the device of rawls's "veil of ignorance" in the "original position". behind the veil of ignorance, i do not know who i will turn out to be and what serious illness or health threat i might encounter, which could require extensive medical attention. given this uncertainty, the institutional arrangement for health care i am likely to favour is one that ensures comprehensive coverage for all. the concept of human security has wide reach and includes multiple concerns. a major concern is protection of people's health, for which comprehensive health coverage for all is an essential requirement. universal health insurance thus contributes directly to furthering human security. this implication is as valid for japan as for other countries in the world. the tragic events of, and responses to, the earthquake of are a powerful reminder of japan's concern for human security. in the past, several distinguished politicians, civil servants, and academics in japan have drawn on and developed the concept of human security-including former prime minister keizo obuchi, japan international cooperation agency president sadako ogata, global health expert keizo takemi, and japan center for international exchange president tadashi yamamoto. , [ ] [ ] [ ] [ ] indeed, universal health coverage in japan, now in existence for years, is indicative of the priority that japan accords to human security. over the decades, japan has also undertaken policies to advance human security in other dimensions, such as basic education, social protection, and economic safety nets. internationally, japan has used the concept of human security to guide assistance to developing countries through bilateral aid and multilateral policies. the range and reach of the idea of human security are extensive, as japanese actions have shown. a central manifestation of these actions is the country's commitment to universal health insurance. department of economics, university of oxford, oxford ox uq, uk sudhir.anand@economics.ox.ac.uk i declare that i have no confl icts of interest. the "impossible patient": organizational response to a clinical problem long-term opioid contract use for chronic pain management in primary care practice: a fi ve year experience contracting for safety with patients: clinical practice and forensic implications contracts between patients and healthcare practitioners for improving patients' adherence to treatment, prevention and health promotion activities limiting exposure to medical malpractice claims and defamatory cyber postings via patient contracts systematic review: treatment agreements and urine drug testing to reduce opioid misuse in patients with chronic pain are no-suicide contracts eff ective in preventing suicide in suicidal patients seen by primary care physicians? partnerships in patient care: a contractual approach a rose by any other name: pain contracts/agreements nonabandonment: a central obligation for physicians the use of contracts in the inpatient treatment of the borderline personality disorder motivational interviewing in health care: helping patients change behavior economic security. paper presented at common security forum conference concepts of human development and poverty: a multidimensional perspective human security now: protecting and empowering people commodities and capabilities why human security? health as a human security priority for the st century. human security track iii. the helsinki process a theory of justice opening remarks common security in asia: new concepts of human security common security in asia: new concepts of human security the asian crisis and human security: an intellectual dialogue on building asia's tomorrow key: cord- -n bk m authors: bhala, neeraj; curry, gwenetta; martineau, adrian r; agyemang, charles; bhopal, raj title: sharpening the global focus on ethnicity and race in the time of covid- date: - - journal: lancet doi: . /s - ( ) - sha: doc_id: cord_uid: n bk m nan tackling injustices, including those that result from prejudice and racism globally, is essential in the response to the coronavirus disease (covid- ) pandemic. here, we focus on uk south asian and black and african-american populations, using internationally recognised terminology and definitions, and consider the uk and the usa as globally relevant examples. we recognise other minorities also need consideration in the covid- response, and we hope our principles apply broadly. given their settled status either after migration or by birth in the country, ethnic/racial minority populations should experience health-care outcomes equal to those of others. sadly, this seems untrue. , data on covid- cases and deaths are plentiful, but detailed data on covid- by age, sex, or ethnicity/ race are scant but should be available routinely and automatically. in the uk, collection of data by ethnicity in hospitals is mandatory - and in the usa the national institutes of health revitalization act requires the publication of data by race/ethnicity and sex by federal agencies. the uk's intensive care national audit and research centre reported on may , , that ( %) of critically ill covid- patients were from ethnic/racial minority groups. for comparison, the census shows that ethnic minority groups made up about % of the uk population. additionally, national health service (nhs) health-care staff from ethnic minority groups seem to have died in disproportionate numbers from covid- , even when accounting for the high proportion of people from these groups who are employed in the nhs and work on the front line. these matters are being investigated in a uk government-initiated inquiry by public health england and have been highlighted by health-care workers, advocates, the uk's chief medical officer, and politicians. detailed scrutiny with accurate counts of numerators and denominators together with understanding explanatory factors and accompanying health-care environments will be required to interpret the findings of the inquiry. in the usa, analyses of covid- deaths from some states show that there are more deaths in african americans than in white americans. for example, in chicago, nearly % of deaths from covid- were among african americans, although they represent only about % of the city's population. in new york state and in some other us states, covid- has been more deadly for african american and hispanic people than for white people. these noticeable disparities [ ] [ ] [ ] [ ] have been highlighted by advocates, the us surgeon general, and politicians. why are ethnic/racial minority groups, seemingly, being disproportionately affected by covid- ? we support socioeconomic and environmental rather than biological explanations, which have been damaging to science and populations alike historically, are unlikely, and could lead to prejudice or victim blaming. , we also note, however, that socioeconomic factors did not fully explain ethnic variations in hospitalisation and death for respiratory infections, including influenza, in scotland. older age, male sex, and underlying chronic non-communicable problems, including cardiovascular diseases, hypertension, diabetes, obesity, and chronic obstructive pulmonary disease (copd), are associated with worse outcomes in covid- . , , routine largescale data on the risk factors and potential underlying causes of covid- complications for ethnic/racial minorities are not available globally as yet, so our explanations are tentative, but comorbidities might explain some of the differences. however, covid- has sharpened the focus on structural and societal inequalities that have long existed in the uk, the usa, and other countries. many people from ethnic/racial minorities hold essential jobs in health and social care, retail, public transport, and other sectors, putting them on the front line and at risk of exposure to covid- . , some people from ethnic/racial minority groups have been segregated in overcrowded urban housing centres and workplaces, the conditions of which can make physical distancing and self-isolation difficult, leading to increasing risks for the spread of covid- . , , ethnic/racial minorities exposed in crowded places and becoming seriously ill might be infected from multiple sources and a comparatively large infectious dose of the causative virus (sars-cov- ), which could be relevant in health and social care workers. , health-care disparities are also likely to have a role in the high burden of covid- among ethnic/racial minorities-eg, in the usa, black or african american minorities and hispanic groups are less likely to have health insurance, with consequent reduced healthcare access and use. , the relevant public health messaging, early diagnosis, and treatment of covid- among ethnic/racial minorities might be less effective, leading to later presentation. , , the important role of culture, including places of worship, multigenerational households, and variation in social interactions might also have a role in increased risks of covid- . , these complicated social determinants of health might explain the increased risk of infection but not necessarily worse outcomes and all these factors need deeper examination before we can draw valid conclusions. chronic conditions, especially diabetes, are comparatively common in african and south asian minority groups in europe and the usa. stroke is more common in african populations in the uk and the usa, with moderate increased risk of coronary heart disease in south asian groups compared with white populations. other comorbidities including copd, asthma, and infections such as tuberculosis might also be contributing to comparatively adverse outcomes in covid- . moreover, the heterogeneity of ethnic/racial minority groups, whether african, caribbean, south asian (indian, pakistani, or bangladeshi in the uk), chinese, or other ethnicities, have diverse risk factor profiles, which might be important for covid- outcomes. , the high prevalence of chronic diseases in us and uk ethnic/racial minorities reflects social and economic disadvantages, and factors such as diet, cigarette smoking, alcohol use, and exposure to psychosocial stressors. , , the effects of hostile environments against immigrants, particularly failed asylum seekers and undocumented immigrants, might affect settled ethnic/racial minority populations adversely through heightened prejudice and societal tensions. do these ethnic/racial variations apply to treatments also? there might be ethnic/racial variations in prescribing and adherence to medications; a broad range of commonly prescribed drugs might be relevant in covid- and potential beneficial, adverse, and neutral effects require reliable study. for example, very low serum concentrations of -hydroxyvitamin d are common in ethnic/racial minorities with darker skins in the uk and the usa. meta-analyses of randomised trials suggest a protective effect of vitamin d against acute respiratory infections. research is underway on varied pharmacological measures to treat and prevent covid- infection. pending the findings of these studies, we suggest following the rapidly evolving clinical and public health guidance on current medications, intakes of micronutrients, including vitamin d, , and relevant health behaviours. ethnic/racial disparities in the health outcomes of people with covid- need to be studied alongside age, sex, gender, socioeconomic status, and comorbidities in disaggregated public health data. , a provisional analysis by the uk office for national statistics suggests that the risk of covid- -related death among some ethnic groups is higher than that among those of white ethnicity in the uk. after adjustment for age, black men are · times more likely to have a covid- -related death and black women are · times more likely than white ethnicity men and women in the uk. after taking account of age and other sociodemographic characteristics and measures of self-reported health and disability, people of bangladeshi, pakistani, indian, and mixed ethnicities also had a significantly increased risk of covid- -related death compared with those of white ethnicity. these results suggest that the difference between ethnic groups in covid- mortality is partly a result of socioeconomic disadvantage and other circumstances, but a remaining part of the difference has not yet been explained. the evidence in the uk and the usa in the time of covid- has sharpened the focus on inequalities neglected for a long time. therefore, hand in hand, political action is needed to tackle xenophobia and racism, with concerted efforts to resolve long-standing societal inequalities globally. reliable collaborative evidence must underpin clinical, public health, and societal interventions by policy makers that address these injustices and tackle the covid- pandemic and its sequelae. we declare no competing interests. provisional death counts for coronavirus disease (covid- ): weekly state-specific data updates by select demographic and geographic characteristics covid- and african americans covid- fatalities hospitalization rates and characteristics of patients hospitalized with laboratory-confirmed coronavirus disease -covid-net, states is ethnicity linked to incidence or outcomes of covid- ? institute of medicine committee on understanding and eliminating racial and ethnic disparities in health care. unequal treatment: confronting racial and ethnic disparities in health care the retreat of scientific racism ethnic variations in morbidity and mortality from lower respiratory tract infections: a retrospective cohort study covid- lombardy icu network. baseline characteristics and outcomes of patients infected with sars-cov- admitted to icus of the lombardy region us centers for disease control and prevention. health of black or african american non-hispanic population non-communicable diseases in migrants: an expert review heterogeneity in blood pressure in uk bangladeshi, indian and pakistani, compared to white, populations: divergence of adults and children trends in the incidence of testing for vitamin d deficiency in primary care in the uk: a retrospective analysis of the health improvement network (thin) vitamin d supplementation to prevent acute respiratory tract infections: systematic review and metaanalysis of individual participant data scientific advisory committee on nutrition. vitamin d and health institute of medicine (us) committee to review dietary reference intakes for vitamin d and calcium. dietary reference intakes for calcium and vitamin d coronavirus (covid- ) related deaths by ethnic group, england and wales key: cord- -p vfo ne authors: chan, eyy; griffiths, sm; chan, cw title: public-health risks of melamine in milk products date: - - journal: lancet doi: . /s - ( ) - sha: doc_id: cord_uid: p vfo ne nan news stories about the contamination of milk with melamine in china fi rst emerged on sept , , and the situation has since become an international health scare. melamine (also known as tripolycyanamide) is an industrial chemical in the production of melamine resins, which are used in laminates, glues, adhesives, and plastics. when added to milk, melamine increases the nitrogen concentration, which suggests a false increase in protein concentration. melamine has low oral acute toxicity but excessive exposure in animals causes renal stones. when consumed by human beings, babies and children are aff ected the most because of their dependence for nutrition, compounded by immaturity of their organs, which renders them vulnerable to chemical damage. the practice of mixing preservatives and chemicals, including antibiotics, with milk to make it last longer, taste better, and record higher protein values refl ects an inadequately regulated and managed supply-chain and an agricultural industry in need of reform. chinese people have only recently started to appreciate milk products and many producers are small farmers, under pressure to maximise milk yield in the face of rising grain prices. middlemen between milk producers and some of the big dairy companies have been selling substandard milk at discount prices. although china has a monitoring system for nutritional contents, there is no regular reporting system for the concentration of common chemicals (illegal preservatives), veterinary antibiotic use, and carcinogenic components in dairy products. the government has now recognised the need for support, training, and investment in the industry to safeguard potential risk to public health. meanwhile, by sept , the chinese authorities had reported that children had been treated for renal complications. at least four children have died as a direct result. by sept , in hong kong where % of food is imported, much of it from the mainland, children had attended designated clinics. five of these children were found to have kidney stones, and four of these fi ve had a history of living in the mainland. because infant formula has been supplied to a large number of countries as far afi eld as burundi, yemen, and tanzania, the un has issued a worldwide alert and the european union banned china-made baby-food. in the uk, all products from china containing more than % milk as an ingredient will be subject to documentary, identity, and physical checks and those products containing more than · mg melamine per kg will be destroyed. the usa has advised those travelling to china with small children to take their own baby-food and formula. the chinese government's response has been to curb the risks, punish the perpetrators, and help the victims. the government has enacted the emergency public health response regulations drawn up in in response to the outbreak of severe acute respiratory syndrome (sars). this plan formulates a contingency response for major emergencies. however, the plan was drafted for infectious diseases such as sars, and there are no clear guidelines or regulations which govern responsibilities and liabilities in a case such as that of melamine contamination. the minister of health has promised care will be provided free to aff ected children and the government is providing screening to reassure anxious parents. however, for those with permanent clinical problems and aff ected children beyond china's borders, fi nancial compensation and long-term follow-up is less certain and questions of liability are as yet unresolved. public concern was raised after new-zealand-based food-giant fonterra learnt from its chinese partner sanlu group that infant formula was contaminated. the printed journal includes an image merely for illustration although mortality rates from cardiovascular and cerebral vascular diseases are increasing, chronic obstruc tive pulmonary disease (copd), lung cancer, and tuberculosis continue to rank in the top-ten leading causes of death in china. prevalence of copd remains high, aff ecting · % of the population older than years ( · % in men, · % in women). incidence of lung cancer has also increased rapidly in recent years. little doubt exists that smoking and use of solid fuels are the two most important risk factors contributing to copd, lung cancer, tuberculosis, and related deaths. liu and colleagues reported a highly signifi cant association between copd and exposure to biomass fuel for cooking in a subpopulation of non-smoking women in rural yunyang, southern china. prevalence of copd was two times higher and mortality from lung cancer six times higher in smokers than in non-smokers. in today's lancet, hsien-ho lin and colleagues used validated methods to predict deaths from copd, lung cancer, and tuberculosis. with several scenarios, they showed that reducing smoking and solid-fuel use would signifi cantly lower the social burden of these diseases in china between and . these fi ndings are important as a serious warning for policy makers. however, it would be diffi cult to predict a picture after years, in view of rapid changes in living standards, rural-to-urban transformation, and better drugs, as well as the methods they used for predictions. for instance, because urban areas are expanding rapidly, about - % of the population in sanlu, working with the chinese health authorities, then instituted a full public recall of aff ected formula. unfortunately, melamine contamination is not the fi rst instance of unsafe milk formula in china. in , children died of malnutrition in anhui province as a result of being fed infant formula of poor quality. diff erent infant formulas, corporations, and ten provinces were involved in these incidents, which exposed key public-health gaps in food safety and public protection. china is now facing not only the requirement to respond to the needs of sick children, but also the need to radically reform its milk-production processes and restore public confi dence. engaging local-level bureaucracies, addressing corruption and malpractice, and providing fi nancial support to the many farmers whose livelihood is aff ected are all essential for public-health protection, as is the need for open and transparent processes for surveillance and monitoring of food quality with community engagement at all levels to ensure good practice in the future. but the underlying ethics of a society in which profi t motive over-rides public good also needs to be addressed. to quote premier wen jibao, "many factories and milk dealers are lacking the most fundamental business morals and social responsibility. they are just cold blooded. therefore we will investigate them leaving none to escape". ); and international pediatric association melamine and cyanuric acid: toxicity, preliminary risk assessment and guidance on levels in food centre for food safety. frequently asked questions two held for sanlu-brand baby milk food scam supervision of dairies to be unifi ed: shijiazhuang govt admits delay in reporting threat caused crisis help worried parents, but sick patients must also get treatment. south china morning post china's tainted infant formula sickens nearly babies chinese milk advice melamine in chinese-manufactured infant formula emergency public health incident response regulation. in: public health law and surveillance statement by fonterra ceo andrew ferrier to media conference anhui province poisonous infant formula incident. in: public health security wen apologises to victims of tainted milk key: cord- -a srympy authors: haines, andy; de barros, enrique falceto; berlin, anita; heymann, david l; harris, matthew j title: national uk programme of community health workers for covid- response date: - - journal: lancet doi: . /s - ( ) - sha: doc_id: cord_uid: a srympy nan an observation that could not be readily explained by the authors. benefits of esett are its doubleblind design and the inclusion of valproate. however, the study did not include infants younger than years, which probably reflects concerns of the potential hepatotoxicity of the drug in this age group. esett has a few limitations. the first limitation is the subjective nature of assessing seizure cessation in the absence of electroencephalography, a feature shared by eclipse and consept. this measure reflects real life and also clinical practice and acumen in an emergency situation. another potential limitation is the conjoint nature of the primary outcome, clinically apparent seizure and improving consciousness. such an endpoint might have influenced the primary efficacy outcome, which has been acknowledged by the authors. additionally, unlike in eclipse and consept, a seizure is assumed to be a convulsive seizure, which was not made explicit in their results. the esett team concluded that levetiracetam, fosphenytoin, or valproate could be used as the first choice, secondline treatment, which mirrors the conclusions of eclipse and consept (levetiracetam or phenytoin). the consept team have taken a further leap of faith, and largely into the unknown, suggesting that clinicians should consider the sequential use of levetiracetam and phenytoin (in any order) before progressing to thirdline management of rapid sequence induction with anaesthesia. the inclusion of valproate in a threedrug sequence would inevitably extend the duration of status epilepticus and risk irreversible neurological sequelae. a more rational first step would be a metaanalysis of these and other relevant randomised controlled trials. , such an analysis would subsequently inform a multidisciplinary debate between, and output from, general paediatricians and paediatric specialists in emergency medicine, neurology, anaesthetics, and intensive care. esett has substantially improved the evidence base in the secondline management of paediatric convulsive status epilepticus. the collective results of these three trials now demand careful interpretation and application of the evidence. i declare no competing interests. the roald dahl neurophysiology department, alder hey children's health park, liverpool, l ap, uk the coronavirus disease (covid ) pandemic threatens to kill large numbers of people in the uk and to place unprecedented demands on the national health service (nhs). the case fatality rate is increased in older people and those with preexisting disease and is reported to be about % in people with covid who are older than years, although this does not take into account the underreporting of mildly affected cases. there are about · million people aged years or older in the uk and many others with health conditions that increase their vulnerability to covid . in the face of the rapid spread of severe acute respiratory syndrome coronavirus , older people and other vulnerable groups are being asked to selfisolate for a considerable time to reduce the risks of infection, with potential adverse effects on physical and mental health. we propose a largescale emergency programme to train community health workers (chws) to support people in their homes, initially the most vulnerable but with potential to provide a longterm model of care in the uk. experience from brazil, pakistan, ethiopia, and other nations shows how a coordinated community workforce can provide effective health and social care support at scale. [ ] [ ] [ ] to respond to the covid pandemic, we suggest that chws would be young people, aged - years, in whom the likelihood of serious consequences from covid is currently deemed low. this demographic is increasingly likely to have been exposed to covid and therefore have acquired immunity. largescale unemploy ment as a consequence of the economic impact of this pandemic makes this a group potentially in need of employment opportunities. despite the uk government's enormous package of benefits designed to retain people in employment, substantial job losses are likely. furthermore, up to medical and physician associate students could be involved who cannot participate in usual clinical placements, possibly until september, , because clinical attachments are being suspended. in brazil, chws are trained over - weeks to deliver a wide range of health promotion activities. this model suggests that a - week basic training programme on covid and on public health surveillance could provide core skills and knowledge, particularly when combined with ongoing training and supervision. online courses are available from some academic institutions on covid and emergency measures to accredit and certificate these courses to agreed standards could be implemented. recruitment and training could be overseen by health education england, commissioned from a higher edu cation provider or devolved to an organisation such as public health england. chws could undertake regular review of vulnerable people at home in person or virtually, depending on need, and when patients become ill chws could undertake simple assessment of the need for more advanced care, reporting to other members of the primary care team, including to the covid health management team that is being commissioned. chws would need to be provided with personal protective and other equipment and trained to follow protocols to assess temperature, blood pressure, and, with the provision of portable pulse oximeters, early detection of severe illness, thus collecting data for clinical and epidemiological purposes. similar protocols are already in place and used by chws in diverse settingseg, as part of the integrated management of newborn and childhood illness. additionally, home visits for vulnerable people would allow chws to assess whether individuals have adequate supplies of food and medicines for long term conditions, are aware of basic hygiene precautions, and whether they have mental health problems. in future, chws might be involved in covid community testing and possibly supporting vaccine trials. over time, chws might also contribute to the management of longterm conditions through monitoring physical and mental health, and reviewing availability and use of medicines. entry criteria could include occupations that provide basic training in first aid or assessing medical emergencies, such as flight attendants, or registration on a health professional training programme. although final year medical students might shortly be deployed in acute hospital settings, other senior medical students could be trained to provide supervision of chws. they could be overseen by public health trainees and ultimately by qualified public health professionals in a pyramidal structure, in collaboration with general practitioners and practice pharmacists. virtual chat rooms could be used for working out solutions to common problems and virtual mentorship. the clinical students could work as volunteers in return for accreditation of valuable experiential learning in community health. this approach would meet a gap in uk undergraduate experience and might become a longterm feature of medical education. for a future scaled workforce, there will be financial implications, but the costs should be affordable. on the basis of the brazilian chw model, estimates of the cost of a scaled chw workforce in england suggest this could amount to about £ · billion per annum for chws. such an amount is a small proportion of the existing nhs budget that is projected to increase in the coming years. some would argue that it is too risky to put chws with only limited training in contact with vulnerable members of society. however, there are risks associated with prolonged wellbeing, and economic stability of women, girls, and vulnerable populations. people whose human rights are least protected are likely to experience unique difficulties from covid . women, girls, and marginalised centring sexual and reproductive health and justice in the global covid- response unmonitored isolation, from the effects of covid , as well as loneliness and mental health deterioration. the risks of using chws in this way could be reduced by supervision, with independent monitoring and evaluative research to identify problems early and correct them. the chws could visit in pairs to reduce the risks. people might resist or be reluctant to be visited by chws, and they could opt out of home visits at any time, but experience with chws in brazil in the past years suggests this would happen rarely. in brazil, chws provide a much needed and relied upon service. chws in brazil have been established for many years, are well integrated into their communities, and provide a wide range of health and social care support activities to each of the - households that they are responsible for. therefore, in brazil, additional roles for preventing the spread of and supporting those infected with covid or in selfisolation could be integrated into the work of chws. much can be learned from countries with successful experiences of radical, largescale workforce interventions. it could be argued that this is an unrealistic proposal and that adapting the existing system or training so many people is too challenging. however, current health and social care systems in the uk are under extreme pressure and could become overwhelmed. in a time of fear, isolation, and growing health inequalities, use of chws for the covid response would boost social coherence and fill gaps that have begun to emerge between health and social care and inperson and virtual access to health care. our proposal for chws would produce a large cadre of people with an understanding of basic epidemiological and public health concepts who could challenge scientific misinformation and explain the rationale for specific health policies and interventions to the public. this approach would also help build a new generation of leaders who can help tackle the complex challenges of our age. efdb is chair of the working party on the environment of the world organization of family doctors. mjh is a nonexecutive director of primary care international. mjh is supported in part by the nw london national institute for health research (nihr) applied research collaboration. imperial college london is grateful for support from the nw london nihr applied research collaboration and the imperial nihr biomedical research centre. the views expressed in this comment are those of the authors and not necessarily those of the nihr or the department of health and social care. we declare no other competing interests. incidence, cause, and shortterm outcome of convulsive status epilepticus in childhood: prospective populationbased study drug management for acute tonic clonic convulsions including convulsive status epilepticus in children advanced paediatric life support: a practical approach to emergencies, th edn epilepsies: diagnosis and management. clinical guideline evidencebased guideline: treatment of convulsive status epilepticus in children and adults: report of the guideline committee of the randomized trial of three anticonvulsant medications for status epilepticus efficacy of levetiracetam, fosphenytoin, and valproate for established status epilepticus by age group (esett): a doubleblind, responsiveadaptive, randomised controlled trial levetiracetam versus phenytoin for secondline treatment of paediatric convulsive status epilepticus (eclipse): a multicentre, openlabel, randomised trial levetiracetam versus phenytoin for secondline treatment of convulsive status epilepticus in children (consept): an openlabel, multicentre, randomised controlled trial randomized controlled trial of levetiracetam versus fosphenytoin for convulsive status epilepticus in children iv levetiracetam versus iv phenytoin in childhood seizures: a randomized controlled trial who. report of the whochina joint mission on coronavirus disease (covid ) the potential contribution of community health workers to improving health outcomes in uk primary care one million community health workers: technical taskforce report brazil's family health strategy: delivering community based primary care in a universal system dalglish sl on behalf of the strategic review study team. towards a grand convergence for child survival and health: a strategic review of options for the future building on lessons learnt from imnci. geneva: world health organization public health education in uk medical schools-towards consensus integrating community health workers in primary care: a solution to the workforce crisis budget : what you need to know delivering cost effective healthcare through reverse innovation health equity in england: the marmot review years on. london: institute of health equity epidemiology-a science for the people key: cord- - etje qs authors: dickens, borame l; koo, joel r; wilder-smith, annelies; cook, alex r title: institutional, not home-based, isolation could contain the covid- outbreak date: - - journal: lancet doi: . /s - ( ) - sha: doc_id: cord_uid: etje qs nan relative to the baseline with no control measures (figure), our models showed that home-based isolation causes an -day delay (iqr - ) in the epidemic peak, with a corresponding reduction of cases (iqr - ) at this peak and cases averted throughout the epidemic (iqr - ). institution-based isolation created a peak delay of days and a reduction of cases ( - ). a total of cases (iqr - ) are averted throughout the epidemic, representing roughly a % reduction in comparison to % reduction through home-based isolation. these results show the need for institution-based isolation to reduce household and community transmission. they also provide theoretical support for the approach successfully implemented in wuhan, where fangcang isolation shelters were established for all infected and potentially exposed individuals. these shelters provided triage, basic medical care, frequent monitoring, rapid referrals, and essential living and social engagements for the wellbeing of those isolated. crucially, the fangcang obviated most of the risk of within-household transmission, which frequently occurs as viral loads can be high for mild infections. home-based isolation, which is reliant on personal in the absence of vaccines, non-pharmaceutical interventions such as physical distancing, intensive contact tracing, and case isolation remain frontline measures in controlling the spread of severe acute respiratory syndrome coronavirus . in wuhan, china, these measures were implemented alongside city lockdown, mass quarantine, and school closure during the coronavirus disease (covid- ) outbreak in january and february, . critical to wuhan's success, cases identified through liberal testing, regardless of symptom profile, were immediately isolated in purpose-built shelters, as delays in isolation from symptom onset increase transmission risk substantially. european countries and the usa have mostly followed these measures, except, in most cases, only people with severe symptoms are being admitted to hospital, whereas people with mild symptoms are asked to self-isolate at home. test kit shortages and limited health-care facility capacity have also led to unconfirmed cases self-isolating at home. compliance with home isolation, however, is partial. in israel, % of people with unconfirmed infection did not self-isolate because they were not financially compensated and because the lay public is not informed on how to keep strict isolation measures at home. we modelled and compared two types of isolation measures: institution-based isolation and home-based isolation. the former is modelled after china, with isolation of confirmed cases in quarantine facilities resulting in no further onward within-household transmission, and the quarantining of contacts with legal enforcement. once quarantined, contact rates are reduced by % in the household and by % in the community. we contrasted this with homebased isolation, modelled after europe and the usa, where home isolation of confirmed cases is the current policy. this approach is assumed to cause a % reduction in contact within the home and a % reduction in contact in the community. contact cases have an overall reduced interaction at an assumed contact rate of %. no reduction in transmission is assumed to occur for asymptomatic infections because asymptomatic cases are not being identified and isolated. we used geodemos-r, an agentbased respiratory illness simulation model that estimates the total number of infections through time and measures the effects of quarantining, physcial distancing, and school closure on a city population. a different calibration procedure, however, was used to estimate the number of infections over time. we assumed a basic reproduction number of for the initial -week phase of the covid- epidemic, with a subsequent decrease in the effective reproduction number due to the implementation of physical distancing control measures. the model represents a large city of million residents, modelled upon the city-state of singapore. compliance, will therefore inevitably lead to increased transmission. although cities within europe and the usa might not be able to create make-shift isolation centres similar to those in wuhan, due to a lack of social acceptability or negative public perceptions, other strategies should be considered to reduce transmission, such as repurposing hotels or dormitories. we urge policy makers in countries with or facing overburdened health-care facilities to consider such measures as countries emerge from lockdowns. isolation, quarantine, social distancing and community containment: pivotal role for old-style public health measures in the novel coronavirus ( -ncov) outbreak deciphering the power of isolation in controlling covid- outbreaks feasibility of controlling covid- outbreaks by isolation of cases and contacts self-isolation compliance in the covid- era influenced by compensation: findings from a recent survey in israel. a cross sectional study of the adult population of israel to assess public attitudes toward the covid- outbreak and self-isolation fangcang shelter hospitals: a novel concept for responding to public health emergencies interventions to mitigate early spread of sars-cov- in singapore: a modelling study comparative estimation of the reproduction number for pandemic influenza from daily case notification data household transmission of sars-cov- covid- : emergency departments lack proper isolation facilities, senior medic warns we declare no competing interests. key: cord- - yiqlg authors: kirschenbaum, daniel; imbach, lukas l; ulrich, silvia; rushing, elisabeth j; keller, emanuela; reimann, regina r; frauenknecht, katrin b m; lichtblau, mona; witt, martin; hummel, thomas; steiger, peter; aguzzi, adriano; frontzek, karl title: inflammatory olfactory neuropathy in two patients with covid- date: - - journal: lancet doi: . /s - ( ) - sha: doc_id: cord_uid: yiqlg nan we report two cases of olfactory neuropathy diagnosed at autopsy in patients with severe acute respiratory syndrome coronavirus (sars-cov- ) infection. one patient experienced anosmia. information about anosmia was not available in the other patient. patient , a man aged years, and patient , a man aged years, both tested positive for sars-cov- . patient was a renal transplant recipient with coronary artery disease and arterial hypertension. he developed progressive respiratory failure due to covid- pneumonia and required mechanical ventilation. he was treated with hydroxychloroquine (total mg). patient was previously diagnosed with severe pulmonary hypertension and was admitted with fever, cough, and increasing dyspnoea as well as loss of taste and smell. he was also treated with hydroxychloroquine (total mg); however, he declined invasive treatment. patient died days after hospital admission; patient died days after hospital admission. patient consent for research was obtained from both patients. postmortem histological analysis of the olfactory epithelium in both patients showed prominent leukocytic infiltrates in the lamina propria and focal atrophy of the mucosa. the histological analysis of olfactory epithelium from both patients is in the appendix. we found a slight predominance of cd -positive t cells over cd -positive b lymphocytes. expectedly, olfactory nerve fibres in the lamina propria were negative for myelin basic protein. however, they showed so-called digestion chambers, which stained positive for cd on immunohistochemistry, suggestive of axonal damage. scattered cd positive leukocytes were consistent with an inflammatory neuropathy; the infiltrates comprised both cd -positive and cd -positive t lymphocytes. cd staining was negative. in both patients, the olfactory tracts showed few isolated cd -positive infiltrates; the olfactory striae were unremarkable. both brains showed perivascular leukocytic infiltrates, predominantly in the basal ganglia and intravascular microthrombi. anosmia is a common symptom in patients with covid- . inflammation of the olfactory system and anosmia have been reported in other viral diseases, as was age-related atrophy of the olfactory epithelium. the observed neuritis is most likely associated with axonal damage, as olfactory fila lack myelin. consistent with previous reports, the olfactory tracts were largely unremarkable, except for a few endoneurial leukocytes in both patients. sars-cov- induced damage might be medi ated by viral entry through its receptor angiotensin converting enzyme and the transmembrane serine protease , which are ex pressed in non-neural cells of the olfactory epithelium. it is unclear whether the observed inflammatory neuropathy is a result of direct viral damage or is mediated by damage to supporting non-neural cells. due to the rapidly evolving pandemic, unravelling the neuroinvasive properties of sars-cov- will have major implications for patients with covid- . ps anosmia and dysgeusia in patients with mild sars-cov- infection the olfactory nerve: a shortcut for influenza and other viral diseases into the central nervous system olfaction and aging: a mini-review olfactory system and demyelination neuropathological features of covid- sars-cov- receptor ace is an interferonstimulated gene in human airway epithelial cells and is detected in specific cell subsets across tissues key: cord- -gwhb e q authors: khan, ali s; lurie, nicole title: health security in : building on preparedness knowledge for emerging health threats date: - - journal: lancet doi: . /s - ( ) - sha: doc_id: cord_uid: gwhb e q nan ideas, information, and microbes are shared worldwide more easily than ever before. new infections, such as the novel infl uenza a h n or middle east respiratory syndrome coronavirus, pay little heed to political boundaries as they spread; nature pays little heed to destruction wrought by increasingly frequent natural disasters. hospital-acquired infections are hard to prevent and contain, because the bacteria are developing resistance to the therapeutic advances of the th century. indeed, threats come in ever-complicated combinations: a combined earthquake, tsunami, and radiation disaster; black outs in skyscrapers that require new thinking about evacuations and medically fragile populations; or bombings that require as much psychological profi ling as chemical profi ling. response requires up-to-date laboratories with genetic sequencing capabilities for infectious agents and rapid detection methods for chemical and radiological threats, nimble medical and epi demiological response units, and an alert and prepared workforce. these complex and interconnected problems have spurred innovation across government to create interconnected solutions. increasingly, the usa is building national capabilities to improve health security, which is defi ned as a state in which the nation and its people are prepared for, protected from, and resilient in the face of health threats. to ensure a nation's health security entails preventing, protecting, mitigating, responding to, and recovering from all hazards that adversely aff ect health, requiring strengthening health and response systems at the local, state, and national levels. these capabilities are being built to address a wide range of hazards so that a strong base of readiness for any threat is developed. public health advances that have resulted in a more resilient and prepared nation and that have led to such system strengthening at all levels of government have been described, and include improvement and coordination of public health infrastructure through the national incident management system (nims), expansion of the strategic national stockpile (sns), upgrading of medical care and countermeasures capabilities, and improvement of laboratory expertise and capacity. we describe continued progress in the ongoing commitment to keep people in the usa healthy and safe (panel ). in an emergency, capabilities from all sectors are used to mitigate the acute event. however, the public health consequences of an event are not always visible, and health expertise has historically been conspicuously absent from emergency management. over the past decade, awareness has grown that health is part of almost every event; much progress has been made in emergency management to use public health expertise in planning, response, and recovery. this integration is core to national activities to promote health security. nims was established in as a comprehensive, systematic, principle-driven approach to management of emergencies of all causes and sizes. the department of health and human services (hhs) uses, supports, and promotes nims with local and state health departments through both the centers for disease control and prevention's (cdc) public health emergency preparedness programme and the offi ce of the assistant secretary of preparedness and response's hospital preparedness program to be used whether responding to daily incidents or natural disasters. as seen in the boston marathon bomb attack on april , , these investments and use of nims are very worthwhile. in boston, the city's public health commission oversees citywide emergency response, requiring close integration of emergency response and public health. immediately after the bombings, medical and health department personnel began treating more than injured people, and coordinated hospital transportation for people-all within min. boston's health authorities credited their quick response to robust exercise and planning, the city's strong interagency partnerships, and support from the state and federal government. this support included use of a capabilities-based approach to preparedness, with concrete measures of performance (panel ). part of the city's training also included a seminar in with doctors from india, spain, israel, the uk, and pakistan-countries that had managed blast injury terror attacks. on the day of the boston marathon bomb attack, local hospitals were able to draw from lessons learned in those and other exercises to respond with great speed and success. additionally, hhs used a new mental and behavioural health concept of operations to deploy federal mental health responders. this mental health framework is an integral part of eff orts throughout hhs to identify, study, and facilitate activities that promote resilience and recovery in communities across the nation. public health information sharing has improved rapidly. so-called digital epidemiology has enabled practitioners and researchers to use electronic databases and information to enhance traditional surveillance methods. in , hhs launched its now trending developer challenge to create programmes for health departments to monitor social media during an outbreak. the challenge resulted in mappyhealth, a twitter monitoring programme now being piloted for digital health surveillance around the country, helping offi cials examine real-time events. digital surveillance was used by public health workers during the infl uenza a h n outbreak to monitor chinese social media for events, myths, and concerns. improvements in digital surveillance have also improved public communication. local health departments that can monitor twitter can give immediate feedback to correct dangerous mistruths that are contagious on social media. cdc's @cdcemergency twitter feed, fi rst established during the infl uenza a h n response, now reaches more than · million people with emergency health information. during the japan nuclear disaster response, twitter was used to correct the dangerous myth that healthy people in the usa should take potassium iodide to prevent harm from radiation. these technological advances have been developed in parallel with diplomatic information sharing advances. who's international health regulations and multilateral collaborations, such as the global health security initiative, have provided a framework for international cooperation during public health disasters. improved capacity and the high priority placed on rapid information sharing led to china's timely reporting in of clinical and genetic information about infl uenza a h n and early sharing of isolates, by contrast with the response to sudden acute respiratory syndrome (sars) a decade earlier, when information was slower to emerge. , cloud computing allowed for distribution of validated epidemiological and analytical programmes to the global community, while allowing china to share genomic sequences, providing the opportunity for immediate actions to analyse the viral genome and develop vaccine candidates. the public health emergency medical countermeasure enterprise was established by hhs to coordinate federal eff orts and build new ways to respond to st century health threats-from discovery to deployment. the programme generated a government-wide strategic plan to build all-hazards capabilities and countermeasures throughout federal public health agencies. one cornerstone of the programme is the development of new medical countermeasures. since july, , seven products for anthrax, botulism, and infl uenza have received approval from the food and drug administration. the sns contains substantial formulary to provide prophylaxis or treatment to address the deliberate dissemination of anthrax, plague, botulism, or tularaemia, and enough smallpox vaccine to immunise every person in the usa. botulism antitoxin, anthrax immune globulin, and vaccinia immune globulin are also routinely made available for distribution for routine public health indications as needed. sns materials can be delivered anywhere within the usa within h. furthermore, the hhs medical care and countermeasures strategy-which includes a focus on development of the next generation of infl uenza vaccines, diagnostics, and novel antivirals-has also led to advances in vaccines for seasonal infl uenza, and better prepared the nation for the next pan demic. for example, the us government now has licensed cell-based and recombinant seasonal infl uenza vaccines and have stockpiled pre-pandemic cell-based vaccine. network and can test for biological agents. regional chemical laboratories are also able to measure human exposure to toxic chemicals through tests of clinical specimens. • the select agent regulations, updated in , came into full eff ect in april, . the regulations prioritised selected agents and toxins on the basis of risk to the public, established suitability standards for people with access to the most threatening (tier ) agents and toxins, and established personal reliability measures to improve biosafety and biosecurity. • the national disaster medical system has improved how it organises and deploys more than of its nationally distributed disaster medical assistance teams, mortuary response teams, and veterinary response teams, in addition to other specialised units that provide medical response surge during disasters and emergencies through on-scene medical care, patient transport, and the delivery of defi nitive care through its participating hospitals. • the biomedical advanced research and development authority (barda) is mandated to support the advanced development of medical countermeasures, and has built a pipeline of more than novel drugs or diagnostics for chemical, biological, radiological, and nuclear threats and pandemic infl uenza. seven of these products have received approval from the food and drug administration. barda has provided new products under project bioshield that can be distributed in a public health emergency. • the strategic national stockpile was authorised and expanded, ensuring the availability of key medical supplies. all states have plans to receive, distribute, and dispense these assets. increasingly, the usa seeks to develop products that can address countermeasure requirements and also day-to-day needs. as a result, these government investments in products such as next-generation antimicrobials for biological threats can be supported by the market to address routine public health problems, such as antimicrobial resistance. in addition to storing these medical countermeasures, the sns has established a nationwide readiness programme with metropolitan areas in its cities readiness initiative. cities receive technical assistance in developing plans to receive, distribute, and dispense medical assets, and must plan to respond to a large-scale bioterrorist event within h. this initiative refl ects the value of having all the components of the system work together: research scientists work alongside logistics experts to ensure that as they build new life-saving products, others are making sure that they can get them to the right place, under the right conditions, in the right amount of time. the ndms is made up of more than citizen responders, including physicians, mid-level providers, nurses, emergency medical service personnel, and leadership staff ; and civilian hospitals across the country that can support the defi nitive care for patients who are evacuated from an aff ected area of all kinds of hazards. federal medical stations, components of which are also stored in the sns, can be deployed and staff ed by the us public health service and ndms medical personnel. after hurricane sandy, these stations were deployed along with more than mobile fi eld care sites to provide both human and animal care. these resources provided relief for overworked local medical responders and facilities, and helped community members maintain access to critical services. multidisciplinary medical teams were able to assess and treat both acute and chronic medical needs, and either discharge or transfer patients for further care as necessary, helping to relieve the medical surge that the local hospitals were experiencing. the teams also assisted responders who got sick or injured in going back to work quickly, strengthening community resilience. cdc and hhs have supported public health laboratories around the country since the mid- s, through epidemiology and laboratory capacity-building cooperative agreements and the laboratory response network (lrn). the -member lrn, founded in , assures standardised equipment, reagents, and protocols for testing, quality assurance and quality control, and result messaging. funding has gone towards renovation of old state and local public health laboratory facilities, purchasing of state-of-the-art testing equipment, and paying for more than laboratory worker positions each year. nowadays, lrn laboratories can undertake rapid tests for high-priority biological agents such as those that cause anthrax, smallpox, and plague. receipt of test results within hours, not days, is crucial in the event of a biological or chemical attack. state laboratories showed their response capacity and the benefi ts of these investments during the multistate fungal meningitis outbreak, during which around people were infected and more than killed by contaminated spinal and paraspinal steroid injections. the tennessee department of health identifi ed and raised the alarm on the initial cluster of cases. the virginia department of health and state public health laboratory identifi ed a rare fungal pathogen, exserohilum rostratum, which contaminated the steroid injections-a critical discovery. the michigan department of community health identifi ed the fi rst case of a joint infection from the injections. these fi ndings aided the response in several ways. tennessee's actions to identify the cluster led to a nationwide patient notifi cation eff ort so that cases were quickly discovered and treated. by identifi cation of the fungus involved, time was saved in developing specifi c diagnostic, patient management, and treatment guidelines. the michigan discovery of the joint infection led to instructions for doctors to look for medical complications that were related to the injections. the department of health and human services (hhs) identifi ed the following public health and health-care preparedness capabilities (shown in their corresponding domains) as the basis for state and local public health and health-care preparedness. health-care coalitions supported by hhs helped states to assist hospitals in managing the surge of patients. these enhancements in our national public health laboratory system capabilities have helped to support the development of laboratories worldwide. in this interconnected world, fostering this and the other public health preparedness capabilities overseas is crucial to us health security. hhs has worked to build infrastructure and provide technical assistance with partner countries in asia, africa, and latin america. as a result, us partners are building the scientifi c capacity to detect, contain, and respond to novel threats before they become global threats. bioterrorism, pandemics, and other global threats to the nation's health security remain major concerns. we must ensure that lessons learned locally, such as those of the boston marathon bombing or response to hurricane sandy, are shared and implemented widely in us states and cities with adequate funding and support. much work remains to make the eff orts and improvements of the past few years integral components of routine health systems, addressing existing gaps in preparedness, and to duplicate these eff orts globally as part of the new international global health security agenda in support of the international health regulations. all this work has to be accomplished in the midst of substantial decreases in federal and state funding for public health and health-care preparedness. in view of the challenging fi scal environment, additional progress will need increased emphasis on a risk-based approach and focus on a very limited number of priorities. one of the most pressing priorities is meeting the needs of vulnerable populations who tend to have poor health outcomes during and after disasters. although some innovative eff orts have been launched at hhs to increase access to federal data to address the needs of vulnerable populations, this population is often not included in emergency planning processes despite their disproportionate vulnerability and numbers. they include a large part of society, not limited to children; elderly, poor, and disabled people; and those not fl uent in english. although the public health community is aware of this need and many important eff orts are being made across the country, [ ] [ ] [ ] we need more strategies to locate, engage, and communicate with vulnerable populations and make them the focus of our preparedness planningnot the annex. addressing the needs of these populations and other related eff orts to foster better personal and community preparedness are concrete measures to create resilient communities. this shared responsibility for resiliency is implicit in the all-community approach to ensure us health security. previous major disasters and mass casualty events drew attention to continued stress points for health-care services including insuffi cient back-up emergency power and decision points for evacuating patients versus sheltering in place; shortages of emergency medical services and medical supplies and insuffi ciently trained staff ; and the inability to refi ll prescription medications. the cornerstone of eff orts to improve the health-care delivery system's ability to surge and be resilient has been to establish and sustain health-care coalitions. establishment of broad-based health-care coalitions are a solid beginning, but this approach will be successful only if we learn from and not just record lessons from previous disasters. eff orts should incorporate changes on the basis of these lessons, and include robust integrated planning and exercising of the health-care and public health systems that are coordinated with emergency management. we need to foster improved and expanded stakeholder engagement in health-care coalitions with increased inclusion of emergency medical services, public safety offi cials, and other crucial infrastructure partners such as the power and water sectors. information systems will be critical in helping these coalitions to work together, share information and resources, and coordinate a system-wide response. additionally, alternative models are needed for fi nancing both preparedness and response activities. other priorities include embracing new technology for disease monitoring and real-time information sharing; improving the evidence base; expanding preparedness principles to include climate disruption; and encouraging even more cross-sector integration between public health, health care, emergency management, and, especially, the private sector. these are just a few necessary eff orts across public health agencies that seek to make americans more resilient and prepared. building on this integrated and systematic approach to health security will strengthen us health security for decades to come. us department of health and human services. national health security strategy public health preparedness and response in the usa since / : a national health security imperative public healthspecifi c national incident management system trainings: building a system for preparedness public health workers at center of boston bombing response: preparedness pays off during crisis digital epidemiology infl uenza a (h n ) and the importance of digital epidemiology the dynamics of health behavior sentiments on a large online social network the h n infl uenza virus in china-changes since sars arms race: getting ahead of killer microbes us centers for disease control and prevention. multistate fungal meningitis outbreak investigation the critical role of state health departments in the us fungal meningitis outbreak: key eff orts asph/cdc vulnerable populations collaboration group preparedness resource kit applying community engagement to disaster planning: developing the vision and design for the los angeles county community disaster resilience initiative responding to the deaf in disasters: establishing the need for systematic. training for state-level emergency management agencies and community organizations both authors contributed equally to the writing and editing of this viewpoint, and approved the fi nal draft. we declare no competing interests. we thank vivi abrams siegel for research, drafting the initial outline, and editorial assistance, and kacey wulff for editorial assistance. key: cord- -ykko al authors: takian, amirhossein; raoofi, azam; kazempour-ardebili, sara title: covid- battle during the toughest sanctions against iran date: - - journal: lancet doi: . /s - ( ) - sha: doc_id: cord_uid: ykko al nan number of casualties. despite who and other international humanitarian organisations dispatching supplies and medical necessities, the speed of the outbreak and the detrimental effects of sanctions have resulted in reduced access to life-saving medicines and equipment, adding to the health sector's pre-existing requirements for other difficult health conditions. it is shameful that besides the lives lost to this deadly virus, extreme sanctions limit access to necessary materials and therefore kill even more iranian people. although sanctions do not seem to be physical warfare weapons, they are just as deadly, if not more so. jeopardising the health of populations for political ends is not only illegal but also barbaric. we should not let history repeat itself; more than half a million iraqi children and nearly venezuelans were killed as a result of un security council and us sanctions in and - , respectively. the global health community should regard these sanctions as war crimes and seek accountability for those who impose them. given the covid- pandemic and its alarming outcomes in iran, the international community must be obliged to stand against the sanctions that are hurting millions of iranians. it is essential for the un security council and the usa to ease, albeit temporarily, the barriers to providing life-saving medical supplies to iran. in the future, the global community must anticipate possible impacts of sanctions on humanitarian aid and move to prevent further disasters from happening. viruses do not discriminate, nor should humankind. introduction of preventive measures such as social distancing to reduce the pace of the spread, providing valuable time for upgrading of the medical services, and preparing the community. if the use of the term pandemic is delayed too long, the declaration of the pandemic could convey a message to the public that the authorities have lost control, generating irrational panic reactions. since it is expected, and even perhaps desirable, that the public experience some fear during a pandemic, an early declaration of a pandemic might be helpful in mitigating panic. recruiting public cooperation is much more feasible when the society in general and the health services in particular are not yet under considerable pressure, and there is time for appropriate explanations to the public as to how the pandemic will be controlled. the question remains as to what is the optimal timing for declaring a pandemic. following the h n pandemic, morens and colleagues provided useful criteria for defining a pandemic. they included the following components: the cause should be a new virus that has not circulated in humans previously, the disease should be widespread geographically, there should be clear person-to-person spread, and outbreaks should be explosive in nature, with a relatively high casefatality rate. it seems to me that for some time, the covid- outbreak met all these criteria. since there continues to be a lack of consensus about when it is appropriate to use the term pandemic, i suggest that a multi-disciplinary group of epidemiologists, infectious disease specialists, risk communicators and health administrators be convened to create new, clearer, expanded definitions of the terms outbreak, epidemic, and pandemic. i declare no competing interests. the economic loss caused by the spread of covid- in iran coincides with the ever-highest politically induced sanctions against the country. although various sanctions have been in place for the past four decades, since may, , the unilateral sanctions imposed by the usa against iran have increased dramatically to an almost total economic lockdown, which includes severe penalties for non-us companies conducting business with iran. the iranian health sector, although among the most resilient in the region, has been affected as a consequence. all aspects of prevention, diagnosis, and treatment are directly and indirectly hampered, and the country is falling short in combating the crisis. lack of medical, pharmaceutical, and laboratory equipment such as protective gowns and necessary medication has been scaling up the burden of the epidemic and the www.thelancet.com vol march , of the disease and evidence pertaining to effective public health interventions is increasingly available. however, this is only advantageous if we incorporate the best available evidence from observations elsewhere and use the time this affords us to refine a comprehensive response based on input and scrutiny from a broad base of scientific experts. with the uk increasingly becoming an outlier globally in terms of its minimal social distancing populationlevel interventions, transparency is key to retaining the understanding, cooperation and trust of the scientific and health-care communities as well as the general public, ultimately leading to a reduction of morbidity and mortality. we declare no competing interests. most other countries are responding globally, including elsewhere in europe. as the government has stressed, it is imperative to delay and flatten the epidemic curve to ensure the national health service can cope. this is particularly essential for the uk, which only has · hospital beds per population, fewer than in italy ( · per ), france ( · ), and germany ( · ). initial data from italy have shown that - % of actively infected patients with covid- required intensive care during the first days of march, . it is not clear how the uk's unique response is informed by the experiences of other countries, particularly those that have achieved relative control over the virus as a result of widespread testing, contact tracing, and state-imposed social distancing measures, such as singapore, hong kong, taiwan, and south korea. the who-china joint mission on coronavirus disease shows very clearly that only immediate and decisive public health responses worked to prevent or delay hundreds of thousands of cases in china, and who has advised that it is vital to tackle the virus at the early stages with social distancing. we welcome the uk government's announcement that the modelling and data considered by its scientific advisory group for emergencies will be published in the future. however, we request that the government urgently and openly shares the scientific evidence, data, and models it is using to inform current decision making related to covid- public health interventions within the next h and then at regular intervals thereafter. time is a luxury we simply do not have as we face this critical public health crisis. as we have already seen in other countries, a matter of a few days can prove critical in terms of saving lives and avoiding health system collapse. as the uk was not the first country to face a covid- outbreak, knowledge the uk government asserts that its response to the coronavirus disease (covid- ) pandemic is based on evidence and expert modelling. however, different scientists can reach different conclusions based on the same evidence, and small differences in assumptions can lead to large differences in model predictions. our country's response to covid- is demonstrably different from how who-directorgeneral-s-opening-remarks-at-the-mediabriefing-on-covid iranian ministry of health and medical education so near, so far: four decades of health policy reforms in iran, achievements and challenges assessment of the effects of economic sanctions on iranians' right to health by using human rights impact assessment tool: a systematic review how countries in crisis can prepare for a coronavirus epidemic who. who team arrives in tehran to support the covid- response impacts of international sanctions on iranian pharmaceutical market the harsh effects of sanctions on iranian health who. novel coronavirus ( -ncov) situation report - we declare no competing interests. key: cord- - nc d v authors: aylward, r bruce; acharya, arnab; england, sarah; agocs, mary; linkins, jennifer title: global health goals: lessons from the worldwide effort to eradicate poliomyelitis date: - - journal: lancet doi: . /s - ( ) - sha: doc_id: cord_uid: nc d v the global polio eradication initiative was launched in . assessment of the politics, production, financing, and economics of this international effort has suggested six lessons that might be pertinent to the pursuit of other global health goals. first, such goals should be based on technically sound strategies with proven operational feasibility in a large geographical area. second, before launching an initiative, an informed collective decision must be negotiated and agreed in an appropriate international forum to keep to a minimum long-term risks in financing and implementation. third, if substantial community engagement is envisaged, efficient deployment of sufficient resources at that level necessitates a defined, time-limited input by the community within a properly managed partnership. fourth, although the so-called fair-share concept is arguably the best way to finance such goals, its limitations must be recognised early and alternative strategies developed for settings where it does not work. fifth, international health goals must be designed and pursued within existing health systems if they are to secure and sustain broad support. finally, countries, regions, or populations most likely to delay the achievement of a global health goal should be identified at the outset to ensure provision of sufficient resources and attention. the greatest threats to poliomyelitis eradication are a financing gap of us$ million and difficulties in strategy implementation in at most five countries. increasing travel and globalisation of commerce has farreaching implications for health. , substantial attention has been given to the threats that globalisation poses to the management of infectious diseases, but less to its opportunities. , heightened international awareness of the burden and threat of many infectious diseases has spawned partnerships and alliances to coordinate additional resources for their control. though the most cited example of international collaboration is the global fund to fight aids, tuberculosis and malaria, it is only the most recent. perhaps the best example of such collaboration was the successful international effort to eradicate smallpox in the s and s. more recently, coordinated efforts to combat global health threats have included the global partnership to stop tb, the roll back malaria initiative, and the global alliance for vaccines and immunization (gavi). innovative strategies have also been established to tackle non-communicable diseases, most notably through the framework convention on tobacco control. common to these initiatives has been the conviction that coordinated international action is in the interest of all countries. it has even been argued that these initiatives are "global public goods for health". the effort to eradicate poliomyelitis is one such initiative, since once eradication has been achieved, everyone will be protected from the virus and one person's protection will not reduce that available to others. , in this paper, we assess the politics, production, financing, and economics of poliomyelitis eradication to identify lessons that might be relevant to the pursuit of other global health goals. the decision to pursue eradication the successful conclusion of the international smallpox eradication campaign in created substantial interest in further eradication efforts. however, enthusiasm was countered by concerns that targeted objectives could compromise efforts to develop strong primary health-care systems and by doubts about the technical feasibility of eradicating any organism after smallpox. , the most important factor in overcoming scientific concerns was the interruption of poliovirus transmission in large areas of the americas by use of a four-pronged strategy. the leadership for launching a global poliomyelitis eradication initiative was secured at a meeting in march, , at which the who director-general was convinced of the merit of such an effort. , months later, the world health assembly, consisting of the ministers of health of all member states, unanimously adopted a poliomyelitis eradication resolution. the eradication goal was subsequently reviewed and endorsed by the world summit for children-the largest ever gathering of heads of state. leaders from lowincome, middle-income, and high-income countries have continued to reaffirm their commitment to poliomyelitis eradication through resolutions adopted in forums such as the organization of african unity, the south asian association for regional cooperation, and g summits. [ ] [ ] [ ] implementation of strategies by the end of , every country had introduced the who-recommended poliomyelitis eradication strategies or a variant thereof, but the effort required to do so was correlated inversely with countries' incomes. in the few high-income countries in which poliomyelitis cases were reported in (eg, france and spain) elimination of the virus was relatively straightforward because of temperate climate, higher vaccine effectiveness in such settings, high levels of sanitation, and strong health systems. by contrast, eliminating endemic poliomyelitis from low-income countries has required massive efforts sustained for - years. implementation of national immunisation days (nids) has been a huge challenge; in china and india, for example, about million and million children, respectively, were immunised in a few days-the achievement was repeated month later, and then annually global health goals: lessons from the worldwide effort to eradicate poliomyelitis the global polio eradication initiative was launched in . assessment of the politics, production, financing, and economics of this international effort has suggested six lessons that might be pertinent to the pursuit of other global health goals. first, such goals should be based on technically sound strategies with proven operational feasibility in a large geographical area. second, before launching an initiative, an informed collective decision must be negotiated and agreed in an appropriate international forum to keep to a minimum long-term risks in financing and implementation. third, if substantial community engagement is envisaged, efficient deployment of sufficient resources at that level necessitates a defined, time-limited input by the community within a properly managed partnership. fourth, although the so-called fair-share concept is arguably the best way to finance such goals, its limitations must be recognised early and alternative strategies developed for settings where it does not work. fifth, international health goals must be designed and pursued within existing health systems if they are to secure and sustain broad support. finally, countries, regions, or populations most likely to delay the achievement of a global health goal should be identified at the outset to ensure provision of sufficient resources and attention. the greatest threats to poliomyelitis eradication are a financing gap of us$ million and difficulties in strategy implementation in at most five countries. for more than years. , because of the huge numbers of people and vehicles required to implement nids, governments of many countries have drawn heavily on the private sector, as well as on ministries of information, transport, and defence, among others, to help reach all children. people crossing borders can transmit poliomyelitis during the interval between nids being held in one country and in its neighbour. recognising this factor, many countries have synchronised their nids (figure ). in operation mecacar for example, asian, european, and middle eastern countries immunised million children in april and may, , and repeated the activity each year for years. similar coordination followed in south asia, west africa, , and then central africa, where the conflict-affected countries of the democratic republic of the congo, angola, congo, and gabon synchronised three rounds of nids in july-september, , to immunise million children. , by the year , all poliomyelitis-affected countries were reporting standardised data for acutely paralysed children and surveillance performance to who either weekly or monthly. central to this surveillance capacity has been a worldwide laboratory network for enterovirus diagnosis that now comprises facilities. even in conflict-affected areas such as afghanistan, the democratic republic of the congo, and somalia, surveillance in was nearing the international standard that will be required for poliomyelitis-free certification. coordination though poliomyelitis eradication activities have been led, coordinated, and implemented by the governments of poliomyelitis-affected countries, the support of a publicprivate partnership has been essential. this partnership, spearheaded by who, rotary international, the us centers for disease control and prevention (cdc), and unicef has facilitated the inputs of donor governments and a vast array of other organisations. the most remarkable of these partners is rotary international, a private-sector service organisation, which will have contributed nearly us$ million of its own resources by the end of in addition to mobilising much of the money contributed by governments. to coordinate this partnership, mechanisms were established at global, regional, and country levels for strategic planning, policy development and priority setting, resource mobilisation, and financing. additional mechanisms were established to manage the laboratory network and govern the process for eventually certifying the world as free from poliomyelitis. direct costs a conservative estimate of the financial and in-kind expenditures in poliomyelits-endemic countries was generated on the basis of the number of hours worked per country to implement nids, the most expensive and labour-intensive eradication strategy. without wishing to diminish the broader significance of this largely volunteer effort to the success of the initiative, for the purposes of economic evaluation it has been valued by use of labour market rates from the statistical database for the year world development indicators. on the basis of these calculations, poliomyelitis-endemic countries will have contributed at least $ · billion in wages alone between and . this figure does not include substantial government and private-sector resources to pay for petrol, social mobilisation, training, and other costs. many of these people were government employees who were temporarily released from regular duties. between and , external sources will have provided at least $ billion to poliomyelitis-endemic countries. of more than external donors to date, have already contributed more than $ million and at least $ million (table ) ; some, such as rotary international, are not traditional sources of overseas development assistance. central tracking of resource requirements and funding flows, and multilateral and bilateral funding mechanisms, have enabled efficient accommodation of the needs of donors and recipient countries. the total cost of poliomyelitis eradication during - will be more than $ billion. a cost-benefit analysis of the paho regional programme noted ". . . polio eradication appeared economically justified solely in terms of reduced treatment costs, irrespective of reduced pain, suffering and incapacitation", calculating that the net present value of discounted savings during a -year period from the start of the campaign was $ · million. a similar analysis for worldwide eradication throughout - showed that even when including only the savings in direct costs for treatment and rehabilitation, " . . . the 'break-even' point at which benefits exceeded costs was the year , with a saving of us$ million by the year ". the cost-effectiveness of global poliomyelitis eradication was reassessed for - to analyse the potential effects of poliomyelitis immunisation policies that might be adopted after worldwide certification of eradication. from an economic perspective, the best-case scenario was assumed to be cessation of routine immunisation with the oral poliomyelitis vaccine as soon as possible after interruption of wild poliovirus. the worst-case scenario was assumed to be replacement of this vaccine by universal childhood immunisation with the more expensive inactivated poliovirus vaccine to reduce the risk of vaccine-associated paralytic poliomyelitis or poliomyelitis outbreaks due to a circulating vaccine-derived poliovirus. [ ] [ ] [ ] in this analysis, even in the worst-case scenario, poliomyelitis eradication would save money in all countries, apart from low-income countries where the cost per discounted disabilityadjusted life-year (daly) saved would still be low, at about $ (table ) . the world health assembly resolution that launched the global polio eradication initiative stated that eradication should be pursued in ways that strengthened the delivery of primary health-care services in general and immunisation programmes in particular. what has been the effect of poliomyelitis eradication activities on the delivery of specific health services or the development of health systems? three irrefutable benefits have included widespread vitamin a distribution, enhanced global surveillance capacity, and improved worldwide cooperation between enterovirus laboratories. , by distributing vitamin a supplements during poliomyelitis nids, an estimated childhood deaths were averted during - alone, and the value of using immunisation contacts to deliver micronutrient supplements was widely reinforced. , the surveillance capacity developed for poliomyelitis eradication has also been used to detect and respond to outbreaks of diseases such as measles, meningitis, cholera, and yellow fever. the poliomyelitis-eradication infrastructure and capacity was also used to assist in the international effort to control severe acute respiratory syndrome (sars). however, effects on routine immunisation services have been controversial. [ ] [ ] [ ] the poliomyelitis initiative has invested heavily in physical and human resources for routine immunisation. the cold chain, communications, and transport capacity have been replaced or refurbished in many low-income countries, especially in sub-saharan africa, and tens of thousands of people have been trained or retrained worldwide in giving vaccinations. questions have been asked, however, as to whether short-term disruptions by nids in the delivery of routine immunisation and other services will have long-term consequences. evaluation of the effect on health systems has been hampered by a lack of credible baseline data, the absence of control groups, and the concurrent implementation of major health-system reforms, such as decentralisation and sector-wide approaches. , most commentators agree that there are positive synergies between poliomyelitis eradication and development of health systems, but opportunities have yet to be fully exploited. , status of eradication and risks to completion when the world health assembly voted to eradicate poliomyelitis in , more than countries (defined by year geographic borders) on five continents were known or suspected to have indigenous transmission of wild poliovirus (figure ). though only cases were reported worldwide that year it is estimated that more than children were actually paralysed. , more than % of the reported cases in were in low or lower-middle income countries and half were in the asian subcontinent-mostly in india. outside the americas, few areas were free of poliomyelitis-mainly industrialised countries and small island nations. by the end of , poliomyelitis was on the brink of eradication, with only ten countries in which it was endemic and virologically confirmed cases that year. by the end of , only seven countries-the lowest number ever-were known to have endemic poliomyelitis (figure ). the total number of cases exceeded that of , however, because of marked increases in india and nigeria ( figure ). in india, the increase was due to an epidemic that originated in the northern state of uttar pradesh and spread rapidly to adjoining and distant states, many of which had been free from poliomyelitis for some years. by contrast, the increase in nigeria was largely due to improved reporting in the north of the country. complete eradication of poliovirus transmission will require overcoming challenges at national and international levels. at the national level, it will be essential to close gaps in the quality of supplementary immunisation activities in the six states or provinces of india, nigeria, and pakistan that accounted for % of poliomyelitis cases in . northern india in particular poses challenges, since the combination of a weak health infrastructure, fragile political alliances and, to a lesser degree, suspicion of government services by minority communities, has hampered efforts to mobilise all sectors of society and reach every child. in parts of afghanistan, eastern angola, and the mogadishu area of somalia, continued improvement in access to children is needed to break the few remaining chains of virus transmission in these areas. internationally, the main challenge will be closing the $ million funding gap for activities planned for - , while maintaining political visibility of, and commitment to, the eradication of a disappearing disease. increasingly, international discussion and debate has focussed on future poliomyelitis immunisation policy. from the outset of the eradication initiative, much of the attraction of this international health goal has been the argument that its achievement would reap economic as well as humanitarian benefits. these economic benefits would accrue mainly if and when poliomyelitis immunisation could stop. that these economic benefits could accumulate in perpetuity underpinned the arguments of the champions of poliomyelitis eradication, engaged political leadership, and mobilised stakeholders, in particular those from the private sector. however, several factors have complicated the development of, and consensus on, future immunisation policy. these factors range from increasing evidence that vaccine-derived polioviruses can, albeit rarely, regain the capacity to circulate and cause outbreaks, to increasing concerns about the use of biological agents. [ ] [ ] [ ] [ ] although cessation of immunisation with the oral poliovirus vaccine remains a major objective of the eradication initiative, much work is required to establish the scientific soundness, operational feasibility, and economic rationale for the strategies that have been proposed to achieve this end. in this review of the poliomyelitis eradication initiative, we have derived six lessons that could assist the planning and pursuit of worldwide health goals, whether global public goods for health or other health efforts in which international collective action might be warranted. first, and perhaps foremost, is the need for proven tools and technically sound strategies. additionally, their operational feasibility should be demonstrated conclusively on a large geographical scale, under as many conditions as possible, before attempting to launch a worldwide effort. international consensus on poliomyelitis eradication was achieved only after it had been shown in the americas during the s that strategies could be massively scaled i n d i a n i g e r i a p a k i s t a n a f g h a n i s t a n up and implemented in regions with extremely weak health systems, or that were affected by conflict, or both. such proof is essential for obtaining and sustaining the political and financial support required for the - years needed to pursue most international health goals. the second lesson is that any international health goal should be strongly endorsed at the highest possible level, arguably the world health assembly. such endorsement will be essential for dealing with the debate and concerns that will arise as the programme is scaled up and opportunity and other costs are increasingly evident and better understood. although prominent champions had a major role in promoting global eradication of poliomyelitis, the decision to launch the initiative followed debate at the world health assembly. despite consensus at that forum, an often heated debate has flared as to whether the opportunity costs of eradication outweigh benefits. of especial concern has been whether the deployment of resources has compromised the strengthening of health systems in resource-poor countries, or limited their capacity to control other diseases. it has also been noted that some delegates to the assembly in might not have made a truly informed decision on the launching of the initiative, since there had been no clear statement on resource requirements or strategies. these debates have contributed to the programme's chronic funding gap, and to the late introduction of key strategies in some countries. the cost-effectiveness analyses summarised in this paper suggest that all countries stand to benefit from this investment irrespective of income level, but this assessment is not universally accepted. a third lesson is that efficient management is needed to achieve the necessary scale of collective action. two major factors facilitated participation in the eradication initiative: a well defined, time-limited ( - days) demand on the community, and sufficient resources to enable the community to implement activities. ensuring sufficient resources required moving beyond building an international health partnership to managing one efficiently. critical to achieving efficiency was the use of common strategic plans, clear roles and responsibilities, and national and international forums to coordinate financing, human resources, and institutional arrangements. fourth, given the amount of external financing required to achieve international health goals, strategies will usually necessitate targeting political decision-makers, by means such as professional lobbying firms and international forums to establish the commitment of heads of state. because all countries will benefit economically from poliomyelitis eradication, rotary international, as part of its advocacy strategy, calculated so-called fair shares of the total budget to be financed by each major donor country, based on their contributions to who's regular budget. however, only of the who member states that traditionally give overseas development assistance had contributed to the eradication initiative by mid- . of these, seven contributed the equivalent or more than their estimated fair share and nine substantially less. the six countries that did not contribute are free riders in economic terms, since they will share in the benefits. while the fairshare concept is of great value for setting resource mobilisation targets and negotiating appropriate contributions with interested donors, it has substantial limitations. most importantly, it will not mobilise funds from donors who did not fully endorse the goal in the first place. pursuing the fair-share argument can also unveil basic, irreconcilable disagreements on their calculation. such limitations must be recognised early and alternate strategies developed for settings where this argument alone is not sufficient. fifth, worldwide health goals should be designed so that they can be pursued within existing health systems and, ideally, contribute to the strengthening of these systems. although proponents have stated that poliomyelitis eradication strengthens other health services, they and their detractors have used anecdotal information to argue their cases because of a lack of objective criteria and indicators. of note, some of the largest donors to poliomyelitis eradication are those who are institutionally committed to the strengthening of health systems, but who joined the initiative after reconciliation of concerns about the effect on the delivery of other services. however, proponents of future worldwide health goals should recognise the challenge of measuring such indirect benefits, be modest in arguing their worth, and ensure there are agreed indicators and the capacity and mechanisms for their monitoring. the final lesson is the need to identify countries, regions, or populations where strategy implementation will be particularly challenging, and to establish appropriate contingency plans. failure in just one country could be catastrophic for an eradication effort. however, other international health goals might be similarly compromised. for example, the emergence of multidrug-resistant strains of tuberculosis in one country could hamper worldwide efforts to combat that disease. similarly, uncontrolled use of antibiotics in a few countries could seriously affect international work to contain antimicrobial resistance. as the poliomyelitis eradication programme began to be implemented on a truly worldwide scale in the mid- s, substantial attention was given to the ten countries that had been identified as at particularly high risk for delaying global eradication. as a result of focusing additional human, financial, and political resources in these areas, five of those countries (bangladesh, the democratic republic of the congo, sudan, ethiopia, angola) now seem to have eradicated poliomyelitis, and only three (india, nigeria, pakistan) continue to have high-intensity transmission. although it is tempting to suggest that even greater attention earlier in the programme might have accelerated progress in these areas, the reality is that scant resources necessitated a more pragmatic approach. other international health goals will require a similar, pragmatic approach to achieve and secure gains where possible, while developing the necessary political, financial, and human resources to address the most challenging areas. contributors r b aylward wrote the introductory, status, and lessons sections, and edited the manuscript. s england developed the concept and original structure and wrote the first draft of the manuscript. m agocs did research, in particular on the background, history, and indirect benefits of poliomyelitis eradication, and wrote those sections. a acharya did the cost-effectiveness analysis. j linkins did the analysis of the direct national and international costs of poliomyelitis eradication and wrote the section in which they are detailed. none declared. macroeconomics and health: investing in health for economic development: report of the commission on macroeconomics and health. geneva: world health organization the globalization of public health, i: threats and opportunities the global fund to fight aids the intensified public health the lancet • geneva: world health organization donor responsibilities in rolling back malaria a paradigm for international cooperation: the global alliance for vaccines and immunization (gavi) and the vaccine fund who framework convention on tobacco control: a global "good" for public health health is wealth communicable disease control: a global public good perspectiveworking paper. geneva: world health organization global public goods: international cooperation in the st century global eradication of poliovirus: history and rationale report on the international conference on 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blower, sally title: preventing major outbreaks of covid- in jails date: - - journal: lancet doi: . /s - ( ) - sha: doc_id: cord_uid: e p wnil nan the mathematical expression for the basic reproduction number for sars-cov- in a jail ( " #$ ) is equal to: in this expression is the probability an infected inmate is symptomatic, − is the probability an infected inmate is asymptomatic, is the transmissibility (per contact) of sars- to generate the figure we calculated the values for and / that would ensure that the above expression was equal to one. for the remaining parameters we set: = · , = · , / = days, and / = days. we set such that " #$ ∈ · , · . covid- : what proportion are asymptomatic? the centre for evidence-based medicine substantial undocumented infection facilitates the rapid dissemination of novel coronavirus (sars-cov ) the incubation period of coronavirus disease (covid- ) from publicly reported confirmed cases: estimation and application los angeles county jail system by the numbers. los angeles almanac key: cord- -ilsupfl authors: schuchat, anne; tappero, jordan; blandford, john title: global health and the us centers for disease control and prevention date: - - journal: lancet doi: . /s - ( ) - sha: doc_id: cord_uid: ilsupfl nan anne schuchat, jordan tappero, john blandford why is an article about global health included in a special issue on health in the usa? about half the produce that americans consume is cultivated in other countries, million americans travel or work outside the usa, and most patients with measles and tuberculosis in the usa acquired their infection elsewhere. emerging diseases, globalisation of foods and medicines, the rise in antimicrobial resistance, and the ease with which pathogens can be manipulated for good or harm increase each nation's vulnerability and interdependence. the centers for disease control and prevention (cdc) has engaged in global health for more than years. although tackling infectious disease threats has been a constant, the agency has also provided humanitarian assistance in natural disasters, refugee crises, and famines; improved child survival; and strengthened scientifi c measurement of health metrics. cdc's workforce includes more than internationally deployed public health professionals in addition to around locally employed staff working in about countries (fi gure). cdc's global health strategy aims to: achieve optimum health eff ects; strengthen global health capacity; improve global health security; and strengthen the organisation's capacity. this report describes selected programmes that illustrate these goals. leveraging the strengths of the us-implementing agencies for a whole-of-government approach, the us president's emergency plan for aids relief (pepfar) targets resource-constrained countries that are hardest hit by the hiv epidemic. cdc has played a central role in pepfar since its inception, bringing more than years of experience of work in hiv/aids. cdc staff work with peers in ministries of health and other host country entities to implement eff ective national programmes in hiv care and treatment, tuberculosis-hiv integration, maternal and child health, hiv prevention, and hiv counselling and testing. through pepfar, cdc is also strengthening public health systems through focused investments in local workforce capacity and health systems that are essential to the scale-up and sustainability of priority pepfar programmes and to the strengthening of the broader public health system. for example, growing hiv treatment pro grammes were shown to be positively correlated with increased rates of facility deliveries by non-hiv infected women. in late , president obama and then-secretary of state hillary clinton advanced the vision of an aids-free generation, defi ned as almost complete elimination of vertical transmission of hiv, greatly reduced incidence of sexual transmission of hiv in adults and adolescents, and universal access to antiretroviral therapy (art) to people who become infected. president obama announced in december, , ambitious new targets for priority evidence-based interventions that were to be realised in just years' time: pepfar, in , was committed to directly support million patients receiving treatment, an increase of % over the previous target; provision of therapy to · million pregnant women to prevent vertical infection of hiv; and to cumulatively reach · million men with voluntary medical male circumcisions. , cdc and its partners worked to make these bold targets a reality. pepfar has directly supported · million patients receiving treatment; provided more than · million pregnant women with antiretroviral prophylaxis to prevent mother-to-child transmission of hiv during the preceding years; and with cumulative support of · million medical male circumcisions, was on track to achieve that target by the end of . cdc implemented an innovative approach to prevent mother-to-child transmission of hiv in malawi by working with the ministry of health and local partners. the new approach, called option b+, off ers all pregnant or breastfeeding women infected with hiv lifelong art. year after this approach was implemented in , the number of hiv-positive pregnant and breastfeeding women receiving art increased by more than %, from to . option b+ not only reduces motherto-child transmission to less than % but also maintains the mother's health, provides lifelong reduction of hiv transmission to uninfected sexual partners, and prevents mother-to-child transmission in future pregnancies. other african and caribbean countries are now initiating this approach. although each country must weigh the potential eff ect and costs of option b+ in reaching the goal of elimination of mother-to-child hiv transmission, this approach could overcome barriers such as inadequate immunological testing capacity, substantial distances between antenatal clinic and art-initiation sites, and human resource constraints. further, cdc and the us health resources and services administration initiated the track · programme in , to rapidly scale up art delivery initially through us-based partners. in its fi rst phase, pepfar was undertaken as an emergency response to provide accelerated access to crucial, lifesaving services and programmes. with pepfar's reauthorisation in , cdc worked to further strengthen programme sustainability, country stewardship, and local implementation of core programmes. cdc worked with ministries of health to transition service delivery of hiv/ aids care and treatment to local stewardship in countries. as of february, , these countries had contracts or awards in place with indigenous partners to establish local country ownership of their art programmes. the transition of treatment programmes to indigenous partners is consistent with cdc's approach across programme areas of working through partner ministries of health and other local entities. % of cdc's pepfar programme funding goes through indigenous entities, and this share should continue to grow as cdc provides the technical support and capacity building to maintain continuity and quality of treatment services. cdc's infl uenza programme contributes to strengthened global health security. infl uenza viruses spread rapidly without respect to geographical borders. control of disease caused by these viruses requires accurate laboratory detection, epidemiological response, and development and delivery of appropriately targeted vaccines and other countermeasures. eff orts that focus on seasonal infl uenza strengthen preparedness for pandemics. addressing avian infl uenza has assumed greater priority since emergence of h n and more recently h n infl uenza viruses. the cdc is the national infl uenza center for the usa and one of fi ve who international collaborating centers for surveillance, epidemiology, and control of infl uenza. cdc scientists participate in strain selection for seasonal vaccines and prepare candidate vaccine virus strains for vaccine manufacturers. since the emergence of cases of h n avian infl uenza in people more than a decade ago, cdc has expanded support to and collaborations on infl uenza with dozens of countries. after a local outbreak in in hong kong, , avian h n infl uenza resurfaced in , initiating a decade of major epizootics aff ecting birds in asia, northern africa, and europe, prompting intensifi ed national, regional, and global responses. to date, animal-to-human transmission has caused nearly human fatalities, and millions of poultry have been culled in aff ected areas. the cdc contributed to a comprehensive us government response to h n avian infl uenza. it established cooperative agreements with ministries of health in more than countries to strengthen capacity for epidemiological response, laboratory detection, and emergency preparedness; seconded staff to who, world animal health organization, and un food and agriculture organization; collaborated on vaccine and diagnostic studies with the us national institutes of health, the food and drug administration, the biomedical research and advanced development authority, academic investigators, and industry; and established a strategic national stockpile of antiviral drugs and other emergency supplies. by april, , when cdc fi rst detected a novel strain of infl uenza a h n , cdc had already enhanced capacity for pandemic response. an infl uenza reagent repository facilitated the surge in laboratory testing in the usa and other countries. cdc shipped reagents for the detection of novel h n infl uenza virus beginning may , . in addition to kits shipped to public health laboratories in all states, diagnostic kits were shipped to laboratries in countries. cdc's investments in strengthening countries' surveillance for severe acute respiratory illness (sari) provided recognition of severe disease in many countries caused by the new infl uenza strain and helped to monitor changes in clinical severity that might signal viral mutations of concern. in , the sari surveillance systems monitored the spread of the new middle east respiratory syndrome (mers) coronavirus. on march , , chinese authorities reported to who their detection of a novel h n avian infl uenza virus that caused severe pneumonia in three people in shanghai and anhui. , from oct , , to march , , human cases and deaths had been reported by china's national health and family planning commission, and the novel virus had been isolated from live bird markets. the chinese rapidly completed whole genome sequencing of several viral isolates, posted their sequence data, closed live bird markets in several cities, and initiated targeted culling of birds. the virus is of low pathogenicity in poultry, and subclinical avian infection has complicated animal control eff orts. although no sustained human-to-human transmission has occurred, it is too early to be certain of the full eff ect that this novel virus will have on human or animal populations. the chinese authorities responded rapidly and shared information about human disease and genetic sequence data openly. the us cdc has collaborated with china's infl uenza scientists and public health authorities for decades. cdc provided substantial technical assistance, several visiting scientists from china completed training and research projects in atlanta, and senior scientists from the us cdc provided onsite technical support in china. a major milestone was achieved in , when china was designated as the fi fth who international collaborating center for reference and research on infl uenza in human beings. china is also the location of one of cdc's global disease detection (gdd) regional centers. at gdd sites, us cdc epidemiology, laboratory, and veterinary staff work closely with counterparts from the ministries of health to strengthen early detection and response to public health threats. china also hosts a field epidemiology training program (fetp), at which a us cdc resident advisor works closely with epidemiology trainees in a year programme modelled after the cdc's elite epidemic intelligence service. in recognition of these broad partnerships, china designates national, provincial, and district public health departments as cdcs. infl uenza events highlight the importance of strengthening global health security worldwide. emerging threats such as avian infl uenza or severe acute respiratory syndrome can occur anywhere. acceleration of improvements in the capacity for each nation to protect its own citizens and detect and report public health threats of international concern promptly to the global community is urgently needed. cdc's experience in haiti addresses how programmes designed for health eff ect can strengthen capacity and improve preparedness for health security threats. on jan , , a devastating earthquake struck port-au-prince, haiti, killing an estimated people, injuring more, displacing more than % of the country's million residents, and destroying much of the capital's infrastructure. the public health response benefi ted from cdc's partnership with the ministry of public health and population (mspp), and the administrative and non-governmental organisation implementation platforms established under pepfar in . hiv services recovered to baseline rapidly. yet an urgent need remained to strengthen reportable disease surveillance because of overcrowding and poor living conditions, , expand capacity to identify reportable pathogens at the national public health laboratory, and train a public health workforce. the us government committed more than us$ billion in new funds for post-earthquake relief, recovery, and reconstruction; facilitated mspp's rapid detection of vibrio cholerae within days of its introduction; and contributed to an eff ective emergency response to the worst national cholera epidemic in the modern era. after these back-to-back crises, in early mspp, cdc, and other organisations identifi ed seven measurable public health eff ect goals to transform health services and disease outcomes. with the aim to achieve an aids-free generation, in , mspp and pepfar-haiti expanded hiv counselling and testing sites for pregnant women, implemented a case management programme for all hiv-infected women to reduce loss to follow-up, and in adopted the b+ option that provides all hiv-infected pregnant and breastfeeding women with lifelong art irrespective of cd cell count. , hiv testing of pregnant women has increased by %, from in , to in . the proportion of identifi ed hivinfected pregnant women who received prophylaxis or art increased from % to % during this period. since the earthquake, overall access to art has nearly doubled; , in , more than % of all eligible hivinfected haitians were receiving art. from oct , , to april , , haiti reported cases of cholera and deaths. the inadvertent introduction of cholera, which had not been seen in haiti in more than a century, accounted for % of the reported global cholera burden in and . although the annual case fatality rate has been sustained at the international standard of % or less since , elimination will need substantial investment in infrastructure to address inadequate access to improved drinking water ( %) and sanitation ( %). outbreaks, and use data to drive public health policy. cdc has helped to establish fetps that have trained nearly graduates from countries. the world is more interconnected than ever, and weak links in public health capacity anywhere can have profound eff ects at distant locations. governments have responsibilities to their citizens and other nations to detect problems rapidly, communicate promptly, and respond eff ectively. the cdc focuses on the protection of americans and improvements in the health and capacity of people worldwide through partnerships with ministries of health, other us government agencies, non-governmental organisations, and multilateral organisations. the goal of these eff orts is to improve health and strengthen capacity while striving for a world more secure from emerging threats. as contributed to the overall planning and writing of the manuscript, the literature search, and the development of the fi gure. jt contributed to the writing of the manuscript, the literature search, and the development of the fi gure. jb contributed to the writing of the manuscript and the literature search. we declare no competing interests. human infection with highly pathogenic avian infl uenza a (h n ) virus: review of clinical issues detecting pandemic infl uenza a (h n ) virus infection: availability of diagnostic testing led to rapid pandemic response infl uenza surveillance in countries in africa emergence of avian infl uenza a (h n ) virus causing severe human illness-china human infections with the emerging avian infl uenza a h n virus from wet market poultry: clinical analysis and characterisation of viral genome global concerns regarding novel infl uenza a (h n ) virus infections moving forward to : global ihr ( ) implementation international health regulations-what gets measured gets done lessons learned during public health response to cholera epidemic in haiti and the dominican republic recovery of hiv service provision post-earthquake launching a national surveillance system after an earthquake-haiti rapid establishment of an internally displaced persons disease surveillance system after an earthquake-haiti public health in haitichallenges and progress cholera surveillance during the haiti epidemic-the fi rst years cautious optimism on public health progress in post-earthquake haiti prevention of mother-to-child transmission of hiv and the health-related millennium development goals: time for a public health approach unaids. unaids report on the global aids epidemic unaids. unaids report on the global aids epidemic ministère de la santé publique et de la population daily reports on the cholera epidemic in haiti the cure for choleraimproving access to safe water and sanitation world health organization, unicef. world health organization/ unicef joint monitoring programme (jmp) for water supply and sanitation pepfar programs linked to more deliveries in health facilities by african women who are not infected with hiv voluntary medical male circumcision: an hiv prevention priority for pepfar progress in voluntary medical male circumcision service provision-kenya shared responsibility-strengthening results for an aids-free generation impact of an innovative approach to prevent mother-to-child transmission of hiv-malawi scale-up of hiv treatment through pepfar: a historic public health achievement isolation of avian infl uenza a(h n ) viruses from humans-hong kong human infection with a novel avianorigin infl uenza a (h n ) virus human infl uenza a h n virus related to a highly pathogenic avian infl uenza virus update: isolation of avian infl uenza a (h n ) viruses from humans-hong kong, - we thank ezra barzilay, sally ezra, barbara marston, and ann moen for assistance with manuscript and fi gure preparation; and harold jaff e and tom frieden for review of the manuscript. the fi ndings and conclusions of this report are those of the authors and do not necessarily refl ect the offi cial position of the centers for disease control and prevention. key: cord- -l b jk authors: freudenthal, bernard title: misuse of sars-cov- testing in symptomatic health-care staff in the uk date: - - journal: lancet doi: . /s - ( ) - sha: doc_id: cord_uid: l b jk nan an initiative to screen asymptomatic health-care workers for severe acute respiratory syndrome coronavirus (sars-cov- ) was timely and logical, and contrasted markedly with the uk government's testing strategy stated. [ ] [ ] [ ] [ ] [ ] this misconception applies to both human and ruminant brains. we declare no competing interests. about - , leonardo da vinci's studies of the brain culminated in fil ling the ventricles of an ox with melted wax, a pioneer accomplishment in medical science. an otherwise excellent review in the lancet claimed that these drawings of the casted ventricles show the interventricular foramen of monro and the paired lateral ventricles in a correct manner. this misconception has repeatedly been stated in the literature. [ ] [ ] [ ] we believe leonardo neither did depict the two separate interven ricular foramina (often named after the erroneous description of alexander monro) nor did he draw the two lateral ventricles properly. his drawing (figure c) renders an unpaired broad anterior part of the foremost ventricle. a single tube or channel connects it with the middle ventricle, and another single tube connects the middle one with the posterior ventricle, the latter representing the aqueduct. leonardo then cut a midline section and opened the brain "like a book", thus cutting both connecting tubes at least graphically in halves. the opened-out drawing can easily be folded together to prove this assumption (figure). leonardo did not depict a transverse section, which would not halve the aqueduct and the other single tube in front, not to mention the third and fourth ventricle. the seemingly two lateral ventricles are in fact a single one cut in two halves. macroscopic anatomy and neuroimaging prove that a true midline section cannot show both lateral ventricles with their bilateral connec tions to the third ventricle. leonardo must be credited for being the first to give a graphic representation of the connection between all the cerebral ventricles. however, he did not show their true anatomy. his opened-out presentation of a brain does not show the paired lateral ventricles and the foramen of monro, as several authors erroneously down, and the way to do that is to get the amount of testing up". this testing approach was then also applied to other groups of public sector workers. the uk government's approach of using sars-cov- testing as a strategy to reduce absenteeism rather than to increase the detection of otherwise asymptomatic spreaders was surely symptomatic of flawed analysis and misunderstanding of the utility of the sars-cov- pharyngeal swab rt-pcr test. who expressly advises against using this test as a rule-out in the event of negative results. sensitivity of the test might be as low as %, and in our practice many colleagues believe it to be lower still. overzealous redirection of self-isolating staff back to work before they had completed sufficient self-isolation to exclude infectivity was therefore likely to increase spread of the virus to other staff and to patients or care-receivers in a substantial number of cases, especially given the high prevalence and likelihood of sars-cov- infection among exposed health-care workers during the epidemic. surely the only defensible policy would have been national opportunistic and frequent testing of nhs and social care sector staff regardless of symptomology, and the test should be used exclusively as a rule-in and not a rule-out test as per existing who guidance. i declare no competing interests. robust epidemiological studies help detail asymptomatic spread. results have been heterogeneous; assumptions vary between studies which might be subject to recall bias, definitions of symptoms are inconsistent, and some studies do not account for the critical presymptomatic phase of infection. nonetheless, most such studies find evidence of asymptomatic sars-cov- transmission. false-positive results can also limit hcw screening utility. they can be biological, with dead virus detected in non-infectious cases, and technical, where a test is positive in the absence of viral rna. regular screening risks identification of biological false positives; however, more research is required to understand the biology of persistent viral rna shedding. technical false positives might be reduced to manageable levels by testing in duplicate. we believe a symptom-agnostic testing approach for sars-cov- among hcws is an effective measure of reducing viral transmission. this approach is advocated on a population level and might be particularly beneficial among hcws given reports of hospitals acting as hotbeds of covid- . arguments against mass testing approaches previously have suggested a lack of resources might make this ineffective. however, uk daily testing capacity has increased tenfold since the publication of our correspondence, while rapid point-of-care antigen tests facilitate early intervention to limit transmission. screening for sars-cov- in asymp tomatic hcws could be a vital weapon in the fight against covid- now and over the winter months. this will help the national health service to maintain the capacity to treat other diseases in the face of a second wave. we must act to prevent further virus spread, economic disruption, and unnecessary death. covid- : the case for health-care worker screening to prevent hospital transmission number of nhs doctors off sick 'may be nearly triple the official estimate the guardian. uk covid- testing expanded to police, fire service and judiciary laboratory testing for coronavirus disease (covid- ) in suspected human cases diagnosis of the coronavirus disease (covid- ): rrt-pcr or ct? we thank bernard freudenthal for his response to our previous correspondence. we agree that use of severe acute respiratory syndrome coronavirus (sars-cov- ) testing among health-care workers (hcws) solely to reduce absenteeism is inappro priate. freudenthal correctly outlines the risks, posed by falsenegative results, of advising potentially infec tious hcws to return to work. moreover, staffing levels are currently far less problem atic within uk health-care settings than during the peak of the pandemic.hcw testing should aim to identify infectious cases and reduce nosoco mial transmission of sars-cov- : testing only selfreported symptomatic cases risks missing many infectious cases. for instance, hcws might unwittingly attend work with mild or non-specific symptoms. furthermore, although the relationship between rt-pcr cycle threshold (ct) values and infectivity requires further elucidation, evidence suggests that ct values among asymptomatic and symptomatic cases are similar. crucially, viable virus has been isolated up to days before symptom onset. key: cord- -mon loph authors: williams, bryan; zhang, yi title: hypertension, renin–angiotensin–aldosterone system inhibition, and covid- date: - - journal: lancet doi: . /s - ( ) - sha: doc_id: cord_uid: mon loph nan few could have imagined that hypertension and its treatment with inhibitors of the renin-angiotensinaldosterone system (raas) would become a hot topic during the global covid- pandemic. two factors have contributed to this: first, the observation that hypertension is one of the most common comorbidities associated with severe cases of covid- in patients who have been admitted to hospital and their risk of death; and second, that like the severe acute respiratory syndrome coronavirus (sars-cov), sars-cov- infects cells via specific binding to angiotensin-converting enzyme (ace ), which is ubiquitously expressed in the lung and other tissues. these factors have fuelled speculation that use of raas inhibitors, particularly ace inhibitors or angiotensin-receptor blockers, could lead to increased expression of ace in the respiratory tract, thereby increasing the risk of both becoming infected and developing severe life-threatening complications due to covid- . the fact that no evidence supports any aspect of this speculation mattered little as the hypothesis gained traction, initially via social media and subsequently via the medical press. anxiety among patients and physicians has been profound because ace inhibitors and angiotensinreceptor blockers are the foundation of drug treatment for hypertension, heart disease, and chronic kidney disease, and are among the most widely prescribed drugs globally. patients have subsequently been withdrawing and substituting these treatments, prompting international cardiovascular and hypertension specialist societies to issue statements of reassurance, while acknowledging the lack of high-quality data to refute the increasing alarm. this debate, fuelled by speculation, has at last become enriched by data, with the publication of several observational cohort studies. [ ] [ ] [ ] [ ] [ ] [ ] [ ] in the lancet, francisco de abajo and colleagues present data from a casepopulation pharmacoepidemiological study of adult patients (cases) who had been admitted to hospital in madrid, spain, due to covid- during march, , who were each carefully matched with ten population controls with data from , to give a total of matched controls. ( %) cases were female and the mean age was · years (sd · ). the main outcome measure was admission to hospital of patients with pcr-confirmed covid- , comparing the current use of raas inhibitors with other antihypertensive drugs. the raas inhibitors were predominantly ace inhibitors and angiotensinreceptor blockers, with few individuals currently using aldosterone antagonists or renin inhibitors. compared with the use of other antihypertensive drugs, current use of raas inhibitors was not associated with increased risk of covid- requiring admission to hospital (odds ratio [or] · , % ci · - · , adjusted for potential confounding factors), or increased risk of severe complications from covid- needing intensive care or leading to a fatal outcome ( · , · - · ). these findings were uninfluenced by age, sex, or background cardiovascular risk. moreover, excluding aldosterone antagonists and renin inhibitors and focusing only on ace inhibitors or angiotensin-receptor blockers made no difference to these conclusions. potential differences exist between ace inhibitors and angiotensin-receptor blockers in the context of risk associated with covid- . in the study by de abajo and colleagues, no difference was found between ace inhibitors and angiotensin-receptor blockers for the main outcome, which was most notable when comparing monotherapy with these drugs (adjusted or for ace inhibitor monotherapy was · [ % ci · - · ] and for angiotensin-receptor blocker monotherapy was · [ · - · ]). this finding is also consistent with most other recent observational studies. [ ] [ ] [ ] the exception among these studies was one study using observational data from hospitals in asia, europe, and north america that reported possible enhanced benefit of ace inhibitors compared with angiotensin-receptor blockers on mortality, but the authors rightly cautioned against overinterpretation of these data because of potential unmeasured confounding. diabetes is a common comorbidity associated with poorer outcomes in patients with covid- and these patients often have hypertension and are prescribed raas inhibitors. thus, an interesting and potentially clinically important finding in the study by de abajo and colleagues is that the use of raas inhibitors compared with other antihypertensive drugs almost halved the risk of adverse outcomes in patients with covid- who had diabetes (adjusted or · , % ci · - · ). other studies have also suggested that use of raas inhibitors might confer protective effects against complications and death in patients with covid- versus other antihypertensive drugs, although these studies were not restricted to patients with diabetes. , a notable feature of the emerging data is the excess risk of admission to hospital, admission to intensive care units, and fatal outcomes in patients who are given any kind of antihypertensive drug versus non-users. although this potential association of antihypertensive treatment and increased risk of severe covid- has caused alarm, generally people are accepting that it most likely reflects the use of these drugs for patients who are older and who invariably have multiple comorbidities, and despite rigorous attempts to adjust for comorbidities in observational studies, fully adjusting for confounding by indication is not possible. the limitations of the study by de abajo and colleagues apply to all of the observational studies we have discussed here, which are not randomised controlled trials, and despite multiple statistical adjustments are invariably subject to confounding, either unmeasured or unknown. controlling for whether patients were compliant with their raas inhibitor treatment, either before or after becoming infected with sars-cov- , is also not possible. nevertheless, the aforementioned studies, - each with its own important nuances, all reached similar overarching conclusions from which a reasonable interpretation is that no evidence exists to support the speculation that raas inhibitors increase the risk of covid- . nor does evidence exist to suggest that, once infected, the risk of admission to hospital due to covid- , progression to more severe complications, or death is increased with raas inhibitor use compared with treatment with other antihypertensive drugs. findings from some studies even suggest that treatment with raas inhibitors might reduce risk of severe complications or death due to covid- , , but this potentially important finding needs confirmation in randomised controlled trials. for the moment, we should applaud the remarkable achievement of investigators globally, in the face of considerable adversity, for rapidly generating scientific data that should diminish the speculation about the safety of raas inhibitors during this global covid- pandemic and provide a degree of reassurance to patients and their doctors. clinical features of patients infected with novel coronavirus in wuhan, china structure analysis of the receptor binding of -ncov are patients with hypertension and diabetes mellitus at increased risk for covid- infection? use of renin-angiotensinaldosterone system inhibitors and risk of covid- requiring admission to hospital: a case-population study association of renin-angiotensin system inhibitors with severity or risk of death in patients with hypertension hospitalized for coronavirus disease (covid- ) infection in wuhan, china renin-angiotensinaldosterone system blockers and the risk of covid- renin-angiotensin-aldosterone system inhibitors and risk of covid- cardiovascular disease, drug therapy, and mortality in covid- association of inpatient use of angiotensin converting enzyme inhibitors and angiotensin ii receptor blockers with mortality among patients with hypertension hospitalized with covid- treatment with ace-inhibitors is associated with less severe disease with sars-covid- infection in a multisite uk acute hospital trust key: cord- - iqtj db authors: elachola, habida; memish, ziad a title: oil prices, climate change—health challenges in saudi arabia date: - - journal: lancet doi: . /s - ( ) - sha: doc_id: cord_uid: iqtj db nan foods, such as sugar-sweetened beverages and energydense, nutrient-poor foods, in the school environment; informed nutrition education as part of the core curriculum; and ensuring levels of physical activity for all children according to who recommendations. in addition to the new approaches, the imperative to implement existing standards has been underlined. echo noted the disappointing lack of progress on implementation of who's set of recommendations on the marketing of foods and non-alcoholic beverages to children. it reiterates the need to implement regulatory measures, such as the international code of marketing of breast-milk substitutes, and to develop regulations on the marketing of complementary foods and beverages for infants and young children. echo's recommendations call for various stakeholders to take action, such as who to institutionalise a crosscutting and life-course approach to ending childhood obesity and for civil society, philanthropic and academic institutions, and the private sector to mobilise their comparative advantage to end childhood obesity (panel ). these actions notwithstanding, echo remains fi rmly of the opinion that it is the primary responsibility of governments to ensure that policies and actions address the obesogenic environment and to provide guidance and support for optimum development at each stage of the life-course. by improving and integrating these actions, there will be major benefi ts to other parts of the maternal, reproductive, child health, and non-communicable disease prevention and control and health systems agendas. first, along with the rising oil revenues in recent decades, saudi arabia has seen a rapid epidemiological transition in the population (table). the uptake of some health-promoting behaviours has been limited by saudia arabia's unemployment rate ( · % in ), moderate levels of education, and climatic and sociocultural conditions. , , the high burden of undiagnosed and uncontrolled diabetes and hypertension, , will consume a large proportion of the health budget. second, future temperature in the region is projected to increase consistently and exceed the threshold deemed unsuitable for human adaptability. this changing climate will have an eff ect on the promotion of some healthy lifestyle habits, the country's production of fresh fruits and vegetables, and micronutrient defi ciencies. for example, vitamin d defi ciency from inadequate exposure to sun and limited intake of enriched products is common in saudi arabia. finally, there is a need for sustained investment in the control of emerging infectious diseases in the region. such control eff orts are important given the risk of emerging diseases within saudi arabia, such as middle east respiratory syndrome, and as a result of disease importation through the large expatriate workforce and the - million pilgrims for hajj and - million pilgrims for umrah who come to saudi arabia each year from more than countries. , although economic recession is often feared as a "health tragedy", evidence from high-income countries is mixed and related to variations in social and political contexts. , in high-income countries, some health indices showed counter-cyclical eff ects with economic contractions (eg, increases in suicides, depression, and anxiety disorders and worsening reproductive health outcomes). , however, mortality is shown to be pro-cyclical and it decreases during rapid economic contractions. in high-income countries, there are generally slower declines in mortality during periods of economic growth and greater declines in mortality during recessions. in low-income countries, economic growth seems to improve health through improvements in basic services, until a country reaches $ - gdp per person. declines in mortality in high-income countries during recession could be related to decline in excess mortality from modifi able causes of death, such as those arising from alcohol abuse and motor vehicle accidents. , given that saudi arabia has one of the highest rates of traffi c-related deaths globally, the country might benefi t from the austerity measures in this regard. if saudi arabia maintains increased relief spending on child health, improvements in access to nutrition and health, and strong infectious diseases control then these approaches can also help reduce mortality. since saudi arabia's sociodemographic and geopolitical foundation is diff erent from that of the case studies available thus far, it is diffi cult to predict potential health eff ects of the present economic recession and newly proposed health-sector reforms. saudi nationals (and pilgrims coming to mecca for the hajj) are entitled to free health care and the government accounted for % of health care spending in (about % of gdp). the expatriate workforce of saudi arabia, which accounts for % of the total population and about % of the private sector workforce, are not covered by the government health-care system. , the proposed nationalisation process to reduce the expatriate workforce by employing more saudi nationals in the employment sector could adversely aff ect the health-care workforce since about % of physicians and % of nursing staff in saudi arabia are expatriates. a much needed boost in the country's health promotion portfolio would require expertise in various public health disciplines that are currently in short supply in saudi arabia. the greatest burden of economic recession generally falls on the unemployed. , about a third of the million population of saudi arabia are younger than years, and the child dependency ratio is % (ratio of people below working age to workforce). in , the rate of unemployment in saudi arabian nationals was · % for people aged - years (men · %, women · %). , a recent emphasis on privatisation of health and preventive care, or even cost sharing of preventive care, could lead to an increase in overall health-care costs if people forego essential medications, immunisations, or routine clinic visits such as antenatal care. high body-mass index dietary risks raised fasting plasma glucose high blood pressure we do not know how long the current economic downturn will last in saudi arabia. anticipating potential eff ects of recession at an early stage of the crisis can inform health-sector reforms to diminish or avoid its harmful consequences on nation's health. despite saudi arabia's unique challenges, the ministry of health has so far been successful in providing state-of-the-art medical services to its citizens. for example, saudi arabia's premarital sickle cell screening is a unique initiative. despite free health care, saudi arabia's shortcomings are in the control of non-communicable diseases and mitigation of risk factors for disease. only % of saudi adults have had a preventive care visit. , there is a need to consider multipronged approaches to health promotion and avoidance of risk factors, including those that fall outside the services of health ministry (eg, enforcement of motor vehicle accident prevention advisories, point of sale restrictions on tobacco). by training primary care providers to serve as advocates for health promotion, each encounter between the provider and patient can be used as an opportunity to educate patients about a set of prevention messages. informed personal decision making is important to increase the uptake of healthy lifestyles and prevention recommendations; this is a process achieved through education and a sense of personal empowerment that comes with employment. outreach to civic organisations for partnerships in health promotion initiatives can help increase visibility and uptake. beyond the immediate eff ects of the current economic crisis, saudi arabia needs to target its policies to mitigate the eff ects of climate change. agricultural approaches such as hydroponics, vertical farming, and landscaping with food-producing plants can increase food production, enable healthy eating habits, and improve air quality. additionally, enrichment of food products (vitamin d, folic acid, iodine) is an easy and cheaper alternative to promotion of supplement use by individuals. the transition in the country's health-care delivery to the private sector and cost-sharing should be implemented without compromising services for the unemployed and uninsured. similarly, eff orts to nationalise the health labour force should consider continuity in essential service delivery. saudi arabia's religious leadership can encourage the population to adhere to guidance on health promotion, which is particularly important for mental health where health-care infrastructure is not adequate. health security cannot be achieved by focused eff orts from the health ministry alone; nations that off er greater social safety nets are better positioned to diminish the health eff ects of economic recession. finally, implementation of evidence from case studies on the health eff ects of the economic crisis are useful and can contribute to the emerging body of literature on economics and health. health-care reform was long overdue in saudi arabia and the current crisis aff ords the country an opportunity to do it right. saudi arabia's future health security will rely on the choices made today by its health policy makers. ministry of health, riyadh, saudi arabia (zam); college of medicine, alfaisal university, riyadh , saudi arabia (zam); and atlanta, georgia, usa (he) zmemish@yahoo.com we declare no competing interests. saudi arabia's economic time bomb. the brookings institution riyadh plans radical surgery to rejuvenate saudi health sector demography, migration and labour market in saudi arabia burden of disease, injuries, and risk factors in the kingdom of saudi arabia kingdom of saudi arabia status of the diabetes epidemic in the kingdom of saudi arabia hypertension and its associated risk factors in the kingdom of saudi arabia, : a national survey cost of diabetes in the kingdom of saudi arabia future temperature in southwest asia projected to exceed a threshold for human adaptability defi ciencies under plenty of sun: vitamin d status among adults in the kingdom of saudi arabia hajj: infectious disease surveillance and control years of austerity takes its toll on greek health care the eff ect of economic recession on population health six-year outcome of the national premarital screening and genetic counseling program for sickle cell disease and β-thalassemia in saudi arabia breast cancer screening in saudi arabia: free but almost no takers low uptake of periodic health examinations in the kingdom of saudi arabia key: cord- -j o cfkv authors: wang, jigang; xu, chengchao; wong, yin kwan; he, yingke; adegnika, ayôla a; kremsner, peter g; agnandji, selidji t; sall, amadou a; liang, zhen; qiu, chen; liao, fu long; jiang, tingliang; krishna, sanjeev; tu, youyou title: preparedness is essential for malaria-endemic regions during the covid- pandemic date: - - journal: lancet doi: . /s - ( ) - sha: doc_id: cord_uid: j o cfkv nan the coronavirus disease (covid- ) pandemic that first emerged in wuhan in china's hubei province has quickly spread to the rest of china and many other countries. within months, more than people have been infected and the death toll had reached over worldwide on march , . in an attempt to contain the virus, the chinese government has made unprecedented efforts and invested enormous resources and these containment efforts have stemmed the spread of the disease. as of march , , malariaendemic regions in africa have reported a few imported covid- cases including in nigeria, senegal, and the democratic republic of the congo. africa needs to be prepared to deal with covid- , given the infectious potential of the disease and its capacity to undermine malaria control efforts. in addition to the shared vigilance that countries around the world should maintain, regions need to consider their local malaria epidemic and take additional measures for preparation. there are relevant lessons from the - outbreak of ebola virus disease in west africa. the emergence of ebola in malaria-endemic countries, including guinea, liberia, and sierra leone, led to a public health emergency and dealt a heavy blow to malaria control efforts. in guinea alone, an estimated fewer malaria cases than expected were seen at health facilities compared with years without ebola because of decreases in the number of patients with malaria seeking appropriate health care and the volume of malaria treatments being dispensed. contributing factors to this situation were the close resemblance of early ebola symptoms with malaria, leading to difficulties in early diagnosis, and the fear on the part of community members of contracting ebola in the health-care facilities. as ebola over whelmed health-care infrastructure, insufficient resources for malaria control in these regions led to increased mortality and morbidity. in guinea, the official number of reported deaths from malaria in was (who estimate ) compared with reported in , and there were deaths from ebola virus disease in . more alarmingly, it was estimated that there were about additional malaria-associated deaths among children younger than years in guinea, liberia, and sierra leone due to the ebola outbreak. there is, therefore, a real and pressing danger for malaria-endemic regions when faced with the threat of a novel infectious disease outbreak. while our knowledge of covid- is still developing, it is a highly contagious disease that is thought to spread primarily from human to human through direct contact and inhalation of respiratory droplets. carriers with mild or no symptoms can probably transmit the virus. in addition to china, italy, iran, and south korea are among the countries with local outbreaks that could be exporting the disease and increasing exposure risks. with africa's increasing global connectivity, the unfortunate likelihood of a continental outbreak cannot be ruled out. much like ebola, the early symptoms of covid- , including fever, myalgia, and fatigue, might be confused with malaria and lead to challenges in early clinical diagnosis. these features of covid- and the previous experiences of the ebola outbreak point to the need for malaria-endemic countries to consider preventive measures against not only the covid- threat but also its likely impact on existing malaria control efforts. the containment efforts and research impetus being taken by china and other affected countries have bought valuable time for the rest of the world, and this time window should be used effectively by vulnerable regions. who is monitoring the fast-evolving situation of the covid- epidemic and needs to advise the countries in the malaria-endemic regions on how to establish and effectively execute public health policies. preventive measures for covid- , including case and contact tracing, quarantine and screening, as well as education to encourage good hand hygiene practices, should be in place. additional and pre-emptive measures must be taken for malaria control in these countries, anticipating the potential challenge that would be faced by the public health system during an outbreak of covid- . in the case of ebola, it was estimated that malaria cases in guinea, liberia, and sierra leone could have increased by up to million in as a result of a cessation of distribution of insecticide-treated bednets (itns). governments and health leaders in malaria-endemic regions must ensure that such stresses to medical infrastructure are minimised in the event of an outbreak of covid- . resource allocation should be optimised whenever possible to ensure minimal disruption to malaria control should covid- management become necessary. management of medical supplies and stockpiling of surgical masks and other protective equipment should be done in advance and medical staff should be adequately trained in their use. in cases of emergency, mass drug administration and the distribution of itns might be considered for short-term malaria relief in hyperendemic areas. such measures would also aid efforts in covid- management by reducing the strain on medical resources and minimising confounding factors in diagnosis. previous successful implementation of such measures occurred during ebola outbreaks in sierra leone in - and in the democratic republic of the congo in , in accordance with who guidelines. , in malaria-endemic regions, malaria diagnostics should be systematically added to fever management, including for suspected cases of covid- , and health-care facilities should be well stocked with artemisinin combination therapy drugs. infection management protocols, such as social distancing, mask-wearing, and prompt seeking of diagnostic testing and necessary treatment, should be communicated in advance. these measures will require collective political will and unity in a coordinated effort by african countries. although an outbreak of covid- in malaria-endemic regions might not happen, we must nevertheless advocate caution and recognise that such pre-emptive measures are ultimately worthwhile. preparedness is the key to navigating any public health crisis, and malariaendemic countries must be prepared for the challenges that covid- might bring while minimising disruption to malaria control. a novel coronavirus from patients with pneumonia in china covid- ) situation report- report of the who-china joint mission on coronavirus disease (covid- ). geneva: world health organization looming threat of covid- infection in africa: act collectively, and fast effect of the ebola-virusdisease epidemic on malaria case management in guinea, : a cross-sectional survey of health facilities geneva: world health organization effects of response to - ebola outbreak on deaths from malaria, hiv/aids, and tuberculosis, west africa evidence of sars-cov- infection in returning travelers from wuhan, china preparedness and vulnerability of african countries against importations of covid- : a modelling study malaria morbidity and mortality in ebola-affected countries caused by decreased health-care capacity, and the potential effect of mitigation strategies: a modelling analysis impact of the mass drug administration for malaria in response to the ebola outbreak in sierra leone malaria control campaign launched in democratic republic of the congo to save lives and aid ebola response we declare no competing interests. key: cord- -ea au c authors: gostin, lawrence o; debartolo, mary c; friedman, eric a title: the international health regulations years on: the governing framework for global health security date: - - journal: lancet doi: . /s - ( ) - sha: doc_id: cord_uid: ea au c nan report, who seeks verifi cation from states parties in whose territory the event occurs. the declaration of a public health emergency of international concern is the crucial governance activity of the international health regulations. the director-general has sole power to declare and to terminate a public health emergency of international concern but must consider information provided by a state party; the decision instrument; emergency committee advice; scientifi c principles and evidence; and a risk assessment of human health, international spread, and interference with international traffi c. if the director-general declares a public health emergency of international concern, she must issue temporary, non-binding recommendations describing health measures that states parties should take. since , the director-general has declared three public health emergencies of international concern. during the h n infl uenza pandemic, who declared the fi rst ever public health emergency of international concern but was criticised for fuelling public fear. state parties widely disregarded who's temporary recommendations; , however, in , the review committee on international health regulations functioning during the h n infl uence pandemic cautioned, "the world is ill-prepared to respond to a severe infl uenza pandemic." in , the director-general declared two further public health emergencies of international concern, for polio and for ebola. the designation of polio seemed counterintuitive because only a handful of cases had been diagnosed compared with previous years. yet, small pockets of polio in afghanistan, pakistan, and nigeria were putting global eradication at risk. in the case of ebola, the director-general waited months after médecins sans frontières announced an "unprecedented outbreak" to declare a public health emergency of international concern on aug , . who's ebola interim assessment panel in july, , said urgent warnings "either did not reach senior leaders or senior leaders did not recognise their signifi cance." several health emergency events have not resulted in a declaration of a public health emergency of international concern. currently, the world is watching outbreaks of middle east respiratory syndrome, which has not triggered a public health emergency of international concern declaration despite reaching more than countries and causing deaths by november, . , the emergency committee advised that, without sustained community transmission, the conditions for a public health emergency of international concern have not been met. the director-general did not even convene an emergency committee for major events such as cholera in haiti, the fukushima nuclear disaster in japan, and the use of chemical weapons in syria. despite shortcomings, the international health regulations is an important governing framework. yet, a crisis of confi dence in the regulations exists, with the review committee on international health regulations functioning during ebola currently deliberating. we propose a series of operational and legal reforms. operational reforms are often preferable. amendments to the text of the international health regulations require world health assembly approval, do not enter into force immediately, and must be operationalised to be successful. furthermore, reopening the full text could entail a multiyear negotiating process, which risks weakening the international health regulations' norms and protection of human rights. even for our proposed legal reforms, we suggest ways to achieve them by textual interpretation and annex amendments in an attempt to avoid renegotiating the main text of the international health regulations. as shown in the fi gure, although none of the following proposed reforms is a solution on its own, collectively they could help to build a well functioning global detection and response system. some proposals will be easier to achieve than others, although all are needed reforms. achievement of core capacities by all states parties remains an indisputable baseline for preparedness. the initial deadline to meet the international health regulations' core capacities was , but who extended the deadline to for states parties. only states parties have affi rmed meeting core capacities. a well funded, prioritised, and comprehensive global plan is now past due. the november, , international health regulations review committee off ered a sound roadmap: strengthen self-assessment; test capacities through simulations; promote regional and crossregional learning; and measure performance through peer review and external assessments. such capacity building must go hand-in-hand with universal health coverage, a major target in the sustainable development goals. the following three recommendations could ( ) help with unofficial event reporting of potential public health emergencies of international concern develop publicly accessible online training platforms to assist in use of annex decision instrument develop a gradient for public health emergency of international concern declaration require states to automatically notify who of additional diseases that could become a public health emergency of international concern further increase transparency of emergency committee deliberations and findings the increasing assessed dues, although important to who's future, is politically fraught. alternative fi nancing mechanisms could include the global health security agenda, the world bank's proposed pandemic emergency financing facility, or a donors' conference. , , irrespective of the funding mechanism, ensuring sustainable resources would strengthen security for all. second, who should establish an independent peer-review core capacity evaluation system, with a feedback loop for continuous quality improvement. more rigorous evaluation of core capacities need to be undertaken. who allows states parties to self-assess their capacities, with many not reporting whether they have met their obligation to develop core capacities. states often resist external assessment because of sovereignty concerns, but the new system would aim to foster cooperation. domestic and external experts would work constructively with governments to identify capacity gaps, develop a jointly funded roadmap, and identify measurable benchmarks for success. if evaluations consistently led to technical and fi nancial assistance, states parties would be more likely to cooperate. third, civil society participation in reviewing core capacities should be enhanced. states parties' reports and who evaluations should be open to public scrutiny to increase transparency. as with other spheres of international law, such as human rights and climate change, civil society could off er "shadow" reports to states parties' reports and who evaluations and advocate for full funding of national capacities and fulfi lling international obligations. after facing criticism for disclosing the names of emergency committee members only after the h n public health emergency of international concern was terminated, who improved public trust by releasing member names for all subsequent emergency and review committees. who also pledged transparency about confl icts of interest. concerns persist, however, that emergency committees are infl uenced by politics rather than strictly reviewing scientifi c evidence. to increase transparency, who could publish full meeting minutes, provide web access to documents, and off er live updates through social media platforms. transparent emergency committee deliberations showing independence would build public trust, but reforms are of little value if the director-general does not convene an emergency committee. outside who's governing structure and drawing on civil society, an expert independent committee could convene to review data for disease outbreaks and recommend actions to the director-general. the world health assembly could amend the decision instrument to reduce states parties' reporting discretion, avoiding delayed notifi cation or verifi cation. presently, four diseases automatically require notifi cation. annex of the international health regulations could be modifi ed to require that additional listed diseases become automatically reportable. limiting states parties' discretion could simplify decision making and reinforce the norm of early notifi cation. routine notifi cations, moreover, would reduce the risk of under-reporting. guinean offi cials, for example, initially downplayed the risk, reporting only confi rmed ebola cases. procedurally, the world health assembly could update annex of the international health regulations as it did with annex regarding yellow fever vaccination. the ebola interim assessment panel said there was unawareness or incomplete understanding of international health regulations requirements at many levels. who could assist states parties in using the decision instrument by making international health regulations training publicly accessible through online platforms. the health security learning platform is a promising start, but is hard to fi nd on who's website; tutorials should be accessible without needing registration. furthermore, who should publicly acknowledge information received from non-governmental sources, and help with unoffi cial reporting. for example, to help gather real-time intelligence, who could develop web, phone, and tablet applications to report to who's strategic health operations centre. even if a state party does not corroborate an unoffi cial source, who should undertake its own analysis, sharing information transparently to the fullest extent possible in accordance with article of the international health regulations. the new web portal that who is developing for information sharing and transparency may assist in implementing this recommendation. a public health emergency of international concern declaration is the public face of who's outbreak response, but who has several instruments supporting earlier action. in view of the public symbolism of a public health emergency of international concern declaration, we believe that these emergency response frameworks must be integrated with international health regulations' processes. for example, who uses the emergency respons e frame work to inform the international community of an outbreak's severity in a graduated manner. a public health emergency of international concern declaration, however, would still be needed to raise the global alert, stiff en political resolve, and mobilise further resources. state and private industry disregard for who temporary recommendations-particularly travel and trade restrictions and injudicious quarantines-undermine the international health regulations. temporary recom mendations for ebola did not succeed on two fronts: the ebola-aff ected countries' health systems did not have the resources to implement who temporary recommendations; and states parties, because of domestic political pressure, disregarded temporary recommendations and did not discourage private disruptions of travel and trade, such as airlines cancelling fl ights. governments imposed additional measures, impeding deployment of health workers and medical supplies to the aff ected region. to enhance compliance, who should publicly request states parties to justify additional measures and urge businesses to reconsider restrictions. who should publicly acknowledge states parties and businesses that comply with temporary recommendations, while publicly naming those that impose unnecessary travel and trade restrictions. states parties should consider pursuing dispute mediation through the director-general or compulsory arbitration (article of the international health regulations). successful cases by states parties harmed by travel or trade restrictions or human rights violations would be a powerful precedent to enhance compliance. lastly, the world health assembly could amend the international health regulations to increase temporary recommendations to a binding status. even if temporary recommendations remain non-binding, trade restrictions could be challenged through the world trade organization, as mexico did during the h n pandemic. the inter national health regulations (article ) requires who to cooperate and coordinate its activities with intergovernmental bodies, including entering into formal agreements. these agreements could focus on one-health strategies, approaches based in the connections between human, animal, and environmental health. cooperative arrangements can help one-health strategies, such as reducing antibiotic use in animals and misuse in humans; monitoring and preventing zoological infections; ensuring secure handling of hazardous materials; and facilitating vaccine research. furthermore, equitable sharing of the benefi ts and burdens of scientifi c technology is crucial. the world health assembly should expand the pandemic infl uenza preparedness framework during its upcoming review of the framework and integrate it with the international health regulations. years after its adoption, the time has come to realise the international health regulations' promise. the unconscionable ebola epidemic opened a window of opportunity for fundamental reform-both for the international health regulations and the organisation that oversees the treaty. that political window, however, is rapidly closing. donor fatigue, fading memories, and competing priorities are diverting political attention. empowering who and realising the international health regulations' potential would shore up global health security-an important investment in human and animal health, while reducing the vast economic consequences of the next global health emergency. who. report of the ebola interim assessment panel ebola virus disease outbreak and follow-up to the special session of the executive board on ebola us departments of agriculture, state, and defense, and usaid. global health security agenda: toward a world safe and secure from infectious disease threats g . g- leaders' declaration who. states parties to the international health regulations swine infl uenza: statement by who director-general, dr. margaret chan responding to public health emergencies: report by the director-general who. implementation of the international health regulations ( ): report of the review committee on the functioning of the international health regulations ( ) in relation to pandemic (h n ) , doc. a / ebola toll rises in "unprecedented" epidemic ebola interim assessment panel. report of the ebola interim assessment panel mers in korea: why this outbreak can be stopped soon middle east respiratory syndrome (mers): frequently asked questions and answers who. who statement on the eighth meeting of the ihr emergency committee regarding mers-cov who. report of the fi rst meeting of the review committee on the role of the international health regulations report of the review committee on second extensions for establishing national public health capacities and on ihr implementation: report by the director-general pandemic emergency facility: frequently asked questions ebola: what lessons for the international health regulations report of the review committee on the functioning of the international health regulations ( ) in relation to the pandemic (h n ) , doc. a / who. frequently asked questions on ihr emergency committee emails: un health agency resisted declaring ebola emergency international health regulations: strategic health operation centres director-general addresses g health ministers on ebola emergency response framework who. current who phases of pandemic alert for pandemic (h n ) all authors contributed equally to the report. key: cord- - nhgxoim authors: huang, chaolin; wang, yeming; li, xingwang; ren, lili; zhao, jianping; hu, yi; zhang, li; fan, guohui; xu, jiuyang; gu, xiaoying; cheng, zhenshun; yu, ting; xia, jiaan; wei, yuan; wu, wenjuan; xie, xuelei; yin, wen; li, hui; liu, min; xiao, yan; gao, hong; guo, li; xie, jungang; wang, guangfa; jiang, rongmeng; gao, zhancheng; jin, qi; wang, jianwei; cao, bin title: clinical features of patients infected with novel coronavirus in wuhan, china date: - - journal: lancet doi: . /s - ( ) - sha: doc_id: cord_uid: nhgxoim background: a recent cluster of pneumonia cases in wuhan, china, was caused by a novel betacoronavirus, the novel coronavirus ( -ncov). we report the epidemiological, clinical, laboratory, and radiological characteristics and treatment and clinical outcomes of these patients. methods: all patients with suspected -ncov were admitted to a designated hospital in wuhan. we prospectively collected and analysed data on patients with laboratory-confirmed -ncov infection by real-time rt-pcr and next-generation sequencing. data were obtained with standardised data collection forms shared by who and the international severe acute respiratory and emerging infection consortium from electronic medical records. researchers also directly communicated with patients or their families to ascertain epidemiological and symptom data. outcomes were also compared between patients who had been admitted to the intensive care unit (icu) and those who had not. findings: by jan , , admitted hospital patients had been identified as having laboratory-confirmed -ncov infection. most of the infected patients were men ( [ %] of ); less than half had underlying diseases ( [ %]), including diabetes (eight [ %]), hypertension (six [ %]), and cardiovascular disease (six [ %]). median age was · years (iqr · – · ). ( %) of patients had been exposed to huanan seafood market. one family cluster was found. common symptoms at onset of illness were fever ( [ %] of patients), cough ( [ %]), and myalgia or fatigue ( [ %]); less common symptoms were sputum production ( [ %] of ), headache (three [ %] of ), haemoptysis (two [ %] of ), and diarrhoea (one [ %] of ). dyspnoea developed in ( %) of patients (median time from illness onset to dyspnoea · days [iqr · – · ]). ( %) of patients had lymphopenia. all patients had pneumonia with abnormal findings on chest ct. complications included acute respiratory distress syndrome ( [ %]), rnaaemia (six [ %]), acute cardiac injury (five [ %]) and secondary infection (four [ %]). ( %) patients were admitted to an icu and six ( %) died. compared with non-icu patients, icu patients had higher plasma levels of il , il , il , gscf, ip , mcp , mip a, and tnfα. interpretation: the -ncov infection caused clusters of severe respiratory illness similar to severe acute respiratory syndrome coronavirus and was associated with icu admission and high mortality. major gaps in our knowledge of the origin, epidemiology, duration of human transmission, and clinical spectrum of disease need fulfilment by future studies. funding: ministry of science and technology, chinese academy of medical sciences, national natural science foundation of china, and beijing municipal science and technology commission. coronaviruses are enveloped non-segmented positivesense rna viruses belonging to the family coronaviridae and the order nidovirales and broadly distributed in humans and other mammals. although most human coronavirus infections are mild, the epidemics of the two betacoronaviruses, severe acute respiratory syndrome coronavirus (sars-cov) [ ] [ ] [ ] and middle east respiratory syndrome coronavirus (mers-cov), , have caused more than cumulative cases in the past two decades, with mortality rates of % for sars-cov and % for mers-cov. , the coronaviruses already identified might only be the tip of the iceberg, with potentially more novel and severe zoonotic events to be revealed. in december, , a series of pneumonia cases of unknown cause emerged in wuhan, hubei, china, with clinical presentations greatly resembling viral pneumonia. deep sequencing analysis from lower respiratory tract samples indicated a novel coronavirus, which was named novel coronavirus ( -ncov). thus far, more than confirmed cases, including in health-care workers, have been identified in wuhan, and several exported cases have been confirmed in other provinces in china, and in thailand, japan, south korea, and the usa. - we aim to describe epidemiological, clinical, laboratory, and radiological characteristics, treatment, and outcomes of patients confirmed to have -ncov infection, and to compare the clinical features between intensive care unit (icu) and non-icu patients. we hope our study findings will inform the global community of the emergence of this novel coronavirus and its clinical features. following the pneumonia cases of unknown cause reported in wuhan and considering the shared history of exposure to huanan seafood market across the patients, an epidemiological alert was released by the local health authority on dec , , and the market was shut down on jan , . meanwhile, suspected cases with fever and dry cough were transferred to a designated hospital starting from dec , . an expert team of physicians, epidemiologists, virologists, and government officials was soon formed after the alert. since the cause was unknown at the onset of these emerging infections, the diagnosis of pneumonia of unknown cause in wuhan was based on clinical characteristics, chest imaging, and the ruling out of common bacterial and viral pathogens that cause pneumonia. suspected patients were isolated using airborne precautions in the designated hospital, jin yintan hospital (wuhan, china), and fit-tested n masks and airborne precautions for aerosol-generating procedures were taken. this study was approved by the national health commission of china and ethics commission of jin yin-tan hospital (ky- - . ). written informed consent was waived by the ethics commission of the designated hospital for emerging infectious diseases. local centres for disease control and prevention collected respiratory, blood, and faeces specimens, then shipped them to designated authoritative laboratories to detect the pathogen (nhc key laboratory of systems biology of pathogens and christophe mérieux laboratory, beijing, china). a novel coronavirus, which was named -ncov, was isolated then from lower respiratory tract specimen and a diagnostic test for this virus was developed soon after that. of suspected cases, patients were confirmed to be infected with -ncov. the presence of -ncov in respi ratory specimens was detected by nextgeneration se quencing or real-time rt-pcr methods. the primers and probe target to envelope gene of cov were used and the sequences were as follows: forward primer ′-acttctttttcttgctttcgtggt- ′; reverse primer ′-gcagcagtacgcacacaatc- ′; and the probe ′cy -ctagttacactagccatccttactgc- ′bhq . conditions for the amplifications were °c for min, °c for min, followed by cycles of °c for s and °c for s. initial investigations included a complete blood count, coagulation profile, and serum biochemical test (including renal and liver function, creatine kinase, lactate dehydrogenase, and electrolytes). respiratory specimens, including nasal and pharyngeal swabs, bronchoalveolar lavage fluid, sputum, or bronchial aspirates were tested for common viruses, including influenza, avian influenza, respiratory syncytial virus, adenovirus, parainfluenza virus, sars-cov and mers-cov using real-time rt-pcr assays approved by the china food and drug administration. routine bacterial and fungal examinations were also performed. given the emergence of the -ncov pneumonia cases during the influenza season, antibiotics (orally and intravenously) and osel tamivir (orally mg twice daily) were empirically administered. corticosteroid therapy evidence before this study human coronaviruses, including hcov- e, oc , nl , and hku , cause mild respiratory diseases. fatal coronavirus infections that have emerged in the past two decades are severe acute respiratory syndrome coronavirus (sars-cov) and the middle east respiratory syndrome coronavirus. we searched pubmed and the china national knowledge infrastructure database for articles published up to jan , , using the keywords "novel coronovirus", " novel coronavirus", or " -ncov". no published work about the human infection caused by the novel coronavirus ( -ncov) could be identified. we report the epidemiological, clinical, laboratory, and radiological characteristics, treatment, and clinical outcomes of laboratory-confirmed cases infected with -ncov. ( %) of patients had a history of direct exposure to the huanan seafood market. the median age of patients was · years (iqr · - · ), and ( %) patients had underlying disease. all patients had pneumonia. a third of patients were admitted to intensive care units, and six died. high concentrations of cytokines were recorded in plasma of critically ill patients infected with -ncov. implications of all the available evidence -ncov caused clusters of fatal pneumonia with clinical presentation greatly resembling sars-cov. patients infected with -ncov might develop acute respiratory distress syndrome, have a high likelihood of admission to intensive care, and might die. the cytokine storm could be associated with disease severity. more efforts should be made to know the whole spectrum and pathophysiology of the new disease. (methylprednisolone - mg per day) was given as a combined regimen if severe community-acquired pneumonia was diagnosed by physicians at the designated hospital. oxygen support (eg, nasal cannula and invasive mechanical ventilation) was administered to patients according to the severity of hypoxaemia. repeated tests for -ncov were done in patients confirmed to have -ncov infection to show viral clearance before hospital discharge or discontinuation of isolation. we reviewed clinical charts, nursing records, laboratory findings, and chest x-rays for all patients with laboratoryconfirmed -ncov infection who were reported by the local health authority. the admission data of these patients was from dec , , to jan , . epidemiological, clinical, laboratory, and radiological characteristics and treatment and outcomes data were obtained with standardised data collection forms (modified case record form for severe acute respiratory infection clinical characterisation shared by who and the international severe acute respiratory and emerging infection consortium) from electronic medical records. two researchers also independently reviewed the data collection forms to double check the data collected. to ascertain the epidemiological and symptom data, which were not available from electronic medical records, the researchers also directly communicated with patients or their families to ascertain epidemiological and symptom data. to characterise the effect of coronavirus on the production of cytokines or chemokines in the acute phase of the illness, plasma cytokines and chemokines (il b, il ra, il , il , il , il , il , il (also known as cxcl ), il , il , il p , il , il , il a, eotaxin (also known as ccl ), basic fgf , gcsf (csf ), gmcsf (csf ), ifnγ, ip (cxcl ), mcp (ccl ), mip a (ccl ), mip b (ccl ), pdgfb, rantes (ccl ), tnfα, and vegfa were measured using human cytokine standard -plex assays panel and the bio-plex system (bio-rad, hercules, ca, usa) for all patients according to the manufacturer's instructions. the plasma samples from four healthy adults were used as controls for crosscomparison. the median time from being transferred to a designated hospital to the blood sample collection was days (iqr - ). each µl plasma sample from the patients and contacts was added into µl of trizol ls ( ; thermo fisher scientific, carlsbad, ca, usa) in the biosafety level laboratory. total rna was extracted by direct-zol rna miniprep kit (r ; zymo research, irvine, ca, usa) according to the manufacturer's instructions and µl elution was obtained for each sample. µl rna was used for real-time rt-pcr, which targeted the np gene using agpath-id one-step rt-pcr reagent (am ; thermo fisher scientific). the final reaction mix concentration of the primers was nm and probe was nm. real-time rt-pcr was per formed using the following conditions: °c for min and °c for min, cycles of amplification at °c for s and °c for s. since we did not perform tests for detecting infectious virus in blood, we avoided the term viraemia and used rnaaemia instead. rnaaemia was defined as a positive result for real-time rt-pcr in the plasma sample. acute respiratory distress syndrome (ards) and shock were defined according to the interim guidance of who for novel coronavirus. hypoxaemia was defined as arterial oxygen tension (pao₂) over inspiratory oxygen fraction (fio₂) of less than mm hg. acute kidney injury was identified and classified on the basis of the highest serum creatinine level or urine output criteria according to the kidney disease improving global outcomes classification. secondary infection was diagnosed if the patients had clinical symptoms or signs of nosocomial pneumonia or bacteraemia, and was combined with a positive culture of a new pathogen from a lower respiratory tract specimen (including the sputum, transtracheal aspirates, or bronchoalveolar lavage fluid, or from blood samples taken ≥ h after admission). cardiac injury followed the definition used in our previous study in h n patients. in brief, cardiac injury was diagnosed if serum levels of cardiac biomarkers (eg, troponin i) were above the th percentile upper reference limit, or new abnormalities were shown in electrocardiography and echocardiography. continuous variables were expressed as median (iqr) and compared with the mann-whitney u test; categorical variables were expressed as number (%) and compared by χ² test or fisher's exact test between icu care and no icu care groups. boxplots were drawn to describe plasma cytokine and chemokine concentrations. a two-sided α of less than · was considered statistically significant. statistical analyses were done using the sas software, version . , unless otherwise indicated. the funder of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report. the corresponding authors had full access to all the data in the study and had final responsibility for the decision to submit for publication. by jan , , admitted hospital patients were identified as laboratory-confirmed -ncov infection in wuhan. [ %]) of the -ncov-infected patients were aged - years, and ( %) were aged - years (figure a). the median age of the patients was · years (iqr · - · ; table ). in our cohort of the first patients as of jan , no children or adolescents were infected. of the patients, ( %) were admitted to the icu because they required high-flow nasal cannula or higher-level oxygen support measures to cor rect hypoxaemia. most of the infected patients were men ( ). the symptom onset date of the first patient identified was dec , . none of his family members developed fever or any respiratory symptoms. no epidemiological link was found between the first patient and later cases. the first fatal case, who had continuous exposure to the market, was admitted to hospital because of a -day history of fever, cough, and dyspnoea. days after illness onset, his wife, a -year-old woman who had no known history of exposure to the market, also presented with pneumonia and was hospitalised in the isolation ward. the most common symptoms at onset of illness were fever ( most patients had normal serum levels of procalcitonin on admission (procalcitonin < · ng/ml; [ %] patients; table ). four icu patients developed secondary infections. three of the four patients with secondary infection had procalcitonin greater than · ng/ml ( · ng/ml, · ng/ml, and · ng/ml). on admission, abnormalities in chest ct images were detected among all patients. of the patients, ( %) had bilateral involvement (table ). the typical findings of chest ct images of icu patients on admission were bilateral multiple lobular and subsegmental areas of consolidation ( figure a) . the representative chest ct findings of non-icu patients showed bilateral groundglass opacity and subseg mental areas of consolidation (figure b). later chest ct images showed bilateral ground-glass opacity, whereas the consolidation had been resolved (figure c). initial plasma il b, il ra, il , il , il , il , basic fgf, gcsf, gmcsf, ifnγ, ip , mcp , mip a, mip b, pdgf, tnfα, and vegf concentrations were higher in both icu patients and non-icu patients than in healthy adults (appendix pp - ). plasma levels of il , il p , il , eotaxin, and rantes were similar between healthy adults and patients infected with -ncov. further comparison between icu and non-icu patients showed that plasma concentrations of il , il , il , gcsf, ip , mcp , mip a, and tnfα were higher in icu patients than non-icu patients. all patients had pneumonia. ; table ). invasive mechanical ventilation was required in four ( %) patients, with two of them ( %) had refractory hypoxaemia and received extracorporeal membrane oxygenation as salvage therapy. all patients were administered with empirical antibiotic treatment, and ( %) patients received antiviral therapy (osel tamivir). additionally, nine ( %) patients were given systematic corticosteroids. a comparison of clinical features between patients who received and did not receive systematic corticosteroids is in the appendix (pp - ). as of jan , , ( %) of patients have been dis charged and six ( %) patients have died. fitness for discharge was based on abatement of fever for at least days, with improvement of chest radiographic evidence and viral clearance in respiratory samples from upper respiratory tract. we report here a cohort of patients with laboratoryconfirmed -ncov infection. patients had serious, sometimes fatal, pneumonia and were admitted to the designated hospital in wuhan, china, by jan , . clinical presentations greatly resemble sars-cov. patients with severe illness developed ards and required icu admission and oxygen therapy. the time between hospital admission and ards was as short as days. at this stage, the mortality rate is high for -ncov, because six ( %) of patients in this cohort died. the number of deaths is rising quickly. as of jan , , laboratory-confirmed -ncov infec tions were reported in china, with fatal cases. reports have been released of exported cases in many provinces in china, and in other countries; see online for appendix some health-care workers have also been infected in wuhan. taken together, evidence so far indicates human transmission for -ncov. we are concerned that -ncov could have acquired the ability for efficient human trans mission. airborne precautions, such as a fit-tested n respirator, and other personal protective equipment are strongly recommended. to prevent further spread of the disease in health-care settings that are caring for patients infected with -ncov, onset of fever and respiratory symptoms should be closely moni tored among health-care workers. testing of respiratory specimens should be done immediately once a diagnosis is suspected. serum antibodies should be tested among health-care workers before and after their exposure to -ncov for identification of asymp tomatic infections. similarities of clinical features between -ncov and previous betacoronavirus infections have been noted. in this cohort, most patients presented with fever, dry cough, dyspnoea, and bilateral ground-glass opacities on chest ct scans. these features of -ncov infection bear some resemblance to sars-cov and mers-cov infections. , however, few patients with -ncov infection had prominent upper respiratory tract signs and symptoms (eg, rhinorrhoea, sneezing, or sore throat), indicating that the target cells might be located in the lower airway. furthermore, -ncov patients rarely developed intestinal signs and symptoms (eg, diarrhoea), whereas about - % of patients with mers-cov or sars-cov infection had diarrhoea. faecal and urine samples should be tested to exclude a potential alternative route of transmission that is unknown at this stage. the pathophysiology of unusually high pathogenicity for sars-cov or mers-cov has not been completely understood. early studies have shown that increased amounts of proinflammatory cytokines in serum (eg, il b, il , il , ifnγ, ip , and mcp ) were associated with pulmonary inflammation and extensive lung damage in sars patients. mers-cov infection was also reported to induce increased concentrations of proinflammatory cytokines (ifnγ, tnfα, il , and il ). we noted that patients infected with -ncov also had high amounts of il b, ifnγ, ip , and mcp , probably leading to activated t-helper- (th ) cell responses. moreover, patients requiring icu admission had higher concentrations of gcsf, ip , mcp , mip a, and tnfα than did those not requiring icu admission, suggesting that the cytokine storm was associated with disease severity. however, -ncov infection also initiated increased secretion of t-helper- (th ) cytokines (eg, il and il ) that suppress inflammation, which differs from sars-cov infection. further studies are necessary to characterise the th and th responses in -ncov infection and to elucidate the pathogenesis. autopsy or biopsy studies would be the key to understand the disease. in view of the high amount of cytokines induced by sars-cov, , mers-cov, , and -ncov infections, corticosteroids were used frequently for treatment of patients with severe illness, for possible benefit by reducing inflammatory-induced lung injury. however, current evidence in patients with sars and mers suggests that receiving corticosteroids did not have an effect on mortality, but rather delayed viral clearance. [ ] [ ] [ ] therefore, corticosteroids should not be routinely given systemically, according to who interim guidance. among our cohort of laboratory-confirmed patients with -ncov infection, corticosteroids were given to very few non-icu cases, and low-to-moderate dose of corticosteroids were given to less than half of severely ill patients with ards. further evidence is urgently needed to assess whether systematic corticosteroid treatment is beneficial or harmful for patients infected with -ncov. no antiviral treatment for coronavirus infection has been proven to be effective. in a historical control study, the combination of lopinavir and ritonavir among sars-cov patients was associated with substantial clinical benefit (fewer adverse clinical outcomes). arabi and colleagues initiated a placebo-controlled trial of interferon beta- b, lopinavir, and ritonavir among patients with mers infection in saudi arabia. preclinical evidence showed the potent efficacy of remdesivir (a broad-spectrum antiviral nucleotide prodrug) to treat mers-cov and sars-cov infections. , as -ncov is an emerging virus, an effective treatment has not been developed for disease resulting from this virus. since the combination of lopinavir and ritonavir was already available in the designated hospital, a randomised controlled trial has been initiated quickly to assess the efficacy and safety of combined use of lopinavir and ritonavir in patients hospitalised with -ncov infection. our study has some limitations. first, for most of the patients, the diagnosis was confirmed with lower respiratory tract specimens and no paired nasopharyngeal swabs were obtained to investigate the difference in the viral rna detection rate between upper and lower respiratory tract specimens. serological detection was not done to look for -ncov antibody rises in patients with undetectable viral rna. second, with the limited number of cases, it is difficult to assess host risk factors for disease severity and mortality with multivariableadjusted methods. this is a modest-sized case series of patients admitted to hospital; collection of standardised data for a larger cohort would help to further define the clinical presentation, natural history, and risk factors. further studies in outpatient, primary care, or community settings are needed to get a full picture of the spectrum of clinical severity. at the same time, finding of statistical tests and p values should be interpreted with caution, and non-significant p values do not necessarily rule out difference between icu and non-icu patients. third, since the causative pathogen has just been identified, kinetics of viral load and antibody titres were not available. finally, the potential exposure bias in our study might account for why no paediatric or adolescent patients were reported in this cohort. more effort should be made to answer these questions in future studies. both sars-cov and mers-cov were believed to originate in bats, and these infections were transmitted directly to humans from market civets and dromedary camels, respectively. extensive research on sars-cov and mers-cov has driven the discovery of many sars-like and mers-like coronaviruses in bats. in , ge and colleagues reported the whole genome sequence of a sars-like coronavirus in bats with that ability to use human ace as a receptor, thus having replication potentials in human cells. -ncov still needs to be studied deeply in case it becomes a global health threat. reliable quick pathogen tests and feasible differential diagnosis based on clinical description are crucial for clinicians in their first contact with suspected patients. because of the pandemic potential of -ncov, careful surveillance is essential to monitor its future host adaption, viral evolution, infectivity, transmissibility, and pathogenicity. bc and jw had the idea for and designed the study and had full access to all data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. ywa, gf, xg, jixu, hl, and bc contributed to writing of the report. bc contributed to critical revision of the report. ywa, gf, xg, jixu, and hl contributed to the statistical analysis. all authors contributed to data acquisition, data analysis, or data interpretation, and reviewed and approved the final version. all authors declare no competing interests. the data that support the findings of this study are available from the corresponding author on reasonable request. participant data without names and identifiers will be made available after approval from the corresponding author and national health commission. after publication of study findings, the data will be available for others to request. the research team will provide an email address for communication once the data are approved to be shared with others. the proposal with detailed description of study objectives and statistical analysis plan will be needed for evaluation of the reasonability to request for our data. the corresponding author and national health commission will make a decision based on these materials. additional materials may also be required during the process. clinical virology a novel coronavirus associated with severe acute respiratory syndrome newly discovered coronavirus as the primary cause of severe acute respiratory syndrome identification of a novel coronavirus in patients with severe acute respiratory syndrome middle east respiratory syndrome coronavirus (mers-cov): announcement of the coronavirus study group isolation of a novel coronavirus from a man with pneumonia in saudi arabia summary of probable sars cases with onset of illness from who. middle east respiratory syndrome coronavirus who. novel coronavirus -japan (ex-china) novel coronavirus -republic of korea (ex-china) first travel-related case of novel coronavirus detected in united states a novel coronavirus genome identified in a cluster of pneumonia cases -wuhan 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+ cells in sars patients: relation to the acute lung injury and pathogenesis of sars distinct immune response in two mers-cov-infected patients: can we go from bench to bedside? treatment with interferon-α b and ribavirin improves outcome in mers-covinfected rhesus macaques sars: systematic review of treatment effects corticosteroids as adjunctive therapy in the treatment of influenza corticosteroid therapy for critically ill patients with middle east respiratory syndrome clinical management of severe acute respiratory infection when novel coronavirus (ncov) infection is suspected role of lopinavir/ritonavir in the treatment of sars: initial virological and clinical findings treatment of middle east respiratory syndrome with a combination of lopinavir-ritonavir and interferon-β b (miracle trial): study protocol for a randomized controlled trial broad-spectrum antiviral gs- inhibits both epidemic and zoonotic coronaviruses comparative therapeutic efficacy of remdesivir and combination lopinavir, ritonavir, and interferon beta against mers-cov origin and evolution of pathogenic coronaviruses isolation and characterization of a bat sars-like coronavirus that uses the ace receptor bats as animal reservoirs for the sars coronavirus: hypothesis proved after years of virus hunting we acknowledge all health-care workers involved in the diagnosis and treatment of patients in wuhan; we thank the chinese national health commission for coordinating data collection for patients with -ncov infection; we thank who and the international severe acute respiratory and emerging infections consortium (isaric) for sharing data collection templates publicly on the website; and we thank prof chen wang and prof george f gao for guidance in study design and interpretation of results. key: cord- - xj ys c authors: headey, derek; heidkamp, rebecca; osendarp, saskia; ruel, marie; scott, nick; black, robert; shekar, meera; bouis, howarth; flory, augustin; haddad, lawrence; walker, neff title: impacts of covid- on childhood malnutrition and nutrition-related mortality date: - - journal: lancet doi: . /s - ( ) - sha: doc_id: cord_uid: xj ys c nan the unprecedented global social and economic crisis triggered by the covid- pandemic poses grave risks to the nutritional status and survival of young children in low-income and middle-income countries (lmics). of particular concern is an expected increase in child malnutrition, including wasting, due to steep declines in household incomes, changes in the availability and affordability of nutritious foods, and interruptions to health, nutrition, and social protection services. one in ten deaths among children younger than years in lmics is attributable to severe wasting because wasted children are at increased risk of mortality from infectious diseases. before the covid- pandemic, an estimated million children younger than years were moderately or severely wasted, most living in sub-saharan africa and south asia. the economic, food, and health systems disruptions resulting from the covid- pandemic are expected to continue to exacerbate all forms of malnutrition. estimates from the international food policy research institute suggest that because of the pandemic an additional million people will be thrown into living in extreme poverty on less than us$ · per day in . according to the world food programme, the number of people in lmics facing acute food insecurity will nearly double to million by the end of . sharp declines are expected in access to child health and nutrition services, similar to those seen during the - outbreak of ebola virus disease in sub-saharan africa. early in the covid- pandemic, unicef estimated a % overall reduction in essential nutrition services coverage, reaching - % in lockdown contexts, including in fragile countries where there are humanitarian crises. the accompanying call to action on child malnutrition and covid- from leaders of four un agencies the lancet is an important first step for the international community. alongside these efforts, the standing together for nutrition consortium, a multidisciplinary consortium of nutrition, economics, food, and health systems researchers, is working to estimate the scale and reach of nutrition challenges related to covid- . these efforts link three approaches to model the combined economic and health systems impacts from covid- on malnutrition and mortality: miragrodep's macroeconomic projections of impacts on per capita gross national income (gni); microeconomic estimates of how predicted gni shocks impact child wasting using data on · million children from demographic health surveys (dhs) conducted in lmics between - ; and the lives saved tool (list), which links country-specific health services disruptions and predicted increases in wasting to child mortality. what do our initial analyses and estimates suggest? first, the miragrodep projections suggest that even fairly short lockdown measures, combined with severe mobility disruptions and comparatively moderate food systems disruptions, result in most lmics having an estimated average · % (sd · %) decrease in gni per capita relative to pre-covid- projections. second, the microeconomic model projections indicate that decreases in gni per capita are associated with large increases in child wasting. our own analyses, based on these estimates applied to lmics, suggest there could be a · % increase in the prevalence of moderate or severe wasting among children younger than years due to covid- -related predicted countryspecific losses in gni per capita. we estimate this would translate to an additional estimated · million children with wasting in compared with projections for without covid- ; an estimated · % of these children are in south asia and an estimated · % in sub-saharan africa. third, when the projected increase in wasting in each country is combined with a projected year average of % reduction in coverage of nutrition and health services, we estimate there would be (ranging from to for best and worst case scenarios) additional deaths in children younger than years during , with an estimated % of these deaths in sub-saharan africa. the range reflects coverage scenarios, as previously described by roberton and colleagues, using a low of % and high of % disruption in vitamin a supplementation, treatment of severe wasting, promotion of improved young child feeding, and provision of micronutrient supplements to pregnant women. our projections emphasise the crucial need for the actions to protect child nutrition that are urged by the un leaders in the accompanying comment. these actions require rapid mobilisation of domestic and donor resources at a time when most national economies are reeling from covid- -related losses. in , the word bank estimated that $ billion per year over years is needed to reach the global sustainable development goal nutrition targets. these estimates need to be revised upwards to overcome covid- related setbacks. the covid- pandemic is expected to increase the risk of all forms of malnutrition. the wasting-focused estimates we present here are likely to be conservative, given that the duration of this crisis is unknown, and its full impacts on food, health, and social protection systems are yet to be realised. the disruption of other health services during lockdowns will further compromise maternal and child health and mortality, and with the deepening of economic and food systems crises, other forms of malnutrition, including child stunting, micronutrient malnutrition, and maternal nutrition, are expected to increase. without adequate action, the profound impact of the covid- pandemic on early life nutrition could have intergenerational consequences for child growth and development and life-long impacts on education, chronic disease risks, and overall human capital formation. forthcoming analyses by this consortium will examine a range of diet and nutrition outcomes in women and young children and provide consensus advice on multisectoral actions and resources needed to recover and support optimal nutrition now and into the future. covid- pandemic and mitigation strategies: implications for maternal and child health and nutrition maternal and child undernutrition and overweight in low-income and middle-income countries joint malnutrition estimates, edition poverty and food insecurity could grow dramatically as covid- spreads. ifpri blog covid- will double number of people facing food crises unless swift action is taken rapid assessment of ebola-related implications for reproductive, maternal, newborn and child health service delivery and utilization in guinea situation tracking for covid- socio-economic impacts child malnutrition and covid- : the time to act is now the impact of economic recessions on child acute malnutrition: implications for the covid- crisis early estimates of the indirect effects of the covid- pandemic on maternal and child mortality in low-income and middle-income countries: a modelling study an investment framework for nutrition : reaching the global targets for stunting, anemia, breastfeeding, and wasting. directions in development-human development improved nutrition in the first days and adult human capital and health the work on this study was supported by a grant from the children's investment fund foundation (ciff). the funders were not involved in the writing of this comment. rh and ms report grants from the bill & melinda gates foundation unrelated to the topic of this comment. we declare no other competing interests.derek headey key: cord- -x p n r authors: hope, michael d; raptis, constantine a; shah, amar; hammer, mark m; henry, travis s title: a role for ct in covid- ? what data really tell us so far date: - - journal: lancet doi: . /s - ( ) - sha: doc_id: cord_uid: x p n r nan radiologists have watched the coronavirus disease (covid- ) pandemic unfold, wondering if and how imaging could be useful for diagnosis. perhaps imaging could aid in screening or accelerate the speed of diagnosis, especially with shortages of rt-pcr. some radiology literature suggests a pivotal role for ct. ai and colleagues report on patients who received both rt-pcr and ct in wuhan, china, during their epidemic. they found that % of cases with rt-pcr-confirmed diagnoses had ct findings of pneumonia, and conclude, "ct imaging has high sensitivity for diagnosis of covid- ". other investigators are less optimistic. inui things look different now. the us and uk governments have provided among the world's worst responses to the pandemic, with sheer lies and incompetence from the former, and near-criminal delays and obfuscation from the latter. neither country has widespread testing available, as strongly recommended by who, alongside treatment and robust contact tracing. in neither country do health workers have adequate access to personal protective equipment; nor are there nearly enough hospital beds to accommodate the onslaught of patients. even worse, by refusing to ease sanctions against iran, venezuela, and cuba, the us has crippled the ability of other countries to respond, continuing to block medical supplies and other humanitarian aid. meanwhile, asian countries, including china, south korea, singapore, and taiwan, have provided rapid, effective, and often innovative responses, thanks in part to their recent experience with outbreaks of middle east respiratory syndrome in and the - severe acute respiratory syndrome epidemic. china has convened hundreds of foreign officials to share lessons, and dispatched experts, masks and other supplies to italy and other affected countries. cuba has also sent doctors to help with the response, and welcomed sick cruise ship passengers refused entry by the usa. although it is too early to assess the strength of the covid- response in africa, african countries, despite limited resources, have also adopted measures worth imitating, such as simplified triage strategies and proactive screening (uganda), handwashing stations at transport hubs (rwanda), whatsapp chatbots providing reliable information and rapid testing diagnostics (senegal), and volunteer-staffed call centres and celebrity campaigns to promote responsible actions during the pandemic (nigeria). yet relatively little has been heard on the global stage about these efforts or from african veterans of the ebola epidemics in west africa and central africa, even though covid- appears to spread in similar ways-through family clusters. is preparedness in the eye of the beholder? covid- is giving the lie to prevailing notions of expertise and solidarity. the global health model is based in large part on technical assistance and capacity building by the us, the uk, and other rich countries, whose response has been sclerotic and delayed at best. a recent report by global health / showed that % of global organisations working in health have headquarters in europe and north america; two-thirds are headquartered in switzerland, the uk, and the usa. more than % of global health leaders are nationals of high-income countries, and half are nationals of the uk and the usa. global health will never be the same after covid- -it cannot be. the pandemic has given the lie to the notion that expertise is concentrated in, or at least best channelled by, legacy powers and historically rich states. we must move quickly, for our own security, beyond the rhetoric of equality to the reality of a more democratic, more multipolar, more networked, and more distributed those who have died were older adults, most of whom had underlying health problems. globally, more than million people have dementia, and one new case occurs every s. dementia has emerged as a pandemic in an ageing society. the double hit of dementia and covid- pandemics has raised great concerns for people living with dementia. people living with dementia have limited access to accurate infor mation and facts about the covid- pandemic. they might have difficulties in remembering safeguard procedures, such as wearing masks, or in understanding the public health information issued to them. ignoring the warnings and lacking sufficient self-quarantine measures could expose them to higher chance of infection. older people in many countries, unlike in china, tend to live alone or with their spouse, either at home or in nursing homes. as more and more businesses stop non-essential services or initiate telecommuting work in an attempt to maintain social distancing and limit the further spread of sars-cov- , people living with dementia, who have little knowledge of telecommuni cation and depend primarily on in-person support might feel lonely and abandoned, and become withdrawn. to lessen the chance of infection among older people in nursing homes, more local authorities are banning visitors to nursing homes and longterm care facilities. in january, , the chinese ministry of civil affairs implemented similar social-distancing measures. as a result, older residents lost face-to-face contact with their family members. group activities in nursing homes were also prohibited. as a consequence, the residents of nursing homes became more socially isolated. we have observed that under the dual stress of fear of infection and worries about the residents' condition, the level of anxiety among staff in nursing homes increased and they developed signs of exhaustion and burnout after a monthlong full lockdown of the facilities. patients who require imaging. we urge caution and encourage using published guidelines regarding use of ct imaging. we declare no competing interests. rt-pcr-confirmed covid- from the diamond princess cruise ship. less than two-thirds ( %) of cases had lung opacities on ct; % of symptomatic patients had negative cts. although extremely valuable, these results should not be overstated. the ct findings studied (eg, groundglass opacity, consolidation) are not specific for covid- . similar results would probably be found if ct were used during an influenza epidemic, for example. the positive predictive value of ct will be low unless disease prevalence is high, as we suspect it was in wuhan. their cohort includes "patients suspected of [covid- ]", presumably sick and possibly hospitalised, although details are not provided. rt-pcr to diagnose covid- has some limitations: the test is not universally available, turnaround times can be lengthy, and reported sensitivities vary. nevertheless, it is the accepted standard and only positive in patients who are infected with severe acute respiratory syndrome coronavirus . ct findings in patients with covid- , on the other hand, are seen with numerous pathogens and in many non-infectious aetiologies. we believe ct does not add diagnostic value; positive results can only be believed if the pre-test probability of disease is high. using ct diagnostically is not known to provide clinical benefit and could lead to false security if results are negative. if covid- is suspected, patients should be isolated pending confirmation with (multiple) rt-pcr tests, or until quarantine has lapsed. the results of a ct scan do not change this. we feel that framing ct as pivotal for covid- diagnosis is a distraction during a pandemic, and possibly dangerous. safely using ct to study covid- patients is logistically challenging and can overwhelm available resources. even with proper cleaning protocols, health-care professionals and ct scanners could become vectors of infection to other vulnerable see online for appendix older adults are vulnerable at the onset of natural disasters and crisis, and this has been especially true during the coronavirus disease (covid- ) pandemic. with the aggressive spread of severe acute respiratory syndrome coronavirus (sars-cov- ), the death toll has risen worldwide. according to an interactive online tool that estimates the potential number of deaths from covid- in a population, by age group, in individual countries and regional groupings worldwide under a range of scenarios, most of correlation of chest ct and rt-pcr testing in coronavirus disease (covid- ) in china: a report of cases chest ct findings in cases from the cruise ship "diamond princess acr recommendations for the use of chest radiography and computed tomography (ct) for suspected covid- infection key: cord- -pqonn as authors: nicholls, john m; poon, leo lm; lee, kam c; ng, wai f; lai, sik t; leung, chung y; chu, chung m; hui, pak k; mak, kong l; lim, wilna; yan, kin w; chan, kwok h; tsang, ngai c; guan, yi; yuen, kwok y; malik peiris, js title: lung pathology of fatal severe acute respiratory syndrome date: - - journal: lancet doi: . /s - ( ) - sha: doc_id: cord_uid: pqonn as background: severe acute respiratory syndrome (sars) is a novel infectious disease with global impact. a virus from the family coronaviridae has been identified as the cause, but the pathogenesis is still unclear. methods: post-mortem tissue samples from six patients who died from sars in february and march, , and an open lung biopsy from one of these patients were studied by histology and virology. only one full autopsy was done. evidence of infection with the sars-associated coronavirus (sars-cov) and human metapneumovirus was sought by reverse-transcriptase pcr and serology. pathological samples were examined by light and electron microscopy and immunohistochemistry. findings: all six patients had serological evidence of recent infection with sars-cov. diffuse alveolar damage was common but not universal. morphological changes identified were bronchial epithelial denudation, loss of cilia, and squamous metaplasia. secondary bacterial pneumonia was present in one case. a giant-cell infiltrate was seen in four patients, with a pronounced increase in macrophages in the alveoli and the interstitium of the lung. haemophagocytosis was present in two patients. the alveolar pneumocytes also showed cytomegaly with granular amphophilic cytoplasm. the patient for whom full autopsy was done had atrophy of the white pulp of the spleen. electron microscopy revealed viral particles in the cytoplasm of epithelial cells corresponding to coronavirus. interpretation: sars is associated with epithelial-cell proliferation and an increase in macrophages in the lung. the presence of haemophagocytosis supports the contention that cytokine dysregulation may account, at least partly, for the severity of the clinical disease. the case definition of sars should acknowledge the range of lung pathology associated with this disease. published online may , http://image.thelancet.com/extras/ art web.pdf background severe acute respiratory syndrome (sars) is a novel infectious disease with global impact. a virus from the family coronaviridae has been identified as the cause, but the pathogenesis is still unclear. methods post-mortem tissue samples from six patients who died from sars in february and march, , and an open lung biopsy from one of these patients were studied by histology and virology. only one full autopsy was done. evidence of infection with the sars-associated coronavirus (sars-cov) and human metapneumovirus was sought by reverse-transcriptase pcr and serology. pathological samples were examined by light and electron microscopy and immunohistochemistry. findings all six patients had serological evidence of recent infection with sars-cov. diffuse alveolar damage was common but not universal. morphological changes identified were bronchial epithelial denudation, loss of cilia, and squamous metaplasia. secondary bacterial pneumonia was present in one case. a giant-cell infiltrate was seen in four patients, with a pronounced increase in macrophages in the alveoli and the interstitium of the lung. haemophagocytosis was present in two patients. the alveolar pneumocytes also showed cytomegaly with granular amphophilic cytoplasm. the patient for whom full autopsy was done had atrophy of the white pulp of the spleen. electron microscopy revealed viral particles in the cytoplasm of epithelial cells corresponding to coronavirus. since nov , , an outbreak of severe acute respiratory syndrome (sars) has affected countries in five continents, with reported cases and deaths at the time of writing. local transmission has occurred in at least six countries. the first cases of sars in hong kong special administrative region were recognised in february, . as of may , , there had been cases and deaths in the region. clinically, the disease is characterised by fever, dyspnoea, lymphopenia, and rapidly progressing changes on radiography. , upper-respiratory-tract symptoms are not prominent, but diarrhoea has been reported by some patients. there is no response to conventional antibiotics used to treat atypical pneumonia. the sars-associated coronavirus (sars-cov) has been consistently associated with this disease. although this virus seems to be necessary for the development of sars, it has not been localised at the site of lung pathology. , poutanen and colleagues found human metapneumovirus (hmpv) as a second pathogen in patients with sars and postulated that hmpv potentiates the progression or severity of coronavirus infection. the use of steroids together with ribavirin has been reported to confer clinical benefit, although randomised clinical trials to support its clinical efficacy are not available. to aid understanding of the pathogenesis of the disease and the relation to current therapy, we report the pathological and virological findings in six patients with sars who died. all patients who met a modified who case definition of sars and who underwent lung biopsy or post-mortem examination during march, , at four major hospitals in the kowloon hospital cluster were eligible for inclusion. the case definition was fever (temperature °c or higher), cough or shortness of breath, new pulmonary infiltrates on chest radiograph, and either a history of exposure to a patient with sars or a lack of response to empirical antimicrobial coverage for typical and atypical pneumonia (beta-lactams and macrolides, fluoroquinolones or tetracyclines). owing to the potentially infectious nature of the disorder, full autopsy was done in only one case. in the other cases, the post-mortem examination was limited to the lungs. we included only those patients for whom paired serum samples were submitted for virological studies during the course of the illness. patients with only needle-biopsy samples of organs available were excluded. during the period under study, there were six patients with pathological and virological investigation; one of these also underwent lung biopsy earlier in the course of the illness. in all cases the autopsy material was fixed in % neutral buffered formalin and later processed for electron microscopy. separate pieces of fresh tissue were sent for virological study; if sufficient quantity was available, they were stored at - °c for immunofluorescence studies. patients patient , a -year-old woman, had good health before the illness. she was admitted on march , , with a history of fever, cough, and general muscle pain for days. oxygen saturation on admission was % on % oxygen. the chest radiograph showed patchy haziness. the patient soon developed respiratory failure necessitating mechanical ventilation; ribavirin and antibiotic treatment was then started. the ratio of partial arterial pressure of oxygen (pao ) to fraction of inspired oxygen (fio ) was · kpa on the day before death. she died on march , after days of assisted ventilation. patient , a -year-old woman who was previously well, had indirect contact with a person who developed fever after return from guangzhou, china. she subsequently developed fever with shortness of breath and diarrhoea. she had lymphopenia at admission, and the chest radiograph showed infiltrates in the left upper zone. treatment with ribavirin and steroids was started on march . she developed respiratory failure the next day and was intubated. she had repeated cardiac arrests and died on march . patient , a -year-old man, developed influenza-like symptoms and left pleuritic chest pain on feb . a chest radiograph taken a day later showed haziness in the left lower zone. he subjectively improved after self-medication with levofloxacin and penicillin. he visited hong kong on feb as a tourist, but his condition then deteriorated. he was admitted directly to the intensive-care unit and intubated on feb . investigation showed diffuse bilateral ground-glass changes on chest radiograph and severe oxygen desaturation. despite empirical antimicrobial coverage for typical, atypical, and hospital-acquired pneumonia, his condition continued to deteriorate. he was empirically treated with oseltamivir, foscarnet, intravenous immunoglobulin and, at a later stage, ribavirin and steroids. after ventilation for days with a peak airway pressure of cm water, tidal volume of ml, and pao /fio · kpa, he died on march with acute respiratory distress syndrome and multiorgan failure. patient was a -year-old man with a history of hypertension. he had developed influenza-like symptoms a few days before admission on feb with chest radiographic changes of diffuse bilateral pneumonia and respiratory failure. he did not respond to doxycycline, amantadine, and cefotaxime. an open lung biopsy was done on march . routine microbiological and virological investigations were negative. he was empirically treated with oseltamivir, steroids, and ribavirin. non-oliguric renal failure developed and was later complicated by nosocomial pneumonia due to pseudomonas aeruginosa. he died on march , after ventilation for days with a peak airway pressure of cm water, tidal volume of ml, and pao /fio · kpa patient was a -year-old businessman who had a history of hepatitis b liver cirrhosis and portal hypertension. he developed influenza-like symptoms while in hong kong but still travelled overseas on feb . investigation at his destination showed lymphopenia and thrombocytopenia in the peripheral blood examination, and bilateral pulmonary infiltrates on chest radiograph. he went into respiratory failure on march , and on march was transferred back to hong kong, where he was ventilated. the ventilation pressure was / cm water most of the time. positive end-expiratory pressure was - cm water. the tidal volume was generally kept at - ml, and the pao was between % and % and fio between % and %. his renal function deteriorated progressively from march to march , and at the time of death the urea concentration was · mmol/l and creatinine µmol/l. total bilirubin varied between µmol/l and µmol/l. despite intensive support and antimicrobial coverage with piperacillin-tazobactam, azithromycin, and oseltamivir, he died on march . patient was a -year-old man with good health previously. on march he was admitted to hospital for increasing shortness of breath, fever, and cough for routine microbiological investigations included culture of blood and sputum for bacterial pathogens. serology was done with complement-fixation tests for respiratory viruses, chlamydiae, and mycoplasma pneumoniae. total rna and dna were extracted from nasopharyngeal aspirates with the viral rna minikit and qiamp dna minikit (qiagen, hilden, germany). reverse-transcriptase (rt) pcr was done for influenza a, adenovirus, hmpv, and a newly recognised coronavirus subsequently reported to be associated with sars. the rt-pcr protocol has been described previously. the biopsy sample or post-mortem lung tissue was homogenised in a tissue grinder, and the supernatant was inoculated onto cell cultures. viral rna was extracted from the tissues with the rneasy minikit (qiagen) according to the manufacturer's tissue protocol instructions. rt-pcr for the novel coronavirus and for hmpv was carried out as described above. serial dilutions of serum from acute and convalescent patients were tested in parallel for antibodies to the coronavirus and hmpv by an indirect immunofluorescence test on frhk- cells infected with the respective virus. role of the funding source the sponsors of the study had no role in the study design, data collection, analysis, or interpretation, or in the writing of the report. ante-mortem investigations for routine bacterial and viral respiratory pathogens proved unremarkable. however, all six patients had four-fold or greater rises in antibody titre the clinical presentations of two of these patients (patients and ) have been reported previously. only one patient (patient ) had an open lung biopsy done before death. the material was divided into four pieces; one was sent for viral studies, one frozen at - °c, one fixed in formalin, and the one fixed in · % glutaraldehyde. the latter was processed for transmission electron microscopy. for immunohistochemistry, paraffin-embedded blocks of the lung tissue were sectioned at µm and dewaxed by standard procedures. monoclonal antibodies (dako, carpintaria, ca, usa) to keratin ae / ( : ), cd t-cell ( : ), and cd macrophage marker ( : ) were applied on each section, and staining was done with the ventana nexes automated immunohistochemical stainer. frozen post-mortem lung tissue from one patient (patient ) was available for study. cryostat sections were stained with directly conjugated monoclonal antibodies to influenza viruses a and b, adenovirus, and parainfluenza virus (dako, usa) and examined under a nikon eclipse e m fluorescent microscope. in the biopsy sample from patient , most of the material was pleural tissue with a small amount of lung parenchyma. the architecture was preserved with a mild increase in interstitial lymphocytes. cytomegaly was present in a very few pneumocytes; it was characterised by nuclear enlargement, prominent nucleolus, and amphophilic granular cytoplasm (figure ). no typical viral inclusions were identified. there was a mild to moderate increase in alveolar macrophages and early hyaline-membrane formation. gross findings in the post-mortem lung tissue were similar among patients (table ) . where the lungs were removed en bloc, they weighed - g and were oedematous, with a greyish brown consolidated cut surface. the consolidation was irregular and patchy, with foci of pale tissue measuring up to several millimetres in diameter. more diffuse involvement was seen in one case (patient ); mucopurulent material was seen in the tracheobronchial tree. in cases of disease duration of less than days, the histological involvement of the lung varied, with a mixed inflammatory infiltrate, oedema, and hyaline-membrane formation seen (figure ; table ). the intra-alveolar oedema was granular or vacuolated. desquamation of pneumocytes was a prominent and consistent feature (figure ). all cases showed scattered single enlarged cells that, in most, were associated with large nuclei and prominent nucleoli, similar to the findings in the open lung biopsy sample. clearing of the chromatin was also seen. giantcell formation was seen within the alveolar lumen in four cases, and there were a few cells that contained amphophilic to basophilic cytoplasmic granules within enlarged pneumocytes. one patient (patient ) showed fibrin thrombi within pulmonary vessels, and another (patient ) showed intimal swelling of pulmonary vessels. in three of four cases, the giant cells were cytoplasm. we therefore hypothesise that this cytoplasmic amphophilia may be due to viral assembly within the golgi apparatus-a feature seen on electron microscopy of the open lung biopsy sample from patient . the histological changes of uncomplicated viral pneumonias are rarely described, and reports tend to be derived from post-mortem examination of patients who succumb to the pneumonia; thus, they may not be representative of the majority of pneumonia patients, who survive. , the same is true for sars, because the patients admitted to hospital have not been in a suitable medical condition to warrant biopsy. however, several features of fatal coronaviral pneumonia can be identified. coronavirus infection in the early stages seems to stimulate epithelial cells and results in cellular proliferation and squamous metaplasia in the lung. this type- pneumocyte hyperplasia and hypertrophy has also been identified with porcine reproductive and respiratory syndrome virus (an arterivirus tentatively classified under the coronaviridae ) as well as porcine respiratory coronavirus (previously known as transmissible gastroenteritis virus, respiratory variant). in those infections mild type- pneumocyte proliferation is associated with squamous metaplasia. in sars, macrophage proliferation is more prominent in the consolidated areas of the lung; this distribution is also seen with porcine respiratory coronavirus. in contrast to typical diffuse alveolar damage in which neutrophils and fibroblasts are the main cellular agents and macrophages have a lesser role, in patients with fatal sars macrophages are the prominent leucocyte in the alveoli, even in the early stages of the disease. the finding of haemophagocytosis in the lung and white-pulp atrophy of the spleen identified in sars is reminiscent of that reported in fatal influenza subtype h n disease in . haemophagocytosis has been attributed to cytokine dysregulation. lymphopenia is another feature common to both sars-cov and h n influenza pneumonia. both viruses have crossed to human beings from animals or birds. , experimental studies in which macrophages are infected in vitro suggest that, compared with conventional human influenza viruses, the subtype h n influenza a viruses isolated in are hyperinducers of proinflammatory cytokines. human coronavirus oc can replicate in human macrophages in vitro. taken together, the similarity of clinical and pathological changes in sars-cov pneumonia and h n pneumonia suggest that proinflammatory cytokines released by stimulated macrophages in the alveoli have a prominent role in pathogenesis of sars, resulting in cytokine dysregulation. this idea has implications for the management of coronaviral pneumonia. intervention with steroids might modulate this cytokine response and prevent a fatal outcome, as has been proposed for nonviral acute respiratory distress syndrome. although we did not find pcr evidence of a secondary viral infection, such as hmpv, in pigs infected with some isolates of porcine respiratory coronavirus, the respiratory lesions were severe enough to predispose the pigs to secondary bacterial or mycoplasmal infections or to lead to combined viral infections. as we have already mentioned, the histological features of porcine reproductive and respiratory syndrome virus infection are similar to those of sars-cov infection; it is possible that sars-cov infection in human beings may "open the door" to secondary infections, as previously reported. the patients who received ribavirin therapy still had pcr and electron-microscopic evidence of sars-cov in the lung. this finding supports clinical evidence that a search articles the lancet • vol • may , • www.thelancet.com positive for the macrophage marker cd (figure ); in one case, they were positive for the epithelial marker ae / . in the patient who had frozen tissue available, no staining was identified to adenovirus, parainfluenza virus, or influenza viruses a or b on frozen-section immunofluoresence. one patient, in whom the time from onset of symptoms to death was days, showed squamous metaplasia of the bronchi with loss of cilia ( figure ). in addition, within the parenchyma and also within the interstitium there were increased numbers of cd positive mononuclear cells and focal haemophagocytosis ( figure ). because of the risk of infection, most postmortem examinations were limited to the chest, but in patient , for whom a full autopsy was done, pronounced white-pulp atrophy of the spleen was seen. in this case, electron microscopy showed dilated golgi apparatus in the cytoplasm of pneumocytes, and within these organelles, nm viral particles with small external spikes corresponding to coronavirus were identified (figure ). these particles were of similar morphology to those reported previously. all of the six patients described had serological evidence of recent infection with the sars-cov. five had evidence of viral rna detectable in samples taken before or after death. in previous studies, healthy controls and patients with unrelated disease had no evidence of sars-cov antibody or rna in the serum or the respiratory tract, respectively. in patients with disease of duration less than days there was hyaline-membrane formation, pneumocyte proliferation, and oedema. diffuse alveolar damage was seen in cases of longer duration. this diffuse alveolar damage typically goes through an exudative phase followed by a proliferative phase, although others have described a three-stage process: an inflammatory or exudative phase, a proliferative phase, and a final fibrotic phase. viral infections resulting in diffuse alveolar damage typically fall into two categories; influenza viruses a and b and adenovirus cause most cases of viral pneumonia in immunocompetent adults. immunocompromised hosts are susceptible to pneumonias caused by cytomegalovirus and other herpesviruses, measles virus, and adenovirus. in addition to the diffuse alveolar damage here, morphological features of giant cells and pneumocyte hyperplasia, which appear to be prominent in this viral infection, were seen in these patients. , multinucleate giant cells within the alveoli have previously been reported in patients with sars, , but their derivation has remained unclear. we have documented that in three of the patients these giant cells are of macrophage origin and in one other patient they are epithelial in origin. these giant cells were not present in the ante-mortem lung biopsy sample and were present only in patients with disease progression for longer than days from admission. some animal coronaviruses induce syncytium formation in cell culture, and sars-cov also induces focal syncitium formation in vero cells. bronchial epithelial denudation, loss of cilia, and squamous metaplasia were early features. another notable feature was the presence of large pneumocytes showing an enlarged nucleus and granular amphophilic cytoplasm. these changes were also seen in the open lung biopsy sample from patient . coronavirus assembly takes place in the golgi apparatus of the cytoplasm; in the sections of the coronavirus-infected culture this process was characterised by swelling and increased granularity of the for a more promising antiviral agent is of high priority in the treatment of this disease. the recent who case definition of sars when an autopsy is done states that autopsy features showing changes of respiratory distress syndrome without an identifiable cause can be included, whereas those without respiratory distress syndrome should be excluded. previous reports have featured late cases, in which diffuse alveolar damage is pronounced. , our series of serologically confirmed cases shows there is a range of morphological changes in sars, and that in disease of less than days' duration the changes of respiratory distress syndrome may be focal and dissimilar to those previously published cases. pathologists undertaking these autopsies should be aware of the varied range of these morphological changes. cumulative number of reported cases of severe acute respiratory syndrome a cluster of cases of severe acute respiratory syndrome in hong kong severe acute respiratory syndrome (sars) is associated with a coronavirus a novel coronavirus associated with severe acute respiratory syndrome identification of severe acute respiratory syndrome in canada severe acute respiratory syndrome (sars) detection of influenza a virus from different species by pcr amplification of conserved sequences in the matrix gene clinical assessment of a generic dna amplification assay for the identification of respiratory adenovirus infections common pathways and patterns of injury the pulmonary physician in critical care: , the pathogenesis of ali/ards viral pneumonias in adults: radiologic and pathologic findings a major outbreak of severe acute respiratory syndrome in hong kong world organization for animal health the cytoplasmic tail of infectious bronchitis virus e protein directs golgi targeting influenza pneumonia in lung transplant recipients: clinical features and association with bronchiolitis obliterans syndrome comparison of the pathogenicity of two us porcine reproductive and respiratory syndrome virus isolates with that of the lelystad virus experimental reproduction of pneumonia in gnotobiotic pigs with porcine respiratory coronavirus isolate ar transmissible gastroentertitis virus (respiritory variant) pathology of fatal human infection associated with avian influenza a h n virus hemophagocytic syndromes and infection clinical features and rapid viral diagnosis of human disease associated with avian influenza a h n virus induction of proinflammatory cytokines in human macrophages by influenza a (h n ) viruses: a mechanism for the unusual severity of human disease human macrophages are susceptible to coronavirus oc role for macrophage migration inhibitory factor in acute respiratory distress syndrome pathogenicity of three isolates of porcine respiratory coronavirus in the usa case definitions for surveillance of severe acute respiratory syndrome (sars) we thank klaus stöhr and who for initiating and coordinating the information exchange between members of the who sars laboratories network, which has allowed rapid understanding of the aetiology of this disease; s y lam, s w kwan, k f lo, h y ng, c y cheung, k fung, and o k wong for their assistance; and trevor ellis of the department of agriculture and fisheries, government of the hong kong special administrative region for advice.we acknowledge research funding from public health research grant a from the national institute of allergy and infectious diseases, usa, the wellcome trust grant gr /d/ /z, the university of hong kong, and the hospital authority of hong kong special administrative region. none declared. key: cord- - ocseuz authors: donnelly, christl a; ghani, azra c; leung, gabriel m; hedley, anthony j; fraser, christophe; riley, steven; abu-raddad, laith j; ho, lai-ming; thach, thuan-quoc; chau, patsy; chan, king-pan; lam, tai-hing; tse, lai-yin; tsang, thomas; liu, shao-haei; kong, james hb; lau, edith mc; ferguson, neil m; anderson, roy m title: epidemiological determinants of spread of causal agent of severe acute respiratory syndrome in hong kong date: - - journal: lancet doi: . /s - ( ) - sha: doc_id: cord_uid: ocseuz background: health authorities worldwide, especially in the asia pacific region, are seeking effective public-health interventions in the continuing epidemic of severe acute respiratory syndrome (sars). we assessed the epidemiology of sars in hong kong. methods: we included cases reported up to april , . an integrated database was constructed from several sources containing information on epidemiological, demographic, and clinical variables. we estimated the key epidemiological distributions: infection to onset, onset to admission, admission to death, and admission to discharge. we measured associations between the estimated case fatality rate and patients’age and the time from onset to admission. findings: after the initial phase of exponential growth, the rate of confirmed cases fell to less than per day by april . public-health interventions included encouragement to report to hospital rapidly after the onset of clinical symptoms, contact tracing for confirmed and suspected cases, and quarantining, monitoring, and restricting the travel of contacts. the mean incubation period of the disease is estimated to be . days ( % cl . – . ). the mean time from onset of clinical symptoms to admission to hospital varied between and days, with longer times earlier in the epidemic. the estimated case fatality rate was . % ( . – . ) for patients younger than years and . % ( . – . ) for patients aged years or older assuming a parametric γ distribution. a non-parametric method yielded estimates of . % ( . – . ) and . % ( . – . ), respectively. case clusters have played an important part in the course of the epidemic. interpretation: patients’age was strongly associated with outcome. the time between onset of symptoms and admission to hospital did not alter outcome, but shorter intervals will be important to the wider population by restricting the infectious period before patients are placed in quarantine. published online may , http://image.thelancet.com/extras/ art web.pdf background health authorities worldwide, especially in the asia pacific region, are seeking effective public-health interventions in the continuing epidemic of severe acute respiratory syndrome (sars). we assessed the epidemiology of sars in hong kong. methods we included cases reported up to april , . an integrated database was constructed from several sources containing information on epidemiological, demographic, and clinical variables. we estimated the key epidemiological distributions: infection to onset, onset to admission, admission to death, and admission to discharge. we measured associations between the estimated case fatality rate and patients' age and the time from onset to admission. findings after the initial phase of exponential growth, the rate of confirmed cases fell to less than per day by april . public-health interventions included encouragement to report to hospital rapidly after the onset of clinical symptoms, contact tracing for confirmed and suspected cases, and quarantining, monitoring, and restricting the travel of contacts. the mean incubation period of the disease is estimated to be · days ( % ci · - · ). the mean time from onset of clinical symptoms to admission to hospital varied between and days, with longer times earlier in the epidemic. the estimated case fatality rate was · % ( · - · ) for patients younger than years and · % ( · - · ) for patients aged years or older assuming a parametric ␥ distribution. a non-parametric method yielded estimates of · % ( · - · ) and · % ( · - · ), respectively. case clusters have played an important part in the course of the epidemic. the rapid worldwide spread of the coronavirus that causes severe acute respiratory syndrome (sars) , has led to countries reporting cases as of may , . the evolution, spread, and persistence of infectious diseases are facilitated by the mobility of contemporary society, for example through air travel, the continued growth in the world population, and the steady rise in the number of densely populated urban areas, especially in asia. the asia pacific region, including mainland china, has been badly affected by sars. the impact on the regional economy and health-care systems led to a meeting of health ministers from association of south east asian nations on april - . health authorities are urgently seeking guidance on the public-health measures most likely to be effective in controlling the epidemic. key epidemiological determinants of the magnitude and timescale of the epidemic (figure ) include the interval between infection and onset of symptoms and between onset and hospital admission, the degree and duration of the infectiousness of the agent, and the extent of contact and mixing between infectious and susceptible people enabling transmission of the virus. public-health interventions can affect many of these factors. the hong kong authorities have taken several measures to combat the spread of sars. since formal recognition of the outbreak in the prince of wales hospital, hong kong, on march , these measures have included: public-service announcements about personal protection (march ); addition of sars to the list of notifiable diseases and requests for close contacts of cases to attend designated medical centres for screening (march ) until the later introduction of mandatory home quarantine; a -week suspension of schools' (march ) and universities' (march ) sessions; introduction of health declarations for all incoming residents and visitors (march ); isolation of residents of a building in the amoy gardens estate, at the centre of a cluster of about cases (march ) and their subsequent move to rural isolation camps for days (march ); home quarantining of close contacts and restrictions on their travel out of hong kong (april ); new public announcements urging symptomatic people to seek medical attention (april ); and bodytemperature checks for all air passengers (april ). in the global response to sars, there are three priority tasks: the identification of the causal agent and the development of tests to detect the virus and allow rapid confirmation of cases; the development and assessment of treatment protocols; and the determination of the key epidemiological processes and parameters that affect the spread and persistence of infection to support the formulation of appropriate public-health interventions. we describe the epidemiology in hong kong in the first weeks of the epidemic, during which cases were confirmed, and deaths from sars occurred. we focus on the key distributions and parameters that define the observed pattern of the spread of sars, and their change over time since the introduction of the virus into hong kong. we analysed an integrated database, coordinated by the department of community medicine, university of hong kong on behalf of the health, welfare and food bureau, derived from the hong kong hospital authority esars system, and the department of health's master list, which contains details of all patients with confirmed or suspected sars admitted to hospitals in hong kong since feb , . primary health care in hong kong is provided by private practitioners ( %) and general outpatient departments operated by the public sector. the hospital authority also currently provides % of total inpatient bed-days. the department of health provides the public-health function, including the monitoring and control of communicable diseases. the esars system is designed as a registry and monitoring system. all patients admitted for investigation and observation into the sars cohort wards in all the hospitals under the hospital authority of hong kong are recruited on entry. the patients on the registry are progressively classified into: patient under observation, patient suspected of sars, patient with confirmed sars, and not sars. the criteria for inclusion in the esars register as a patient confirmed with sars are radiographic evidence of infiltrates consistent with pneumonia, and current fever higher than ºc or history of such at any time in the past days, and at least two of the following: history of chills in the past days, cough (new or increased) or breathing difficulty, general malaise or myalgia, and known exposure. patients are listed as suspected of having sars if they do not fulfil this definition but are still thought to be likely cases of sars on the basis of the collective evidence and clinical judgment. however, patients are excluded if an alternative diagnosis can fully explain their illness. a questionnaire was administered to all patients h after confirmation of sars by the department of health, initially by regional community-medicine teams and later by a central interviewing team of nurses, to record symptoms at presentation to hospital and to identify contacts and events of probable relevance to transmission. when possible, patients are classified into infection clusters by location (eg, housing estates), occupation (eg, health-care workers), and workplace (eg, hospitals and other buildings). in addition, we used demographic data on hong kong, which has a population size of · million in districts (figure ). time-delay distributions (infection to onset, onset to admission, admission to death, and admission to discharge) were fitted to ␥ distributions by maximum likelihood estimation methods, with allowance for censoring for incomplete observation of the disease process in all cases. likelihood ratio statistics were used for tests of significance when comparing distributional parameters and for calculating ci. while the epidemic is continuing, the estimation of the admission-to-death and admission-to-discharge distributions must be undertaken jointly with the estimation of the case fatality rate, because among patients still recorded as being in hospital it is impossible to ascertain who will eventually die or be discharged. we assume that no confirmed sars patients who has been discharged from hospital will go on to die of sars-related causes. if f() and g() are the cumulative distribution functions of the admission-to-death and admission-todischarge distributions, respectively, and f is the case fatality rate-ie, the proportion of sars patients who will die of the disease-the following likelihood structure is assumed: if a patient died t days after admission, the likelihood is f ϫ[f(t+ )-f(t)]; if a patient was discharged t days after admission, the likelihood is ; and if a patient remained in hospital t days after admission, the likelihood is . the parameters of the f() and g() distributions are thus jointly estimated along with the case fatality rate. to assess further the case fatality rate, we also used a version of the kaplan-meier survival curve, adapted to allow for two types of outcome (death and discharge). censoring was used to obtain non-parametric estimates of the admission-to-death and admission-to-discharge distributions and the case fatality rate. the sponsors of the study had no role in the study design, data collection, data analysis, data interpretation, or in the writing of the report. the development of the epidemic (figure ) features a period of exponential growth, beginning on march , after the formal announcement of the outbreak, followed by a period of comparative stability throughout early to mid april, with evidence of a slight decay over the week april - . the geographical and age distributions of the cases are presented in figure . % of patients were female and % male. clinical symptoms at presentation were fully recorded for about % of the cases confirmed by the department of health. the frequency of self-reported symptoms is similar to that noted in the early cases. the most common reported symptom was fever ( %), with - % of patients reporting general influenza-like symptoms, chills, malaise, loss of appetite, and myalgia. gastrointestinal symptoms were less common at presentation, including diarrhoea ( %), vomiting ( %), and abdominal pain ( %). % reported fever plus any one other symptom, and % fever plus one of the five most common symptoms (table) . infection events cannot be observed, but for patients with short and defined periods of exposure to known sars cases, data on the timing and duration of exposure can be used to estimate the distribution of the incubation period, the time from infection to the onset of clinical symptoms of sars. the database contained patients with one exposure to sars over a limited time scale with recorded start and end dates. the maximum likelihood estimate of the mean and variance of the time from infection to onset was · days ( ci · - · ) and · days , respectively; therefore % of patients would experience the onset of symptoms within · days of infection. the estimated distribution is presented in figure . however, this distribution is based on a limited number of observations to date, and has high variance and may reflect biases in reporting, different routes of transmission, or varying infectious doses of the virus. onset and admission times are both observable events. however, allowance must be made in the analysis for censoring due to incomplete observation. if censoring is not taken into account, the distribution will be biased towards short onset-to-admission times, because patients are only eligible to be included in the hospital-based database on admission to hospital. patients with recent onsets and long onset-to-admission times are less likely to have been admitted to hospital and thus be included. in the analysis, patients were grouped by their week of clinical onset, and seven weekly time periods were analysed (feb to march , march - , march - , march - , march to april , april - , and april - ). there were too few patients with clinical onset before feb for robust analysis and too little time has elapsed after onset to allow analysis of those with clinical onset after april . we assume that the recorded data are complete up to april . estimated mean onset-toadmission times were obtained for each week, assuming that the times were ␥ distributed: feb to march the estimated mean and variance of the admission-todeath time was · days and · days, respectively, and the estimated mean and variance of the time from admission to discharge was · days and · days, respectively (figure ). if ␥ distribution is assumed, the estimated distributions and case fatality rate varied as a function of patients' age, but not the time from onset to admission (figure ). the estimated case fatality rate for patients younger than years was · % ( · - · ) and · % ( · - · ) for patients aged years and older. the adapted kaplan-meier-like nonparametric method gave estimates of · % ( · - · ) and · % ( · - · ), respectively (figure ). the estimated fatality rates are higher than the estimate obtained from the current cumulative number of deaths divided by the current cumulative number of hospital admissions, because of the incomplete follow-up on patients still in hospital. a key feature of this epidemic is the clustering of cases in place and time linked to a particular individual (in some cases in a particular setting such as a residence block or health-care setting), where one primary case has led to many secondary and tertiary cases. the amoy gardens outbreak is particularly striking, with the onset times of the cases identified as arising from this setting following a ␥ distribution (figure ). work on the clusters is still evolving and will be reported in detail separately. our findings underline the importance of estimating the key epidemiological determinants of the epidemic, the infection-to-onset and onset-to-admission interval distributions. the analysis of the onset-to-admission interval shows that over time there has been a progressive shortening of the time from clinical onset of symptoms to presentation at hospital. the estimation of case fatality rates in the situation of an emerging epidemic is not straightforward. first, our estimates are derived from data on clinical cases that have been admitted to hospital and, hence, estimate the mortality rate only in this population. second, the temporal evolution of the epidemic complicates analysis. finally, the estimates of the case fatality may vary dependent on the methods used and their underlying assumptions, although the estimates we present have statistical validity. all these issues require further investigation as the epidemic evolves, and explain partly the wide range of mortality estimates reported to date. shortening the time between onset of clinical symptoms and admission to hospital does not seem to affect clinical outcome. however, shortening the time from clinical onset to admission expedites isolation and reduces the effective infectious period and, thus, the risk of onward transmission. such changes were already evident in late march and early april, but any additional shortening of the time that symptomatic individuals are in the community will lead to further benefits at the population level. the extent to which this time needs to be shortened to reduce the generation of secondary cases from each primary case to less than one (the effective reproductive number, r ) in hong kong is the subject of a continuing analysis. given the likely benefits to the wider community from early presentation at hospital after the onset of symptoms, there should now be an intensive assessment of the different public-health interventions, including publicity campaigns in various media, to assess their impact on the early reporting of symptoms. the promotion of early reporting of all symptoms will challenge the health-care system in dealing with those caused by other pathogens and the so-called worried well. however, given the high need for intensive care of patients, the case fatality rate, and public alarm worldwide, use of stringent measures to limit the effective infectious period of probable sars cases would seem prudent. this approach alone may contribute substantially to the eventual curtailing or even eradication of the epidemic. the epidemic has shown the need for communication of risk that will inform and warn the public, in a way that will improve personal protection, without inducing raised anxiety and fear, as an essential part of epidemic control. a change in risk perception would potentially lead to an increase in early reporting of symptoms as well as improvements in hygiene and prevention of transmission. further data may reveal that the incubation period depends on the route of transmission and on the infectious dose received by an individual. the duration of the infectious period and its relation to the incubation period is uncertain at present (for example, the onset of infectiousness may precede the onset of clinical symptoms). continuing clinical studies involving quantitative assays of viral load at known times after exposure and after the onset of clinical symptoms should, however, clarify this property of the sars agent. critical questions relating to how long patients should remain in isolation are whether and to what extent virus remains in faeces or in aspirate after overt clinical symptoms have stopped. the occurrence of clusters of cases linked to particular individuals in a particular spatial setting has been an important determinant of the overall magnitude of the epidemic to date. a who team has now joined the hong kong government in examining on-site factors that were apparently associated with a possible point-source outbreak in amoy gardens. the assessment of whether there is variation in the characteristics of the disease, including presenting symptoms by different clusters, requires further investigation as the definition of clusters improves. the occurrence of clusters is not necessarily a feature that can inform public-health interventions in advance, except within health-care settings in which stringent isolation procedures must be adopted in handling suspected and confirmed cases. clusters do, however, provide a focus for contact-tracing studies to assess incubation periods and the nature of the contact that resulted in transmission. the reported cases to date in hong kong and elsewhere may simply reflect people with the most severe clinical symptoms of infection with the new sars virus. we estimated the case fatality rate based on cases in hospital only. if additional infections in the community do not lead to admission to hospital or death, the case fatality rate based on all infections would be lower. community-based serological surveys to assess infection and recovery rates are a priority once a specific and sensitive serological test is available. finally the warm season has begun in hong kong, with daily temperatures now at - ºc. the seasonal risks of figure : non-parametric and maximum-likelihood ␥ probabilities of survival and discharge dengue and influenza will increase, and if serious outbreaks occur, they will complicate the triage of patients with possible symptoms of sars. thus, measures that can be taken now to limit further transmission, such as the shortening of the onset-to-admission interval, should be given high priority. we thank david r cox for developing a suitable non-parametric method for estimation of the case fatality rate. acg and nmf receive fellowship support from the royal society. sr and nmf receive research funding from the howard hughes medical institute, cf, lja-r, and nmf from the medical research council, and rma from the wellcome trust. we thank tom johnston for geographic information system assistance. we thank all our colleagues in the department of health and the hospital authority for their work in data collection and processing, and pay tribute to all the front-line health workers who are caring for patients with sars. coronavirus as a possible cause of severe acute respiratory syndrome coronavirus never before seen in humans is the cause of sars department of health, hong kong government of special administrative region website a cluster of cases of severe acute respiratory syndrome in hong kong cumulative number of reported probable cases of severe acute respiratory syndrome (sars) academic medical center, department of neurosurgery, az amsterdam, netherlands (h van santbrink, p c de witt hamer) a -year old man was admitted after neckpain of sudden onset evolving to intractable headache in minutes. on physical examination he was alert and had no focal neurological deficit. severe meningism caused noticeable opisthotonic fixation of the neck. computed tomography (ct) of the cerebrum suggested subarachnoidal haemorrhage with subtle blood in the perimesencephalic cisterns, beneath the tentorium, and in the fourth ventricle. routine ct angiography, digital subtraction angiography of the four cerebral vessels, and magnetic resonance imaging (mri) of the craniocervical junction did not show a bleeding focus. the combination of persistent opisthotonus and radiological subarachnoidal haemorrhage strongly suggested a bleeding source, and motivated further investigation. mri of the neuraxis revealed an arteriovenous malformation of the medullary cone dorsal from vertebral corpus l (figure). the current finding extends the routine diagnostics for intracranial subarachnoidal haemorrhage without focus to mri of the entire neuraxis. endovascular treatment of the malformation is considered for this patient.clinical picture key: cord- -o z na authors: hien, nguyen tran; farrar, jeremy; horby, peter title: person-to-person transmission of influenza a (h n ) date: - - journal: lancet doi: . /s - ( ) - sha: doc_id: cord_uid: o z na nan by contrast with the d:a:d report, amy cutrell and colleagues from glaxosmithkline (the makers of abacavir) report, in a correspondence letter in today's lancet, that myocardial infarction did not increase in a summary of pooled studies, of which randomly assigned patients to receive abacavir. although the low overall rates of myocardial infarction are somewhat reassuring, cutrell and colleagues' analysis is not powered to detect meaningful diff erences: it was based on only myocardial infarctions and the limitations of summaries of pooled data for uncommon events in studies not designed to detect them are well known. because coronary events were not adjudicated formally in these antiretroviral therapy effi cacy studies, interpretation of the rates of "coronary artery disorders" is diffi cult. available data on coronary heart disease from clinical trials, such as those included in the cutrell report, should be submitted for peer review so their design and analyses can be described in detail and their conclusions fully interpreted. the benefi ts of antiretroviral therapy were gleaned from a strong tradition of randomised trials. by contrast, most of the data on risks of coronary heart disease associated with antiretroviral therapy come from observational and short-term effi cacy studies. because patients are living longer with hiv and coronary heart disease is becoming a real risk to survival, studies lasting - weeks cannot guide what usually is lifelong therapy. studies of antiretroviral effi cacy should be of longer duration so their toxicities can be better understood. at the very least, long-term follow-up registries should be set up. coronary events should be adjudicated in all randomised trials of antiretroviral effi cacy, and well-validated surrogates of vascular outcomes should regularly be incorporated into effi cacy studies. recent randomised studies of antiretroviral therapy that prospectively investigated risk of coronary heart disease have challenged previously held beliefs and improved our understanding of the eff ects of antiretroviral therapy and hiv on vascular disease. , the power of the randomised effi cacy trials should be used to investigate the coronary risks associated with antiretroviral therapy, so our dependence on observational cohorts and short-term effi cacy studies as the only sources of information about the long-term risks of antiretroviral therapy can be reduced. jhs has received research funding from bristol-myers squibb and honoraria from abbott, merck, and pfi zer for serving on scientifi c advisory boards; he has also given talks sponsored by pharmaceutical companies but does not accept personal remuneration and donates all honoraria directly to charity. jcs has received research funding and honoraria from glaxosmithkline, has received honoraria from gliead, has served as an adviser to bristol-myers squibb, pfi zer, merck, and tibotec, receives research grants from merck, tibotec, and theratechnologies, and serves on data safety and monitoring boards for koronnis and achillion. temperatures were running high, and any mention of person-to-person transmission of h n was thought by some to be reckless. although we have moved on, an air of tension still surrounds this disease, particularly in the corridors of power within the international health and political communities, and apprehension remains about what the continued pandemic in poultry means for human health. human h n infections thankfully remain rare, but evidence has accumulated that in some circumstances h n viruses are capable of limited person-to-person trans mission. person-to-person transmission of h n was fi rst mooted after the hong kong outbreak, in which family members and at least two health workers might have been infected by contact with patients. , since then, one report of a family cluster concluded that personto-person transmission was probable, and an additional four reports stated that it could not be ruled out in at least six families. [ ] [ ] [ ] [ ] in today's lancet, another convincing report of probable person-to-person trans mission is published by researchers from china and the usa. transmission of avian infl uenza virus between mammals is not, however, restricted to h n in human beings: h n can also be transmitted from person to person, and there is evidence of transmission of h n among other mammalian species. given that the species barrier can be breached, the intriguing question is why the transmissibility of h n among people remains so low? successfully crossing the species barrier is itself a step that might select viruses partly adapted to the new host and, once infected, the new host might select subpopulations of the virus adapted to the new environment. apparent host-induced selection of a human-adapted h n virus has been reported, but most sequence analyses of viruses isolated from sporadic and clustered cases show no substantial diff erences from the strains found in poultry. however, most of these analyses used viruses isolated from human specimens in cell cultures of animal origin, thus grown under diff erent selective pressures from those in human respiratory tracts. whether better adapted viral subpopulations exist during human infection is unknown, as is the diversity in virus populations in individual human beings or poultry. a possible lack of host-induced evolutionary pressure, disseminated viral replication and high viral loads in infected people, and the rarity of person-to-person transmission suggest that the infecting avian viruses might be already well adapted to the individual in which they fi nd themselves, but not to the wider human population. with the exception of occasional infection in health workers, all published incidents of possible or probable person-to-person transmission report transmission between genetically related individuals. although this fi nding could be related to the intensity and intimacy of contact between family members, host genetic factors might also play a part in susceptibility to h n , and when we see limited person-to-person transmission we might be observing an interaction between two well matched subpopulations. studying both within-host virus diversity and host genetic diversity might help to clarify the nature of the species barrier and the conditions necessary for widespread transmission between people. these studies are hard to do and need sustained, coordinated, and collaborative eff orts, as in wang and colleagues' study, coupled with acceptance that person-to-person transmission of h n can and does happen. whatever the underlying determinants, if we con tinue to experience widespread, uncontrolled out breaks of h n in poultry, the appearance of strains well adapted to human beings might be just a matter of time. in the meantime, all family contacts of a patient with probable or confi rmed h n should be given chemoprophylaxis and placed under surveillance. personal protection and advice must be extended to the family members and health workers visiting and looking after patients in the printed journal includes an image merely for illustration hospital. these steps rely on having systems capable of detecting cases and clusters early enough to start treatment and isolation, to identify and protect contacts, and to assess the extent of transmission. tension around emerging infections has led to often acrimonious and dispiriting debates about sharing of samples, international collaboration, and the roles of academic institutions, governments, and international agencies in fi ghting this common threat. today's study is a superb piece of epidemiological work showing the benefi t of a longstanding and trusting international collaboration that began during the severe acute respiratory syndrome epidemic. such collaborations sustained over several years, centred in aff ected countries, and closely linked with who are our best chance of combating current and future threats to international health and ensuring that benefi ts are shared worldwide. although cardiovascular disease is the leading cause of death worldwide, its epidemic shows remarkable geographic variation. while the mortality associated with cardio vascular dis ease seems to be declining in western europe and north america, the burden of cardiovascular diseases in developing countries continues to rise and is expected to be a major cause of death in adults from low-income and middle-income countries worldwide. south asians have a greater prevalence of coronary risk factors than the rest of the world, and coronary artery disease often manifests at an early age which creates unusual pressure on society and the economy. in today's lancet, denis xavier and colleagues describe the presentation, treatment, and outcome of more than patients with acute coronary syndromes admitted to hospitals across cities in india. patients in india were more likely to be younger and present with st-elevation myocardial infarction than those in the registry data from developed countries. the use of lipid-lowering treatments, β blockers, and angiotensincon verting-enzyme inhibitors was low, and few patients had an invasive approach with coron ary revascularisation. sub stantial underutilisation of evidence-based treatments in poor people was seen, which largely explains the high mor bidity and mortality in this group. this registry is a major milestone, since it provides the fi rst com prehensive view of the epidemic of acute coronary syndrome in india and helps to identify opportunities for improvement in care. as the indian economy grows, there is a possibility for further increase in cardio vascular disease before we see a decline similar to that being witnessed in developed countries. major risk factors of coronary artery disease are the same around the world. tobacco use, dyslipidaemia, and hypertension are the main determinants of population attributable risk world wide. see articles page bird fl u death toll reaches in asia antibody response in individuals infected with avian infl uenza a (h n ) viruses and detection of anti-h antibody among household and social contacts risk of infl uenza a (h n ) infection among health care workers exposed to patients with infl uenza a (h n ), hong kong probable person-to-person transmission of avian infl uenza a (h n ) for the world health organization international avian infl uenza investigative team. avian infl uenza a (h n ) in patients in vietnam three indonesian clusters of h n virus infection in epidemiology of cases of h n virus infection in indonesia two clusters of human infection with infl uenza a/h n virus in the republic of azerbaijan probable limited person-to-person transmission of highly pathogenic avian infl uenza a (h n ) virus in china transmission of h n avian influenza a virus to human beings during a large outbreak in commercial poultry farms in the netherlands ineffi cient transmission of h n infl uenza viruses in a ferret contact model an avian infl uenza h n virus that binds to a human-type receptor fatal outcome of human infl uenza a (h n ) is associated with high viral load and hypercytokinemia key: cord- -ef xg q authors: kelen, gabor d; kraus, chadd k; mccarthy, melissa l; bass, eric; hsu, edbert b; li, guohua; scheulen, james j; shahan, judy b; brill, justin d; green, gary b title: inpatient disposition classification for the creation of hospital surge capacity: a multiphase study date: - - journal: lancet doi: . /s - ( ) - sha: doc_id: cord_uid: ef xg q background: the ability to provide medical care during sudden increases in patient volume during a disaster or other high-consequence event is a serious concern for health-care systems. identification of inpatients for safe early discharge (ie, reverse triage) could create additional hospital surge capacity. we sought to develop a disposition classification system that categorises inpatients according to suitability for immediate discharge on the basis of risk tolerance for a subsequent consequential medical event. methods: we did a warfare analysis laboratory exercise using evidence-based techniques, combined with a consensus process of expert panellists. these panellists were asked to define the categories of a disposition classification system, assign risk tolerance of a consequential medical event to each category, identify critical interventions, and rank each (using a scale of – ) according to the likelihood of a resultant consequential medical event if a critical intervention is withdrawn or withheld because of discharge. findings: the panellists unanimously agreed on a five-category disposition classification system. the upper limit of risk tolerance for a consequential medical event in the lowest risk group if discharged early was less than %. the next categories had upper limits of risk tolerance of about % (iqr – %), % ( – %), % ( – %) and % ( – %), respectively. the expert panellists identified critical interventions with a likelihood of association with a consequential medical event if withdrawn, ranging from to on the -point scale. interpretation: the disposition classification system allows conceptual classification of patients for suitable disposition, including those deemed safe for early discharge home during surges in demand. clinical criteria allowing real-time categorisation of patients are awaited. the ability to provide medical care during sudden increases in patient volume during a disaster or other highconsequence event is a substantial concern for health-care systems. history has shown that during disasters and epidemiological outbreaks, hospitals take the burden of caring for the sick and injured. [ ] [ ] [ ] [ ] [ ] [ ] in most major city hospitals, inpatient capacity is constrained on a daily basis. [ ] [ ] [ ] thus, hospitals are concerned about maintenance of inpatient capacity during normal operating conditions, and they are developing methods to improve resource capabilities during surges. , several measures have been suggested for the creation of hospital surge capacity. [ ] [ ] [ ] [ ] [ ] these include: cancellation of elective admissions and operations; redesign of current inpatient space to accommodate more beds when needed; opening of unlicensed or unstaff ed beds; rapidly outfi tting temporary nearby space, such as cafeterias or outpatient facilities; or deployment of temporary portable inpatient units. all these possibilities present unique operational challenges, such as imposition of unpractised routines in the context of rapid incremental demand for inpatient census. furthermore, most options need hospital staffi ng to be increased at a time when the case-mix index can also be expected to increase. however, during some publichealth emergencies, especially those of a com municable nature, hospitals are likely to have substantial reductions in available staff , as happened during the severe acute respiratory syndrome outbreak. [ ] [ ] [ ] thus, for acute-care hospitals, a means to achieve maximum availability of capacity resources to allow for the care of victims of a disaster is a priority. one novel approach to capacity management during disasters is reverse triage, which includes the safe discharge of current inpatients and refocus of hospital resources to those in even greater need. patients might be discharged home, to facilities set up to care for less acute inpatients (eg, public-health contingency stations specifi cally designed for this purpose), nursing homes, or other acute-care facilities. thus, a need exists to develop an easy method to categorise hospital patients for safe discharge to suitable venues (including early discharge home), taking into account the existence and competence (or lack thereof) of available external resources. we report the fi rst phase in the development of inpatient disposition criteria for the creation of hospital surge capacity during catastrophic or high-consequence events. the aim of this phase was to develop a disposition classifi cation system (reverse triage) based on risk tolerance of a consequential medical event as a result of discharge; assuming that critical interventions were withdrawn or withheld. we focus on the main components of the fi rst phase: ( ) conceptualisation of the disposition classifi cation system; ( ) development of operational defi nitions of consequential medical events and critical interventions; and ( ) derivation of risk estimates related to early discharge from a multidisciplinary panel of experts. subsequent phases of this project will use clinical data obtained from nearly hospital patients to examine the validity of the classifi cation system to correctly identify those who can be discharged early. we used evidence-based materials combined with an expert panel consensus that was approved by the institutional review board on human subjects research. we hosted a warfare analysis laboratory exercise, which was developed by the johns hopkins applied physics laboratory in . the exercise uses networked computers that allow anonymous participation through streaming comments entered into individual laptops by panellists. expert panellists ( clinicians or practitioners, nonclinicians, or non-practising clinicians) took part in the -h exercise. conference organisers determined the composition and the variety of desirable backgrounds of the panel members, who were then identifi ed and specifi cally invited. all panellists were involved in health care, but represented diverse perspectives, including those of nonclinicians. the composition of the expert panel is shown in panel . of the participants were from various components of the johns hopkins medical institutions, and eight were from outside agencies and institutions. almost all the local panellists had experience in other health systems in the usa, and four had experience in other countries. those from the home institution represented three distinctly diff erent establish ments: a major academic health centre, an affi liate teaching centre, and a community hospital. four of the authors participated in the panel discussions. individual panellists received a detailed manual of background information on the day's proceedings, goals, objectives, and expectations from the expert panel. need for written informed consent for participation was waived by the institutional review board on human subjects research because all written comments and risk estimates made by the panellists were anonymous and could not be linked back to an individual. the warfare analysis laboratory is a specialised facility equipped with a network of laptop computers, an integrated audio and visual infrastructure with six large-screen, high-resolution, interactive three-dimensional computer graphics display monitors, a designated data-analysis station, and a -seat observation gallery. plans, defi nitions, and assumptions can be displayed on large-screen monitors at the front of the room. one or more of the screens can be dedicated to continuous display of anonymous comments from panellists on each networked computer in real time. items that need opinions or need to be voted on can also be processed and displayed in real-time. computer comments are numbered consecutively to help with responses to specifi c statements. the exercise is a formally defi ned process and is further described elsewhere. the warfare analysis laboratory has a professional team that oversees the process. a trained facilitator guides the process, allowing for discussion of key issues, and maintaining the focus on the day's objectives. before the exercise was started, eight consensus panel organisers held two separate full-day rehearsals for the conference, to ensure that presentations, discussion, and voting would go smoothly. on the day of the exercise, panellists were shown how to use the facility and computer data-gathering techniques with presimulations unrelated or indirectly related to the planned session. panellists were then exposed to short formal presentations on disaster management, surge-capacity concepts (fi gure), notions of risk and risk tolerance in health care, an overview of the project, and rationale and specifi c objectives. evidencebased information was presented about decision-making devices (eg, patient outcomes research team [port] and acute physiology and chronic health evaluation [apache] iii), peer-reviewed publications, and data for adverse events, readmission rate of discharged patients, and iatrogenic events related to being in hospital. the tasks of the expert panel during the exercise were to: ( ) develop an evidence-based disposition classifi cation system for discharge or transfer based on tolerance for the occurrence of a consequential medical event or the need for a critical intervention during the ensuing h after discharge or transfer; ( ) develop consensus defi nitions of consequential medical event and critical intervention; ( ) assign, for each category of the system, the panel's tolerance for a subsequent consequential medical event, or need for an in-hospital critical intervention; and ( ) compile a list of ( ), psychiatry ( ), infectious diseases ( ), obstetrics/gynaecology ( ), oncology ( ), paediatrics ( ), paediatric emergency medicine ( ), general surgery, paediatric surgery ( ), critical care/anaesthesiology ( ), cardiology ( ), nephrology ( ), trauma surgery ( ), ear nose and throat ( ), military surgery ( ), military emergency medicine ( ), military psychiatry ( ) obstetrics and gynaecology ( ), psychiatry ( ), internal medicine ( ), emergency medicine ( ), surgery ( ), paediatrics ( ), military ( ), oncology ( ) disaster management ( ), disaster and military triage ( ), hospital epidemiology ( ), research methodology ( ), risk management ( ), hospital administration ( ), home health services ( ), social work ( ), medical law ( ), medical ethics ( ), patient safety ( ), data analysis ( ), military public health ( ), city and state public health ( ), public health ( ), public health preparedness and response ( ), homeland security ( ), prehospital care ( ), international health care ( ) numbers in each category are shown in parentheses. some physicians and experts are included in more than one specialist area. critical interventions that would imply the need for continued stay in an acute-care hospital. discussions were held of assumptions to be used for defi nition of the disposition classifi cation system. panellists were presented with proposed assumptions developed by the project leaders and were invited to criticise and include additional assumptions. final assumptions under which the conference proceeded are shown in panel . panellists were shown examples of classifi cation systems used for clinical decision making. [ ] [ ] [ ] [ ] the notion and number of categories were discussed by panellists both via open comment and anonymous computer input. discussion focused on dispositions that defi ne severity of illness and likelihood of treatable complications. the process also included a discussion on the language used to defi ne the categories to help with assignment of tolerance of risk for a consequential medical event. consensus was reached about the number of categories based on tolerance for a consequential medical event. to determine into which category of the disposition classifi cation system a patient falls requires the assessment of risk for a consequential medical event. assessment of risk took into account the possibility of medical deterioration, a new medical event, or the untoward eff ect of the withdrawal of a continuing treatment (ie, withdrawal of a critical intervention). the consensus defi nition of consequential medical event developed by the panellists was: unexpected death, irreversible impairment, or reduction in function within h of hospital discharge for which an in-hospital critical intervention would be initiated to stabilise or ameliorate the medical disorder or disorders. panellists reasoned that medical events were consequential only if acute in-hospital treatment or intervention was needed. thus, when the probability of a consequential medical event was determined, the panellists agreed that likelihood should be judged on the basis of need for a new or continuing in-hospital treatment, termed critical intervention. thus, failure to initiate or continue a critical intervention risked a consequential medical event. to orientate panellists with respect to tolerance of risks taken in daily medical care, panellists were presented data for: -day and -day readmission rates taken from adult discharges during year ( ) for various medical services from one of our hospitals (unpublished data), as well as data of baseline inpatient hospital errors from the institute of medicine. risk, consequential medical event, and the defi nition of critical intervention were then discussed in detail. after the defi nitions had been decided on, the panellists voted to defi ne the upper limit of acceptable risk for the occurrence of a consequential medical event (ie, need for critical intervention), for each of the categories of the disposition classifi cation system. voting was on a scale of - %, with votes given to one decimal point. results of the fi rst vote were revealed and further discussion ensued. a second (and fi nal) consensus vote was then taken. after discussion, a consensus defi nition of critical interventions was formed and became embedded in the defi nition of consequential medical event, as noted above. panellists were then presented with a list of critical interventions to consider, and asked to validate or criticise each in view of the consensus defi nition. a list of possible candidate critical interventions was initially developed by the conference organisers. all panellists were allowed to suggest and add interventions to the list. panellists with clinical experience or responsibilities were then asked to rank on a likert scale of to (whole numbers only), how likely, in their opinion, the withholding or withdrawal of • panellists should think globally and not specifi cally about their facilities • the hospital will remain functional (ie, not a target of terrorist threat or disaster) • government and other disaster response will occur • disaster plans will exist • health-care system will recover or be aided within - h • assume ability to smoothly discharge or transfer patients (specifi c logistical issues will be considered separately). • a model to compare risk profi les of competing new patients requiring hospital resources exists • hospital liability protection exists or is not an issue • inpatient beds could be redistributed across various services • quality of care will not be compromised • only basic (non-professional or family) care will be available to patients discharged into the community (relatives, shelters, or home) • hospital patients with dismal prognosis will be considered separately • other eff orts to improve surge capacity will be continuing each of the listed critical interventions would lead to a consequential medical event. a score of ten was deemed to be synonymous with certainty of a consequential medical event, whereas a score of one implied virtually no associated risk with withholding or withdrawing the specifi c critical intervention. panellists without clinical experience or responsibilities participated in discussions, but did not vote. separate votes were taken for withholding and withdrawing the critical intervention. data generated by these votes were presented. after further discussion, a fi nal vote was taken. data were recorded and stored in a database and were then tabulated. only the fi nal votes were used for analysis. data only from clinicians were used for those questions requiring clinical expertise (clinicians could be identifi ed because they logged on as "clinician" rather than "nonclinician"). because the warfare analysis laboratory exercise requires anonymity in recording participant responses, subgroup analyses by medical specialty were not possible. the study sponsor had no role in the study design, data collection, data analysis, data interpretation, or the writing of the report. the corresponding author had full access to all data in the study and had fi nal responsibility for the decision to submit the paper for publication. the panellists agreed that a fi ve category disposition classifi cation system was optimum, for the intended task (table ) . consensus was reached on the understanding and wording of the categories. the upper limit of risk tolerance for a consequential medical event for the fi rst category was less than %. this category represented patients who the panellists judged to be at low risk of a consequential medical event if discharged early; on the assumption that no skilled medical care was available outside the hospital setting. an example would be a patient admitted for intravenous antibiotics for uncomplicated cellulitis, who could readily be discharged and switched to oral medication. the next categories had upper limits of risk tolerance of about %, %, %, and % respectively. the panellists agreed that category represented those patients who, although at some risk of a consequential medical event, might nonetheless warrant discharge if surge capacity was needed for victims of a disaster; especially if incoming victims are at higher risk of consequential medical event than those patients considered for discharge. panellists also agreed that this category of patients could warrant discharge in certain biothreat or other contagion situations in which spread of disease in hospitals would present a substantial added risk. an example would be a patient with acute coronary syndrome with no evidence of high risk for adverse events. category represented patients who were potentially suitable for transfer to another medical facility. as a group, the risk was judged too high for simple discharge home. an example would be a stable elderly patient who is progressing well days after hip-fracture surgery. category patients were those at substantial risk and judged likely to need continued acute-hospital resources. examples of such patients include those in need of emergency surgery, those in need of pressors, and those in active labour. finally, category patients were those who might be too unstable or critically ill even for transfer to another appropriate facility. most of these patients would require specialised medical care. most patients in intensive-care units would be in this category. table shows the consensus list of critical interventions that if withdrawn would result in a consequential medical event. less than half the critical interventions were assessed as or higher (on a scale of - ). only two-thirds were ranked higher than . for every situation, panellists' scoring for critical interventions that were withdrawn compared with those that were not available or withheld was much the same as that for critical interventions that were withheld. we have proposed the notion of in-hospital disposition classifi cation scheme (reverse triage) of inpatients to deal with increased hospital demand during high consequence disasters. a system of patient categorisation based on risk tolerance developed by an expert panel provides a context for further work to determine which patients can be safely discharged early at the time of overwhelming need for hospital-based resources. mean upper limit of tolerance for consequential medical events (iqr) high consequent events are disasters that overwhelm local or regional infrastructure including the health system. the need to plan for and increase hospital capacity during high consequence disasters is now a standard recommendation. , many techniques have been suggested, such as cancellation of elective admissions and surgeries, opening of licensed but unstaff ed beds, use of other spaces that can be readily converted for clinical use, and triage and treat off site as many victims as possible. most of these techniques need increased staffi ng at a time when either staff are not available, staffi ng is degraded because of the disaster itself, or staff are co-opted by the public-health system for other needs. volunteer staff who are unfamiliar with hospital routine, remain an untested resource, and have yet to be shown as valuable for augmenting hospital capacity in any disaster. thus, other ideas for increasing or preserving capacity become important. much has been written about the appropriate triage of disaster victims. the focus is to concentrate resources on the most severely injured or ill who are likely to survive with defi nitive medical care. [ ] [ ] [ ] one way to create hospital surge capacity-through reverse triage-has received scant attention. in military terms, reverse triage refers to treating those who are not seriously injured fi rst to allow them to return to the battlefi eld sooner. here, we expand the notion to the civilian medical model and include consideration of early discharge of the least sick. with present constraints on hospital capacity, making the most of available resources, rather than hoping that plans to augment them can be implemented, becomes an important consideration. patients are generally not discharged from hospitals if a consequential medical event is potentially foreseeable. however, a zero risk policy, although desirable, is not feasible. forster and colleagues report that up to % of discharged patients have an adverse event in the immediate ( week) post-discharge period. despite a strong patientsafety movement today, zero risk for an out of hospital consequential medical event as a condition of discharge is not attainable, and must be balanced against risk tolerance for various medical adverse events, including iatrogenic ones. , [ ] [ ] [ ] [ ] [ ] despite the accepted risks discussed, our experienced panellists were reluctant to ascribe a substantially higher risk to the category patients. even the risk tolerance assigned for category patients can be regarded as conservative in view of the complex issues faced in major disasters. if a % risk of a consequential medical event is accepted, as was the consensus for category , the rate is still much less than the adverse event rate reported by forster. the iqr for votes on categories , , and were fairly narrow, indicating a cohesive consensus. however, the iqr for categories and were quite wide. categories and would be unlikely to be discharged. this report represents the fi rst part of a multiphase study. once the categories are established, the next step will be to derive a system that allows classifi cation of individual hospital patients in real time. to accomplish this, measurable outcomes and prognostic variables are required. the panel initially defi ned critical interventions as a means to understand the notions of risk. however, the consensus critical interventions will also serve as the outcome measures in subsequent studies. what constitutes a consequential medical event is subjective. thus, the critical interventions that are the outcome proxy measures were weighted for likely importance. future analysis will consider the accuracy of such weighting. the ultimate goal is to produce a disposition classifi cation system that guides clinical decision making during a disaster in a manner similar to the use of the apache score , or port score in everyday clinical practice. in view of the increasing trend toward electronic medical data, prognostic variables of potential interest-eg, vital signs, key laboratory values, diagnostic considerations, co-morbid conditions-could be captured and continuously updated in real-time. thus, in the event of a disaster, patients would be predesignated for the lowest risk disposition options, through the use of a system such as the one proposed here. if such a system were in place, each patient would have a continuously, updated reliable risk score to assist in disposition making. starting with those with the lowest risk, discharges would take place in an ascending order of risk. furthermore, in the future when prognostic scoring of risk for pre-hospital or emergency-department based disaster triage are developed and reliable, the entire demand for inpatient resources from all sources can be simultaneously ascertained and decisions made accordingly. the value of such a device is not only to augment surge capacity, but also to help with rapid decisions when complete or part hospital evacuations are required, such as happened during hurricanes katrina and rita, and the severe acute respiratory syndrome epidemic in toronto. a further and potentially important value of the development of a risk-based disposition classifi cation system is that it is also designed for everyday hospital use. emergency departments in many parts of the world are often overcrowded, mainly as a result of severely restricted in-patient capacity. thus, on a small, but real scale, disaster-like settings arise every day. the device being developed here could have a substantial eff ect on the safe management of hospital capacity on a routine daily basis. in fact, preliminary data from the next phase of the study, available at this time, show that such a device might prove useful for such dual purpose. simulating a disaster, we randomly sampled non-intensive-care unit adult patients from medical units in our three-hospital system during weeks. of the patients sampled, ( %) were discharged routinely on the day of the disaster. of the remaining patients, ( %) either had no critical interventions or were discharged in any event during the next h. although full analysis remains to be completed, these data are consistent with those reported by davis and colleagues. physicians and nurses in this study opined that about % of patients were dischargeable during h. when controlling for patients in intensivecare, the proportion of capacity is similar to ours. finally, a study from a tertiary-care teaching hospital in the uk, also using opinion survey of nurses showed that more than a third of inpatient beds (including those in intensive-care units) could be made available within - h of a disaster if increased care were available in the community. the fundamental problem with estimation of capacity on the basis of opinion surveys is absence of evidence that the estimates would result in safe practice. furthermore, as in the case of the uk study, which called for aug mentation of community resources, it is unclear whether these resources could reasonably be increased during catastrophic events. our approach is to establish the scientifi c basis for a practice that can be modifi able for use both daily and during catastrophic events. comments are needed on concerns that might be raised about the work presented here. the expert panellists were from a wide array of professions. although many of the panellists have varied geographic and institutional experience, we did not attempt to ensure that every hospital structure and size was represented by all disciplines. thus, inherent geographic or regional bias in the established ranges of risk tolerance could have occurred. however, as noted, about % of the panel were not from our system, and most of the panellists had other national and international experience. even so, the model described is suffi ciently robust that risk tolerance notions can be scaled to an individual hospital and even an individual service. if adopted for daily routine use, risk tolerances for categories and might change or be subject to local customs. we did not consider patient or lay perspectives, but again, the variables of the proposed device can be modifi ed in those settings that wish to consider such views. also, simulations used here might not represent reality, but most disaster planning is based on simulated exercises due to an absence of empirical data. furthermore, other systems have been developed on the basis of clinical judgment, in the absence of empirical data. one example is the abbreviated injury scale, , which was originally based on clinical-judgment ratings, and has subsequently been shown to be both valid and reliable in measuring injury severity. more recently, hick and o'laughlin, using a less structured consensus format, developed an ethical framework for the distribution of scarce intensive-care-unit resources during disasters. the - h period of concern is not arbitrary. generally local resources are highly stressed for this duration in the aftermath of a severe and sudden disaster. , in fact, the us joint commission on accreditation of healthcare organizations position on hospital preparedness states that hospitals should "ensure a - hour stand-alone capability through the appropriate stockpiling of necessary medications and supplies." other systems for augmenting surge capacity resources, including those defi ned by the national incident management system, are activated within our period of concern. thus, external validation of our approach by the general community is needed, and this report serves as an appropriate foundation for such discussions. the next step is to derive a real-time decision rule or scoring system based on clinical variables that allows accurate categorisation of individual patients, followed by prospective validation. the experience of st vincent's hospital, manhattan two new york city hospitals' surgical response to the emergency department impact of the oklahoma city terrorist bombing severe acute respiratory syndrome and critical medicine: the toronto experience tornado: assessment of the trauma system response and the resulting injuries emergency department visits for home medical device failure during the north america blackout the role of public hospitals in urban health hospital and emergency department crowding in the united states emergency department overcrowding following systematic hospital restructuring: trends at twenty hospitals over ten years us government accountability offi ce. hospital preparedness: most urban hospitals have emergency plans but lack certain capacities for bioterrorism response health care at the crossroads: strategies for creating and sustaining community-wide emergency preparedness systems health care facility and community strategies for patient care surge capacity bioterrorism preparedness i: the emergency department and hospital lessons learned from the evacuation of an urban teaching hospital impact of a major hurricane on surgical services in a university hospital lessons learned from a nightclub fi re: institutional disaster preparedness clinical course and management of sars in health care workers in toronto: a case series an outbreak of severe acute respiratory syndrome among hospital workers in a community hospital in hong kong sars in three categories of hospital workers implications of hospital evacuation after the northridge, california, earthquake us centers for disease control and prevention. fiscal year justifi cation of estimates for appropriations committee the walex process a prediction rule to identify lowrisk patients with community-acquired pneumonia modeling the severity of illness of icu patients: a systems update a new simplifi ed acute physiology score (saps ii) based on a european/north american multicenter study the apache iii prognostic system. risk prediction of hospital mortality for critically ill hospitalized adults institute of medicine committee on quality of health care in america health care system surge capacity recognition, preparedness, and response casualties treated at the closest hospital in the madrid report of the events and the prehospital emergency response can external signs of trauma guide management? lessons from suicide bombing attacks in israel the incidence and severity of adverse event aff ecting patients after discharge form the hospital incidence of adverse events and negligence in hospitalized patients: results of the harvard medical practice study i the nature of adverse events in hospitalized patients: results of the harvard medical practice study ii institute of medicine medical error fi gures are not exaggerated deaths due to medical errors are exaggerated in the institute of medicine report creation of health system surge capacity by the immediate discharge of inpatients hospital bed surge capacity in the event of a mass-casualty incident accelerated discharge of patients in the event of a major incident: observational study of a teaching hospital rating the severity of tissue damage: i. the abbreviated scale rating the severity of tissue damage: ii. the comprehensive scale concept of operations for triage of mechanical ventilation in an epidemic state and regional responses to disasters: solving the -hour problem learning from disaster: the role of federalism and the importance of grassroots response national incident management system this study was sponsored by funding from the agency for healthcare research and quality (u hs - ). data in this manuscript were presented, in part, at the th world congress of disaster and emergency medicine, may , , edinburgh, scotland. key: cord- - xltmc authors: bozorgmehr, kayvan title: power of and power over covid- response guidelines date: - - journal: lancet doi: . /s - ( ) -x sha: doc_id: cord_uid: xltmc nan the covid- pandemic has shown that ignorance or political influence of scientifically grounded health policies does not pay off. germany's covid- response is evaluated as reasoned and scientifically grounded; however, it has exposed undue political influence on national scientific guidelines due to migration policy concerns. the robert koch institute (rki), germany's national public health institute, has rapidly published an abundance of guidelines and recommendations on covid- . repeated large-scale outbreaks in refugee centres since the end of march, , exposed a troubling gap, with asylum seekers and refugees not specifically considered in pandemic response policies. a review and meta-analysis of media reports in germany until the end of may , , identified outbreaks in federal states with confirmed sars-cov- cases among refugees, corresponding to an incidence risk of · % ( % ci · - · ). of affected centres, % were quarantined en mass and locked down for several weeks by police forces, private security firms, or military forces to contain the outbreaks. the competence network public health covid- raised ethical, legal, and epidemiological concerns about questionable benefits for infection control and high psychosocial burden for refugees, and it urged for national guidelines on prevention and management of sars-cov- in refugee centres. in june, , civil society leaked an unpublished draft guideline by the rki that mandates asylum seekers should be accommodated in single rooms during the pandemic, and that mass quarantine should be avoided without exception. in response to media enquiries, rki confirmed that the leaked guideline was under a consultation process with authorities, including ministries of interior. the final guideline was published on july , , weeks after the draft was leaked. key recommendations on sars-cov- prevention and management in refugee centres remained. however, mass quarantine is now considered a containment option if deemed unavoidable, and although accommodating refugees in single rooms is still recommended, the normative language has been toned down, and refugees sharing a room can be considered a household. this effectively offers a legal loophole to avoid enforcement of physical distancing in refugee centres to the same extent as for the general population, despite court judgements suspending the obligation of individual refugees to live in crowded centres if physical distancing is not possible. the case illustrates key lessons for public health. first, guidelines have power, and authorities circumnavigate scientific evidence when it challenges their own preferences or practice. second, power is exercised over guidelines as a means to control unwanted consequences of scientific recommendations. the intervention of ministries of interior caused considerable delay in publishing an urgently needed guideline during the pandemic, and politically sensitive areas that affect the practice of migration authorities were diluted. this situation raises serious questions about the independence of germany's national public health institute. the casualties of this political intervention are two-fold: on the refugees' right to health protection, and the integrity of the rki. both need to be restored by defending evidencebased recommendations against undue political influence to the same degree that they are defended against commercial and industry influences. political casualties of the covid- pandemic sars-cov- in aufnahmeeinrichtungen und gemeinschaftsunterkünften für geflüchtete: epidemiologische und normativ-rechtliche aspekte hinweise zu prävention und management von covid- -erkrankungen in gemeinschaftsunterkünften für geflüchtete massenquarantäne vermeiden empfehlungen für gesundheitsämter zu prävention und management von covid- -erkrankungen in aufnahmeeinrichtungen und gemeinschaftsunterkünften für schutzsuchende (im sinne von § § s - ( ) -x for more on the competence network public health covid- see https://www. public-health-covid .de/en/ for the rki's covid- guidelines and recommendations see key: cord- -r znjkfo authors: favre, guillaume; pomar, léo; musso, didier; baud, david title: -ncov epidemic: what about pregnancies? date: - - journal: lancet doi: . /s - ( ) - sha: doc_id: cord_uid: r znjkfo nan members of the coronavirus family responsible for severe acute respiratory syndrome (sars-cov) and middle east respiratory syndrome (mers-cov) are known to be responsible for severe complications during pregnancy. , pregnant women were infected with sars-cov during the - pandemic. four ( %) of seven women in the first trimester had a miscarriage. in the second to third trimester, two ( %) of five women had fetal growth restriction, and four ( %) of five women had preterm birth (one spontaneous; three induced for maternal condition). three ( %) women died during pregnancy. in a review of pregnant women infected with mers-cov, ten ( %) presented with adverse outcomes, six ( %) neonates required admission to the intensive care unit, and three ( %) died. two neonates were delivered prematurely for severe maternal respiratory failure. considering that the -ncov seems to have a similar pathogenic potential as sars-cov and mers-cov, pregnant women are at increased risk of severe infections, there are no specific clinical signs of coronavirus infections preceding severe complications, coronaviruses have the potential to cause severe maternal or perinatal adverse outcomes, or both, , and the current lack of data on the consequences of a -ncov infection during pregnancy, we recommend systematic screening of any suspected -ncov infection during pregnancy. if -ncov infection during pregnancy is confirmed, extended followup should be recommended for mothers and their fetuses. situation report- pregnancy and perinatal outcomes of women with severe acute respiratory syndrome middle east respiratory syndrome coronavirus (mers-cov) infection during pregnancy: report of two cases & review of the literature china coronavirus: what do we know so far? clinical features of patients infected with novel coronavirus in wuhan, china we declare no competing interests.guillaume favre, léo pomar, didier musso, *david baud key: cord- - en yey authors: nkengasong, john n; mankoula, wessam title: looming threat of covid- infection in africa: act collectively, and fast date: - - journal: lancet doi: . /s - ( ) - sha: doc_id: cord_uid: en yey nan because of the high volume of air traffic and trade between china and africa, africa is at a high risk for the introduction and spread of the novel coronavirus disease (covid- ); although only egypt has reported the first case, from a non-national. the greatest concern for public health experts is whether covid- will become a pandemic, with sustained year-round transmission, similar to influenza, as is now being observed in several countries. what might happen to africa-where most countries have weak health-care systems, including inadequate surveillance and laboratory capacity, scarcity of public health human resources, and limited financial means-if a pandemic occurs? with neither treatment nor vaccines, and without pre-existing immunity, the effect might be devastating because of the multiple health challenges the continent already faces: rapid population growth and increased movement of people; existing endemic diseases, such as human immunodeficiency virus, tuberculosis, and malaria; remerging and emerging infectious pathogens such as ebola virus disease, lassa haemorrhagic fever, and others; and increasing incidence of non-communicable diseases. models that enable the continent to better allocate scarce resources to better prepare and respond to the covid- epidemic are crucial. the modelling study by marius gilbert and colleagues in the lancet identifies each african country's risk of importation of covid- from china, using data on the volume of air travel from three airports in provinces in china to african countries. gilbert and colleagues use two indicators to determine the capacity of countries to detect and respond to cases: preparedness, using the who international health regulations moni toring and evaluation framework; and vulnerability, using the infectious disease vulnerability index. based on their analysis, egypt, algeria, and south africa had the highest importation risk, and a moderate to high capacity to respond to outbreaks. nigeria, ethiopia, sudan, angola, tanzania, ghana, and kenya had moderate risk with variable capacity and high vulnerability. in the model, the risk mainly originates from guangdong, fujian, and beijing. the study provides a valuable tool that can help countries in africa prioritise and allocate resources as they prepare to respond to the potential introduction and spread of covid- . the study should also be interpreted in light of the fast-evolving nature of the covid- outbreak. first, with the exception of ethiopian airlines, all african airlines have suspended flights to china. although these measures might delay, but not stop, the importation risk of covid- into africa, their implementation is still worthwhile. second, although beijing, shanghai, and fujian do not report the highest number of cases of covid- in china, the volume of travel from these cities to africa is high, which might increase the risk of exporting cases to africa. lastly, almost half of the flights from africa to china are operated by ethiopian airlines, so it is possible that cases might pass through ethiopia and affect destination countries. the report by gilbert and colleagues provides an important tool to map out the continental risk for the spread of covid- in africa, which should be used to inform a framework of action to prepare the continent for any potential importation and spread of covid- . first, collectively, africa needs a unified continent-wide strategy for preparedness and response. the strategy must be comprehensive, and member states, donors, and partners should immediately commit to releasing financial resources to support country-customised implementation plans derived from the strategy. to help develop a common strategy that will allow for effective coordination, collaboration, and communication, the african union commission, africa centres for disease control and prevention (africa cdc), and who, in partnership with african countries, have established the africa taskforce for coronavirus preparedness and response (aftcor). the partnership has six work streams: laboratory diagnosis and subtyping; surveillance, including screening at points of entry and cross-border activities; infection prevention and control in healthcare facilities; clinical management of people with severe covid- ; risk communication; and supply-chain management and stockpiles. because mitigating the potential spread of covid- in africa will require rapid detection and containment, the laboratory work streams of aftcor, africa cdc, and who are working closely to expeditiously scale up diagnostic testing capacity linked to enhanced surveillance and monitoring-eg, at the beginning of february, only two countries in africa had the diagnostic capacity to test for covid- . however, as of feb , , more than countries would have been capacitated to accurately diagnose covid- infection, thanks to the coordination efforts of aftcor. as testing becomes more available, it is possible that more cases might be detected. second, any effective preparedness and response strategy for covid- requires a committed political will; as such, the african union commission, africa cdc, and who convened, on feb , , in addis ababa, ethiopia, an emergency meeting of all ministers of health of member states to commit to acting fast and collectively to develop and implement a coordinated continent-wide strategy. aftcor taskforce was formed, and a continent-wide strategy was endorsed at the end of the emergency meeting, with a call for strong coordination of efforts. to prevent the occurrence of a social, health security, and economic tragedy, actions agreed at the emergency ministerial meeting will need to be acted on quickly, before any additional covid- cases are introduced to the continent, and result in sustained human-tohuman transmission. the potential social, economic, and security devastation that covid- could cause in africa should be enough of an incentive for african governments to invest immediately in preparedness for the worst-case scenario. third, commitment and release of financial resources from partners and donors before a crisis hits africa will help anticipate demand and address supply chain management, mapping, and stockpiling of covid- response needs, such as large quantities of personal protective equipment, gloves, surgical masks, coveralls, and hoods, and medical countermeasures like antiviral agents. supplies of these items will be limited in africa because of reduced manufacturing capacity. fourth, national, regional, and international organisations need to cooperate and collaborate to optimise limited supplies, using a whole of government approach. fifth, all member states will need to urgently develop and put in place proper quarantine and infection control protocols, including procedures for implementing social distancing (mass gathering and potential closure of public facilities). lastly, the capacity-building training efforts that africa cdc and who are conducting must be implemented and cascaded immediately down the health system pyramid in each country. medical staff at major hospitals must be trained in the proper protocols of quarantining individuals who are at-risk of covid- infection, as well as isolation and safe treatment of patients who test positive. as the director general of who has stated several times, the window of opportunity to act is narrowing. africa needs to be supported to act now, and needs to act fast. jnn is the director of the africa cdc and a who special envoy on covid- . wm is an epidemiology analyst at africa cdc. we declare no other competing interests. china's response to a novel coronavirus stands in stark contrast to the sars outbreak response update on covid- in the eastern mediterranean region italy covid- case count now , government introduces urgent measures preparedness and vulnerability of african countries against importations of covid- : a modelling study the effect of travel restrictions on the spread of the novel coronavirus (covid- ) outbreak countries rush to build diagnostic capacity as coronavirus spreads. reuters key: cord- - ym hx authors: betsch, cornelia; wieler, lothar h; habersaat, katrine title: monitoring behavioural insights related to covid- date: - - journal: lancet doi: . /s - ( ) - sha: doc_id: cord_uid: ym hx nan time, assessment of the relations between them, and randomisation of answer options where suitable. among others, included variables relate to demographics, protective behaviours, knowledge, perceptions, and trust. changes in risk perceptions or knowledge can be assessed over time; data on acceptance of new response measures can be made rapidly available; and misinformation or possible stigma can be identified as they emerge. immediate data analysis by means of an automated data analysis website provides fast access to the results. who materials contain commented code (free r studio online software) for data analysis and a website for rapid data presentation. the insights unit and health emergencies programme in the who regional office for europe are offering support to countries for implementation. national teams using the tool are urged to work in partner coalitions to discuss insights gained and implications for outbreak response interventions, policies and messages. making results rapidly available to journalists is also suggested to support high quality and responsible media reporting. journalists need timely knowledge about developing audience behaviour and habits to rapidly tailor information sharing and to develop narrative tools that encourage behaviour changes according to evidence from risk communication research. in sum, rapid data collection and sharing could support effective interaction between authorities, health workers, journalists, and the public to encourage appropriate behavioural change, to manage the crisis, and to protect the most important asset in a crisis: public trust. we declare no competing interests. the authors alone are responsible for the views expressed in this manuscript and they do not necessarily represent the views, decisions, or policies of the institutions with which they are affiliated. the rapidly evolving coronavirus disease (covid- ) pandemic is placing an overwhelming burden on health systems and authorities to respond with effective and appropriate interventions, policies, and messages. a critical element in reducing transmission of the virus is rapid and widespread behavioural change. evidence shows that a perceived lack of consistency, competence, fairness, objectivity, empathy, or sincerity in crisis response in the public could lead to distrust and fear. conversely, when the public perceives measures as having these characteristics, as well as being easily understood and communicated through trusted and accessible channels, and when the necessary services are available, people are able to make informed choices, protect themselves, and comply with recommended practices. , risk perceptions influence individual protective behaviours but paradoxically, how people perceive risk is not necessarily correlated with the actual risk. this was seen during the influenza pandemic in - , where uncertainty and perceived exaggeration were also associated with a reduced likelihood to implement the recommended behaviours. models of crisis and risk communication thus suggest that understanding risk percep tions is critical for an effective and appropriate crisis response. at the same time, not enough is known about the complex interplay of changing epidemiology, media attention, pandemic control measures, risk perception, and public health behaviour. behavioural insights for covid- are, therefore, of critical importance. this includes knowledge about what drives behaviour and awareness of changes in these drivers. , other psychological challenges, such as misinformation, stigmatisation, or herd behaviour (such as hoarding of food or toilet paper) can be monitored to help estimate their prevalence and to identify sources. national authorities and other stakeholders, such as the media, can gain valuable insights into information needs, contextualisation of certain phenomena (eg, stigma tisation), and which target groups need additional attention. a few countries have rapidly initiated studies to gain such insights, and more countries are urged to prioritise such efforts, not in lieu of, but as a necessary supporting mechanism for other response measures. faced with overwhelming response requirements and cost, countries need opportunities to gain such insights through tools that: ( ) are evidencebased; ( ) can be rapidly applied; ( ) can be regularly applied; ( ) are simple and flexible enough to adjust to the changing situation; and ( ) are low cost and cost-effective, particularly for low-income and middle-income countries. who and international partners can share such tools allowing countries to do this. shared tools offer the additional opportunity of preparing syntheses analysis across contexts, providing invaluable insights for the continued response effort as well as for the post-outbreak evaluation, sharing of lessons learnt, and the continued effort to better understand effective mechanisms of crisis response. weekly covid- snapshot monitoring (cosmo) was initiated in germany on march , . and needs to be expanded, and risk assessment frameworks also need to be refined further. preventing global spread of infectious diseases from mass gathering events and protecting global health security require public health decisions based on evidence and an agreed rational framework for decision making. a systematic process to assess the event encourages us to consider explicitly the reasoning behind the decision, what we expect the decision to achieve, and what evidence exists to support that reasoning. this, in turn, helps us evaluate whether the decision achieves what is expected and so informs future decisions. it also requires consideration of the negative impacts of a decision to cancel an event (jobs, mental health, the economy) and to look for ways to mitigate the adverse effects. crucially, we must look to the future. whatever the course of the covid- pandemic, countries, individually and collectively, will reach a point when they want to start removing restrictions and rebuild communities and economies. this will include decisions on re-starting mass gatherings. these decisions will need to be carefully reviewed and phased to ensure that the covid- pandemic is not reignited; here, we advocate our risk-based approach as a sensible and rational way forward to consider those decisions. mass gatherings to be considered in context, including the prevailing advice on physical distancing and movement restrictions. an open and transparent process to explicitly consider the risks of a mass gathering can, in fact, promote public confidence in the decision. the validity of our approach is exemplified by the emergence of the novel middle east respiratory syndrome coronavirus (mers-cov) in saudi arabia in . mers has a fatality rate - times greater than covid- , and has spread globally; it has significant epidemic potential (as illustrated by the mers-cov outbreak in south korea ) and remains on the who blueprint list of priority pathogens, yet we have never advocated cancelling the annual hajj pilgrimage in the epicentre of mers activity. this was because we adopted a risk-based approach and concluded that the risks were manageable in the context of the mitigation measures that saudi arabia had put in place; years of safe and successful hajj since mers-cov emerged suggests that the decision was correct. we have not yet seen what decisions might be made by the saudi government about the impending hajj in , in the context of covid- , but we urge that those decisions are made on the basis of an evidence-based risk assessment process such as the one we describe in our comment. any risk assessment and risk management framework for a mass gathering might inherently result in cancellation or postponement, as in the recent decision by the international olympic committee and japanese government to postpone the olympic games. in the current covid- pandemic, it is inevitable in many countries that the outcome will be to cancel or postpone events, either because the risk is too great or because the capacity for mitigation measures is not available, or both. that is an appropriate and valid use of a risk assessment tool. the evidence base for mass gathering health is still evolving †cosmo group members are listed in the appendix. university of erfurt, erfurt, germany (cb); robert koch institute, berlin, germany (lhw); and who regional office for europe, copenhagen, denmark (kh) memish and colleagues, in their response to our comment, perceive conflict between the current bestpractice risk management advice on physical distancing and the scientific evaluation of cancelling or continuing mass gathering events during the coronavirus disease (covid- ) pandemic. although we have already acknowledged the need to balance these two considerations in order to maintain public understanding and trust, we do not accept that conflict is inevitable as our approach requires all vaccination and trusthow concerns arise and the role of communication in mitigating crises risk communication for public health emergencies communicating risk in public health emergencies: a who guideline for emergency risk communication (erc) policy and practice risk perception and self-protective behavior pandemic public health paradox": time series analysis of the / influenza a/h n epidemiology, media attention, risk perception and public reactions in european countries public perceptions, anxiety, and behaviour change in relation to the swine flu outbreak: cross sectional telephone survey crisis and emergency risk communication as an integrative model covid- snapshot monitoring (cosmo): monitoring knowledge, risk perceptions, preventive behaviours, and public trust in the current coronavirus outbreak az is co-principal investigator of the pan-african network on emerging and re-emerging infections and is in receipt of a uk national institutes of health research senior investigator award. all other authors declare no competing interests. key: cord- - x guveu authors: allen, matilda; braithwaite, isobel; collinson, shelui; oskrochi, youssof; basu, anamika title: a view from uk public health registrars on the challenges of covid- date: - - journal: lancet doi: . /s - ( ) - sha: doc_id: cord_uid: x guveu nan the quotes from frontline workers in richard horton's comment about covid- and the national health service (nhs) make for distressing reading, and the risks currently facing our clinical colleagues weigh heavily on our minds. as public health registrars, we understand that root causes of the current challenges regarding covid- include historical policy decisions that have affected the uk's health workforce and systems, including laboratory capacity. nevertheless, a pandemic caused by a novel highly pathogenic virus would prove profoundly difficult in any context. sourcing personal protective equipment, scaling up testing, and increasing hospital capacity are problematic worldwide, and are exacerbated by global shortages. the statement by richard horton that "they [uk government] didn't isolate and quarantine. they didn't contact trace" is inaccurate. many of the signatories of this correspondence were involved in public health england's extensive early contact tracing, testing, and isolation efforts, done by health protection staff working tirelessly across the country. the transmission dynamics of severe acute respiratory syndrome coronavirus make it challenging to control through these measures alone and, despite these efforts, a proportion of cases went under the radar. by mid-march, , widespread community transmission was evident, precipitating a shift towards advising the public to self-isolate and supporting higher-risk settings such as care homes, prisons, and homeless shelters. we agree that improved testing capacity, combined with innovative ways to contact trace at scale, are vital. however, implementing these strategies presents several practical and ethical challenges and they might not offer a panacea. this pandemic calls for collabo ration rather than division, and we have seen concerted efforts across society to rise to this unprecedented challenge. we must learn from both failings and successes, and seek out solutions, not scapegoats. offline: covid- and the nhs-"a national scandal a critical moment: nhs staffing trends, retention and attrition critical supply shortages -the need for ventilators and personal protective equipment during the covid- pandemic feasibility of controlling covid- outbreaks by isolation of cases and contacts quantifying sars-cov- transmission suggests epidemic control with digital contact tracing see online for appendix key: cord- -dktffiaa authors: gross, oliver; moerer, onnen; weber, manfred; huber, tobias b; scheithauer, simone title: covid- -associated nephritis: early warning for disease severity and complications? date: - - journal: lancet doi: . /s - ( ) - sha: doc_id: cord_uid: dktffiaa nan covid- -associated nephritis: early warning for disease severity and complications? among patients with coronavirus disease , parameters for the prediction of the need for admission to intensive care units (icus) are urgently needed to enable appropriate resource allocation. here we report that analysis of a urine sample on admission to hospital can be used to detect systemic capillary leak syndrome, which can be a predictor of fluid overload, respiratory failure, need for icu admission, and death. at our medical centre (university medical center göttingen, göttingen, germany), we identified abnormalities in the urine samples of patients with covid- who became very sick within a few days. three of these patients had coincidentally submitted urine samples in the few weeks before their infection with severe acute respiratory syndrome coronavirus (sars-cov- ). these urine samples had been normal. however, on march , , since becoming infected with sars-cov- , the urine sample of one of these three patients was also positive for sars-cov- rna. the urine samples of the other two patients have not been tested because of safety concerns. some patients with covid- were eventually admitted to the icu. before their admission to icu, we detected low antithrombin iii concentrations ( - % [reference > %]), severe hypalbuminaemia (serum albumin concentration of · - · mg/dl [reference · - · mg/dl]), and urine samples positive for blood, albumin, and leukocytes. unlike patients in icu, patients with covid- receiving treatment for mild symptoms in the intermediate care unit had serum albumin concen trations above · mg/dl, and antithrombin concentrations were low but within normal limits. patients with covid- on the normal ward had the best serum albumin results (above · mg/dl) and normal urine. on the basis of these findings, we generated an algorithm for early detection of covid- -associated nephritis and to assess the risk of respiratory decompensation by capillary leak syndrome (figure). can covid- cause nephritis, and how might nephritis predict complications? sars-cov- uses the receptor ace for cell entry, and podocytes express ace . syndrome, which in turn induces cardiopulmonary syndrome. , complications of nephrotic syndrome are known to be similar to capillary leak syndrome, and preventive therapies are available. we recommend that patients with covid- who have nephritis be carefully monitored for the following conditions: pulmonary interstitial oedema, due to severe fluid overload similar to nephrotic syndrome; immune incompetence, due to renal loss of immunoglobulins; circulatory insufficiency, due to hypalbuminaemia; poor drug response because of impaired plasma protein binding; and thromboembolic events due to antithrombin deficiency. in summary, the respiratory tract is the gateway for sars-cov- infection, but we postulate that covid- associated nephritis, which can be easily screened for through a simple and inexpensive urine sample analysis, might help predict complications. this algorithm awaits further validation as a prediction tool. we have initiated a multicentre observational study (nct ) in germany to confirm our findings. if validated, we believe this tool could allow early anticipation of later need for icu admission, improved allocation of patients for special therapies (eg, in clinical trials), and initiation of preventive strategies focused on capillary leak syndrome, including treatment that could save lives. the same screening methods could be used for the risk evaluation of outpatients. clinic of anaesthesiology (om), and institute of infection control and infectious diseases (ss) we declare no competing interests. key: cord- -ekgqdjlk authors: anand, shuchi; montez-rath, maria; han, jialin; bozeman, julie; kerschmann, russell; beyer, paul; parsonnet, julie; chertow, glenn m title: prevalence of sars-cov- antibodies in a large nationwide sample of patients on dialysis in the usa: a cross-sectional study date: - - journal: lancet doi: . /s - ( ) - sha: doc_id: cord_uid: ekgqdjlk background: many patients receiving dialysis in the usa share the socioeconomic characteristics of underserved communities, and undergo routine monthly laboratory testing, facilitating a practical, unbiased, and repeatable assessment of severe acute respiratory syndrome coronavirus (sars-cov- ) seroprevalence. methods: for this cross-sectional study, in partnership with a central laboratory that receives samples from approximately dialysis facilities across the usa, we tested the remainder plasma of randomly selected adult patients receiving dialysis in july, , using a spike protein receptor binding domain total antibody chemiluminescence assay ( % sensitivity, · % specificity). we extracted data on age, sex, race and ethnicity, and residence and facility zip codes from the anonymised electronic health records, linking patient-level residence data with cumulative and daily cases and deaths per population and with nasal swab test positivity rates. we standardised prevalence estimates according to the overall us dialysis and adult population, and present estimates for four prespecified strata (age, sex, region, and race and ethnicity). findings: the sampled population had similar age, sex, and race and ethnicity distribution to the us dialysis population, with a higher proportion of older people, men, and people living in majority black and hispanic neighbourhoods than in the us adult population. seroprevalence of sars-cov- was · % ( % ci · – · ) in the sample, · % ( · – · ) when standardised to the us dialysis population, and · % ( · – · ) when standardised to the us adult population. when standardised to the us dialysis population, seroprevalence ranged from · % ( · – · ) in the west to · % ( · – · ) in the northeast. comparing seroprevalent and case counts per population, we found that · % ( · – · ) of seropositive patients were diagnosed. when compared with other measures of sars-cov- spread, seroprevalence correlated best with deaths per population (spearman's ρ= · ). residents of non-hispanic black and hispanic neighbourhoods experienced higher odds of seropositivity (odds ratio · [ % ci · – · ] and · [ · – · ], respectively) compared with residents of predominantly non-hispanic white neighbourhoods. residents of neighbourhoods in the highest population density quintile experienced increased odds of seropositivity ( · [ · – · ]) compared with residents of the lowest density quintile. county mobility restrictions that reduced workplace visits by at least % in early march, , were associated with lower odds of seropositivity in july, ( · [ · – · ]) when compared with a reduction of less than %. interpretation: during the first wave of the covid- pandemic, fewer than % of the us adult population formed antibodies against sars-cov- , and fewer than % of those with antibodies were diagnosed. public health efforts to limit sars-cov- spread need to especially target racial and ethnic minority and densely populated communities. funding: ascend clinical laboratories. severe acute respiratory syndrome coronavirus (sars-cov- ) virus stimulates a rapid antibody response in people with symptomatic - and asymptomatic , , infection. seroprevalence of sars-cov- antibodies in a population thus serves as a reasonable measure of exposure and spread. seroprevalence surveys in the usa, however, have been restricted to single hotspots [ ] [ ] [ ] or under-represented high-risk or vulnerable populations. , moreover, these studies face challenges to timely repetition and longitudinal follow-up, limiting their utility for surveillance. [ ] [ ] [ ] patients receiving dialysis might be considered an ideal sentinel population in which to study the evolution of the covid- public health crisis. patients receiving dialysis in the usa undergo routine monthly laboratory studies to gauge the effectiveness of therapy and to screen for associated complications. in haemodialysis, regular access to the bloodstream abrogates the need for phlebotomy to acquire blood samples. risk factors for acquisition of sars-cov- and for severe covid- , including advanced age, non-white race, poverty, and diabetes, are the rule rather than the exception in the us dialysis population. testing remainder plasma from monthly samples obtained for routine care of patients on dialysis for sars-cov- antibodies therefore represents a practical approach to a population-representative surveillance strat egy, informing risks faced by a susceptible population while ensuring representation from racial and ethnic minorities. in addition, seroprevalence surveys in patients receiving dialysis can be linked to patient-level and community-level data to enable evaluation and quantification of differences in sars-cov- prevalence by demographic and neighbourhood strata, and thus facilitate effective mitigation strategies targeting the highest-risk individuals and communities. in partnership with a commercial clinical laboratory, we tested seroprevalence of sars-cov- antibodies in a randomly selected representative sample of patients. our goal was to provide a nationwide estimate of exposure to sars-cov- during the first wave of covid- in the usa, up to july, , with stratification by region, age, sex, and race and ethnicity. we also harnessed population data on sars-cov- cases and deaths and percentage testing positive using nasal swab testing to assess how seroprevalence estimates correlated with other epidemiological measures of covid- incidence. finally, to inform preventive strategies for the high-risk dialysis population as well as the general population, we investigated communitylevel correlates for seropositivity. we did a cross-sectional analysis of adult (≥ years) patients undergoing monthly laboratory testing at ascend clinical using samples obtained for routine clinical care that otherwise would have been discarded. ascend clinical is a commercial clinical laboratory based in redwood city, california, that receives samples from a nationwide network of around dialysis facilities, serving approximately patients. we randomly selected patients from the patient list on june , , for seroprevalence testing to be done in july, , using implicit stratification by region, age, sex, and race and ethnicity followed by systematic sampling with fractional polynomials. after sample selection and processing, ascend clinical sent anonymised data on patient age, sex, race and ethnicity, and residence and facility zip codes to stanford university investigators for analyses. stanford university investigators further linked patient geographical information (zip code) to census data and publicly avail able covid- burden and community mobility data. the study received expedited approval from the stanford university of medicine institutional review board; informed consent was waived. we used the us food and drug administration-approved siemens healthineers sars-cov- spike protein receptor evidence before this study measuring the seroprevalence of severe acute respiratory syndrome coronavirus (sars-cov- ) antibodies provides a comprehensive assessment of its community spread. community seroprevalence surveys require considerable infrastructure and expense, and face implementation challenges during the covid- pandemic due to restricted outreach in the worstaffected communities. of the two largest seroprevalence surveys in the usa, one was limited only to new york state (n= ) and used convenience sampling at grocery stores. a second survey used remainder plasma from people visiting commercial laboratories in six cities (n= ), but lacked details on race and ethnicity and other community-level risk factors. we tested the remainder plasma of patients receiving dialysis throughout the usa, using a chemiluminescence assay with high sensitivity and specificity. to our knowledge, we provide the first nationally representative estimate of sars-cov- seroprevalence in the us dialysis and us adult population, and estimates for differences in seroprevalence by neighbourhood race and ethnicity, poverty, population density, and mobility restriction. we also evaluate which of the existing measures of covid- incidence most closely correlate with seroprevalence. most importantly, we show that as patients receiving dialysis have monthly blood draws, without fail and without bias, and are a population with increased representation of racial and ethnic minorities, repeated crosssectional analyses of seroprevalence within this sentinel population can be implemented as a practical and unbiased surveillance strategy in the usa. similar to data from other highly affected countries and regions (eg, spain and wuhan, china), despite the intense strain on resources and unprecedented excess mortality being experienced in the usa during the covid- pandemic, fewer than % of us adults had formed antibodies to sars-cov- as of july, . there was significant regional variation from less than % prevalence in the west to more than % in the northeast. public health efforts to curb the spread of the virus need to continue, with focus on some of the highest-risk communities that we identified, such as majority black and hispanic neighbourhoods, poorer neighbourhoods, and densely populated metropolitan areas. a surveillance strategy relying on monthly testing of remainder plasma of patients receiving dialysis can produce unbiased estimates of sars-cov- spread inclusive of hard-toreach, disadvantaged populations in the usa. such surveillance can inform disease trends, resource allocation, and effectiveness of community interventions during the covid- pandemic. binding domain (s rbd) total antibody (immunoglobulin) chemiluminescence assay, which has % sensitivity (≥ days after a positive pcr test) and · % specificity. we chose this assay on the basis of its emergency use authorization in june, , in the context that s rbd is also the target of vaccine development efforts. sample processing is detailed in the appendix (p ). we linked patient-level resi dence data with cumulative and daily cases and deaths per population as compiled on a county level by the center for systems science and engineering at johns hopkins university and with nasal swab test positivity rates, as compiled on a state level by the covid tracking project. for utah, we followed the utah department of health groupings of several smaller counties and extracted data directly. new york city data are not available by county within the johns hopkins university dataset; therefore, we directly extracted data from the new york city dashboard. for county-level mobility restrictions, we used google mobility data that report an average percentage change in the number of workplace visits over the period march - , , before the implementation of shelterin-place restrictions in the majority of the country. percentage changes in the google mobility data are indexed to a corresponding weekday (eg, tuesdays are matched to tuesdays) from jan to feb , . we also linked patient-level residence data with zip code tabulation area (zcta) data from the american community survey (acs) -year estimates to ascertain patient neighbourhood proportion living below the poverty level and race and ethnicity mix, and with american census bureau estimates to ascertain population density. we defined zcta majority race and ethnicity as hispanic, non-hispanic black, or non-hispanic white if the population in the zcta was at least % hispanic, non-hispanic black, or non-hispanic white, respectively; where this was not the case, if the hispanic and black population combined was at least % of the population, the zcta majority was defined as hispanic and black, otherwise as other. for urban versus rural zcta status, we used the rural urban commuting area codes by census tract, categorising a zcta as dense urban, metropolitan, micropolitan, or small town or rural area if more than % of the population in the zcta was living in one of these area codes. we assumed a nationwide prevalence of sars-cov- antibody of %. , to generate prevalence estimates for patients on dialysis using preselected regional strata with precision within · %, a sample of was required (appendix p ). based on previous trends, we expected % of selected samples to be unavailable in july, , due to death, move to other facilities, or other reasons for missing laboratory data (eg, hospitalisation or non-adherence). accounting for this potential dropout, we randomly selected patients. we present prevalence estimates with % cis in our sample, standardised to the us adult dialysis population and to the us adult population. for the us adult dialysis based on the test sensitivity range obtained by schnurra and colleagues in their external validation, we also provide test characteristic-adjusted sample population estimates, ranging sensitivity from % to %. to compute the percentage of estimated sero prevalent cases that were likely to be diagnosed cases, , we compared the estimated seroprevalent cases per adult population with johns hopkins university esti mates of cumulative diagnosed cases per us adult popu lation as of june , . to standardise estimates, we assigned weights to each person based on their membership to each of strata of census regions (northeast, south, midwest, and west), age ( - , - , - , and ≥ years), and sex. we defined post-stratification weights as the proportion of each stratum represented in the us dialysis population or us adult population divided by the analogous proportion in the sample. [ ] [ ] [ ] we then computed weighted frequencies and % cis according to four prespecified strata (region, age, sex, and race and ethnicity) with differences evaluated using rao-scott χ² tests. , due to the missingness of race and ethnicity data in the electronic health records, we used the additional measure of zcta race and ethnicity distribution with categories adapted from moore and colleages. , next, we correlated five measures of covid- incidence-cumulative cases on june , (or first available date between june and june , ); cumulative deaths on june , (or last available date between june and june , ); -day averages of daily cases and daily deaths; and percentage testing positive on nasal swab tests between june and june , -with sars-cov- seroprevalence in patients on dialysis in july, . to do this, we first collapsed all measures to a state level and then assessed the spearman's correlation coefficient ρ for the association of each measure with seroprevalence. because of the high density of ascend clinical facilities in new york, texas, and california, we also chose those states to present county-level correlations. finally, using logistic regression, we determined the age-adjusted and sex-adjusted correlates of seropositivity for patient zcta race and ethnicity distribution, percentage living below poverty level, rural or urban classification, population density, and county mobility restriction. we assumed statistical significance at α< · . all statistical analyses were done with sas enterprise guide (version . ) and stata (version . ). ascend clinical laboratories supported the remainder plasma testing for sars-cov- antibodies. sa, mm-r, and jh had complete access to all data in the study and sa, mm-r, jh, jp, and gmc were responsible for the decision to submit for publication. of the people selected for testing on june , , were tested in july, (figure ), with ( · %) tested in the first weeks (appendix p ). the sampling was representative of the us dialysis patient distribution by age, sex, race and ethnicity (when excluding patients without race and ethnicity data), and region, except sampled patients were less likely to be non-hispanic black (table ) . compared with the us adult population, our sampled patient population was older, had more men, and was more likely to be non-hispanic black and living in non-white neighbourhoods seroprevalence ranged from · % ( · - · ) to · % ( · - · ) in our sampled population (appendix p ). when standardised to the us dialysis population, seroprevalence was · % ( · - · ), with high regional variation in seroprevalence (ranging from · % [ · - · ] in the west to · % [ · - · ] in the northeast; table ). seroprevalence was similar by sex and modestly lower in people aged years or older compared with those aged - years (table ) . differences in seroprevalence by race and ethnicity were similar using both our patient-level (electronic health record) and neighbourhood-level (zcta majority race and ethnicity) measures, with non-hispanic black patients having the highest seropositivity, followed by hispanic patients, and non-hispanic white patients having the lowest. we estimated the sars-cov- standardised seroprevalence in the us population to be · % ( % ci · - · ; table ). based on the johns hopkins university cumulative case data as of june , , the prevalence of (nasal swab) diagnosed cases was per us adult population, compared with our estimate of seropositive people per population, meaning that · % ( · - · ) of sero positive people were diagnosed. using data from our sampled population, variation by state was high, ranging from · % in seven states to · % ( · - · ) in new york, with the highest regional variation occurring in the northeast (figure ; appendix pp - ). when comparing state seropreva lence against cumulative cases and deaths per population, deaths correlated best (ρ= · for cases vs · for deaths; figure ). the percentage of people testing positive by nasal swab test and -day average of daily deaths in the latter half of june, , showed a weaker correlation (ρ= · and · , respectively), whereas -day average of daily cases did not correlate with seroprevalence (ρ=− · ). on a county level in california, new york, and texas, there was even more heterogeneity in the correlation between seroprevalence and other disease measures (ρ≤ · for all correlations for all three states' county-level data; appendix p ). likelihood of sars-cov- seropositivity was lower among older people (odds ratio · [ % ci · - · ] for people aged years or older vs people aged - years), but did not differ by sex ( · [ · - · ] for women vs men). in age-adjusted and sex-adjusted models, neighbour hood racial and ethnic distribution, poverty level, dense urbanisation, population density, and percentage change in workplace visits in early march, , were all strongly associated with seropositivity ( figure ). in our analysis of seroprevalence of sars-cov- spike protein receptor binding antibodies from a nationwide representative sample of patients receiving dialysis, we find that despite the usa contemporaneously leading the world in the numbers of diagnosed cases, overall, fewer than % of us adults had evidence of seroconversion in july, . a vast majority of us adults, including people receiving dialysis who are among the highest risk for mortality upon contracting sars-cov- , do not have evidence of exposure or immune response. furthermore, we find increased likelihood of sars-cov- seropositivity in residents of predominantly black and hispanic neighbour hoods (two to three times higher), poorer areas (two times higher), and the most densely populated areas (ten times higher). early reduction in community mobility in march, , was associated with % lower likelihood of individual-level seroconversion by july that year. unlike most published estimates of sars-cov- seroprevalence from the usa, , , patients included in our study sample had antibodies measured from blood collected as part of routine medical care. thus, our prevalence estimates should not be subject to selection bias due to presence versus absence of symptoms, availability of testing materials, local or regional testing strategies, geography, income, educational attainment, language proficiency, immigration status, mobility, anxiety, fear, or other factors. moreover, since end-stage kidney disease qualifies affected patients for medicare insurance, and since end-stage kidney disease disproportionately affects black, hispanic, and other disadvantaged populations, , , we are able to determine-with a high level of precision-differences in seroprevalence among patient groups within and across regions of the usa. of the two larger seroprevalence surveys published from the usa thus far, one was confined to new york state (n= ), employed a convenience sampling technique at grocery stores, and relied on a microsphere immunoassay with lower sensitivity. the second, the centers for disease control and prevention (cdc) six sites study (n= ), used remainder plasma from people getting testing for undefined clinical indications, and did not have detailed sociodemographic information about the tested people. uncertainty exists as to whether seroprevalence estimates in the dialysis population can be extrapolated to the us population more broadly. a recent analysis of sars-cov- igg antibodies in two dialysis units in london, uk, reported seroprevalence of %, higher than in healthy blood donors ( %) but lower than in healthcare workers ( %) sampled within a similar time frame. our data might overestimate overall seroprevalence in , , , states in white were not included in the sample. the general population since patients on dialysis are disproportionately from racial and ethnic minorities; , for example, black americans have a nearly four-times higher risk of end-stage kidney disease than white americans. moreover, the process of undergoing incentre haemodialysis might include the use of public or non-public shared transportation to and from the facility, and - h of care delivered in indoor facilities. conversely, these data might underestimate overall seroprevalence in the general population. patients receiving dialysis are less likely to be employed and more likely to restrict their mobility and social activity due to advanced age and frailty; therefore, they might have fewer opportunities to acquire the infection, par ticularly from asymptomatic individuals. extrapolating from multiple prospective hepatitis b immunisation studiesin which - % of vaccinated patients receiving dialysis mounted a response compared with % or more people from the general population-patients receiving dialysis might mount a weaker immune response and thus be less likely to seroconvert. finally, patients receiving dialysis might have been more likely to die or have been hospitalised due to complications of sars-cov- infection. if so, these patients would not have been present for testing in the dialysis facilities, creating a survival bias and yielding lower estimates of exposure. nonetheless, the ten-times difference we observed between diagnosed cases per population and our estimates of seropositive people per has been similarly reported in studies from new york, the cdc six sites study, and in a population-representative analysis from geneva. thus, our findings comport with other seroprevalence estimates. we confirm that as in other studies from covid- hotspots, , , a minority of the population has evidence of exposure and immune response, and a vast majority, including people at high risk for mortality (ie, the population on dialysis), remain vulnerable. in fact, even if the seroprevalence estimates derived from the us dialysis population overestimated true seroprevalence in the overall us adult population, our data nonetheless support that fewer than % of the us population has seroconverted as of july, , and all variables are at a neighbourhood (ie, zcta) level, except for reduction in workplace visits, which is at a county level, and are modelled separately, accounting for age and sex. poverty level is defined as percentage of people living below the federal poverty level in the zcta. population density quintiles are derived from the zcta (median people per square mile [iqr - ]). reductions in workplace visits were measured during the first weeks of march, , compared with a baseline in january-february, . or=odds ratio. sars-cov- =severe acute respiratory syndrome coronavirus . zcta=zip code tabulation area. · ( · - · ) age-sex-adjusted or ( % ci, log scale) herd immunity remains out of reach, as has been the conclusion from large international surveys from the uk and spain, where intense outbreaks of covid- occurred during the spring and summer of . furthermore, the seroprevalence differences captured by region, age, sex, and community-level risk factors (ie, internal comparisons) are expected to be similar in the us dialysis and us general adult population. our study provides convincing evidence that the covid- pandemic has dramatically amplified existing health disparities. data from the cdc highlighting sars-cov- health disparities evaluate hospitalisations and deaths by race and ethnicity, , calling into question whether black and hispanic populations are experiencing more severe illness versus facing higher likelihoods of exposure. some us state dashboards also report higher cumulative cases among black and hispanic people compared with non-hispanic white people, but none have as precisely quantified differences on a national level. neighbourhood poverty and population density were also highly correlated with seroprevalence, with a possible threshold effect for population density, such that there was a ten-times higher risk in the highest density zctas (> people per square mile). population density is recognised as a crucial factor, driving the spread in metropolitan areas, in confined spaces (eg, the diamond princess cruise ship), large gatherings (eg, the new orleans' mardi gras), , and in populous regions across the world. rocklöv and sjödin suggest that the basic reproduction number (r ) of sars-cov- increases linearly with population density. our data also show slightly lower likelihood of seropositivity among older people, as was seen in a recent report from geneva and attributed to better adherence to physical distancing measures by the authors. a higher competing risk from hospitalisations or mortality after sars-cov- exposure might be a larger contributing factor in the observed lower seroprevalence in older compared with younger age groups. in addition to providing an overall estimate of sars-cov- seroprevalence and quantifying differences by patient and community characteristics, our study puts forth a viable surveillance strategy for sars-cov- spread in the usa. who and other experts , advocate for repeated cross-sectional analyses of seroprevalence as a disease tracking system able to most completely measure the true incidence of sars-cov- , since these can more likely capture incidence of exposure in both symptomatic and asymptomatic individuals. in fact, we observed substantial heterogeneity in the correlation between seroprevalence and other measures of sars-cov- that are currently being used-with the exception of deaths per , which are a late outcome -supporting the use of rapidly instituted seroprevalence surveys as a complementary surveillance tool. additional public health implications of seroprevalence surveys include assessing testing adequacy. for example, in states where the difference between seropositive and diagnosed cases is decreasing over time, testing capacity is likely to be increasing. furthermore, following seroconversion rates over time can presage hospitalisations and intensive care unit stays, since the time between exposure and seroconversion is relatively short (median days), and can therefore facilitate resource allocation. finally, as we show by assessing community mobility restrictions, seroprevalence surveys can measure the effects of interventions to treat or prevent infection with sars-cov- . repeated serological surveys, if done in a community setting, would require extensive resources and yet remain subject to selection bias. however recurring monthly testing of remainder plasma of randomly selected sets of people-as is practically feasible in patients receiving dialysis-can serve as a representative surveillance system in the usa, with minimal phlebotomy or infrastructure requirement, and as our data show, include traditionally under-represented and socially disadvantaged groups. this analysis has numerous strengths. we used a highly specific and sensitive immunoassay, one which has been robustly linked to sars-cov- exposure. , , , the study sample was highly representative of the us dialysis population and, as noted, we used remainder plasma from specimens used in routine clinical care. the sample size and sampling scheme allowed us to estimate with precision prevalence across several patient characteristics. moreover, linking to us census and other publicly available data sources assembled during the pandemic provides valuable context when considering the implications of these data to the general population. there are also several important limitations. as noted previously, it is plausible that seroprevalence estimates from the us dialysis population overestimate seroprevalence in the us adult population. we do not have patient-level data on symptoms nor nasal swab testing results, and thus cannot test whether the likelihood of seroconversion differs in patients receiving dialysis from generally healthy adults, although preliminary data from london, uk, suggest no differences. we also do not have patient-level data on health status, employment status, income, household size, living space, and other sociodemographic factors, and so relied on neighbourhood proxies for some of these domains. dialysis units are more often located in urban areas, and thus we have under-representation of rural areas. finally, while large, our study was designed for precise regional, not state-level or county-level, estimates. in conclusion, we present sars-cov- seroprevalence data in a broadly representative sample of patients receiving dialysis across the usa and show striking differences in seroprevalence by several patient characteristics, with higher seroprevalence in younger patients, black and hispanic patients, and patients living in poorer and majority-minority neighbourhoods. these data can help to inform surveillance and management strategies during the next phase of the pandemic. serial sampling of dialysis remainder plasma should be used to determine trends in disease prevalence and the effect of various strategies being implemented around the usa to reduce the burden of covid- on the general population. sa assisted with data cleaning and analysis planning, and manuscript writing. mm-r developed the analysis plan, generated census data tables, supervised data analysis, and contributed to manuscript writing. jh undertook data cleaning and analysis, including linkage to external data and figure generation, and contributed to manuscript writing. jb undertook sample processing and data preparation and contributed to manuscript writing. rk selected seroprevalence testing, supervised sample processing, and contributed to manuscript writing. pb co-conceived the study, secured seroprevalence testing, and supervised sample processing and data preparation. jp supervised the study analysis plan, identified relevant external data, contributed to data interpretation, and supervised manuscript writing. gmc co-conceived the study, supervised the study analysis plan, and co-wrote the manuscript. jb, rk and pb are employed by ascend clinical laboratories. gmc is on the board of directors of satellite healthcare, a not-for-profit dialysis organisation. all 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geneva, switzerland (serocov-pop): a population-based study post-stratification or non-response adjustment? post stratification analysis of health surveys the analysis of categorical data from complex surveys: chi-squared tests for goodness of fit and independence in two-way tables on chi-squared tests for multiway contingency tables with cell properties estimated from survey data availability of recreational resources in minority and low socioeconomic status areas the intersection of neighborhood racial segregation, poverty, and urbanicity and its impact on food store availability in the united states a report from the brescia renal covid task force on the clinical characteristics and shortterm outcome of hemodialysis patients with sars-cov- infection neighborhood poverty and racial differences in esrd incidence low income, community poverty and risk of end stage renal disease high prevalence of asymptomatic covid- infection in hemodialysis patients detected using serologic screening white/black racial differences in risk of end-stage renal disease and death racial differences in the progression from chronic renal insufficiency to end-stage renal disease in the united states employment among patients starting dialysis in the united states frailty, dialysis initiation, and mortality in end-stage renal disease review article: hepatitis b and dialysis seroprevalence of immunoglobulin m and g antibodies against sars-cov- in china antibody prevalence for sars-cov- in england following first peak of the pandemic: react study in , adults covidview: a weekly surveillance summary of us covid- activity comparison of weighted and unweighted population data to assess inequities in coronavirus disease deaths by race/ethnicity reported by the us centers for disease control and prevention covid- and african americans geographic differences in covid- cases, deaths, and incidence-united states population density and basic reproductive number of covid- across united states counties ethnic and regional variations in hospital mortality from covid- in brazil: a cross-sectional observational study high population densities catalyse the spread of covid- assessing the extent of sars-cov- circulation through serological studies risk factors associated with mortality among patients with covid- in intensive care units in evaluation of nucleocapsid and spike protein-based enzyme-linked immunosorbent assays for detecting antibodies against sars-cov- evaluation of sensitivity and specificity of commercially available sars-cov- antibody immunoassays ascend clinical laboratories supported the remainder plasma testing for sars-cov- antibodies. sa was supported by k dk . mm-r and gc are supported by national institutes of health niddk k dk . we thank martin gorfinkel (mountain view, ca, usa) for his feedback on sampling design. key: cord- - babe b authors: stewart, ruth; el-harakeh, amena; cherian, sunu alice title: evidence synthesis communities in low-income and middle-income countries and the covid- response date: - - journal: lancet doi: . /s - ( ) - sha: doc_id: cord_uid: babe b nan evidence synthesis specialists have responded to the covid- pandemic. in line with who's global roadmap for covid- research, we are working to summarise the available research to support evidence-informed decision making across all sectors for immediate and anticipated challenges, within the covid- evidence network to support decision-making (covid-end). covid-end is an umbrella organisation involving evidence synthesis or evidence support organisations that are working together to promote collaboration and reduce duplication of effort in the conduct and translation of covid- -related evidence syntheses. as a network we have accelerated investment to enable infrastructure for evidence synthesis and to promote evidence use. covid- and its related impacts are likely to be felt for many years to come. as the low-income and middleincome country (lmic) members of a global partnership, we believe that, for global evidence synthesis initiatives to benefit from lmic expertise and be relevant to lmic settings, it is important to recognise the conceptual and practical challenges that this pandemic presents to our evidence synthesis organisations. lmic evidence communities are well placed to support evidence-informed decision making. they include established, locally driven, experienced centres of excellence that are part of technical and regional networks and trusted by decision makers. our teams and our strong networks are invaluable in promptly getting the best available evidence into the hands of policy makers. however, these achievements are often despite-and not because of-the circumstances in which we work. many of us work in countries where there are complex challenges. weak health systems in lmics are generally struggling to make the necessary responses to the covid- pandemic and the prevalence of comorbidities are putting our populations at increased risk of the direct and indirect consequences of the pandemic. paramount to poorer and conflict-affected states are the pre-existing, and rapidly worsening, vulnerabilities due to inequalities and inequities, unemployment, hunger, and malnutrition. violence against women and children, unintended pregnancies, and risks to incarcerated populations are all escalating, as are disruptions to child vaccination programmes. in addition to the mental health strain caused by a pandemic, lockdowns, and resulting social and economic pressures, we are observing fear and stigma associated with covid- , quarantine, and isolation. home evictions linked to job losses, low levels of public health information in some settings, and the presence of migrant workers and refugees have exacerbated xenophobia and social unrest in some lmics. older people, migrant workers, refugees, and students have all found themselves vulnerable and inadequately supported. in many countries, these challenges have come on top of entrenched economic, social, and political pressures and present considerable demands on researchers seeking to generate evidence in the covid- response. the demand for evidence to inform decision making, and for effective implementation of such policies, typically outweighs our ability to respond. this situation is compounded by an increased demand for transparency, amid all the mistrust about science that some groups, including certain politicians, bring to the public discourse. as a broad community of evidence synthesis specialists based in lmics, many of us are experiencing common difficulties arising from limited access to computer hardware and software, restrictions on database access, limited data storage capacity, inadequate data cov erage, and low internet bandwidth. our institutions, like many in poorer settings, are relying on the commitment of individuals, many of whom are using personal computers, living in unfavourable conditions, and working under pressure as they and their families and friends suffer the health, economic, and social impacts of the pandemic. constrained funds are being repurposed from other projects to enable the increased efforts to generate timely and locally relevant evidence syntheses. in some cases, researchers are working without salaries or with job insecurity. despite these practical challenges, above and beyond those faced by all researchers producing rapid reviews during this period, our networks continue to generate evidence syntheses to support our governments and strengthen their capacities and resilience. the value of the knowledge translation efforts and rapid response mechanisms to provide timely evidence synthesis is coming into its own, with evidence reaching the highest levels of governments. covid- represents an opportunity to further strengthen and institutionalise evidence-informed policy making across lmics. we encourage our governments to continue to make good use of, and invest in, the evidence services available to them. coordination of the research response to covid- is not only crucial to avoid duplication and maximise benefits, but also to ensure that the capacity within lmics is secured and strengthened for the benefit of us all. local voices are important for the contextualisation and integration of evidence into decision making. these voices also have a role in shaping the global research agenda for this and future crises. global initiatives to generate evidence for tackling covid- and for the post-covid- recovery must consider the conceptual and practical challenges faced by research teams in lmics and recognise the need to strengthen and sustain the voices of lmic researchers on a global scale. we call for much needed donor support to bolster lmic evidence synthesis communities and their capacities. we need action from individuals, organisations, govern ments, and donors to enable and sustain the generation and use of evidence synthesis in lmics if we are to tackle covid- globally. we declare no competing interests. who. a coordinated global research map: novel coronavirus. comorbidity in context: part . medical considerations around hiv and tuberculosis during the covid- pandemic in south africa covid- and human trafficking-the amplified impact on vulnerable populations at least million children under one at risk of diseases such as diphtheria, measles and polio as covid- disrupts routine vaccination efforts, warn gavi, who and unicef the coronavirus (covid- ) pandemic's impact on mental health stigma and covid- crisis: a wake-up call. letter to the editor covid- : un counters pandemic-related hate and xenophobia if the world fails to protect the economy, covid- will damage health not just now but also in the future using misinformation as a political weapon: covid- and bolsonaro in brazil rapid review methods more challenging during covid- : commentary with a focus on knowledge synthesis steps key: cord- -srmpzrzj authors: macintyre, c raina; wang, quanyi title: physical distancing, face masks, and eye protection for prevention of covid- date: - - journal: lancet doi: . /s - ( ) - sha: doc_id: cord_uid: srmpzrzj nan the choice of various respiratory protection mecha nisms, including face masks and respirators, has been a vexed issue, from the h n pandemic to the west african ebola epidemic of , to the current covid pandemic. covid guidelines issued by who, the us centers for disease control and prevention, and other agencies have been consistent about the need for physical distancing of - m but conflicting on the issue of respiratory protection with a face mask or a respirator. this discrepancy reflects uncertain evidence and no consensus about the transmission mode of severe acute respiratory syndrome coronavirus (sarscov ). for eye protection, data are even less certain. therefore, the systematic review and metaanalysis by derek chu and colleagues in the lancet is an important milestone in our understanding of the use of personal protective equipment (ppe) and physical distancing for covid . no randomised controlled trials were available for the analysis, but chu and colleagues systematically reviewed observational studies and rigorously synthesised available evidence from comparative studies on sars, middle east respiratory syndrome (mers), covid , and the betacoronaviruses that cause these diseases. the findings showed a reduction in risk of % with a physical distance of m in both healthcare and community settings (adjusted odds ratio [aor] · , % ci · - · ). every additional m of separation more than doubled the relative protection, with data available up to m (change in relative risk [rr] · per m; p interaction = · ). this evidence is important to support community physical distancing guidelines and shows risk reduction is feasible by physical distancing. moreover, this finding can inform lifting of societal restrictions and safer ways of gathering in the community. the - m distance rule in most hospital guidelines is based on outofdate findings from the s, with studies from showing that large droplets can travel as far as m. to separate droplet and airborne transmission is probably somewhat artificial, with both routes most likely part of a continuum for respiratory transmissible infections. protection against presumed droplet infections by use of respirators, but not masks, supports a continuum rather than discrete states of droplet or airborne transmission. both experimental and hospital studies have shown evidence of aerosol transmission of sarscov . [ ] [ ] [ ] one study found viable virus in the air h after aerosolisation and showed greater airborne propensity for sarscov compared with sarscov and merscov. chu and colleagues reported that masks and respi rators reduced the risk of infection by % (aor · , % ci · - · ), with greater effectiveness in health care settings (rr · , % ci · - · ) than in the community ( · , · - · ; p interaction = · ). they attribute this difference to the predominant use of n respirators in healthcare settings; in a sub analysis, respirators were % effective (aor · , % ci · - · ) compared with other masks, which were % effective (aor · , % ci · - · ; p interaction = · ). the other important finding for health workers by chu and colleagues was that eye protection resulted in a % reduction in infection (aor · , % ci · - · ); infection via the ocular route might occur by aerosol transmission or selfinoculation. for healthcare workers on covid wards, a respirator should be the minimum standard of care. this study by chu and colleagues should prompt a review of all guidelines that recommend a medical mask for health workers caring for covid patients. although medical masks do protect, the occupational health and safety of health workers should be the highest priority and the precautionary principle should be applied. preventable infections in health workers can result not only in deaths but also in large numbers of health workers being quarantined and nosocomial outbreaks. in the national health service trusts in the uk, up to one in five health workers have been infected with covid , which is an unacceptable risk for frontline workers. to address global shortages of ppe, countries should take responsibility for scaling up production rather than expecting health workers to work in suboptimum ppe. chu and colleagues also report that respirators and multilayer masks are more protective than are single layer masks. this finding is vital to inform the proliferation of homemade cloth mask designs, many of which are singlelayered. a well designed cloth mask should have waterresistant fabric, multiple layers, and good facial fit. this study supports universal face mask use, because masks were equally effective in both healthcare and community settings when adjusted for type of mask use. growing evidence for presymptom atic and asymptomatic transmission of sarscov further supports universal face mask use and distancing. in regions with a high incidence of covid , universal face mask use combined with physical distancing could reduce the rate of infection (flatten the curve), even with modestly effective masks. universal face mask use might enable safe lifting of restrictions in communities seeking to resume normal activities and could protect people in crowded public settings and within households. masks worn within households in beijing, china, prevented secondary transmission of sarscov if worn before symptom onset of the index case. finally, chu and colleagues reiterate that no one intervention is completely protective and that combinations of physical distancing, face mask use, and other interventions are needed to mitigate the covid pandemic until we have an effective vaccine. until randomised controlled trial data are available, this study provides the best specific evidence for covid prevention. respiratory protection for healthcare workers treating ebola virus disease (evd): are facemasks sufficient to meet occupational health and safety obligations? policies on the use of respiratory protection for hospital health workers to protect from coronavirus disease (covid ) physical distancing, face masks, and eye protection to prevent persontoperson transmission of sarscov and covid : a systematic review and metaanalysis airborne or droplet precautions for health workers treating covid ? the efficacy of medical masks and respirators against respiratory infection in healthcare workers comparative dynamic aerosol efficiencies of three emergent coronaviruses and the unusual persistence of sarscov in aerosol suspensions aerosol and surface distribution of severe acute respiratory syndrome coronavirus in hospital wards transmission potential of sarscov in viral shedding observed at the university of ncov transmission through the ocular surface must not be ignored first experience of covid screening of healthcare workers in england face masks for the public during the covid crisis covid : should cloth masks be used by healthcare workers as a last resort temporal dynamics in viral shedding and transmissibility of covid mathematical assessment of the impact of nonpharmaceutical interventions on curtailing the novel coronavirus reduction of secondary transmission of sarscov in households by face mask use, disinfection and social distancing: a cohort study in beijing, china key: cord- -yzum k authors: moon, suerie; sridhar, devi; pate, muhammad a; jha, ashish k; clinton, chelsea; delaunay, sophie; edwin, valnora; fallah, mosoka; fidler, david p; garrett, laurie; goosby, eric; gostin, lawrence o; heymann, david l; lee, kelley; leung, gabriel m; morrison, j stephen; saavedra, jorge; tanner, marcel; leigh, jennifer a; hawkins, benjamin; woskie, liana r; piot, peter title: will ebola change the game? ten essential reforms before the next pandemic. the report of the harvard-lshtm independent panel on the global response to ebola date: - - journal: lancet doi: . /s - ( ) - sha: doc_id: cord_uid: yzum k nan the west african ebola epidemic that began in exposed deep inadequacies in the national and international institutions responsible for protecting the public from the far-reaching human, social, economic, and political consequences of infectious disease outbreaks. the ebola epidemic raised a crucial question: what reforms are needed to mend the fragile global system for outbreak prevention and response, rebuild confi dence, and prevent future disasters? to address this question, the harvard global health institute and the london school of hygiene & tropical medicine jointly launched the independent panel on the global response to ebola. panel members from academia, think tanks, and civil society have collectively reviewed the worldwide response to the ebola outbreak. after diffi cult and lengthy deliberation, we concluded that major reforms are both warranted and feasible. the panel's conclusions off er a roadmap of ten interrelated recommendations across four thematic areas: preventing major disease outbreaks all countries need a minimum level of core capacity to detect, report, and respond rapidly to outbreaks. the shortage of such capacities in guinea, liberia, and sierra leone enabled ebola to develop into a national, and worldwide, crisis. • recommendation : the global community must agree on a clear strategy to ensure that governments invest domestically in building such capacities and mobilise adequate external support to supplement eff orts in poorer countries. this plan must be supported by a transparent central system for tracking and monitoring the results of these resource fl ows. additionally, all governments must agree to regular, independent, external assessment of their core capacities. • recommendation : who should promote early reporting of outbreaks by commending countries that rapidly and publicly share information, while publishing lists of countries that delay reporting. funders should create economic incentives for early reporting by committing to disburse emergency funds rapidly to assist countries when outbreaks strike and compensating for economic losses that might result. additionally, who must confront governments that implement trade and travel restrictions without scientifi c justifi cation, while developing industry-wide cooperation frameworks to ensure private fi rms such as airlines and shipping companies continue to provide crucial services during emergencies. when preventive measures do not succeed, outbreaks can cross borders and surpass national capacities. ebola exposed who as unable to meet its responsibility for responding to such situations and alerting the global community. • recommendation : a dedicated centre for outbreak response with strong technical capacity, a protected budget, and clear lines of accountability should be created at who, governed by a separate board. • recommendation : a transparent and politically protected who standing emergency committee should be delegated with the responsibility for declaring public health emergencies. • recommendation : an independent un accountability commission should be created to do systemwide assessments of worldwide responses to major disease outbreaks. rapid knowledge production and dissemination are essential for outbreak prevention and response, but reliable systems for sharing epidemiological, genomic, and clinical data were not established during the ebola outbreak. • recommendation : governments, the scientifi c research community, industry, and non-governmental organisations must begin to develop a framework of norms and rules operating both during and between outbreaks to enable and accelerate research, govern the conduct of research, and ensure access to the benefi ts of research. • recommendation : additionally, research funders should establish a worldwide research and development fi nancing facility for outbreak-relevant drugs, vaccines, diagnostics, and non-pharmaceutical supplies (such as personal protective equipment) when commercial incentives are not appropriate. we do not have the capacity to respond to this crisis on our own. if the international community does not stand up, we will be wiped out. we need your help. we need it now.n aimah jackson, team leader, médecins sans frontières ebola treatment center, monrovia. address to the un security council, sept , the west african ebola epidemic that began in was a human tragedy that exposed a global community altogether unprepared to help some of the world's poorest countries control a lethal outbreak of infectious disease. the outbreak engendered acts of outstanding courage and solidarity, but also immense human suff ering, fear, and chaos, largely unchecked by high-level political leadership or reliable and rapid institutional responses. the outbreak continues as of november, . it has infected more than people and claimed more than lives, brought national health systems to a halt, rolled back hard-won social and economic gains in a region recovering from civil wars, sparked worldwide panic, and cost several billion dollars in short-term control eff orts and economic losses. , guinea, liberia, and sierra leone were most badly aff ected. the ebola outbreak is a stark reminder of the fragility of health security in an interdependent world, and of the importance of building a more robust global system to protect all people from such risks. a more humane, competent, and timely response to future outbreaks needs greater willingness to assist aff ected populations, and systematic investments to enable the global community to perform four key functions: . strengthen core capacities within and between countries to prevent, detect, and respond to outbreaks when and where they occur. . mobilise faster and more eff ective external assistance when countries are unable to prevent an outbreak from turning into a crisis. . rapidly produce and widely share relevant know ledge, from community mobilisation strategies to protective measures for health workers, and from epidemiological information to rapid diagnostic tests. . provide stewardship over the whole system, entailing strong leadership, coordination, priority-setting, and robust accountability from all involved. the ebola outbreak emphasised failures in performing all four of these functions. clarity about roles, responsibilities, and rules-and accountability for adherence to them-is essential in a complex system that must involve local, national, regional, and international actors spanning the public, private, and non-profi t sectors. yet, this clarity and accountability was fundamentally absent. without addressing these governance issues, we will remain wholly unprepared for the next epidemic, which might very well be more devastating, virulent, and transmissible than ebola or previous disease outbreaks. [ ] [ ] [ ] the independent panel on the global response to ebola is a joint initiative of the harvard global health institute and the london school of hygiene & tropical medicine to review the global community's response to the ebola outbreak. the members come from academia, think tanks and civil society around the world, with expertise in ebola, disease outbreaks, public and global health, international law, development and humanitarian assistance, and national and global governance. the panel took a global, system-wide view with a special focus on rules, roles, and responsibilities to identify changes necessary to prevent and prepare for future outbreaks. this panel report outlines the main weaknesses exposed during diff erent phases of the ebola outbreak, followed by ten concrete, interrelated recommendations across four thematic areas: preventing major disease outbreaks, responding to major disease outbreaks, research-production and sharing of data, knowledge, and technology, and governing the global system, with a focus on who. our primary goal is to convince high-level political leaders worldwide to make necessary and enduring changes to better prepare for future outbreaks while memories of the human costs of inaction remain vivid and fresh. the ebola outbreak witnessed many types of failures. for analytical purposes, we divide the epidemic roughly into four phases, underlining the most salient issues that arose. during the initial phase from december, , to march, , the fi rst infections occurred in a remote rural area of guinea where no outbreaks of ebola had previously been identifi ed. the lack of capacity in guinea to detect the virus for several months was a key failure, allowing ebola eventually to spread to bordering liberia and sierra leone. this phase underscored the problem of inadequate investments in health infrastructure, despite national governments' formal commitments to do so under the international health regulations ( ), and awareness among donors that many lower income countries would need substantial external support. it also underscored inadequate arrangements between governments and who to share, validate, and respond robustly to information on outbreaks. in march, , a second phase began in which intergovernmental and non-governmental organisations began to respond, starting with médecins sans frontières, which already had teams on the ground. that month, both guinea and liberia confi rmed ebola outbreaks to who. by march , ebola was confi rmed in conakry, home to more than one in seven guineans. two months later ebola had spread to three capital cities with international airports. without any approved drugs, vaccines or rapid diagnostic tests, health workers struggled to diagnose patients and provide eff ective care. without suffi cient protective gear, and initially without widespread understanding of the virus, hundreds of health workers themselves became ill and died. despite médecins sans frontières' warnings about the unprecedented scope of the outbreak, national authorities in guinea downplayed it for fear of creating panic and disrupting economic activity. , internal documents suggest similar concerns might have infl uenced who, which publicly characterised the outbreak in march as "relatively small still". who's global alert and response network sent an expert team to support national eff orts, as did others such as the us centers for disease control and prevention. however, those teams withdrew from guinea and liberia in may when reported cases decreased, even as viral transmission continued. in late may, sierra leone became the third country to declare an ebola outbreak to who. for the fi rst time in the known history of ebola, the virus had spawned sustained outbreaks in three countries. this should have raised substantial alarm, as coordination was weak between the national governments of liberia, guinea, and sierra leone, the borders extremely porous, and human movement and trade highly fl uid. in late june, médecins sans frontières labelled the situation as "out of control" and publicly called for more international attention and resources. this second phase witnessed three interrelated failures. first, in a failure of political leadership, some national authorities did not call for greater international assistance despite the humanitarian crisis, and in some cases downplayed the outbreak. second, who's in-country technical capacity was weak, shown by its decision to withdraw its international team too soon and its poor responses in guinea and sierra leone to requests for technical guidance from ministries of health and health-care providers. , third, who did not mobilise global assistance in countering the epidemic despite ample evidence the outbreak had overwhelmed national and non-governmental capacities-failures in both technical judgment and political leadership. the third phase began in july as cases, global attention, panic, and responses all grew. funding increased, with the world bank committing us$ million in the fi rst major external fi nancing response. media attention and public interest substantially increased after the evacuation of two infected us aid workers from liberia. fear and hysteria in response to ebola infections in the usa later led to quarantines of returning aid workers and other measures counterproductive for controlling the epidemic. dozens of countries, private companies, and universities began implementing travel restrictions, and many airlines ceased fl ying into the region. on aug , who convened the international health regulations emergency committee, and the next day the director-general offi cially designated the ebola outbreak a public health emergency of international concern ("an extraordinary event which is determined...to constitute a public health risk to other states through the international spread of disease and to potentially require a coordinated international response." ) detected cases grew expon entially. ebola treatment centres in all three countries were stretched beyond capacity and forced to turn away patients at their gates. a growing lack of trust between population groups and government authorities hindered community mobilisation and public education. in the ensuing weeks, the global community mobilised, with new commitments of fi nancing, health personnel, and logistical support from the african union, china, cuba, the european union, the uk, the usa, the world bank, the international monetary fund, and the un agencies. the un security council passed resolution declaring the outbreak a threat to international peace and security, the only time it has done so regarding an outbreak and only the second resolution ever (after hiv/aids in ) to focus on a disease. the un secretary general created a new entity to coordinate the international response, the un mission for emergency ebola response. additionally, trials for two candidate vaccines were launched in europe and the usa, and who convened an expert group to develop guidance for the ethics of using experimental therapies. despite increased mobilisation of political attention and resources, this third phase witnessed several failures. first, public and private restrictions on trade and travel further harmed an already suff ering region and hindered control eff orts. , second, the operational response commenced slowly, taking months for funding, personnel, and other resources to reach the region. [ ] [ ] [ ] third, the creation of the un mission for emergency ebola response bypassed the pre-existing un body for emergency coordination, the offi ce for the coordination of humanitarian aff airs, further blurring the lines of responsibility for international coordination. fourth, fi eld staff often reinvented strategies for community mobilisation and contact tracing because relevant lessons from previous ebola outbreaks in uganda and the democratic republic of congo were not eff ectively transferred. fifth, international staff with ebola sometimes received experimental therapies (albeit, the effi cacy and risks of which were unknown) and were evacuated while national staff largely were not, a demoralising and often deadly distinction for many health workers. , sixth, there was poor understanding of how to take into account community beliefs, practices, and solutions, properly address rumours, and involve local leaders-with sometimes fatal consequences for health workers and communities. a fourth phase began towards the end of as the epidemic turned a corner. the total number of cases began to decline in the hardest hit countries as community leaders and organisations joined control eff orts, even before large-scale global assistance arrived. ebola had been imported into nigeria, mali, and senegal in the second half of . nevertheless, rapid information sharing, and mobilisation of health workers for contact tracing and patient care had limited the outbreak in senegal to one confi rmed infection. in nigeria, the nigerian center for disease control, previous experience with polio eradication eff orts and a lead poisoning emergency were all cited as important factors in successful control of the outbreak in africa's most populous country. by the end of january, , more than $ billion had been committed for the ebola response (although the proportion of these funds actually spent on ebola and in the aff ected countries remains unclear). research and development eff orts were quickly operationalised despite uncertainty on processes for regulatory approval, with at least three vaccine candidates, three blood products, and fi ve drug candidates in clinical trials, with who playing a coordinating role. during this phase, the binding constraints were no longer political attention, funding, or human resources, but operational coordination, accountability for eff ective use of funds, and maintaining momentum to prevent new infections. amidst the crisis, many acts of courage, solidarity, innovation, and leadership prevailed, often at a substantial personal cost. in west africa more than local health workers contracted ebola caring for the sick; more than of those caregivers died. community members volunteered to trace contacts, local leaders educated communities, and religious authorities promoted new burial practices to prevent transmission. several non-governmental organisations vocally advocated for a stronger global response, treated patients, trained health workers, supported community mobilisation and longer-term recovery eff orts. additionally to massive funding from traditional donors, the african union, the economic community of west african states, cuba, and china made substantial contributions of personnel, funding, logistics, and technology (huang y, council on foreign relations, personal communication). private foundations and companies contributed funds, with $ million from the top fi ve contributors, along with meaningful in-kind assistance, such as air lifts. the initiation and conduct of clinical trials were accelerated amidst the challenging conditions of an outbreak, enabled by the cooperative eff orts of industry, research funders, regulatory authorities in the usa, europe, and west africa, scientists, and directly aff ected communities. these positive steps notwithstanding, this panel's overarching conclusion is that the long-delayed and problematic international response to the outbreak resulted in needless suff ering and death, social and economic havoc, and a loss of confi dence in national and global institutions. failures of leadership, solidarity, and systems came to light in each of the four phases (panel ). recognition of many of these has since spurred proposals for change. we focus on the areas that the panel identifi ed as needing priority attention and action. preventing small-scale outbreaks from becoming largescale emergencies needs a minimum level of core capacities in all countries to detect, report, and respond rapidly (panel ). in the wake of the severe acute respiratory syndrome (sars) outbreak, governments committed to developing such core capacities by under the revised international health regulations ( ), with the deadline extended for some countries to , then after ebola struck. according to self-assessments, as of , two-thirds of countries had not met their core capacity requirements and countries had not responded to who queries regarding their readiness. the international health regulations did not include binding obligations for donors to provide support to poorer countries to meet these obligations, nor to fund who to fulfi l its mandate to provide technical assistance. these shortcomings did not attract serious action or funding until the ebola outbreak. despite unprecedented international fi nancing during the past decade to combat particular diseases in developing countries, health systems in many resource-poor settings remain ill-prepared for outbreak response. no alternate strategy has been developed to supplement these national-level weaknesses. if countries remain unable to detect outbreaks in a timely way, the rest of the chain of international health regulation-stipulated notifi cations and responses will fail once again. additionally, according to the international health regulations, countries agreed to report potential health emergencies within h to who for joint risk assessment, with the option of doing so confi dentially. who was also permitted to receive, analyse, and ask for verifi cation of outbreak information received from non-governmental sources. governments might hesitate to report outbreaks publicly for fear of political and economic repercussions, as occurred in china with sars in . yet, history has shown that early reporting is essential to reduce both the health toll of an outbreak and its political and economic consequences. governments agreed in the international health regulations to prompt notifi cation, and in return, were reassured of the curtailment of unwarranted trade or travel restrictions and support from who technical assistance. during the ebola outbreak, however, countries and many private fi rms implemented restrictions on travel or trade, despite who's recommendations against such measures and the security council's warnings about the resulting isolation of aff ected countries. , , [ ] [ ] [ ] [ ] we conclude that several concrete steps must be taken to prevent future outbreaks from becoming large-scale catastrophes. who should convene governments and other major stakeholders within months to begin developing a clear global strategy to ensure that governments invest domestically in building core capacities and to mobilise adequate external support to supplement eff orts in poorer countries. there is growing momentum in the wake of ebola for such investments: the us government has committed $ billion to build core capacities in at least developing countries, including guinea, liberia, and sierra leone. this work is being coordinated under the global health security agenda, a us-launched initiative that now consists of nearly countries. at its june, , summit, the group of (g ) announced support for countries, although the g did not explicitly commit funds nor agree to a concrete plan. financial commitments for recovery have also been made at various ebola conferences and summits. - other initiatives might also contribute to core capacity building. these include the gates foundation's child health and mortality prevention surveillance network, the joint institut pasteur-china centers for disease control initiative to train west african scientists in outbreak response, the merieux foundation's laboratory strengthening activities in west africa, and the uk's £ million fleming fund for antimicrobial resistance. these welcome signals need to become sustained budget commitments to support national or regional plans, such as the mano river union post-ebola socioeconomic recovery programme, and reviewed systematically beyond this initial phase at forums such as the g , the g , and the world health assembly. furthermore, dialogues about health security should not be isolated from broader discussions about development fi nancing, including of the sustainable development goals, as ebola exposed how substantially an epidemic could roll back hard-won development gains. a clear, coordinated plan, supported by a transparent central system for tracking and monitoring these resource fl ows, will be needed to minimise fragmentation and ensure that core capacities are systematically built and sustained. the proposed accountability commission for disease outbreak prevention and response (recommendation ) should monitor investments and results for core capacity building. further analysis is needed to estimate the required level of additional funding. strategic investments for international health regulation core capacities can and should also strengthen broader health systems. , for example, health information systems can support surveillance and monitoring of outbreaks and routine health services; training and payment of community health workers and civil society service providers can help achieve universal health coverage, while providing an essential trained workforce during emergencies. additionally, regional and subregional actors should develop capacities to supplement gaps at the national level. for example, in africa, national governments, the african development bank, and other donors should invest in the infrastructural backbone for a network of laboratories, information systems, and training of african national emergency responders based in centres of excellence. the pan american health organization has shown the feasibility of a regional network of centres for disease control, and building such a network could be a central task of the proposed african centres for disease control and prevention. although the african centres for disease control and prevention might be perceived as a competitor to the who regional offi ce for africa, a clear delineation of responsibilities for outbreak response versus other health issues should enable close collaboration between the two. finally, governments must agree to regular, independent, external assessment of their core capacities. monitoring requirements should accompany external fi nancing. assessments will also be needed in self-fi nancing countries. some governments objected at the world health assembly to independent assessment. nevertheless, a method for peer assessment piloted by fi ve countries through the global health security agenda could provide a basis for a monitoring process acceptable for all countries. political leaders, governments, and international organisations must strengthen the set of incentives and disincentives so that governments report disease outbreaks early. among these should be stronger disincentives for implementing trade and travel restrictions without a scientifi c or public health basis. who should promote transparency by publishing lists of countries that delay reporting disease outbreaks, while commending countries that rapidly share public information as mexico did in with h n . who publicly challenged china's government to be more transparent about sars, showing the organisation's potential political power. who should also publicly disclose lists of countries that implement trade and travel restrictions when who temporary recommendations advise against them and countries that do not provide a science or public health rationale for such measures (as required by the international health regulations). doing so will require a delicate balancing act between who's role as trusted interlocutor with governments on sensitive outbreak-related information, and its role as guardian of the international health regulations. although an individual government might object to such scrutiny in the short term, politically supporting who's prerogative to do so serves the long-term interests of global public health. funding bodies such as the world bank, the asian infrastructure investment bank, the african development bank, and the new development bank (previously known as the brics development bank) should create economic incentives for early reporting by committing to disburse emergency funds rapidly to assist countries when outbreaks strike and compensating for economic losses that might result. the world bank's proposed pandemic emergency financing facility or the african union's african risk capacity agency off er the possibility of insurance to mitigate the economic costs linked to outbreak reporting. the trigger for disbursement should be a risk assessment done under the aegis of who. because private fi rms such as airlines and shipping companies are not directly bound by public international law, alternate governance mechanisms are needed to prevent isolating countries when outbreaks strike. the these could include designating a un focal point for the private sector during outbreaks, designing industry-wide cooperation frameworks, and developing codes of conduct. if preventive measures fail and an outbreak escalates into a major crisis, responsibility for taking action and alerting the broader global community must be clearly designated (fi gure ). as noted, countries agreed as part of the international health regulations to notify who of any potential public health emergency of international concern within h of assessment. who rapidly shares information with the global alert and response network, a loose network coordinated by who of academics, government scientists, non-governmental organisations, and health volunteers. the global alert and response network analyses and assesses reports, deploys investigators, conducts laboratory examination and identifi cation of the outbreak cause, and advises on further measures, including, as a fi nal resort, a potential public health emergency of international concern declaration. however, the global alert and response network's skeleton staff is too small to deploy in multiple suspected outbreaks, its budget has been severely cut, and it is not authorised by who to draw public attention to a crisis. responsibility for declaring a public health emergency of international concern belongs to the who director-general, who convenes an emergency committee of independent experts for a recommendation. however, the director-general did not use her international health regulation-granted authority to convene the emergency committee nor declare a public health emergency of international concern until months after guinea and liberia had notifi ed who. in view of the severity of ebola virus disease, rapid cross-border spread, weaknesses of the aff ected national health systems, the post-confl ict setting, and repeated warnings from nongovernmental organisations in the region, the director-general had ample reason to raise international attention by convening the emergency committee or declaring a public health emergency of international concern earlier. the committee responsible for reviewing who's performance during the ebola outbreak (the who ebola interim assessment panel) and leaked internal emails suggest several reasons for the delay including concerns about political opposition from west african leaders, economic ramifi cations, and a culture within who discouraging open debate about sensitive issues, such as emergency declarations. , who might also have hesitated because it was sharply criticised for creating panic by declaring a public health emergency of international concern during the relatively mild h n pandemic. whatever the root causes, the delay emphasised the risks inherent in vesting such consequential decision making power in a single individual. this risk is heightened when there is no institutional mechanism of accountability for leadership failures. after the public health emergency of international concern declaration, a substantial global response was mobilised. however, this response arrived late, was slow to deliver funds and health workers, was infl exible in adapting to rapidly changing conditions on the ground, was inadequately informed about cultural factors relevant to outbreak control, and was poorly coordinated. the result was, in essence, a $ billion scramble. an excessive burden fell on national and international nongovernmental organisations and local communities to do the highest-risk work such as patient care and burials. the creation of the un mission for emergency ebola response as an ad hoc body operating outside established humanitarian response structures reportedly made coordination of the crisis response even more diffi cult. , funding was low until the upsurge of commitments in september, , and, even then, there were long lags between pledges and disbursement. by one account, national surveillance identifies event of concern assessment of public health risk ( h) affected country reports to who ( h) response at who headquarters response in country who director-general convenes emergency committee to assess for public health emergency of international concern; director-general consults affected state emergency committee advises director-general who issues temporary recommendation if national capacity is outstripped, international actors should supplement national efforts director-general withdraws public health emergency of international concern declaration in case of state failure, actors operate under un coordination public health emergency of international concern controlled emergency committee reviews public health emergency of international concern status and recommendation if disease crosses borders, affected governments coordinate responses with support from regional and global organisations nearly $ billion had been pledged by the end of but only a third of this money was disbursed. furthermore, transparency of fi nancial fl ows is crucial to minimise duplication, to ensure aid goes to areas of most need rather than those easiest to assist, and to ward against mismanagement. however, transparency was, and remains, wholly inadequate: on the donor side, multiple tracking systems exist but it remains impossible to construct a clear, comprehensive picture of monetary and in-kind pledges and disbursements across the many public and private donors. on the recipient side, who received what funds to do which tasks also remains an opaque puzzle-and assessing the eff ect or effi cient use of those funds is more diffi cult still. we off er three further recommendations to tackle these issues. high-level political leaders must clearly designate who is responsible for responding when disease outbreaks outstrip national capacities, invest in the capacity to respond, and ensure accountability for fulfi lment of these responsibilities. although national governments and nongovernmental organisations working on the ground are the fi rst line of defence when outbreaks arise, who is crucial for the second line of defence when governments need international support or when an outbreak strikes more than one country. to strengthen who's capacity during outbreaks, we welcome the stocking panel's recommendation to create a who centre for emergency preparedness and response, and off er several additional recommendations regarding its key functions and attributes. the centre should merge the outbreak risk assessment and response capacities that reside in the global alert and response network with who's humanitarian teams, which presently respond to natural disasters, refugee crises, and other large catastrophes. its operational lines of authority from headquarters to regions and countries should be clearly designated. the centre should assess risks on the basis of the information that countries and others provide to who, and mobilise necessary laboratory, epidemiological, clinical, communications, and logistical responses. it should have powerful analytical, data processing, and advisory capacity to command respect in both policy and scientifi c communities. the centre should develop rapid response and strong coordinating capacity, and be able to assemble the world's best expertise to tackle disease threats. between crises, the centre should develop protocols, build relationships, and negotiate agreements with governments, multilateral organisations, non-governmental organisations, private fi rms, and other actors to mobilise rapidly during emergencies, including strengthening capacities in developing countries so that they might better respond nationally and participate internationally. in a multicountry outbreak, the centre should ensure government-to-government coordination by establishing channels of direct communication for rapid information sharing. it should be responsible for building a virtual global health workforce from both industrialised and developing countries by setting standards for certifying crisis responders, ranging from communications experts and logisticians to surgeons and managers. these responders would continue working for their home organisations, but provide surge capacity in a crisis. finally, the centre should provide technical assistance to countries to build and maintain international health regulation-mandated core capacities. the centre should have its own executive director who is accountable for performance jointly to a separate board of directors and to the director-general. the multistakeholder board should include broad repre sentation of governments from each who region, scientifi c expertise including about animal health, operational responders from all sectors, and funders. the executive director should inform the board immediately when the centre's risk analysis suggests that coordinated international action is needed and mobilise an appropriate response. similar governing structures have worked eff ectively for who-affi liated entities including the global polio eradication initiative, the international agency for research on cancer, unitaid, and the special programme for research and training in tropical diseases. the centre's budget should be protected and adequately resourced through a dedicated revolving fund. the fund should immediately disburse money for rapid scale-up when a crisis strikes, then be replenished from funds raised for that crisis to be ready for the next one. the centre and its board should work closely and routinely with the director-general so that the highest levels of leadership are constantly aware of evolving disease threats, and can marshal who's legal, political, and human resources at regional and country levels when needed. who should use its international health regulation-granted authority to expedite access to aff ected sites by technical teams and pressure any state that impedes international responses to, or obscures, disease threats in its territory. the centre must have access to sensitive outbreak information that countries are required to share with who; further analysis is needed as to whether this would require amendment to the international health regulations. a third line of defence will be needed if the initial response does not succeed and an outbreak becomes a humanitarian crisis (eg, a un level emergency ), threatening not only public health, but also political, economic, and social stability. international coordination of the large-scale eff ort needed in this case should be done by the offi ce for the coordination of humanitarian aff airs. however, because the offi ce for the coordination of humanitarian aff airs (and most other humanitarian actors) do not specialise in crises precipitated by disease outbreaks, they should develop in-house capacity and a broad coordination framework with the health sector for such emergencies. member states should amend the international health regulations to broaden responsibility for declaring a public health emergency of international concern. the director-general convenes, and is advised by, an ad hoc emergency committee constituted from a list of independent experts; however, authority and responsibility to declare a public health emergency of international concern rests exclusively with the director-general. we recommend the creation of a standing emergency committee that meets regularly, with the mandate to declare a public health emergency of international concern by a majority vote of its members. the emergency declaration should trigger other actions, such as fi nancial disbursements by development banks, emergency data-sharing and specimen-sharing rules, and emergency regulatory procedures for new drugs, vaccines, and diagnostics (recommendations and ). the director-general should chair, communicate, and explain the standing emergency committee's decisions. following an open call for nominations, the director-general would appoint the fi rst members; thereafter, the standing emergency committee itself would periodically vote in new members to preserve its independent character. minutes and votes of standing emergency committee members should be published immediately following each meeting for the sake of transparency, to build external confi dence, reduce political interference, and strengthen the committee's hand against resistant states. similarly to other institutions responsible for technically complex yet politically consequential decisions, such as central banks or drug regulatory authorities, the standing emergency committee must be protected from political pressure that might interfere with its judgment. the committee should possess high-level public health expertise and base its decisions on scientifi c principles and evidence, assessing risks for human health, disease spread, and international traffi c. the standing emergency committee should have adequate economic expertise to weigh the risks of disrupted trade and travel against those posed by the outbreak and advise on how to ameliorate economic harm. the standing emergency committee should also issue early warnings of major potential risks on the basis of continuing assessments done by the who centre. the committee should also consider replacing the present binary system, which calls for determining the presence or absence of a public health emergency of international concern, with a graded system of warnings. finally, the standing emergency committee should publish an annual report detailing its activities to ensure public accountability and continued political attention to health threats. the committee should be fi nanced purely through assessed contributions to protect against undue donor infl uence. a committee does not by defi nition operate more eff ectively than an individual, and might succumb to risk aversion and dysfunction; nevertheless, the combination of measures described above should provide the standing emergency committee with the autonomy and capacity for credible, authoritative decision making. the un secretary general should create an accountability commission as an independent body comprised of civil society, academia, and independent experts doing realtime and retrospective system-wide assessment of global responses to major disease outbreaks. the accountability commission would track and analyse the contributions and results achieved by national governments, donors, un agencies, international and national nongovernmental organisations, and the private sector. all major actors would be expected to share information promptly with the accountability commission about fi nancial, in-kind, or operational contributions; the the accountability commission should publish the names of organisations unwilling to share such information. the accountability commission would assess aid eff ectiveness, including funds committed, paid, dis bursed, and spent; both short-term and long-term accomplishments achieved with those funds; and the timeliness, eff ectiveness, cultural appropriateness, and equity of the response for intended benefi ciaries. the accountability commission should liaise directly with and provide a forum for representatives of communities directly aff ected by outbreaks. finally, it should monitor eff orts to build and sustain national core capacities. the accountability commission would report to the world health assembly and the security council's global health committee (recommendation ), and publish its fi ndings regularly during and after each public health emergency of international concern. after an open call for nominations, the secretary general would appoint the fi rst members; thereafter, the accountability commission itself would periodically vote in new members to preserve its independent character. the accountability commission would off er an important multistakeholder platform for various constituencies involved in and aff ected by disease outbreak responses. this proposal builds on analogous eff orts to strengthen system-wide accountability for other global eff orts, such as the un commission on information and accountability for women's and children's health and the independent monitoring board of the global polio eradication initiative, credited with helping to reinvigorate the performance of this eff ort. the accountability commission would be a more permanent institution, however, with a broader mandate than these two previous initiatives. producing and rapidly sharing knowledge during outbreaks is essential. however, reliable systems for rapid transmission of epidemiological, genomic, and clinical data were not established during the ebola epidemic. although governments in the three worst aff ected countries transmitted epidemiological information to who, robust channels were not established for direct data exchange and coordination between the three capitals. although some researchers shared genomic sequencing data early in the outbreak through an open access database, other researchers later withheld such data from the public domain. and although care providers and researchers collected thousands of patient samples, now housed in laboratories in west africa and worldwide, no clear arrangements exist for scientists to access those samples, for their safe handling, or to ensure that west african patients benefi t from the fi ndings or technology that might result. previous epidemics show that better arrangements are feasible. during the sars outbreak, who established online systems for data sharing among a worldwide network of scientists, enabling researchers to identify the virus, sequence its genome, and understand its characteristics. in , an international consortium of researchers agreed to data sharing norms for infl uenza, which enabled real-time dissemination and publication of epidemiological and clinical data during h n in . the consortium for the standardization of infl uenza seroepidemiology helps to coordinate a global community of researchers working on infl uenza serology. furthermore, after years of intergovernmental negotiations, the who pandemic infl uenza preparedness framework achieved a delicate balance between sharing samples and access to the resulting technology. , however, no analogous framework exists for other pathogens. access to knowledge embodied in the form of technologies has been a particularly diffi cult issue. as noted, no drugs, vaccines, or rapid diagnostic tests had been approved for ebola when the outbreak began. although scientists had identifi ed the virus nearly four decades earlier and basic research had advanced understanding of the disease, ebola was not an attractive target for industry investment in research and development, nor was it high on the public health research agenda. somewhat serendipitously, the us and canadian governments had years earlier made defence-related investments in ebola, which meant that university and pharmaceutical industry researchers had developed several experimental drug and vaccine candidates when the outbreak hit. as noted, clinical trials for vaccines and drugs were launched in record time (with encouraging results for one vaccine candidate reported in july, ). nevertheless, the overall research and development eff ort could have moved faster if there had been investments beforehand to advance candidate products through phase or trials and a system to prioritise the most important technologies. for example, eff ective rapid point-of-care diagnostics could have enhanced contact tracing, counteracted community resistance and denial, protected health workers, reduced patient loss to follow-up, eased overburdened treatment centres, and supported the continued operation of shipping and airline services. a systematic way of posing and answering operational research questions, such as the relative merits of using intravenous fl uids for patient care, would also have strengthened the response. furthermore, who provided valuable technical leadership about the ethics of using unproven therapies, but little guidance on how strictly limited quantities of drugs should be rationed. west african health workers and patients were largely denied access to the stocks sometimes available to international staff . in several instances, who proved its capacity to lead, convene, coordinate, and establish norms among a broad range of public and private actors on research and development and data sharing. additionally to its guidance about experimental therapies, who convened research and development actors in mid- and late- , and again at a global ebola research and development summit in may, . in july, , who also issued guidance about accelerating regulatory approval of technologies in emergencies. who also convened a meeting in september, , to build norms for open data sharing as part of an eff ort to develop a "blueprint" to guide the collective research and development eff orts of industry and governments for emergencies. these successful eff orts should be institutionalised to better govern knowledge production and sharing in future outbreaks. before the world health assembly, who should convene governments, the scientifi c research community, industry and non-governmental organisations to begin developing a framework of norms and rules for research relevant to disease outbreaks. the framework's goal would be to provide guidance on three interrelated issues: . access to data and samples to enable and accelerate research, which would involve rapid sharing of epidemiological surveillance and clinical data to inform outbreak control strategies; incentives and platforms for open sharing and access to genomic sequencing data; access to specimen samples (with appropriate biosafety measures). . appropriate conduct of research, including improved ethical standards for research and development (eg, including involving aff ected populations in setting research priorities, patient participation and consent); previous agreement about experimental protocols, such as trial design, to speed clinical trials when outbreaks strike; access to clinical trial data, such as publication of negative and positive results; clear pathways for approval by stringent regulatory authorities and in countries of use; and building on and investing in research capacities in epidemicaff ected countries. . equitable access to the benefi ts of research, including priority, aff ordable access to newly developed health technologies for aff ected populations, including health workers; and ethical guidelines for rationing products with limited availability. an overarching framework is needed to bring coherence and fi ll gaps in the fragmented system of international rules shaping outbreak-related research (including the international health regulations, pandemic infl uenza preparedness framework, convention on biological diversity and its nagoya protocol, agreement on trade related aspects of intellectual property rights, and numerous guidelines and agreements for data ownership and sharing among scientists). the framework would include both nonbinding norms such as guidelines or codes of conduct, and binding rules such as contractual obligations or international law. further analysis is needed to specify the most appropriate instruments for each issue area. some norms would apply at all times to prepare for potential outbreaks; others could be limited to and triggered by a public health emergency of international concern declaration. establishment of such norms in advance would strengthen preparedness and reduce counter-productive competition between researchers or institutions during emergencies. ideally, such a normative framework would cover all pathogens with the potential to cause major outbreaks. however, in view of the complexity and political diffi culties reaching agreement on these issues, a feasible starting point might be to develop a pilot framework for one or several diseases such as viral haemorrhagic fevers. lessons from this pilot could subsequently be applied to expanding the framework to other pathogens. the accountability commission (recommendation ) should monitor progress towards developing this framework and subsequently monitor adherence to it. recommendation : establish a global facility to fi nance, accelerate, and prioritise research and development. the un secretary general and the who director-general should convene in a high-level summit of public, private, and not-for-profi t research funders to establish a global fi nancing facility for research and development for health technology relevant for major disease outbreaks. the facility would support manufacturing, research, and development for drugs, vaccines, diagnostics, and other non-pharmaceutical supplies (such as personal protective equipment) where the commercial market does not off er appropriate incentives. for known pathogens, the facility could invest in bringing candidate drugs, vaccines, technology platforms, and other relevant products through proof of concept, phase , and phase testing in humans, so that they are ready for wider testing, manufacturing, and distribution when an outbreak strikes. during an outbreak the facility would rapidly mobilise fi nance for priority research and development projects, such as diagnostics for novel pathogens. the establishment of a similar fund for diseases aff ecting developing countries was a central recommendation of the report of the who consultative expert working group on research and development. as a result, a pooled international fund was created to support "demonstration projects" that test new research and development business models, such as open knowledge innovation and delinkage of research and development fi nancing from end product prices. with a management structure already established, the demonstration projects off er an important option for pursuing research and development for ebola or other diseases. the global fi nancing facility should be a lean, effi cient entity that mobilises and strategically deploys resources. it would not be a monolithic entity nor the sole funder for epidemic-related research and development because some pluralism and competition among funders is desirable. nevertheless, a global facility would off er the advantage of enabling coordination between diff erent research funders through a common framework, strengthening networks between researchers, estab lishing processes for priority setting, and reducing transaction costs for both grantees and smaller donors. , it could also require information sharing between researchers as a condition of funding, thereby giving teeth to the data-sharing framework (recommendation ). intellectual property or any other asset resulting from these investments should be managed as a public good to enable follow-on innovation, open knowledge sharing, access to technology, and a fair public return on investment. support for a global research and development fi nancing mechanism now seems to be growing, as shown in calls for a $ billion global fund for vaccine development for pandemics, a $ billion global fund for antimicrobial resistance, and a $ - billion global fund that would cover emerging infectious diseases, neglected diseases, and antimicrobial resistance. an eff ective global system for preventing and responding to outbreaks needs well coordinated and appropriately resourced actors to fulfi l clearly defi ned roles and responsibilities and to hold each other accountable for doing so (table). many actors have crucial roles in this complex system: national governments have the main responsibility for their populations' health. national governments are also responsible for immediately sharing information with neighbouring countries and the international community in the event of a potential public health emergency of international concern. they also hold responsibility for calling for international assistance if domestic capabilities prove inadequate. in turn, international actors are responsible for supporting national governments individually and collectively. who should play a central part in monitoring, assessing, and responding to disease outbreaks. national and regional agencies for disease control and academies of science also off er important technical capacities for managing outbreaks. development banks are responsible for mobilising and disbursing fi nancing to support governments and collective action. the international humanitarian system, including the offi ce for the coordination of humanitarian aff airs, unicef, the world food programme, the un high commissioner for refugees, other un bodies, and non-governmental organisations are responsible for mounting an eff ective operational response if an outbreak escalates into a humanitarian crisis. the research community is responsible for producing relevant knowledge on the outbreak, and developing and producing technologies to intervene. civil society, including academia and the media, play a crucial part in drawing attention to unmet needs, neglected challenges, and systemic failings, and demanding accountability from responsible actors. finally, the un security council is responsible for addressing threats to international peace and security. ebola developed from a relatively small outbreak into a large-scale emergency because of the failures of multiple actors to fulfi l their mandated roles and responsibilities. our fi nal three recommendations outline the institutional changes needed to prevent such failures from recurring. in recognition of health as an essential facet of human and national security, the un security council should establish a global health committee consisting of government representatives. the com mittee's main goal would be to expedite and elevate political attention to health issues posing a serious risk to international peace and security and provide a prominent arena to mobilise political leadership. specifi cally, the committee would monitor and publish an annual report on progress in building a strong and eff ective global health security system, taking into account analyses from the accountability commission and who. the committee would also address alleged non-compliance with international health regulation provisions on trade and travel measures. the committee would not declare public health emergencies of international concern. this decision would remain technically driven and under the authority of who. the committee would not be able to strengthen core capacities within and between countries to prevent, detect, and respond to outbreaks support governments with technical and scientifi c knowledge and advice financing by major public and private donors; technical assistance by specialised agencies and non-governmental organisations mobilise external assistance when countries unable to prevent an outbreak from becoming a crisis raise awareness of major disease events; declare public health emergencies of international concern as appropriate; early-stage rapid response to outbreaks; convening for resource mobilisation who is an essential hub in the global system for health security. however, evidence of confusion and disagreement about its role is ample. since the th century, cross-border disease control was the fi rst and most widely accepted rationale for intergovernmental health cooperation. yet, in the wake of the global fi nancial crisis when who laid off more than a tenth of its headquarters staff , outbreak response capacity was deeply and disproportionately cut. disease outbreaks are not the only important work for who, but they are foundational to the organisation's mandate. within a global system for disease outbreak response, what should be who's essential role? who's near-universal state membership, governance structure, and deep relationships with health ministries situate it uniquely to perform four core functions (table): support governments in building national core capacities for prevention, surveillance, and response through technical and scientifi c knowledge and advice; assess and provide rapid early response to outbreaks, raise awareness of major disease events, and declare public health emergencies of international concern when appropriate; establish technical norms, standards and guidance; and convene actors to set goals, mobilise resources, resolve confl icts, and negotiate rules. performance of these functions needs strong political, scientifi c, and normative leadership with solid backing from member states. however, who's failings on these core functions during the ebola outbreak have now produced an existential crisis of confi dence. ebola exacerbated a trend since the s of many governments and other organisations working around who. decades of reducing assessed contributions in real terms has starved the organisation of resources. donors have earmarked voluntary contributions, eff ectively controlling nearly % of who's budget by . the result is an organisation that seems to have lost its way. although the budget has more than doubled from us$ · billion in - to us$ billion in - , the organisation itself controlled an ever-shrinking share. one casualty of recent decisions was who's reduced ability to control cross-border disease outbreaks, a core task for which it was created in . in the wake of ebola, the organisation's traditional claims of legitimacy based on near-universal state membership no longer seem suffi cient. a true recovery will need far greater willingness by member states to entrust resources and delegate authority to who, but it has rarely been in a weaker position to command such trust and authority. confi dence in the organisation's capacity to lead is at an all-time low. calling for additional staff or a larger budget will not address this. who must fi nd a way to prioritise what it does, and regain its credibility, independence, and legitimacy to perform its core functions (table) . breaking out of this -year impasse will demand clear commitment and a diff erent kind of leadership by who to implement fundamental reforms under a tight timeline, matched by an equally clear commitment by member states to reward such reform with appropriate authority and resources. who performed a key coordinating function in research and development during the ebola epidemic. it was also central to controlling nine previous ebola outbreaks, sars, and other epidemics. these examples are important reminders of what who can do under determined leadership. who is in a formal reform process that was spurred by a budget crisis in ; in some ways, it has been in a perennial process of reform since at least the s. these previous eff orts are a reminder that high-level political leadership, such as the engagement of heads of state, will be needed if the outcome is to be diff erent this time. at this point, anything less than fundamental reform will mean continued marginalisation and decline, alongside increasing vulnerability for global public health. to rebuild trust, respect, and confi dence within the international community, who should maintain its broad defi nition of health, but substantially scale back its expansive range of activities to focus on core functions. the scope of who's work would thus continue to embrace the full range of health issues, but its functions should be far more circumscribed. we restrict our analysis to core functions in infectious disease outbreaks. however, there remains the need to defi ne who's core functions in other key areas of work, such as non-communicable diseases, injuries, environmental health, health systems, and social determinants of health. for this purpose, the january executive board should launch a fundamental review of the organisation's constitution and mandate to defi ne its core functions. this review should identify and hand over non-core activities to other actors, thereby streamlining who's activities. it should also examine which core functions are not being fulfi lled or adequately funded. the fi nancing model for who is unstable and politically vulnerable. the january executive board should also begin developing a new fi nancing model for assessed contributions focused on core functions and draft a transparently implemented policy about when to accept or reject voluntary contributions at headquarters, regional, and country offi ces. if who strictly defi nes its core functions and accelerates other good governance reforms (recommendation ), member states should shift most of its fi nancing to assessed and non-earmarked voluntary contributions. recommendation : good governance of who through decisive, timebound reform, and assertive leadership. restoring credibility demands that who institutionalises accountability mechanisms, strengthens and clarifi es how it works with other actors, and fosters strong leadership. the january executive board should launch a process to implement four new policies for who to meet basic principles of good governance: establish a freedom of information policy, with appropriate safeguards; create a permanent inspector general's offi ce to monitor overall performance of the organisation and its entities, reporting to the executive board; conclude continuing work on the framework of engagement with non-state actors to better govern the way who interacts with civil society, academia, foundations, and the private sector; and revise human resource policies to attract or retain well qualifi ed staff , including for leadership positions, while letting go of chronic underperformers. the executive board should seize the short window of opportunity available for such reforms by giving a strong mandate to an interim deputy for managerial reform reporting to the director-general to implement these policies by july, (before the next director-general takes offi ce). in line with the reformed approach to human resources, all upcoming leadership selection and election processes at headquarters, regional, and country offi ces should be based on personal, technical, and leadership merits. the executive board, with the participation of civil society, should do an annual appraisal of senior leadership to strengthen accountability. as the next director-general election approaches, member states should insist on a dynamic leader with a strong record of focusing on people, able to manage crises, implement reforms, and communicate strategically. a key attribute should be proven high-level political leadership with the character and capacity to challenge even the most powerful governments when necessary to protect public health. it is in the collective interest of member states to have a strong, empowered leader heading the who. taken together, the panel's ten recommendations provide a vision for a more robust, resilient global system able to manage infectious disease outbreaks (panel , fi gure ). preventing small outbreaks from becoming large-scale emergencies demands investment in minimum capacities in all countries and encouragement of early international reporting of outbreaks by adhering to agreed international rules. responding eff ectively to outbreaks demands much stronger operational capacity within who and within the broader aid system if outbreaks escalate into humanitarian emergencies, a politically protected process for who's emergency declarations, and strong mechanisms for the accountability of all involved actors, from national governments to non-governmental organisations and from un agencies to the private sector. mobilisation of the knowledge needed to combat outbreaks will require an international framework of rules to enable, govern, and ensure access to the benefi ts of research, and fi nancing to develop technology when commercial incentives are inappropriate. finally, eff ective governance of this complex global system demands high-level political leadership and a who that is more focused and appropriately fi nanced and whose credibility is restored through the implementation of good governance reforms and assertive leadership. the human catastrophe of the ebola epidemic that began in shocked the world's conscience and created an unprecedented crisis. it exposed deep inadequacies in the national and international institutions responsible for protecting the public from the far-reaching human, social, economic and political consequences of disease outbreaks. the reputation and credibility of who has suff ered a particularly fi erce blow. ebola brought to the forefront a central question: is major reform of international institutions feasible to restore confi dence and prevent future catastrophes? or should leaders conclude the system is beyond repair and take ad hoc measures when the next major outbreak strikes? research: producing and sharing data, knowledge, and technology . develop a framework of rules to enable, govern, and ensure access to the benefi ts of research . establish a global facility to fi nance, accelerate, and prioritise research and development governing the global system . sustain high-level political attention through a global health committee of the security council . a new deal for a more focused, appropriately fi nanced who . good governance of who through decisive, time bound reform and assertive leadership international health regulation emergency committee. the standing emergency committee will meet and receive information from the emergency centre regularly, with the mandate to declare a public health emergency of international concern by a majority vote of its members. the director-general would chair this committee. a permanent inspector general's offi ce is proposed, along with other good governance reforms (not depicted in the fi gure) such as a freedom of information policy. after diffi cult and lengthy deliberation, our panel concluded major reforms are warranted and feasible. the panel refi ned its recommendations into a roadmap of ten interrelated reforms that in combination can strengthen the global system for outbreak prevention and response. the roadmap gives greatest weight to clarifi cation of the roles and responsibilities of the many actors involved in outbreak response, investing in capacities to fulfi l those roles, and demanding accountability for meeting those responsibilities. these measures are concrete, actionable, and measurable. success requires one other essential ingredient: high-level political leadership determined to translate this roadmap into enduring systemic reform so that the immense human suff ering of the ebola outbreak will not be repeated. msf addresses un security council emergency session on ebola ebola situation reports un offi ce of the special envoy on ebola. resources for results iii appeal: ebola virus outbreak-overview of needs and requirements (inter-agency plan for guinea global health security: the wider lessons from the west african ebola virus disease epidemic governance challenges in global health the next epidemic-lessons from ebola preparing for the next outbreak report of the review committee on the functioning of the international health regulations ( ) in relation to pandemic (h n ) ground zero in guinea: the outbreak smouldersundetected-for more than months pushed to the limit and beyond: a year into the largest ever ebola outbreak inside the troubled early days of guinea's ebola response emails: un health agency resisted declaring ebola emergency who says guinea ebola outbreak small as msf slams international response ebola's lessons: how the who mishandled the crisis doctors without borders canada/médecins sans frontières (msf) canada. ebola in west africa: "the epidemic is out of control investigation: bungling by un agency hurt ebola response ahf: failed global ebola response demands new leadership ebola: world bank group mobilizes emergency funding to fi ght epidemic in west africa why we fail at stopping outbreaks like ebola yale global health justice partnership and american civil liberties union. fear, politics, and ebola how quarantines hurt the fight against ebola and violate the constitution. connecticut: yale global health justice partnership who. statement on the st meeting of the ihr emergency committee on the ebola outbreak in west africa liberia's military tries to remedy tension over ebola quarantine. monrovia: the new york times with spread of ebola outpacing response, security council adopts resolution ( ) urging immediate action, end to isolation of aff ected states special representative of the un secretary general arrives in accra to establish the un mission for ebola emergency response headquarters ethical considerations for use of unregistered interventions for ebola virus disease ebola: the failures of the international outbreak response international donations to the ebola virus outbreak: too little, too late? as ebola rages, poor planning thwarts eff orts community-centered responses to ebola in urban liberia: the view from below we are dying of ebola; where is the world? africa review disease outbreak: finish the fi ght against ebola importation and containment of ebola virus disease-senegal and the centers for disease control and prevention (cdc) when losing track means losing lives: accountability lessons from the ebola crisis who. ebola r&d eff ort-vaccines, therapeutics, diagnostics who. ebola situation report- how cuba could stop the next ebola outbreak responding to health emergencies ebola: towards an international health systems fund overseeing global health implementation of the international health regulations ( )-report of the review committee on second extensions for establishing national public health capacities on ihr implementation. geneva: world health organization who. statement on the nd meeting of the ihr emergency committee regarding the ebola outbreak in west africa statement on the rd meeting of the ihr emergency committee regarding the ebola outbreak in west africa. geneva: world health organization who. statement on the th meeting of the ihr emergency committee regarding the ebola outbreak in west africa statement on the th meeting of the ihr emergency committee regarding the ebola outbreak in west africa. geneva: world health organization the white house offi ce of the press secretary uniting in seoul to extinguish epidemic threats through the global health security agenda leaders declaration international ebola recovery conference world bank group provides new fi nancing to help guinea, liberia and sierra leone recover from ebola emergency the bill & melinda gates foundation to fund disease surveillance network in africa and asia to prevent childhood mortality and help prepare for the next epidemic train africa's scientists in crisis response clinical laboratory networks contribute to strengthening disease surveillance: the resaolab project in west africa fleming fund launched to tackle global problem of drug-resistant infection a wake up call: lessons from ebola for the world's health systems the ebola review: parts i and ii who criticizes china over handling of mystery disease. hong kong: the new york times african risk capacity insurance mechanism report of the ebola interim assessment panel ebola virus disease epidemic in west africa: lessons learned and issues arising from west african countries saving lives: the civil-military response to the ebola outbreak in west africa ebola virus outbreak -overview of needs and requirements (inter-agency plan for guinea inter-agency standing committee working group. humanitarian system-wide emergency activation: defi nitions and procedures commission on information and accountability for women's and children's health. keeping promises, measuring results the power of straight talk: the independent monitoring board of the global polio eradication initiative data sharing: make outbreak research open access ebola researchers plead for access to virus samples proposed ebola biobank would strengthen african science sars: a global response to an international threat a global initiative on sharing avian fl u data infl uenza preparedness framework advisory group technical expert working group on genetic sequence data the who pandemic infl uenza preparedness framework: a milestone in global governance for health effi cacy and eff ectiveness of an rvsv-vectored vaccine expressing ebola surface glycoprotein: interim results from the guinea ring vaccination cluster-randomised trial opting against ebola drug for ill african doctor who consultative expert working group on research and development. research and development to meet health needs in developing countries: strengthening global fi nancing and coordination establishing a global vaccine-development fund demonstration fi nancing: considerations for the new international fund for r&d securing new drugs for future generations: the pipeline of antibiotics a global biomedical r&d fund and mechanism for innovations of public health importance what's the world health organization for?: fi nal report from the centre on global health security working group on health governance the world health organization. abingdon: routledge cuts at w.h.o. hurt response to ebola crisis who. proposed programme budget all authors contributed to study concept, data analysis and interpretation, and provided critical revisions of the manuscript for important intellectual content. pp, akj, map, and ds chaired and co-chaired the panel, respectively, providing high level content and directional oversight. sm supervised the study design, data collection, data analysis, and data interpretation; drafted the manuscript; and led all revisions. bh, jal, and lrw contributed to the data collection, data analysis and data interpretation; creation of fi gures; and provided administrative, technical, and material support. we thank julio frenk for initial discussions that led to the creation of the panel, and robert marten and the rockefeller foundation for supporting the london meeting of the panel, and research and dissemination eff orts. we are grateful to emily anne robinson for research and organisational support for the boston meeting, and to zoe mark lyon for research support. key: cord- -q xhcxtc authors: ouyang, pingbo; zhang, xinyu; peng, yinghui; jiang, bing title: seeking clarity on retinal findings in patients with covid- date: - - journal: lancet doi: . /s - ( ) - sha: doc_id: cord_uid: q xhcxtc nan paula m marinho and colleagues described hyper-reflective lesions in ganglion cell and inner plexiform layers on optical coherence tomography (oct) images from eyes of adults who had symptoms of covid- . marinho and colleagues argued that these lesions could be associated with covid- -related neurological events in humans. on the basis of the fundamental principles of oct, we hold different views as to how the hyper-reflective foci were generated and their relevance to covid- . because of high light absorption and reflection of the retinal blood and vessel walls, retinal blood vessels can be visualised in oct images as hyperreflective, tube-like structures with shadows underneath. , therefore, all hyper-reflective lesions marked out by marinho and colleagues by arrows in the figure of their correspondence can be adequately explained by normal retinal blood vessels extending into the ganglion cell and inner plexiform layers. in the appendix, we share two oct images (spectralis oct, heidelberg engi n eering, heidelberg, germany) and two infrared fundus images of the same eye from one healthy person. the retinal blood vessels in the infrared fundus images correspond to the hyper-reflective, tube-like structures with obvious shadows in the ganglion cell and inner plexiform layers of the oct images. in summary, relating the retinal oct findings of patients to the consequences of covid- is not well validated. marinho and colleagues should provide further elaborate analysis and scientific comparison to confirm the hyper-reflective characteristics of the retinas and their conclusion. we declare no competing interests. pingbo ouyang, xinyu zhang, yinghui peng, *bing jiang retinal findings in patients with covid- a first case of meningitis/encephalitis associated with sars-coronavirus- an easy method to differentiate retinal arteries from veins by spectral domain optical coherence tomography: retrospective, observational case series retinal vessel structure measurement using spectral-domain optical coherence tomography see online for appendix key: cord- -g pfc x authors: nepomnyashchiy, lyudmila; dahn, bernice; saykpah, rachel; raghavan, mallika title: covid- : africa needs unprecedented attention to strengthen community health systems date: - - journal: lancet doi: . /s - ( ) - sha: doc_id: cord_uid: g pfc x nan united nations educational, scientific and cultural organization (unesco). comprehensive sexuality education to prevent gender-based violence. . https://en.unesco.org/news/comprehensive-sexualityeducation-prevent-gender-based-violence (accessed june , as the first cases of covid- were confirmed in liberia, in march, , former president ellen johnson sirleaf, among others, highlighted the need to adopt lessons learned from the response to the - outbreak of ebola virus disease in west africa. ebola claimed about lives in months across liberia, sierra leone, and guinea. comparisons to ebola benefit from remembering the key differences between the two viruses. severe acute respiratory syndrome coronavirus (sars-cov- ) is a respiratory virus and is infectious among asymptomatic carriers. sars-cov- differs from ebola virus in terms of the reproduction number (sars-cov- · vs ebola · - · ), , incubation period ( - days vs - days on average), , and case fatality rate (this varies for sars-cov- but average is estimated at · % as of july , , vs up to % for ebola). , covid- is easier to transmit, harder to diagnose, and can quickly spread in communities. the ebola response showed the importance of investments that build health system resilience, notably investments in the health workforce. unfortunately, community engagement largely occurred too late in the ebola response. , to date, there are no studies of how well countries adopted the lessons learnt from ebola for covid- and this will be a critical future exercise. at the onset of the covid- pandemic in sub-saharan africa, governments took swift action to institute lockdown measures, activate incident management response systems, and mobilise front-line health workers to be trained. however, some months into the pandemic preliminary evidence suggests that human resources for health in sub-saharan africa have been inadequately prepared. community health workers (chws) have insufficient personal protective equipment (ppe) to ensure they can continue providing essential care and most countries face severe shortages of health workers. this situation is concerning because of the importance of chws in the covid- response. chws are a key component of pandemic response strategies, they were used in the covid- response in china, recommendations on how chws can be supported to interrupt virus transmission while maintaining essential services and shielding vulnerable populations. feedback from the field in liberia is, however, alarming. in rivercess county, liberia, where there has only been one suspected covid- case that was confirmed negative as of june , , some caregivers refuse to attend mobile clinics or facilities for vaccinations and there has been a reduction in care seeking among some adults (saykpah r, unpublished). people fear health workers are spreading covid- and chws, while trusted neighbours, have insufficient ppe to convince people otherwise. the stakes are high for people's health if there is any reduction in care-seeking behaviour for preventable diseases. to its credit, liberia, scarred from the ebola outbreak, has been training its national community health assistants to prevent, detect, and respond to covid- while maintaining essential services and is in the process of procuring ppe for chws. covid- is the new public health backdrop and we cannot wait to strengthen community health systems. chws matter because they are trusted members of the community who are often the most accessible point of care, particularly for vulnerable populationseg, in sierra leone, chws outnumber doctors to one. indeed, the africa centres for disease control and prevention is planning to recruit million community health volunteers to support contact tracing across sub-saharan africa, relying on existing chw cadres. ongoing efforts to leverage chws for the covid- response must not be one-offs in the face of an emergency. chws must be equipped, trained, and supported in the long term as a crucial human resource for health. trillions of dollars have been committed in just over months for the covid- response globally. a covid- vaccine or therapy will take months to become commercially available and likely longer to access in lowincome countries. if a vaccine, treatment, or reliable diagnostic is available, adoption in places with shortages of human resources for health will be a struggle. a comparative us$ billion annual investment to bolster chws as a health system strengthening platform for primary care is a drop in the ocean. now is the time to invest in community health systems in sub-saharan africa and avert a greater crisis. we declare no competing interests. the health of populations across the planet is in a perilous state during the covid- pandemic, with more than deaths worldwide as of july , . the disease burden is falling mainly on the most disadvantaged groups worldwide and there are major impacts on health systems across high, middle, and low-income countries. in parallel with these direct health impacts, the economic effects of lockdowns are leading to an unprecedented global recession which will have ramifications well into the future. but while the focus is, rightly, on responding to the immediate threat of the pandemic, it is important to remember that over million people die each year from non-communicable diseases (ncds), more than % of all global deaths. meanwhile, the climate and extinction crises pose unprecedented challenges to our planet, with government responses-as yet-inadequate. global temperatures are set to increase substantially over the coming decades, leading to untold health, environmental, and economic consequences, , while the unfolding sixth mass extinction threatens to unravel many of the essential ecosystems on which we all depend. there are, however, some reasons for cautious optimism. responses to the covid- pandemic show that nations can act rapidly and radically in response to major immediate threats to health, even at huge economic cost. these actions have generated important co-benefits in terms of reductions in urban air pollution and carbon dioxide emissions, at least over the short term. maintaining resilience during this pandemic-and those yet to come-will require these and many more long-term changes in patterns of travel, development, and human interactions. as economies open up and lockdowns ease, this resilience will once again be under threat, as will both the environment and population health. it will be even more important to take urgent action on climate change, environmental sustainability, economic policy, and health inequalities. [ ] [ ] [ ] [ ] [ ] [ ] these three major threats to population and planetary health-communicable diseases, ncds, and the climate and environmental emergencies-are too often treated as distinct problems, but they are intimately entwined in a global syndemic as reflected in the top global risks identified by the world economic forum in . they possess common underlying causes including unsustainable systems of agriculture, subsidies for harmful products, and overcrowded cities. the transmission of a novel coronavirus from bats to humans might be the dominant model of the genesis of the covid- pandemic, but without urbanisation and global hypermobility it would have spread much more slowly and might have been contained; without high prevalence of ncds and air pollution it would have exerted a much lower toll. breaking the clinical, academic, and policy boundaries that promote separation of these threats demands new ways of understanding and tackling them in order to respond effectively to the combination of the worst pandemic for over a century with the largest economic downturn in modern history. foregrounding this economic context will be essential for any credible attempt to address these threats. the dominant policy focus for tackling the key behaviours that contribute to ncds worldwideunhealthy diets, smoking, alcohol consumption, and physical inactivity-largely ignores the roles of commercial and other non-state actors, publics, policy makers, and others in driving these behaviours. as with covid- , the lancet-chatham house commission on improving population health post covid- ); and last mile health coronavirus: what the world can learn from ebola fight congo's ebola fight has lessons for covid- bbc. ebola: mapping the outbreak. bbc asymptomatic spread makes covid- tough to contain high contagiousness and rapid spread of severe acute respiratory syndrome coronavirus estimating the basic reproductive ratio for the ebola outbreak in liberia and sierra leone clinical questions about covid- : questions and answers html#:~:text=the% incubation% period% for% ebola,is% % to% % days coronavirus pandemic (covid- ). our world in data ebola virus disease what is a resilient health system? lessons from ebola community health workers during the ebola outbreak in guinea, liberia, and sierra leone community health worker programmes after the - ebola outbreak covid : it ain't over until there's ppe all over africa: covid exposes healthcare shortfalls community health workers and pandemic preparedness: current and prospective roles xi focus: xi replies to letter from community workers fighting covid- in wuhan prioritising the role of community health workers in the covid- response more harm than good? the net impact of covid- policies is what matters for health. center for global development prevent, detect, respond: how community health workers can help in the fight against covid- physicians per , and community health workers per african union rolls out partnership to accelerate covid- testing interactive: who's funding the covid- response and what are the priorities. devex opinion: to deliver a covid- vaccine equitably, we must start planning now. devex strengthening primary health care through community health workers: closing the $ billion gap key: cord- -uy s authors: rao, bl; basu, atanu; wairagkar, niteen s; gore, milind m; arankalle, vidya a; thakare, jyotsna p; jadi, ramesh s; rao, ka; mishra, ac title: a large outbreak of acute encephalitis with high fatality rate in children in andhra pradesh, india, in , associated with chandipura virus date: - - journal: lancet doi: . /s - ( ) - sha: doc_id: cord_uid: uy s background: an outbreak of acute encephalitis of unknown origin with high case fatality ( of cases) was reported in children from andhra pradesh state in southern india during . we investigated the causative agent. methods: cell lines and peripheral blood lymphocyte co-cultures were used to isolate the causative agent from clinical samples. identity of the agent was established by electron microscopy and serological and molecular assays. findings: clinical samples tested negative for igm antibodies to japanese encephalitis, west nile, dengue, and measles viruses, and for rna of coronavirus, paramyxovirus, enterovirus, and influenza viruses. virus was isolated from six patients with encephalitis and was identified as chandipura virus by electron microscopy, complement fixation, and neutralisation tests. chandipura virus rna was detected in clinical samples from nine patients. sequencing of five of these rna samples showed · – · % identity with the reference strain of . chandipura viral antigen and rna were detected in brain tissue of a deceased child by immunofluorescent antibody test and pcr. neutralising, igg, and igm antibodies to chandipura virus were present in some patients' serum samples. serum samples obtained after days of illness were more frequently positive for igm to chandipura virus than were those obtained earlier (p< · ). a similar trend was noted for neutralising antibodies. interpretation: our findings suggest that this outbreak of acute encephalitis in andhra pradesh was associated with chandipura virus, adding to the evidence suggesting that this virus should be considered as an important emerging pathogen. viral encephalitis is an important global public-health problem. in india, although many encephalitis outbreaks have been associated with japanese encephalitis virus, several outbreaks have remained undiagnosed. one such outbreak was documented in jamshedpur as early as . a group of patients was characterised by sudden onset of high-grade fever ( - °f), occasional vomiting, rigors, and drowsiness leading to unconsciousness, followed by death in - h. the age of the affected children ranged from · months to years. the case fatality rate was · %, and csf findings were within normal limits. the cause was thought to be viral, but laboratory findings were inconclusive. subsequently, outbreaks of a similar nature were described from nagpur, raipur, bilaspur, and nearby areas of central india in the years , , , , and . similar outbreaks were reported from warangal in andhra pradesh in and . in the absence of a defined cause, these outbreaks were tentatively attributed to reye's syndrome, dengue, chikungunya, japanese encephalitis, measles, and so on. [ ] [ ] [ ] an outbreak of encephalitis was reported between june and september, , in andhra pradesh and adjoining areas in the maharashtra state of india. we report our investigation into the cause of this outbreak. andhra pradesh is a state in southern india situated between - °east and - °north . it is divided into three main regions: telangana (ten districts), rayalseema (four districts), and a coastal region of nine districts. most of the encephalitis cases were reported from the telangana region. the state's general population density is - people per km . there are three distinct seasons: summer (march to july with temperature range of - °c), monsoon (july to december having an average rainfall of · mm), and winter from december to february (temperature range - °c). the state health authorities of andhra pradesh undertook surveillance to detect cases of encephalitis, with a broad case definition of acute fever with cns involvement and negative for other known causes of illness. clinical samples were collected from three groups: an encephalitis group, based on the case definition used by the state government; a fever groupie, fever without cns involvement; and a family-contact group-ie, no fever and no cns involvement. samples obtained were: blood samples, throat swabs, ten csf samples, and one brain aspirate from patients with encephalitis; five blood samples and nine throat swabs from fever cases; and ten blood samples and one throat swab from ten family contacts (including specimens from the brother and mother of a patient who methods cell lines and peripheral blood lymphocyte co-cultures were used to isolate the causative agent from clinical samples. identity of the agent was established by electron microscopy and serological and molecular assays. findings clinical samples tested negative for igm antibodies to japanese encephalitis, west nile, dengue, and measles viruses, and for rna of coronavirus, paramyxovirus, enterovirus, and influenza viruses. virus was isolated from six patients with encephalitis and was identified as chandipura virus by electron microscopy, complement fixation, and neutralisation tests. chandipura virus rna was detected in clinical samples from nine patients. sequencing of five of these rna samples showed · - · % identity with the reference strain of . chandipura viral antigen and rna were detected in brain tissue of a deceased child by immunofluorescent antibody test and pcr. neutralising, igg, and igm antibodies to chandipura virus were present in some patients' serum samples. serum samples obtained after days of illness were more frequently positive for igm to chandipura virus than were those obtained earlier (p< · ). a similar trend was noted for neutralising antibodies. interpretation our findings suggest that this outbreak of acute encephalitis in andhra pradesh was associated with chandipura virus, adding to the evidence suggesting that this virus should be considered as an important emerging pathogen. died from encephalitis). the confirmed chandipura virus encephalitis group consisted of individuals from whose samples we isolated the virus, viral rna, or reactive igm antibodies. the state government did laboratory tests to rule out bacteria and malaria, and to study csf profiles. we tested for japanese encephalitis virus, west nile virus, measles virus, dengue virus, paramyxoviruses, rabies virus, enteroviruses, influenza virus, coronaviruses, and mycoplasma, by use of serological tests, pcr, or both. [ ] [ ] [ ] [ ] all handling of material and tests were done with appropriate biosafety practices. isolation of virus was done by inoculation of clinical specimens ( throat swabs, five csf, and one brain aspirate from a patient who died) into vero, madin-darby canine kidney (mdck), and rhabdomyosarcoma (rd) cell lines, with standard procedures. white blood cells were obtained from ten patients' blood clots by lysing red blood cells, and were co-cultured with phytohaemagglutininstimulated peripheral-blood mononuclear cells from normal donors. all cultures inoculated with the clinical material were frequently checked for cytopathic effects. five csf samples were also inoculated into the brains of -day-old swiss-albino mice to grow virus. tissue culture fluids from cultures showing cytopathic effects were negatively stained with % sodium phosphotungstic acid ph · and examined with the kv mode of a transmission electron microscope (tecnai biotwin, fei, eindhoven, netherlands). complement fixation tests were done with hyperimmune chandipura virus antiserum raised against a prototype strain of the virus ( ). in-vitro virus neutralisation tests were done in vero cells as described previously with tcid ( % tissue culture infective dose) of chandipura virus. the titre of virus-neutralising antibody was assigned as the reciprocal of the antibody dilution capable of neutralising the virus. hyperimmune serum raised in mice against a standard strain of chandipura virus served as a positive control and was used for identification of virus isolate. an immunofluorescence assay was used to test for virus in brain-tissue suspension, which was spread on glass slides, air dried, acetone fixed, and immunolabelled with mouse anti-chandipura-virus hyperimmune serum and anti-mouse fluorescein-isothiocynate-conjugate, by use of standard procedures, along with appropriate controls. rt-pcr for chandipura virus rna was done on the basis of the g gene sequence for an indian chandipura virus isolate (chpi- , genebank accession number j ) the primers shown in the panel were synthesised and used in hemi-nested format for the detection of chandipura viral rna in clinical specimens. pcr products were purified by use of wizard ready reaction kit (applied biosystems, foster city, usa) and an automatic sequencer (abi prism genetic analyser, applied biosystems). both strands were sequenced. we did phylogenetic analysis of the partial g gene sequence ( nt) with mega software. the jukes-cantor algorithm was used with the neighbour-joining method. to assess the reliability of the groupings obtained, we used bootstrap analysis ( bootstraps) available in the software (seqboot: boot strap replications). greater than % bootstrap support was judged to be reliable phylogenetic grouping. igm and igg antibodies against chandipura virus were detected by locally developed capture elisa (patent pending). igm or igg from patient's serum were captured on wells coated with anti-human igm or igg, respectively. chandipura virus extracted from mouse brain by sucroseacetone was the source of antigen. captured antigen was detected with the igg fraction of polyclonal anti-chandipura-virus mouse serum conjugated with biotin (sigma chemicals, st louis, usa) followed by avidin-horseradish peroxidase. o-phenyline-diamine-hydrogen peroxide was added for colour development. negative controls included: age-matched serum from apparently healthy children from an area not affected by the outbreak, and serum and csf from children with flavivirus encephalitis. the cutoff value was determined as mean optical density for negative controls plus sd. for comparison of proportions, fisher's exact test was used. the mann-whitney test was used to compare neutralising antibody titres. the sponsors of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report. on the basis of the broad case-definition used by the andhra pradesh state government, cases of encephalitis were reported between june and september, , with deaths (case fatality rate · %). most deaths occurred within h of admission to hospital. the distribution of cases was mainly rural, spread over districts of the state, and was spotty without clustering (figure ). age of patients ranged from months to years. the male to female ratio was to · . limited data suggested that csf was usually under pressure; pleocytosis was absent. neurological sequelae were rare in the children who recovered. the typical clinical manifestations in the group with confirmed chandipura virus encephalitis (n= ) included rapid onset of fever ( patients, %), followed by vomiting ( , %), altered sensorium ( , %), convulsions ( , %), diarrhoea (five, %), neurological deficit (four, %), and meningeal irritation (two, %). brain tissue was obtained after death from only one patient: a -year-old, previously healthy girl developed fever, vomiting, and generalised tonic-clonic convulsions, became unconscious, and had severe dehydration. on admission she developed tachycardia, dyspnoea, irregular breathing, bilateral papilloedema, decerebrate posture, and no response to painful stimuli. blood pressure at admission was / mm hg and subsequently dropped to mm hg/not recordable. the girl was put on a mechanical ventilator. she continued with fever ( °f) and developed bradycardia and pupillary dilatation. potassium rose substantially in her serum (to mmol/l). the patient was treated with intravenous fluids, antibiotics, phenytoin, diazepam, and mannitol, and died within h of admission. routine laboratory investigations screening for japanese encephalitis virus, west nile virus, paramyxovirus, coronavirus, measles virus (serum and csf), dengue virus, rabies virus, influenza viruses, and mycoplasma (throat swab and csf) yielded negative results. in the encephalitis group, all ten csf samples were negative for virus isolations. virus was isolated from three of throat swabs (one in mdck; one in rd, vero, and mdck; one in vero and rd), one brain aspirate in rd and vero cell cultures, and two of ten blood clots in peripheral-blood mononuclear cell co-culture. five of the six samples from which virus was isolated had been obtained within days of onset of illness. in the fever group, one of eight throat swabs yielded virus in the rd cell line. assessment of the culture isolates with transmission electron microscopy showed the presence of bulletshaped particles that were - nm long and - nm wide, with distinct surface projections - nm in length and a stain-filled canal at the base of the particle-all features suggestive of rhabdoviruses (figure ). isolates were identified as chandipura virus by complement fixation and neutralisation tests. chandipura viral antigen and rna were detected in brain tissue by immunofluorescence assay ( figure ) and pcr, respectively. four of throat swabs, one of seven csf samples, five of serum samples, and one brain aspirate were positive for chandipura virus rna. one of the five positive serum samples was from the patient (table ) . all isolates were also positive for chandipura viral rna. partial g gene sequences of nt (accession number ay - ) representing clinical specimens from five patients showed - · % identity (mean · %, % ci · - · ; figure ) . these sequences were · - · % ( · , % ci · - · ) identical with the reference sequence. all chandipura virus sequences clustered together with % bootstrap support and were closer to piry virus than to vesicular stomatitis virus (figure ). table shows igm, igg, and neutralising antibody status for patients with confirmed chandipura virus encephalitis, three patients with fever, and two contacts. table shows antibody status in patients with encephalitis, including of the patients with confirmed chandipura virus infection mentioned in table (data were incomplete for the other three patients). since no paired samples of serum from the acute and convalescent phases of illness could be obtained from the patients during this outbreak, the results from testing of singlebleed serum samples were assessed in relation to the time after disease onset at which samples were obtained. a smaller proportion (four of [ %]) of serum samples obtained up to days after onset of illness (early samples) were positive for igm reactive with chandipura virus, compared with samples obtained later than days after onset of illness ( of [ %]; p< · ). a similar trend was also noted for chandipura virus-reactive igg antibodies ( % of early samples positive vs % of late samples) and neutralising antibodies ( % vs %). the geometric mean titres in early versus late samples were significantly different ( · vs · , p< · ) . chandipura virus-reactive igm antibodies were also found in two of five patients with fever but no cns involvement, and in two of ten family contacts. unfortunately, because of the nature of the outbreak response and local resources, we were unable to obtain serum samples from a larger control group. the viruses isolated in different cell lines from clinical samples from patients with encephalitis were confirmed as chandipura virus with various techniques including complement fixation, neutralisation test, and immunofluorescence assay. analysis of partial g gene sequences showed that the genome of the chandipura virus strain associated with this outbreak was distinct from that of the reference strain obtained in . importantly, in one fatal encephalitis case from this outbreak, both chandipura viral antigen and rna were detected in situ in the post-mortem brain tissue. the clinical presentation of this patient was representative of the symptoms seen in most of the other patients reported during the present outbreak. chandipura virus was also subsequently isolated from this tissue. therefore, the presence of the virus in the brain was probably the cause of cns pathology leading to encephalitis in this patient. moreover, the presence of chandipura virus rna in nine patients with encephalitis, all from samples obtained before day after onset of illness, suggests an early viraemic phase of the infection process. that five of six virus isolates were obtained from such early samples further strengthens this observation. further evidence that chandipura virus was the primary causal agent for this outbreak is the pattern of immune response to the virus. substantially higher proportions of positive test results for chandipura virusreactive antibodies were noted among samples obtained more than days after onset of illness, compared with samples obtained earlier, suggesting a seroconversion window period and primary exposure to the virus in the people from whom samples were taken early. of the cases of encephalitis investigated, evidence of recent infection with chandipura virus could be established conclusively in cases ( %) based on either the presence of virus or viral rna, igm antibodies, or both. the absence of evidence of such an infection in some samples could be because samples were obtained very soon after disease onset. a small proportion of the remaining cases might represent encephalitis due to the presence of igm reactive with chandipura virus in two patients with fever and in two family contacts of a patient with encephalitis suggests that infection with the virus may remain asymptomatic or lead to fever without encephalitis; the disease spectrum needs careful study. evidence of igg against chandipura virus detected in adults probably indicates environmental exposure to the virus. several earlier outbreaks of encephalitis recorded in central india from onwards that showed similarities to the present outbreak (clinical features, seasonality, and undetermined aetiology) might perhaps have been due to chandipura virus, which could be endemic in these regions. most of the vesiculoviruses are transmitted by sandflies. interestingly, chandipura virus was detected by pcr in a sandfly pool obtained from the house of an affected patient in the present outbreak (unpublished report). this finding and earlier isolation of the virus from sandflies both in india and africa strongly suggest that sandflies might be the vector of this disease. in india, these insects are more prevalent in the early monsoon period, a season that coincided with the present outbreak. the isolation of chandipura virus from sandflies, , human beings, and vertebrates; the presence of reactive antibodies in human beings and other vertebrate hosts; and the ability of sandflies and mosquitoes to transmit the virus to susceptible hosts; - represents a broad eco-cycle of the virus in nature. the previous isolation of the virus from human beings with febrile and encephalopathy , and association of this virus with the present large encephalitis outbreak, implicates chandipura virus as an emerging pathogen of substantial public-health importance. b l rao isolated and characterised virus, collected and analysed laboratory data, and had substantial intellectual input into manuscript writing. a basu did electron microscopy and laboratory studies related to primary virus identification, analysed data, and had substantial intellectual input into manuscript writing. n s wairagkar did clinico-epidemiological studies of the outbreak, examined patients, obtained and analysed clinical material, compiled data, and had substantial intellectual input into manuscript writing. m m gore did virus isolation studies, planned execution analysis of virus neutralisation data, and had substantial intellectual input into manuscript writing. v a arankalle designed and did molecular virology experiments and had substantial intellectual input into manuscript writing. j p thakare did serology tests, including development of elisas for chandipura virus, igm, and igg, and took part in manuscript preparation. r jadi participated in virus isolation studies and manuscript preparation. a k rao contributed clinical data and took part in patient management, including data analysis. a c mishra was the group leader, substantially contributed to design, interpretation, and data analysis, and had significant intellectual contribution in developing the manuscript. www.thelancet.com vol september , in person and extensive constructive review and suggestions that went into the present manuscript. we also gratefully acknowledge the help and co-operation of the directorate of health services, government of andhra pradesh, india. we would also like to sincerely thank s tikute, s d pawar, g n sapkal, mr hanumaiah, s v gangodkar, v m ayachit, n j shaikh, s p shrotri, and b kundu for their technical support; a walimbe for statistical assistance, mr murlikrishna for photographic help, and m v joshi for providing standard immune serum samples. funds were provided by the indian council of medical research, ministry of health and family welfare, government of india. epidemiology of japanese encephalitis in india: national conference on japanese encephalitis jamshedpur fever etiology of the epidemic of febrile illness in nagpur city, maharashtra state isolation of chandipura virus from the blood in acute encephalopathy syndrome outbreak of killer brain disease in children: mystery or missed diagnosis? laboratory diagnosis of common viral infections of the central nervous system by using a single multiplex pcr screening assay phylogenetic analysis of a highly conserved region of the polymerase gene from coronaviruses and development of a consensus polymerase chain reaction assay nipah virus: a recently emergent deadly paramyxovirus evaluation of a single step multiplex rt-pcr for influenza virus type and subtype detection in respiratory samples application of microtechniques to viral serological investigation ethanethiol sensitive and resistant antibodies to enterovirus in post conjunctivitis neurological syndromes mega · : molecular evolutionary genetics analysis software rapid detection of herpes simplex virus in clinical specimen by use of a capture biotinstreptavidin enzyme linked immunosorbent assay isolation of chandipura virus from sandflies in aurangabad arbovirus surveillance from to in the barkedji area (ferlo) of senegal, a possible natural focus of rift valley fever virus chandipura virus: a new arbovirus isolated in india from patients with febrile illness viruses other than arenaviruses from west african wild mammals: factors affecting transmission to man and domestic animals emerging arboviruses of zoonotic and human importance in india growth and transovarial transmission of chandipura virus (rhabdoviridae:vesiculovirus) in phlebotomus papatasi experimental transmission of chandipura virus by mosquitoes susceptibility of four species of mosquitoes to chandipura virus and its detection by immunofluorescence antibody response to chandipura virus in experimental animals we express our sincere gratitude to stuart nichol (chief, molecular biology laboratory, special pathogens branch, division of viral and rickettsial diseases, centers for disease control and prevention, atlanta, ga, usa) who gave us a unique opportunity to discuss the data key: cord- -s xufes authors: mccloskey, brian; zumla, alimuddin; ippolito, giuseppe; blumberg, lucille; arbon, paul; cicero, anita; endericks, tina; lim, poh lian; borodina, maya title: mass gathering events and reducing further global spread of covid- : a political and public health dilemma date: - - journal: lancet doi: . /s - ( ) - sha: doc_id: cord_uid: s xufes nan at mgs in response to the world health assembly's endorsement on dec , , of the th executive board decision "global mass gatherings: implications and opportunities for global health security" that encompassed joint planning, enhancement of health infrastructures, and taking proper pre-emptive and preventive measures to control infectious diseases on an international scale. since then, many mgs have been held safely and successfully without any major communicable disease issues arising, , - even for mg events held during three who declared public health emergencies of international concern: the vancouver winter olympics and the fifa world cup in south africa during the h n influenza pandemic; the africa cup of nations football tournament in equatorial guinea during the outbreak of ebola virus disease; and the rio olympics during the zika virus outbreak. , the emergence of sars-cov- in china in - as a pathogen transmitted by the respiratory route leading to the covid- pandemic has refocused global attention on national, regional, and pandemic spread through mgs events. since early march, , there has been a step increase in cancellation of international and national religious, sporting, musical, and other mgs as countries worldwide take measures to contain the spread of sars-cov- . many prominent mgs have been cancelled or postponed, including sports fixtures such as the union of european football associations euro football championship, the formula grand prix in china, the six nations rugby championship in italy and ireland, olympic boxing qualifying events, the mobile world congress in barcelona, and the umrah in saudi arabia. although appropriate public health surveillance and interventions for reducing the risk of disease transmission at mgs are informed by previous experiences, the evidence base for infectious disease transmission during mgs is still evolving and needs to be more comprehensive. , for covid- , in addition to the major public health risks at mgs, the management of enhanced media interest and public and political perceptions and expectations are major challenges. fear, uncertainty, and a desire not to be seen to get things wrong can influence decisions about the risks of mgs, rather than an understanding of the risks and of the interventions available to reduce that risk. panel: risk assessment for mgs during covid- pandemic , ( ) general considerations at the beginning of the planning phase: • risk assessment must be coordinated and integrated with the host country's national risk assessment • comprehensive risk assessment (with input from public health authorities) reviewed and updated regularly • action plans should be developed to mitigate all risks identified in the assessment. action plans should include: who, working with global partners in mg health, many of whom were involved in the riyadh conferences and the lancet's mass gatherings medicine series, [ ] [ ] [ ] [ ] has developed comprehensive recommendations for managing the public health aspects of mgs that have been updated with interim key recommendations for covid- . these recommendations have to be used in consultation with updated technical guidance on covid- . risk assessments for covid- (panel) need to consider the capacity of host countries to diagnose and treat severe respiratory illness. who's risk assessment tool enables organisers to methodically review key considerations and risk management steps for hosting an event, assess risks with a weighted-system approach, and factor in risk reduction through various mitigation measures. the covid- risk assessment for mgs builds on existing guidance for mgs. the standard risk questions for a mg involve assessment of how well prepared and equipped the host country health system is to detect an usual health event, such as a disease outbreak, and to respond quickly and effectively to the event if it happens. the new risk assessment tool adds an element to assess the additional risk from the mg in relation to covid- (panel). this risk assessment includes questions on the range of countries participants will come from, the prev alence and transmission pattern of covid- in these countries and in the host country, the extent of social interactions that is likely to arise at the mg, and the demographic profile of participants. the covid- risk assessment for mgs tool then involves consideration of the possible mitigation actions that could be put in place at the mg to reduce the risk against a list of questions about the host's understanding of, and preparedness for, covid- response measures. at present there is scant evidence on the effectiveness of individual mitigation actions for covid- . as better epidemiology about covid- and evidence on the effectiveness of different mitigation strategies become available, the covid- risk assessment for mgs tool will be continuously refined to reflect changing knowledge. this rigorous process can inform risk assessment and decision making about mgs during the covid- pandemic. such mg risk assessments should be reviewed regularly during planning and updated immediately before the mg operational phase, especially in light of the evolving national and international epidemiological situations. there is no specific evidence base yet specific to planning and implementing a mg during the covid- pandemic. detection and monitoring of mg-event-related covid- should be considered in the context of surveillance schemes that are already in place and if new or enhanced surveillance is deemed necessary. in collaboration with local health authorities, organisers should agree in advance the circumstances in which risk-mitigation measures would need to be enhanced or the event postponed or cancelled. despite the development of the covid- risk assessment for mgs tool, events continue to be cancelled without this risk assessment being done and without clear communication of justification in terms of the expected impact on the spread of covid- . these cancellations have social and economic impacts on public morale, on national economies, and on individual livelihoods. the effect of mg cancellations on reducing the spread of covid- needs to be determined. the global public health community needs to consider the effects of mg cancellations on the future wellbeing of communities through economic recession or job losses, as well as through the spread, or otherwise, of covid- . a precautionary approach is often used to explain mg cancellations, but when does an abundance of caution become counterproductive? the overarching advice during the ongoing covid- pandemic is that events should be cancelled or postponed on the basis of a context-specific risk assessment. if a decision is made to proceed with mg events, risk mitigation measures should be put in place, consistent with who guidance on social distancing for covid- , and the rationale for the decision should be clearly explained and communicated to the public. it is natural during the unfolding coronavirus disease (covid- ) pandemic to focus on emergency response planning, including containment, treatment procedures, and vaccine development, and nobody would doubt the need for these measures. however, an emergency can also open a window of opportunity for reflection and learning. we live in increasingly global, interdependent, and environmentally constrained societies and the covid- pandemic exemplifies these aspects of our world. we would therefore be wise to take a broad integrated perspective on this disease, the impacts of which are already spilling over into the realms of economics, international trade, politics, and inequality. resilience planning needs to cope with these cascading impacts, and prevention efforts require a similarly wide lens to encompass ecosystems, wild animal disease surveil lance, agricultural practices, eating habits, and cultural traditions and contexts. in other words, we need a planetary health perspective that cuts across traditional domains of knowledge, governance, and economic sectors to properly address the challenge posed by covid- . we welcome submissions on all aspects of the covid- pandemic across the lancet titles, but here we are calling for submissions to the lancet and the lancet planetary health. we particularly welcome interdisciplinary research that integrates across important knowledge domains to provide a fuller understanding of the causes and socioeconomic impacts of covid- , as well as public understanding and responses, the efficacy of management and prevention interventions, and approaches for the identification and prevention of future such events within the wider context of the sustainable development goals. submit your paper through our respective online systems and please mention in your cover letter that your submission is in response to this call for papers. who. coronavirus disease (covid- ) situation report- report of the who-china joint mission on coronavirus disease (covid- ). geneva: world health organization looming threat of covid- infection in africa: act collectively, and fast effect of the ebola-virus-disease epidemic on malaria case management in guinea, : a cross-sectional survey of health facilities geneva: world health organization effects of response to - ebola outbreak on deaths from malaria, hiv/aids, and tuberculosis, west africa evidence of sars-cov- infection in returning travelers from wuhan, china preparedness and vulnerability of african countries against importations of covid- : a modelling study malaria morbidity and mortality in ebola-affected countries caused by decreased health-care capacity, and the potential effect of mitigation strategies: a modelling analysis impact of the mass drug administration for malaria in response to the ebola outbreak in sierra leone malaria control campaign launched in democratic republic of the congo to save lives and aid ebola response covid- ) outbreak public health for mass gatherings: key considerations mass gatherings medicine: public health issues arising from mass gathering religious and sporting events global mass gatherings: implications and opportunities for global health security mass gatherings medicine: international cooperation and progress olympic and paralympic games: public health surveillance and epidemiology european football championship finals: planning for a health legacy hosting of mass gathering sporting events during the - ebola virus outbreak in west africa: experience from three african countries rapid spread of zika virus in the americas-implications for public health preparedness for mass gatherings at the brazil olympic games saudi arabia's measures to curb the covid- outbreak: temporary suspension of the umrah pilgrimage transmission of respiratory tract infections at mass gathering events toning down the -ncov media hype and restoring hope hajj: infectious disease surveillance and control key planning recommendations for mass gatherings in the context of the current covid- outbreak. interim guidance country and technical guidance-coronavirus disease (covid- ) covid- ) advice for the public key: cord- - sypsfba authors: ferigato, sabrina; fernandez, michelle; amorim, melania; ambrogi, ilana; fernandes, luísa m m; pacheco, rafaela title: the brazilian government's mistakes in responding to the covid- pandemic date: - - journal: lancet doi: . /s - ( ) - sha: doc_id: cord_uid: sypsfba nan submissions should be made via our electronic submission system at http://ees.elsevier.com/ thelancet/ www.thelancet.com published online october , https://doi.org/ . /s - ( ) - the brazilian government's mistakes in responding to the covid- pandemic it is unfortunate to read the unsub stantiated and misguided opinion of a few physicians about the role of the current administration during the covid crisis in brazil. for those of the international scien tific community who base their understanding on reliable data, the conclusion that brazil has shown one of the worst responses to the pan demic is unequivocal. the gravity of the pandemic in brazil is evidenced by the current epidemiological facts: brazil is among the three countries with the largest number of confirmed cases (more than million as of oct , , according to who), with high mortality, evidence of underreporting, and a high number of deaths among health professionals, pregnant women, and the indigenous population. the federal government's denial of science and, consequently, of the seriousness of the pandemic to the health and wellbeing of brazilians has led to a failure to coordinate, promote, and finance internationally sanctioned public health measures. the ministry of health has not developed a national plan to combat the pandemic, nor has any other federal government agency. states and municipalities continue to be neglected and receive insufficient assistance. influenced by political interests, the federal government has disrupted the flow of financial transfers and slowed the deliveries of essential supplies to certain regions. furthermore, brazil's public health system, sistema Único de saude (sus), is the largest in the world and provides universal coverage without any cost to patients. it is accessible nationwide and provides communitybased primary health care to more than % of the population. yet, primary health care has been overlooked by the federal government as a key element in this public health crisis response. financial emergency aid to the most vulnerable populations was gravely delayed, insufficient, and cumbersome to obtain. moreover, the federal administration denies international recommendations for nonpharmacological interventions, refusing to establish a national man date for social isolation and mask use. it is necessary to analyse the brazilian government's response to the covid pandemic based on trustworthy knowledge built upon scientific facts. the negative effects of governmental decisions represent important risks to the health of brazilians and for the pandemic's global situation. a coordinated politi cal response guided by social justice and evidencebased knowledge is essential to managing any public health emergency, especially one with as broad economic and health impacts as covid . regretfully, this is not what is happening in brazil. we declare no competing interests. brazil's covid response lancet covid commission statement on the occasion of the th session of the un general assembly covid : public policies and society's responses. quality information for refining public policies and saving lives the tragedy of covid in brazil: maternal deaths and counting for more on covid- in brazil's indigenous population see key: cord- -xyuj j authors: lee, lennard y w; cazier, jean baptiste; starkey, t; turnbull, c d; kerr, rachel; middleton, gary title: covid- mortality in patients with cancer on chemotherapy or other anticancer treatments: a prospective cohort study date: - - journal: lancet doi: . /s - ( ) - sha: doc_id: cord_uid: xyuj j background: individuals with cancer, particularly those who are receiving systemic anticancer treatments, have been postulated to be at increased risk of mortality from covid- . this conjecture has considerable effect on the treatment of patients with cancer and data from large, multicentre studies to support this assumption are scarce because of the contingencies of the pandemic. we aimed to describe the clinical and demographic characteristics and covid- outcomes in patients with cancer. methods: in this prospective observational study, all patients with active cancer and presenting to our network of cancer centres were eligible for enrolment into the uk coronavirus cancer monitoring project (ukccmp). the ukccmp is the first covid- clinical registry that enables near real-time reports to frontline doctors about the effects of covid- on patients with cancer. eligible patients tested positive for severe acute respiratory syndrome coronavirus on rt-pcr assay from a nose or throat swab. we excluded patients with a radiological or clinical diagnosis of covid- , without a positive rt-pcr test. the primary endpoint was all-cause mortality, or discharge from hospital, as assessed by the reporting sites during the patient hospital admission. findings: from march , to april , , we analysed patients with a diagnosis of cancer and symptomatic covid- . ( %) patients had a mild covid- disease course. ( %) patients died and risk of death was significantly associated with advancing patient age (odds ratio · [ % ci · – · ]; p< · ), being male ( · [ · – · ]; p= · ), and the presence of other comorbidities such as hypertension ( · [ · – · ]; p< · ) and cardiovascular disease ( · [ · – · ]). ( %) patients had received cytotoxic chemotherapy within weeks before testing positive for covid- . after adjusting for age, gender, and comorbidities, chemotherapy in the past weeks had no significant effect on mortality from covid- disease, when compared with patients with cancer who had not received recent chemotherapy ( · [ · – · ]; p= · ). we found no significant effect on mortality for patients with immunotherapy, hormonal therapy, targeted therapy, radiotherapy use within the past weeks. interpretation: mortality from covid- in cancer patients appears to be principally driven by age, gender, and comorbidities. we are not able to identify evidence that cancer patients on cytotoxic chemotherapy or other anticancer treatment are at an increased risk of mortality from covid- disease compared with those not on active treatment. funding: university of birmingham, university of oxford. the risk of morbidity and mortality from covid- as a consequence of severe acute respiratory syndrome coronavirus (sars-cov- ) infection is not uniform across the uk population. patients with cancer receiving systemic anticancer treatments have been generally assumed by many to be at a higher risk from the disease than their counterparts are who are not receiving anticancer treatment. the evidence to support this claim is scarce and limited to retrospective series arising from china, the epicentre of the covid- pandemic, and involving small numbers of patients. - however, despite these severe limitations, the promulgation of this hypothesis has led to widespread global changes to patterns of prescribing chemotherapy and anticancer treatment. in a global health emergency, oncologists must secure evidence from a large dataset, which can then inform their risk-benefit analyses for individual patients in terms of the use of anticancer treatments. , on march , , we launched the uk coronavirus cancer monitoring project (ukccmp), with widespread support across our national cancer network. within weeks, the ukccmp had generated the largest prospective database of covid- in patients with cancer that had been generated to date. we aimed to describe the clinical and demographic characteristics and covid- outcomes in this cohort of patients with cancer and symptomatic covid- , and attempted to assess how the presence of cancer and the receipt of cytotoxic chemotherapy and other anticancer treatments affects the covid- disease phenotype. the ukccmp database of uk patients covid- who have cancer with was launched with the support of the uk oncology professional bodies, including the association of cancer physicians, the royal college of radiologists, the national oncology trainees research collaborative for healthcare research, patient support groups including macmillan cancer support, and charities including action radiotherapy. the database was designed as a public health surveillance registry to support rapid clinical decision making, in accordance with the uk policy framework for health and social care research, the uk national research ethics service, and the uk governance arrangement for research ethic committees. at an institutional level, this cohort study was approved according to local information governance processes. all patients with active cancer and presenting to our network of cancer centres from march , , to april , , with covid- were eligible for enrolment into the ukccmp. in keeping with international practice, patients were deemed to have covid- if an rt-pcr assay test from a throat or nose swab was positive for sars-cov- . patients with a radiological or clinical diagnosis of covid- , without a positive rt-pcr test were not included in this analysis. as such, these patients evidence before this study we searched pubmed for all studies related to the effect of severe acute respiratory syndrome coronavirus , the cause of covid- , on patients with cancer, using the search terms "covid- ", "sars-cov- ", "cancer", "treatment", "chemotherapy", "immunotherapy", "radiotherapy", "targeted therapy", "outcomes," "death", "mortality", and "risk". we included publications in english only. to date, only two studies have described the effect of cancer treatments on covid- outcomes. both studies consist of small retrospective analyses from china in a few cancer centres. one study reported four patients who had chemotherapy or surgery in the past month, and identified that three had a clinically severe disease course. another study described a cohort of cancer patients with covid- , of whom had received chemotherapy within the past days and six had received immunotherapy. the authors reported that four of the six patients on immunotherapy had critical symptoms. no conclusions were drawn about chemotherapy and the authors stressed the importance of a further study with a large case population. in summary, to date, no high-quality evidence exists to identify risks from use of recent anticancer treatments during the covid- pandemic. this uk coronavirus cancer monitoring project study is a national monitoring project. we have analysed the interaction between recent anticancer treatments and covid- morbidity and mortality in the largest cohort of patients with cancer with covid- presented to date, consisting of patients. recent chemotherapy use in patients with cancer before severe acute respiratory syndrome coronavirus infection was not significantly associated with increased mortality. although the numbers of patients are smaller, we did not observe any significant risk from recent use of immunotherapy, hormonal therapy, targeted therapy, or radiotherapy. our data are strongly indicative that covid- mortality in patients with cancer is principally driven by advancing age and the presence of other non-cancer comorbidities. at a population level, our data do not suggest that chemotherapy or anticancer treatments will necessarily increase the risk of mortality from covid- , and gives confidence to oncologists and other clinicians that delivery of effective anticancer regimens should continue during this difficult time. are, by definition, symptomatic, requiring secondary care review for potential hospitali sation. these patients were not part of a proactive surveillance programme. patients with active cancer were defined as those with metastatic cancer, or on anticancer treatment in any setting (curative, radical, adjuvant, or neoadjuvant setting) or treated within the past months with surgery cytotoxic chemotherapy, or radiotherapy. stages of tumour were divided into those into primary tumour localised, which were localised to organ and therefore potentially resectable; primary tumour locally advanced, which had spread locally from the primary organ and was not resectable; metastatic, when there has been distant spread (stage iv); and patients in remission. patients were assessed by the local teams and review of their medical history as to whether they had received chemotherapy (which did not include treatment with denosumab), immunotherapy, hormonal therapies, or radiotherapy within weeks of contraction of covid- . non-palliative chemotherapy was defined as chemotherapy that was used in a neoad juvant, adjuvant, or radical setting. outcomes were monitored until april , . prospective data collection was done by the pan-uk cancer centre emergency response network. case reporting was led by a covid- emergency response reporting individual (erri), supported by a local emergency response reporting group (lerrg) at each centre. the role of the lerrg was to ensure near continuous reporting of cases in situations of absence of the erri. the ukccmp encouraged all local reporting sites to enter data in a real-time basis, as soon as a positive sars-cov- test had been identified. the data fields were then updated as soon as treatment and outcomes had been identified and also to reflect the worse covid- severity categories during hospitalisation. the erri was an oncologist who was trained or in training, who did data review, annotation, and entry. in a few centres, data entry was done by data managers but with direct oversight by the erri. all registry entries were de-identified at source to ensure data anonymity to researchers. data was entered with the research electronic data capture (redcap) application, an electronic data capture software system that is browser based and metadata driven. this secure electronic data capture platform is hosted by the institute of translational medicine at the university of birmingham, birmingham, uk. patient demographics, treatment details, covid- disease course, and cancer features were obtained by the direct assessment of the erri and lerrg, or through hospital medical records. the covid- severity category was determined according to who guidelines. cancer type was defined according to the international classification of disease ( th revision) diagnostic codes. the data entered through redcap was transfer red securely through to the compute and storage for life science (castles) infrastructure as part of the birmingham environment for academic research local cloud at the centre for computational biology, university of birmingham. within castles, the data are curated to avoid duplications and errors, then annotated with further information such as geolocation before they can be analysed and disseminated. the deployment of an automatic workflow system, with human interaction (human-in-theloop), enables the delivery of near real-time robust data analytics to medical health professionals in oncology through a weekly report in addition to a secured interactive web portal. importantly, castles enables delivery of national and local analytics with a dynamic level of granularity. we assessed whether the patient died or eventually achieved discharge, and observed the effect of anticancer treatment on outcomes. the two-sided welch's t test was used to compare continuous data and two-sided fisher's exact test was used to compare categorical data from different categories with multivariate bonferroni (multi-test) adjustment. a primary endpoint of all-cause mortality was defined a priori. this definition included deaths described as related to covid- during admission, as well as deaths reported as a consequence of any other cause during admission, such as due to cancer progression or treatment toxicity. this definition was used for all regression analyses. multivariate analyses were done in spss (version . . . ) and fisher's exact tests in r (version . . ), using the fisher.test () function. multivariable logistic regression was used to estimate odd ratios and % cis of each factor after adjustment for clinically relevant potential confounders of age, gender, diabetes, hypertension, chronic obstructive pulmonary disease, or other comor bidities at admission. goodness of fit was checked using the hosmer-lemeshow test and, unless otherwise reported, had p> · . where this goodness of fit criterion was not met, further multivariable logistic regression models using the aforementioned potential confounders was done using a forward selection of p< · . patients with either no information or missing relevant data were not included in these regression analyses. subgroup analyses of patients on chemotherapy were done to better identify risk in this cohort of patients. these analyses included non-palliative versus palliative chemotherapy, first-line versus later lines of palliative chemotherapy, palliative chemotherapy versus no anticancer treatment, and palliative chemotherapy versus no recent chemotherapy (ie, within weeks of admission). the justifi cation for these analyses is that the cancer chemotherapy group is heterogeneous. these subgroup analyses have a well-established oncological and clinical rationale, eg, non-palliative (curative) chemotherapy aims to pre vent recurrence or eradicate disease, whereas palliative chemotherapy aims to maintain quality of life, or extend life usually by a matter of months to years, and both the patient's condition and chemotherapy treatment (drugs, dose, and intensity) necessarily evolve as a patient progresses from first-line to later lines of chemo therapy. we used r (version . . ) for data processing and visualisation. the funder of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report. gm, rk, jbc, and lywl had full access to all the data in the study and had final responsibility for the decision to submit for publication. cancer centres had appointed a covid- lerrg and formed part of this clinical network of cancer centres. this network covered a patient population of nearly · million patients with active cancer, with good coverage across all regions of the uk (figure ). our patient cohort consisted of the first patients with active cancer who had documented sars-cov- infection presenting as symptomatic covid- disease. across the cohort, ( %) patients were reported by sites as having their anticancer treat ments interrupted because of the covid- pandemic, although, the exact nature of this interruption was not captured in this study. compared with patients who had not received chemotherapy within weeks of testing positive for covid- , those who had received recent chemotherapy did not suffer increased mortality when analysed by univariate analysis ( % death rate with chemotherapy vs % death rate without recent chemotherapy). to explore this relationship in greater detail, we did an in-depth analysis of the patients who had received recent chemotherapy (ie, within weeks of testing positive for covid- ; figure ). we found no significant differences in underlying cancer primary site in the recent chemo therapy versus no chemotherapy group. however, compared with patients who had not received recent chemotherapy, the chemotherapy cohort was younger (median age · years vs · ; p< · ). therefore, we did a multivariate analysis with adjustment for age, gender, and comorbidities and found that deaths in patients with covid- who have cancer who had received recent chemotherapy were still no more likely than in those who had not (table ) . this analysis had a borderline fit (hosmer-lemeshow p= · ) . we also did a forward regression model analysis (hosmer-lemeshow p= · ) with similar findings (odds ratio · [ % ci · - · ]; p= · ). on further multivariate analysis of the group of patients who had received recent chemotherapy, decreased odds of death was found in patients receiving non-palliative chemotherapy (neoadjuvant, adjuvant, or radical) com pared with those receiving palliative chemotherapy ( % vs %; table ), after adjustments for age, gender, and comorbidities. however, the odds of death in patients receiving palliative chemotherapy were still not significantly different to those of patients receiving no anticancer treatment at all (table ) , or compared with those with no recent chemotherapy (table ) . we found no significant differences in mortality in patients receiving first-line palliative chemotherapy compared with those receiving later lines of palliative treatment after adjust ments for age, gender, and comorbidities (table ) . finally, we analysed the use of other forms of anticancer therapies within weeks of testing positive for sars-cov- infection and presenting with covid- . compared with patients who were not on these therapies, patients on immunotherapy (n= ; or · [ % ci · - · ]; p= · ), hormonal therapy (n= ; · , [ · - · ]; p= · ), radiotherapy (n= ; · [ · - · ]; p= · ), and targeted therapies (n= ; . [ · - · ]; p= · ) were also not at any additional risk of death after adjustment for age, gender, and comorbidities (figure ). global health-care systems are dealing with the covid- pandemic, a disease caused by sars-cov- infection; a situation that is set to be a generational challenge to all clinicians. the clinical phenotype and interactions of covid- with pre-existing disease and systemic anticancer treatments drugs is poorly described and based on small retrospective studies. the disruption from the pandemic to normal oncological care has been huge for several reasons. first, cancer clinicians and the rest of the cancer team are under unprecedented pressures. these pressures include increasing concern from patients about their perceived vulnerability, cancelled cancer operations, a substantial drive to do telemedicine rather than face-toface consultations, and a high degree of absence from work across the cancer team due to personal illness and self-isolation. second, many oncologists are being redeployed to general or acute medicine roles to support the many covid- admissions requiring intensive medical support and input. third, two small studies , reporting covid- outcomes in patients with cancer have resulted in the community being fearful of giving odds ratios were adjusted for age, gender, and comorbidities. whiskers indicated % ci. chemotherapy radiotherapy immunotherapy targeted therapy hormone therapy · · · · · · · · odds ratio for death the vertical coloured bars denote the patient cohort, split into different groups. the grey horizontal bars denote associations between the different groups, with wider bars denoting more overlap. effective anticancer treatments. these studies concluded that cancer patients are not only more susceptible to contracting the virus compared with the general population, but also at risk of developing more severe sequelae. , in the largest cohort of cancer patients, consisting of only on chemotherapy, six patients on immunotherapy, and four on targeted therapies, strong recommendations were made about the covid- risk from anticancer treatments. all of these studies are small cohorts and limited to a few cancer centres. we felt that the studies raised important hypotheses but were in no way unequivocal and indeed a single-centre study from the usa yielded contradictory results. to clarify the relationship between cancer, anticancer treatments, and covid- , larger-scale datasets are necessary. because of the low prevalence of the coexistence of cancer and covid- , individual health-care centres and physicians will only see a few patients with both diseases. additionally, because of the nature of the pandemic, much of the usual infrastructure of medical professional data dissemination has been completely dismantled: local, national, and international clinical meetings have been delayed or cancelled as part of public health measures to prevent covid- spread. therefore, the creation of national and international strategies to share data quickly and effectively is important during this time of unprecedented need for rapid learning and evidence regarding best practice. the ukccmp was designed to serve as a public health surveillance registry to answer important questions about the interaction of cancer, cancer treatments, and covid- , and to support rapid clinical decision making. close alignment of health-care systems, physicians, and patients has meant that the project was launched and produced clinically meaningful output over the course of weeks. we described the demographics of patients with covid- who have cancer and explored the effect of cytotoxic chemotherapy and other anticancer treatments on the trajectory of covid- . we identified that the phenotype of diagnosed covid- disease in over half of cancer patients is mild, but death from covid- in this cohort was observed in a substantial proportion of patients. this mortality is higher than that observed in the general non-cancer uk population, and might be reflective of the severity of symptoms of the cancer patients who choose to seek treatment in secondary health-care settings. the rate of admission to itu was low, at about %, compared with a death rate of approximately %. using our dataset, we are unable to answer the question as to whether this finding might arise as a result of advance patient health-care directives, hospital and itu admis sion policies, a reluctance of treating physicians to use itu resources for patients with cancer, or historically fewer itu beds available in the uk. the itu admission rate was notably low and reflective of findings from the uk intensive care national audit and research centre. this finding does raise questions as to whether having a diagnosis of cancer decreases the potential access of these patients to the most intensive support. from this dataset, using multivariate analysis, we concluded that cytotoxic chemotherapy given within weeks before confirmed covid- is not a significant contributor to a more severe disease or a predictor of death from covid- , compared with patients with cancer who have not received chemotherapy in that period. although numbers of patients were smaller, similar observations were observed for immunotherapy, hormonal therapy, targeted therapy, and radiotherapy. again, further interrogation with higher numbers of patients will allow us to confirm or refute this finding. overall, in interpreting these data and putting them into context, we suggest that continuing to shield patients with cancer from exposure to sars-cov- is important, through self-isolation, safely minimising the number of hospital visits (which might mean a substitution or oral drugs in place of intravenous drugs), avoiding the mixing of covid- -negative and covid- positive workstreams within the hospital environment, and by mitigating the risk of neutropenia to avoid the risk of simultaneous covid- and bacterial septicaemia. patients with cancer must have equivalent access to itu care. however, in answer to the frequent question from patients as to whether chemotherapy or anticancer treatments will increase their risk of dying from covid- , in addition to the increased risk due to their cancer, our answer should be not necessarily so. in patients presenting to uk national health service trusts or cancer centres, our data are strongly indicative that cancer plus covid- mortality is principally driven by advancing age and the presence of other non-cancer comorbidities. we concluded that withholding effective cancer treatments from many cancer patients during the pandemic runs the very real risk of increasing cancer morbidity and mortality, perhaps much more so than covid- itself. the ukccmp has some limitations. our analysis is partly dependent on the uk national covid- testing policy, which is less permissive than that of other nations, , and also relies on rt-pcr, which has a well described false-negative result. the project might therefore under-report total covid- cases in patients with cancer, particularly those with no or mild symptoms and who do not require treatment at or present to healthcare centres. however, because we are in such close and frequent contact with our patients, and have a high index of suspicion on their behalf, we might also repeat testing and potentially overreport sars-cov- infection in these patients compared with in the general population. a selection bias might exist, in that those patients who were not on chemotherapy might have stopped chemotherapy because of a poor performance status, thus increasing the risk of death from covid- disease, and reducing our ability to assess the real risk of anticancer treatments in a population with a better performance status. however, we have attempted to address this limitation through multivariate analyses with age and comorbidity correction. finally, we have not commented on overall incidence of covid- positivity among cancer patients because we do not yet have secure numerators and denominators for that calculation. however, the total number of cases remains thankfully low, probably reflecting effective physical distancing measures for cancer patients in hospitals. despite these limitations, the ukccmp covers most of the uk cancer population, with universal access to cancer care and has been achieved through the rapid set up of a dedicated and coordinated emergency cancer network. we will continue to update the ukccmp register data weekly and share our outcomes with the oncological community. with greater numbers of patients analysed we will be able to answer more nuanced questions and guide further research. future studies should investigate whether the grading of covid- could be further refined to add granularity to our understanding of the heterogeneity between different tumour subtypes, to clarify the risks of specific anticancer treatments, to discoverer whether risks relating to more specific timing of anticancer treatments exist, and to gain a better understanding of the interaction between the host immune response and risk from covid- . some interesting questions exist surrounding the differential effects of various anticancer treatments on different components of the immune system (neutrophils, cytotoxic t cells, regulatory t cells, and macrophages) and how these factors will interplay with the risk of contracting sars-cov- infection, or with the possibility of severe covid- disease sequelae such as the cytokine storm. lywl, rk, and gm were involved in the study design; lywl, jbc, gm, rk, and ukccmp in the data collection; and lywl, jbc, ts, cdt, rk, and gm in the analysis, interpretation, writing of manuscript, and decision to submit. we declare no competing interests. patients with cancer appear more vulnerable to sars-cov- : a multi center study during the covid- outbreak cancer patients in sars-cov- infection: a nationwide analysis in china sars-cov- transmission in patients with cancer at a tertiary care hospital in wuhan, china covid- : global consequences for oncology caring for patients with cancer in the covid- era effect of the covid- pandemic on cancer treatment and research the uk coronavirus cancer monitoring project team. the uk coronavirus cancer monitoring project: protecting patients with cancer in the era of covid- research electronic data capture (redcap)--a metadata-driven methodology and workflow process for providing translational research informatics support characteristics of and important lessons from the coronavirus disease (covid- ) outbreak in china: summary of a report of cases from the chinese center for disease control and prevention castles (compute and storage for the life sciences): a collection of compute and storage resources for supporting research at the university of birmingham skeel's handbook of cancer therapy do patients with cancer have a poorer prognosis of covid- ? an experience in covid- : track coronavirus cases the variability of critical care bed numbers in europe covid- ) tests carried out in europe by country covid- )-the data comparative accuracy of oropharyngeal and nasopharyngeal swabs for diagnosis of covid- characteristics of those dying from covid- see online for appendix the authors thank the oncologists, acute physicians, and health-care staff working tirelessly on the frontlines of the covid- pandemic. we would like to thank david adams for giving support and approval for this project. this project was funded by the university of birmingham (data collection and grants to jpc, lywl, ukccmp, and gm) and the university of oxford (rk grants). lywl is supported by the national institute for health research oxford biomedical research. expanded ukccmp acknowledgments are given in the appendix. key: cord- -w u rcnv authors: crear-perry, joia; maybank, aletha; keeys, mia; mitchell, nia; godbolt, dawn title: moving towards anti-racist praxis in medicine date: - - journal: lancet doi: . /s - ( ) - sha: doc_id: cord_uid: w u rcnv nan moving towards anti-racist praxis in medicine "there must exist a paradigm, a practical model for social change that includes an understanding of ways to transform consciousness that are linked to efforts to transform structures." bell hooks, killing rage: ending racism the devastating effects of police brutality, maternal mortality, and covid- all have one commonality: they render disproportionate, deadly impact on marginalised and minoritised communities in the usa. after worldwide anti-racism protests in response to the murders of ahmaud arbery, george floyd, and breonna taylor, among others, several predominantly white health organisations denounced racism-specifically structural racism-and unprecedentedly declared "black lives matter". however, these declarations will require long-term commitments to equity and antiracism, specifically anti-black racism, within their organisations and within the health system and society at large. as ibram x kendi has written, "one either believes problems are rooted in groups of people, as a racist, or locates the roots of problems in power and policies, as an anti-racist". being anti-racist necessitates that institutions challenge structural racism and other intersecting oppressive systems-eg, ableism, classism, ethnocentrism, homophobia, sexism, transphobiaby shifting power-eg, funding and other critical resources, policies, processes, leadership, culture-so that marginalised and minoritised peoples can live healthily and thrive. structural racism-how societies foster racial discrimination through mutually reinforcing systems including the health-care system-violates the human rights of minoritised people. and structural racism is associated with adverse health outcomes-eg, poor health-care quality and access, increased risk of preterm birth and low birthweight, increased risk of cancer-and perpe tuates health inequities through mechanisms including racial segregation-ie, residential, school, workforce-immigration policy, and discriminatory incarceration. , practical steps to incorporate an antiracist lens are needed to remedy structural racism in medicine. for instance, the recognition of racism, not race, as a root cause or driver of health inequities and the establishment of systems that collect and disaggregate health outcome data by race and ethnicity as well as how racism may be operating (eg, discrimination, not meeting required standards of care) can be used as the basis for community-engaged quality improvement in health-care settings. , moreover, hardeman and colleagues recommend adopting universal single-payer health care, diversifying the health-care workforce, implementing medical training and competency that includes not only an awareness of racism but also how to address it, establishing performance standards related to structural racism and equity for health-care systems, and advocating for patients unjustly impacted by health inequities, even victims of police brutality. applying an anti-racist lens is not only a moral imperative in health care, it is also an efficient, equitable strategy. advances in digital health are increasingly shaping clinical practice in the usa and elsewhere and will continue to do so. it is negligent to produce inequitable health outcomes, even inadvertently so, including within algorithmic-based medical innovations, such as artificial intelligence, digital health, precision medicine, wellness genomics, and other innovations that are intended to empower individuals for better health. each is a doubleedged instrument if not forged in anti-racism. medical innovation offers great potential for refining clinical decision making to move towards health equity. yet algorithmic bias in medical innovation can be deadly, as shown, for example, where biased algorithms were used to allocate patients into "high risk care management" programmes, but instead systematically discriminated lev radin/pacific press/lightrocket/getty images against and endangered thousands of patients in the usa. medical innovations produced without an anti-racist, structural justice lens are harmful. medical innovations as equity instruments need to be designed by a meaningfully diverse cadre of engineers, social scientists, community and patient advocates, and healthcare providers. designers must test their algorithms in health-care settings that serve different patient populations-eg, younger, white, relatively healthier patients, and predominantly minoritised communities. as such innovation develops and increases its reach within health care by function and intentional design, so too must anti-racism in causal algorithmic pathways to achieve equity in effect. medical innovation must be an unbiased estimator that ever aspires toward equitable outcomes, albeit that unbiased innovation does not eviscerate bias. health system data need to be collected and used with an "algorithmic scrutiny", ensuring equity as a built-in process outcome in medical innovation tools. it is important that physicians who use innovations, and the designers who make them, are confident in their abilities to address legacies of structural racism within the clinical setting as it bears on health outcomes. this is arguably a non-negotiable skill and should be a tenet of st-century medicine. the usa is shifting demographically, epidemiologically, and in terms of opportunities to which some are exposed and others are not. projections are that the nation is approaching a shortage of health professionals, particularly among minoritised physicians, for whom the trajectory into medicine is often rife with barriers. health care in the usa is becoming more expensive to manage as use of clinical services increases. research shows that about - % of health outcomes are determined by social, structural, and root cause factors outside of clinical settings. in the spirit of bell hooks, there must be a paradigm shift such that health-care providers are trained to legitimate and incorporate anti-racist models into their practice which recognise these structural determinants of health. this level of consciousness-raising must start no later than premedical education, continuing throughout ongoing licensure, accountability, and accreditation processes. , a priority for medical education must be building an anti-racist, structural competency skill set. this involves training at the interdisciplinary nexus of medicine and the disciplines that highlight how deeply entrenched social dynamics of power, opportunity, and wellness are delineated along racial lines. anti-racist, structural competency training needs to start from pre-medicine pathways and will be essential for reimagining justice in the medical workforce pipeline. undergraduate students who are trained in anti-racist, structural competency have increased capacities for understanding root structural causes of disease. it is not enough for burgeoning clinicians to know the body, inside and out. they must also know the historical body of work about enduring medical practices based on exploitation and/or exclusion and long-standing medical policies that render certain populations sicker than others; such knowledge informs their structural competency skills development. for the same reason, new and established physicians must undergo consistent, continuing medical education that includes anti-racist, structural competency training. such level training makes for better doctors who are well prepared to address the needs of a changing nation and a changing world. this is what medical education justice in practice should look like. an anti-racist, structural justice approach is the crucial narrative frame that health-care practitioners need so that they can dismantle, reimagine, and redesign health care in a changing society. unequivocally, health is a right and anti-racism is its right-bearer. we declare no competing interests. the views expressed in this comment are those of the authors and do not necessarily represent the policy of the american medical association. killing rage: ending racism stolen breaths how to be an antiracist structural racism and health inequalities in the usa: evidence and interventions structural racism and health inequities race isn't a risk factor in maternal health on racism: a new standard for publishing on racial health inequities why does the shift from "personalized medicine" to "precision health" and "wellness genomics" matter? dissecting racial bias in an algorithm used to manage the health of populations race after technology: abolitionist tools for the new jim code artificial intelligence in health care: the hope, the hype, the promise, the peril can ai help reduce disparities in general medicine and mental health care? new findings confirm predictions on physician shortage physicians of color are far too rare: study highlights one potential reason national health expenditures highlights county health rankings: relationships between determinant factors and health outcomes structural racism and supporting black lives-the role of health professionals developing and evaluating an innovative structural competency curriculum for pre-health students responding to the covid- key: cord- -fe ixqdv authors: pareek, manish; bangash, mansoor n; pareek, nilesh; pan, daniel; sze, shirley; minhas, jatinder s; hanif, wasim; khunti, kamlesh title: ethnicity and covid- : an urgent public health research priority date: - - journal: lancet doi: . /s - ( ) - sha: doc_id: cord_uid: fe ixqdv nan as the coronavirus disease (covid- ) pandemic continues advancing globally, reporting of clinical outcomes and risk factors for intensive care unit admission and mortality are emerging. early chinese and italian reports associated increasing age, male sex, smoking, and cardiometabolic comorbidity with adverse outcomes. striking differences between chinese and italian mortality indicate ethnicity might affect disease outcome, but there is little to no data to support or refute this. ethnicity is a complex entity composed of genetic make-up, social constructs, cultural identity, and behavioural patterns. ethnic classification systems have limitations but have been used to explore genetic and other population differences. individuals from different ethnic backgrounds vary in behaviours, comorbidities, immune profiles, and risk of infection, as exemplified by the increased morbidity and mortality in black and minority ethnic (bme) communities in previous pandemics. as covid- spreads to areas with large cosmopolitan populations, understanding how ethnicity affects covid- outcomes is essential. we therefore reviewed published papers and national surveillance reports on notifications and outcomes of covid- to ascertain ethnicity data reporting patterns, associations, and outcomes. only two ( %) of publications reported ethnicity disaggregated data (both were case series without outcomes specific to ethnicity). we found that none of the ten highest covid- case-notifying countries reported data related to ethnicity; uk mortality reporting, for example, does not require information on ethnicity. this omission seems stark given the disproportionate number of deaths among health-care workers from bme backgrounds. , recent uk data from intensive care units indicate that over a third of patients are from bme backgrounds. given previous pandemic experience, it is imperative that policy makers urgently ensure ethnicity forms part of a minimum dataset. more importantly, ethnicity-disaggregated data must occur to permit identification of potential outcome risk factors through adjustment for recognised confounders. bme communities might be at increased risk of acquisition, disease severity, and poor outcomes in covid- for several reasons (figure). specific ethnic groups, such as south asians, have higher rates of some comorbidities, such as diabetes, hypertension, and cardiovascular diseases, which have been associated with severe disease and mortality in covid- . ethnicity could interplay with virus spread through cultural, behavioural, and societal differences including lower socioeconomic status, health-seeking behaviour, and intergenerational cohabitation. disentangling the relative importance of these factors requires both prospective studies, focusing on quantifying absolute risks and outcomes, and qualitative studies of behaviours characteristics of and important lessons from the coronavirus disease (covid- ) outbreak in china: summary of a report of cases from the chinese center for disease control and prevention race'' and ''ethnicity'' in biomedical research: how do scientists construct and explain differences in health? ethnicity, deprivation and mortality due to pandemic influenza a(h n ) in england during the / pandemic and the first post-pandemic season uk government urged to investigate coronavirus deaths of bame doctors coronavirus cases to be tracked by ethnicity intensive care national audit and research centre. icnarc covid- study case mix programme. london: intensive care national audit and research centre the relationship between metabolic risk factors and incident cardiovascular disease in europeans, south asians, and african caribbeans key: cord- -ym uiqy authors: strathdee, steffanie a; davies, sally c; marcelin, jasmine r title: confronting antimicrobial resistance beyond the covid- pandemic and the us election date: - - journal: lancet doi: . /s - ( ) - sha: doc_id: cord_uid: ym uiqy nan globally, the usa has recorded the highest number of covid- cases and deaths, and still needs to simultaneously respond to another looming potential pandemic. the rise in multidrug-resistant bacterial infections that are undetected, undiagnosed, and increasingly untreatable threatens the health of people in the usa and globally. in and beyond, we cannot afford to ignore antimicrobial resistance (amr). bacterial infections unsuccessfully treated due to amr claim at least lives per year worldwide and are projected to be associated with the deaths of million people per year by , at a cost of us$ trillion to the global economy through loss of productivity. in the usa, more than · million multidrugresistant bacterial infections occur annually, causing at least deaths and $ billion in health-care expenditures. covid- is exacerbating amr (panel). data from five countries suggest that · % of covid- diagnoses are associated with bacterial infections ( · % diagnosed concurrently and · % post-covid- ), with higher prevalence in patients who require intensive critical care. however, a us multicentre study reported that % of covid- patients received antibiotics even when not clinically indicated, which can promote amr. amr might worsen under covid- due to the overuse of antibiotics in humans, continuing misuse in agriculture, and the dearth of antimicrobials in the development pipeline. competing global priorities are reducing amr eradication activities, including measures for multidrug-resistant tuberculosis. in , the white house released a comprehensive action plan for the usa proposing milestones to curtail antibiotic misuse and accelerate new antimicrobials and vaccines. steps taken to address these targets have been uneven and, at times, contradictory. in , the us food and drug administration banned use of antibiotics as growth promoters in livestock-a welcome move, following several other countries. yet that same year, the us department of agriculture (usda) rejected who's guidance to limit antibiotic use in livestock feed and maintained that appropriate use includes "treating, controlling and preventing" disease under veterinary supervision. the us federal government also proposed unprecedented nationwide budget cuts to hospital-based amr programmes. in , the us environmental protection agency condoned expansion of medically important antibiotics such as streptomycin and oxytetracycline as pesticides to maximise crop yields, the us approach to amr has been mixed and, looking ahead, needs to move beyond priority setting to concrete action. curtailing the spread of amr is possible. laudable progress is being made to mitigate amr worldwide through regulations and policies. in january, , the indian government introduced draft legislation to place limits on antibiotic residues released into the environment at pharmaceutical manufacturing sites. in norway, the implementation of a vaccine to prevent furunculosis at salmon farms reduced antibiotic use by · %, while chile's salmon industry pledged to reduce its antibiotic use by % by . in the uk, human antibiotic use decreased by · % between and , and the uk government launched the world's first experiment to pay for antibiotics by subscription rather than per pill, which could incentivise market entry of two new antibiotics by . the speed at which new antibiotic resistance genes emerge and spread globally requires that the usa and other countries take immediate action. the recommendations of the un interagency coordination group on amr provide a roadmap by taking a one health approach to intervene on amr at the interface between humans, animals, and the environment. the us federal government could accelerate progress on its amr national action plan in several ways: first, by permanently ceasing use of medically important antibiotics in agribusiness; second, by supporting antibiotic stewardship programmes; third, by encouraging the development of new antibiotics through bipartisan initiatives such as the developing an innovative strategy for antimicrobial resistant microorganisms (disarm) act, , which some legislators have proposed as part of a covid- relief bill, as well as the pioneering antimicrobial subscriptions to end up surging resistance (pasteur) act, which incorporates an antibiotic subscription programme similar to that in the uk; and, finally, by simultaneously investing in innovation to identify and evaluate other anti-infectives. as the covid- pandemic has shown, efforts are needed to strengthen amr surveillance and health-care infrastructure and create policies to ensure global equitable access to antimicrobials, diagnostics, and vaccines. no matter the outcome of the us election, the path forward is not only one that builds back from the covid- pandemic, but also addresses amr in the context of pandemic preparedness (panel). a coordinated one health response is needed, with action from multisectoral and cross-sectoral stakeholders in human and veterinary medicine, agriculture, finance, environment, industry, and consumers, to address what is as much an environmental issue as an economic one. , , , the usa cannot do this alone, but should be an active participant in the global system to accelerate action and advance a shared global vision on tackling amr. through leadership and accountability, national governments can be greater than the sum of their parts. finally, to accelerate and sustain progress against amr, the usa should support the multilateral global architecture needed to confront amr, including who, the un food and agriculture organization, and the world organisation for animal health. failing to confront amr will undermine decades of advances in medicine and public health and progress towards the un sustainable development goals. , , , the covid- pandemic is a wake-up call that global collaboration is the most effective way to tackle global health threats. sas no time to wait: securing the future from drug-resistant infections potential impact of the covid- pandemic on hiv, tuberculosis, and malaria in low-income and middle-income countries: a modelling study us centers for disease control and prevention. national action plan for combating antibiotic-resistant bacteria usda chief scientist statement on who guidelines on antibiotics final registration decision for the new use of the active ingredient oxytetracycline hydrochloride on citrus crop group - presidential advisory council on combating antibiotic-resistant bacteria. priorities for the national action plan on combating antibiotic-resistant bacteria vaccinating salmon: how norway avoids antibiotics in fish farming tackling antimicrobial resistance bad bugs, no drugs - : progress, challenges, and call to action key: cord- -btalafo authors: carlet, jean; payen, didier; opal, steven m title: steroids for sepsis and ards: this eternal controversy remains with covid- date: - - journal: lancet doi: . /s - ( ) - sha: doc_id: cord_uid: btalafo nan ) covid- cases have a very complex presentation. they can mimic sepsis and septic shock, with moderate lung abnormalities. others mimic ards, with various abnormalities in gas exchange, and with a large scale of severity. many patients have both severe infections symptoms with organ failure and ards. of note, those two syndromes are not the same. a particularity is that the symptoms of severity of or ards usually appear around one week after the onset of the disease, which is rather unusual in other severe infections ( )). the term "cytokines storm", which is a naïve concept, is often used in the literature, and by the public. in the last decades, many double blind rcts with various anti-cytokines failed to decrease mortality of those two syndromes (anti-il , anti-tnf alpha, il ra). therefore, we do not think that it would be wise to try again those drugs in covid- ) we used in the above paragraph the term "sepsis", just because it is a well-, known severe syndrome due to infectious agents. many "sepsologists" push very hard and without any doubt to include covid- severe cases in the sepsis syndrome. we disagree with this position. covid- induces an acute activation of inflammatory mediated, but with some differences with other types of severe infections. for example, the activation of the coagulation system is very important, with arterial and venous thrombosis body-wide, and not only in the lung. moreover, cytokines levels are far lower than in "sepsis", for the same level of severity. the long delay between the onset of the disease and occurrence of acute symptoms of severity is another particularity. ) some authors pointed out that the past negative rcts might be due, in most part, to their huge heterogeneity and the lack of inflammatory or anti-inflammatory markers allowing to select appropriate and "a la carte" drugs. however, although covid - is due to a single viral pathogen, the methodology of the various studies is still very heterogenous, mixing, particularly in the recovery trial, and the who metaanalysis, very different patterns and patients. in addition, secondary infections with nosocomial pathogens are very frequent in severe covid- disease, making the prognosis even more complex to evaluate. ) a large ( patients), recent, phase ii b double-blind rct, showed no effect of cs in severe covid- patients. although this study was not a phase iii one, it's double blind design and the relatively high number of patients makes it a key information ) we are surprised to read that on september th, the guidelines of the infectious diseases society of america (idsa) recommend the use of cs in severe covid- cases, without any doubt or comments on the methodology of the various studies ( ). the idsa and who recommendation will certainly not help to convince ethical committees that additional new rcts are needed. this kind of behavior would be very unfortunate. steroid controversy in sepsis and septic shock: a meta-analysis r lefering and ea neugebauer adarsh bhimraj infectious diseases society of america guidelines on the treatment and management of patients with covid- key: cord- - dwyv vk authors: gellin, bruce title: why vaccine rumours stick—and getting them unstuck date: - - journal: lancet doi: . /s - ( ) - sha: doc_id: cord_uid: dwyv vk unknown why vaccine rumours stick-and getting them unstuck infectious diseases have long shaped human history, from the plague of athens ( - bce) that killed around a third of the athenian population, the black death in the th century that killed about - % of all europeans, and the - influenza pandemic that took the lives of at least million people globally. in the months since the emergence of sars-cov- , more than people worldwide have died from covid- as of july , . no sector of society has been spared and the full economic and societal reckoning will be grim by any account. economists estimate global economic growth could drop by - % and global trade could decline by - % in . traditional public health measures have been used to mitigate the spread of the virus and com munity-wide lockdowns have been enforced in many areas. sustaining these measures has been challenging. we will be living with the pandemic's social and economic disruption for some time. as only population-wide immunity will end the pandemic, there has been an unprecedented effort to rapidly develop safe and effective vaccines that can be deployed globally. who is currently tracking more than vaccine candidates, with of them in clinical development in july, . while there is more to public health than vaccines, the health of the public continues to be shaped by vaccines and vaccina tion programmes. this year gavi, the vaccine alliance, an organisation founded on the principle of equitable access to life-saving vaccines by addressing the supply side of vaccination, celebrated its th anniversary. gavi has helped to vaccinate over million children in low-income countries, preventing more than million deaths. beyond their obvious benefits to health, vaccination programmes have indirect economic and societal benefits, including on cognitive development, educational attainment, labour productivity, income, savings, investment, and fertility. because the full impact of vaccines requires widespread public accep tance to achieve population-level immunity, from their earliest days, vaccination policies have been subject to political and ideological debate, pitting individual rights against public health. the origins of vaccine hesitancyrecognised by who in as one of the top ten threats to global healthreach back to compulsory smallpox vaccination laws and the thread of this long history continues today. putting all of this in cultural and scientific context, heidi larson's compelling new book stuck: how vaccine rumors start-and why they don't go away looks at the dynamics of the evolving debate through the lens of an anthropol ogist who has been studying vaccine confidence for decades. largely written before covid- surfaced, this book is timely as the world has its eyes longingly set on a covid- vaccine. as larson notes, "the quality of life that most of us enjoy today is dependent on vaccines. in many ways it is one of the biggest worldwide social experiments in collectivism and cooperation in modern times. the challenge is that it depends on a social contract whose fabric is eroding in a broader context of anti-globalization, nationalism, and populism. vaccines can, as they have in the past, serve as a form of soft diplomacy to keep at least a fundamental level of global cooperation alive and well." the foundation that underpins vaccination acceptance is trust. trust in the processes, practices, and policies of vaccine development, licensure, and manufacturing; in the policy makers who set vaccine recommendations; and in the health-care system-the doctors, nurses, and community immunisers who administer vaccines as part of routine care and during mass vaccination campaigns. without understanding and addressing trust, efforts to improve vaccine confidence will be a steep climb. that will certainly be the case when covid- vaccines arrive, especially given the many new vaccine technologies that are being tested and the speed at which they are being developed. larson's book draws from a vast array of findings from her vaccine confidence project that has established an information surveil lance system for early detection of public concerns around vaccines. from this large body of work, larson explores several important themes in stuck: rumour, dignity, distrust, risk, emotional contagion, choice, the power of beliefs over facts, and the power of stories over data. her analysis of these issues covers a broad range of events, settings, and countries, including ebola virus vaccine trials in west africa, routine mmr vaccination in the somali community in minnesota, usa, human papillomavirus vaccination in japan and columbia, dengue vaccine introduction in the philippines, and the ramifications of a cia-inspired sham hepatitis vaccination campaign in pakistan as part of the hunt for osama bin laden. the calculus of vaccination decision making is the balance of benefit and risk coupled with uncertainty and larson argues that it is these same elements that breed rumours. because no vaccine-and no medical productis risk free there will always be fertile ground for rumours. the challenge, larson stresses, is "managing the rumours and mitigating purposeful "…there is a need to address the complex challenges related to vaccine hesitancy that larson's book illuminates." www.thelancet.com vol august , scare tactics while listening for important clues that need further investigation". these are not moles to be whacked, but signals that call for a deeper understanding not only about why they came about but why they stick. only by doing this are we likely to get unstuck. despite tremendous gains that have resulted from making vaccines more accessible and affordable and the delivery programmes that make them available, as larson highlights in this book there has been stagnation of vaccine uptake. although vaccination remains the social norm in all countries, this plateau in uptake together with outbreaks of vaccine-preventable diseases has led to a sharper focus on the quality of vaccination services and on the last inch of the last mile: the decision to accept or decline a vaccine that is available and being offered. in the pre-covid- era, measles was a litmus test. reported cases of measles rose globally by % in the first months of compared with the same period in , with outbreaks in all regions. in the future, the covid- vaccines now in development will be our case study. although many other measures-eg, surveillance, testing, contact tracing, isolation, quarantine, physical distancing, handwashing, provision of ppe, investments in resilient health and social care systems and research, and socioeconomic support, among others-are key elements in the covid- response, a longer-term goal is the possibility of population-level immunity from a vaccine. thus, it is little surprise that the race to develop covid- vaccines is running at full steam. yet, even before any of the many vaccine candidates have worked their way through the rigorous clinical testing gauntlet to show safety and efficacy, expectations for a covid- vaccine are unrealistically high. portrayed as the saviour from our current plight, covid- vaccines are spoken about in some quarters as if they will be % effective and % safe-bars that have yet to be cleared by a vaccine or medical product. if we don't adequately reset such high expectations, they might further fuel the narrative that questions the value of vaccines more broadly. as if that uphill climb wasn't steep enough there is already a global chatter-the rumours, distrust, and wildfires-surrounding the virus and vaccines. these elements are contributing to what who director-general tedros adhanom ghebreyesus, has characterised as an "infodemic"the fake news that "spreads faster and more easily than this virus", which intermingles misinformation and disinformation about covid- and vaccines. the fact-checkers have taken on a sisyphean challenge as they strive to ensure the integrity of the world's information ecosystem. but larson asks that we do more because it isn't only about getting the facts right. as she frames the core problem: "we don't have a misinformation problem, we have a relationship problem". the misinformation can be deleted, but the underlying distrust that has caused it and allowed it to stick remains. rather than countering and dismissing rumours, larson encourages the health community and other stakeholders to listen to these rumours and recognise what people are saying. these analyses can reveal deeper issues such as the feeling of being disenfranchised and not being heard. it is from these insights, she argues, "lie the cues to building new and more trusting relationships". intent may not be a predictor of behaviour, but we shouldn't assume that when covid- vaccines are developed they will be welcomed by all. a us poll in may, , found that only half of the people surveyed said they will take a covid- vaccine and many are unsure. in a survey this spring from larson's vaccine confidence project, a fifth of swiss respondents and % of those in france would refuse a covid- vaccine. a more recent yougov poll in the uk found that nearly one in six british adults said they would either probably or definitely turn down a covid- vaccine and another % were not sure. we will not only need to monitor this sentiment over time but will need a deeper understanding of the implications of the social media chatter, social networks, and social norms and their impact on vaccination decision making. there is also reason for hope. last year the wellcome global monitor survey of more than people from over countries found that % trust scientists, and % and %, respectively, agree that vaccines are safe and effective. but hope is not a strategy and there is a need to address the complex challenges related to vaccine hesitancy that larson's book illuminates. she captures in a single sentence the crux of the issue: "today we are in the paradoxical situation of having better vaccine science and more vaccine safety regulations and processes than ever before, but a doubting public." to avoid getting stuck before covid- vaccines become available, concerted efforts by health and other sectors, governments, and civil society will be needed to explain what we know and don't know about the vaccines that have been approved for widespread use, their benefits and risks, and the value to individuals and communities that make the case for vaccination. it will be crucial that such efforts listen to, involve, and engage all communities at the local level. as the covid- pandemic sweeps the world, leaving disease, death, stigma, suspicion, and fear in its wake, covid- vaccine development is running a marathon at a sprinter's pace. at this inflection point, we should take note of larson's warning and hope: "we are yet to see how we will emerge from this crisis. perhaps we have been shaken enough to get unstuck from our old ways and be open to a new future." sabin vaccine institute, washington, dc , usa bruce.gellin@sabin.org global immunization at the sabin vaccine institute. further reading congressional research service. global economic effects of covid- draft landscape of covid- candidate vaccines moving beyond traditional valuation of vaccination: needs and opportunities infodemic" of misinformation and cybercrime in covid- crisis expectations for a covid- vaccine nearly one in six britons would refuse covid- vaccinesurvey. the guardian wellcome global monitor meeting the challenge of vaccination hesitancy: a report of the sabin-aspen vaccine science and policy group on immunity: an inoculation how behavior spreads: the science of complex contagions key: cord- -gmasuqov authors: king, tania; hewitt, belinda; crammond, bradley; sutherland, georgina; maheen, humaira; kavanagh, anne title: reordering gender systems: can covid- lead to improved gender equality and health? date: - - journal: lancet doi: . /s - ( ) - sha: doc_id: cord_uid: gmasuqov nan covid- has delivered a shock to existing gender systems that could recalibrate gender roles, with beneficial effects on population health. the economic arrangements, policy frameworks, and market forces that determine the distribution of paid and unpaid labour across society are powerful structural determinants of health. the way that paid and unpaid labour is inequitably divided between men and women is central to the perpetuation of gender inequalities across the globe, and the ways that such divisions can be shifted or disrupted offer critical opportunities to modify the gender-differentiated effects of covid- on health. occupational gender segregation generates particular vulnerabilities for women in relation to covid- . globally, two-thirds of the health and social care workforce are women. this includes occupations that are often undervalued and poorly paid, despite being essential in the pandemic response, such as aged-care and disabilitysupport workers. being at the front line of the pandemic response places these women at risk of infection with severe acute respiratory syndrome coronavirus , as well as physical and psychological pressures. less immediately tangible, but potentially more damaging, are the effects of economic contraction and job loss related to the covid- pandemic. evidence suggests there are likely to be more covid- -related job losses for women than men. , this differential exposure to job loss arises because women are more likely to be employed in sectors at high risk of impacts from covid- , and also because women are more likely to be employed part time or in temporary or casual arrangements. such employment arrangements are often precarious with fewer legal protections, meaning that women are particularly vulnerable to job loss during this pandemic, placing them at increased risk of the adverse health outcomes associated with unemployment. globally, women do more unpaid work than men. much of this is unpaid care work, of which more than % is done by women. unpaid care work contributes substantially to global economies, and is estimated to be equivalent to % of the global gross domestic product. the unequal distribution of unpaid care work serves as a barrier to female labour force participation and is one way that gender inequalities are reinforced. , the covid- pandemic exacerbates this in two main ways. first, women's caring for sick family members reduces their capacity to be in paid employment, and places them at increased risk of infection. second, confinement at home due to work at home requirements and school closures may compound the unequal division of domestic tasks. intensifying this situation, responsibility for schooling children at home may be disproportionately borne by women. gender-differentiated exposure to work and household stressors as they strive to fulfil paid and unpaid responsibilities contributes to poor mental health in women, including depression. this inequitable division of paid and unpaid labour aligns with pervasive and entrenched gender norms that define women as caregivers-nurturing, self-sacrificing, and caring-and men as breadwinners. gender norms also define who and what is valued, with the consistent undervaluing of many female-dominated occupations. there is a risk that these female-caregiver and malebreadwinner norms could intensify the inequitable division and perceived value of paid and unpaid labour during the pandemic and future recovery. in previous economic crises, a retreat from gender egalitarian beliefs has occurred, with increasing support for the notion that men are more entitled to jobs than women. how, then, can the covid- pandemic be disruptive to the gender system? the gender norms and beliefs that help shape our gender systems are not immutable. they can be transformed. proactive policies related to exit from the covid- pandemic should aim to redistribute a proportion of women's unpaid caring responsibilities to support female labour force participation. to do this, governmental and organisational policies must increase the opportunities for both women and men to combine paid employment and unpaid caring; policies that only target women may reinforce gender inequalities. such policies should be supported by the provision of high-quality and affordable child care and elder care. , as covid- shifts the ways in which we work, workplaces must enable women and men to work from home and share caring responsibilities. workplace practices, policies, and culture regarding leave and flexible work arrangements are an important influence on fathers' abilities to combine work and caring responsibilities, underscoring the importance of gender-neutral approaches to leave and flexible working. normalising men's sharing of caring and household responsibilities is also essential for the redistribution of unpaid care. initiatives should include non-transferable parental leave entitlements with income replacement for both fathers and mothers, as is available in some northern european countries. in norway, of the weeks of fully compensated parental leave that parents are entitled to, a proportion of nontransferable leave is specifically assigned to each parent. this use-it or lose-it approach has led to a substantial upswing in the number of fathers taking parental leave. normative acceptance of this at the individual and workplace levels is reinforced and achieved through the non-transferable conditions of this leave. finally, the underfunded and neglected domain of care work has been exposed by the covid- pandemic, highlighting the importance of recognising the value of paid and unpaid care provision. redressing the underpayment and poor employment conditions of many female-dominated occupations, particularly those that provide paid care including health care, is vital. accurate quantification of unpaid care should be a priority, and estimates should be incorporated into macroeconomic analyses to enable the assessment of gender-differentiated policy effects. for unpaid carers, financial support and pension systems that acknowledge unpaid care provision could offer protection from economic disadvantage. the covid- pandemic has temporarily reshaped our domestic and working lives and could sow the seeds for change to advance gender equality, and deliver long-term health benefits. effective policies that target normative and structural drivers of gender inequality could parlay the upheaval caused by covid- into enduring changes to gender systems that will ultimately benefit the health and wellbeing of all. we declare no competing interests. gender inequality and restrictive gender norms: framing the challenges to health the impact of covid- on gender equality: working paper gender equity in the health workforce: analysis of countries. geneva: world health organization international labour office. care work and care jobs: for the future of decent work international labour organization. policy brief. the covid- response: getting gender equality right for a better future for women at work. geneva: international labour organization international labour organization. world employment and social outlook: trends . geneva: international labour organization the health consequences of unemployment: the evidence gender inequality in work-family balance mitigating the wider health effects of covid- pandemic response gendered depression: vulnerability or exposure to work and family stressors? gender norms and the economy: insights from social research occupational sex-segregation, specialized human capital and wages: evidence from britain gender, crisis and the welfare state: female labor market outcomes across oecd countries improving health with programmatic, legal, and policy approaches to reduce gender inequality and change restrictive gender norms regulating for gender equality: a policy framework to support the universal caregiver vision making use of work-family balance entitlements: how to support fathers with combining employment and caregiving who cares? assessing generosity and gender equality in parental leave policy designs in countries workplace support of fathers' parental leave use in norway towards an integrated approach for the analysis of gender equity in policies supporting paid work and care responsibilities key: cord- -bzeqs oh authors: wang, yeming; zhang, dingyu; du, guanhua; du, ronghui; zhao, jianping; jin, yang; fu, shouzhi; gao, ling; cheng, zhenshun; lu, qiaofa; hu, yi; luo, guangwei; wang, ke; lu, yang; li, huadong; wang, shuzhen; ruan, shunan; yang, chengqing; mei, chunlin; wang, yi; ding, dan; wu, feng; tang, xin; ye, xianzhi; ye, yingchun; liu, bing; yang, jie; yin, wen; wang, aili; fan, guohui; zhou, fei; liu, zhibo; gu, xiaoying; xu, jiuyang; shang, lianhan; zhang, yi; cao, lianjun; guo, tingting; wan, yan; qin, hong; jiang, yushen; jaki, thomas; hayden, frederick g; horby, peter w; cao, bin; wang, chen title: remdesivir in adults with severe covid- : a randomised, double-blind, placebo-controlled, multicentre trial date: - - journal: lancet doi: . /s - ( ) - sha: doc_id: cord_uid: bzeqs oh background: no specific antiviral drug has been proven effective for treatment of patients with severe coronavirus disease (covid- ). remdesivir (gs- ), a nucleoside analogue prodrug, has inhibitory effects on pathogenic animal and human coronaviruses, including severe acute respiratory syndrome coronavirus (sars-cov- ) in vitro, and inhibits middle east respiratory syndrome coronavirus, sars-cov- , and sars-cov- replication in animal models. methods: we did a randomised, double-blind, placebo-controlled, multicentre trial at ten hospitals in hubei, china. eligible patients were adults (aged ≥ years) admitted to hospital with laboratory-confirmed sars-cov- infection, with an interval from symptom onset to enrolment of days or less, oxygen saturation of % or less on room air or a ratio of arterial oxygen partial pressure to fractional inspired oxygen of mm hg or less, and radiologically confirmed pneumonia. patients were randomly assigned in a : ratio to intravenous remdesivir ( mg on day followed by mg on days – in single daily infusions) or the same volume of placebo infusions for days. patients were permitted concomitant use of lopinavir–ritonavir, interferons, and corticosteroids. the primary endpoint was time to clinical improvement up to day , defined as the time (in days) from randomisation to the point of a decline of two levels on a six-point ordinal scale of clinical status (from =discharged to =death) or discharged alive from hospital, whichever came first. primary analysis was done in the intention-to-treat (itt) population and safety analysis was done in all patients who started their assigned treatment. this trial is registered with clinicaltrials.gov, nct . findings: between feb , , and march , , patients were enrolled and randomly assigned to a treatment group ( to remdesivir and to placebo); one patient in the placebo group who withdrew after randomisation was not included in the itt population. remdesivir use was not associated with a difference in time to clinical improvement (hazard ratio · [ % ci · – · ]). although not statistically significant, patients receiving remdesivir had a numerically faster time to clinical improvement than those receiving placebo among patients with symptom duration of days or less (hazard ratio · [ · – · ]). adverse events were reported in ( %) of remdesivir recipients versus ( %) of placebo recipients. remdesivir was stopped early because of adverse events in ( %) patients versus four ( %) patients who stopped placebo early. interpretation: in this study of adult patients admitted to hospital for severe covid- , remdesivir was not associated with statistically significant clinical benefits. however, the numerical reduction in time to clinical improvement in those treated earlier requires confirmation in larger studies. funding: chinese academy of medical sciences emergency project of covid- , national key research and development program of china, the beijing science and technology project. the ongoing pandemic of severe acute respiratory syndrome coronavirus (sars-cov- ) infections has led to more than cases and deaths globally as of april , . although most infections are selflimited, about % of infected adults develop severe pneumonia that requires treatment with supplemental oxygen and an additional % progress to critical illness with hypoxaemic respiratory failure, acute respiratory distress syndrome, and multiorgan failure that necessitates ventilatory support, often for several weeks. [ ] [ ] [ ] at least half of patients with coronavirus disease (covid- ) requiring invasive mechanical ventilation have died in hospital, , and the associated burden on health-care systems, especially intensive care units, has been overwhelming in several affected countries. although several approved drugs and investigational agents have shown antiviral activity against sars-cov- in vitro, , at present there are no antiviral therapies of proven effectiveness in treating severely ill patients with a multicentre, open-label, randomised controlled trial (rct) of hydroxychloroquine involving adults admitted to hospital for covid- reported no significant effect of the drug on accelerating viral clearance. an rct enrolling patients within days of symptom onset found that favipiravir was superior to arbidol in terms of the clinical recovery rate at day in patients with mild illness ( [ %] of with arbidol vs [ %] of with favipiravir), but not in those with critical illness ( vs [ %]). in severe illness, one uncontrolled study of five patients given convalescent plasma suggested a possible benefit, although the patients already had detectable anti-sars-cov- neutralising antibodies before receipt of the plasma. an open-label rct of oral lopinavir-ritonavir found no significant effect on the primary outcome measure of time to clinical improve ment and no evidence of reduction in viral rna titres compared to control. however, per-protocol analyses suggested possible reductions in time to clinical improvement (difference of day), particularly in those treated within days of symptom onset. further studies of lopinavir-ritonavir and other drugs are ongoing. remdesivir (also gs- ) is a monophosphoramidate prodrug of an adenosine analogue that has a broad antiviral spectrum including filoviruses, paramyxoviruses, pneumoviruses, and coro na viruses. , in vitro, remdesivir inhibits all human and animal coronaviruses tested to date, including sars-cov- , [ ] [ ] [ ] and has shown antiviral and clinical effects in animal models of sars-cov- and middle east respiratory syndrome (mers)-cov infections. , , in a lethal murine model of mers, remdesivir was superior to a regimen of combined interferon beta and lopinavir-ritonavir. remdesivir is a potent inhi bitor of sars-cov- replication in human nasal and bron chial airway epithelial cells. in a non-lethal rhesus macaque model of sars-cov- infection, early remdesivir admin istration was shown to exert significant antiviral and clinical effects (reduced pulmonary infiltrates and virus titres in bronchoalveolar lavages vs vehicle only). intra venous remdesivir was studied for treatment of ebola virus disease, in which it was adequately tolerated but less effective than several monoclonal antibody therapeutics, and has been used on the basis of individual compas sionate use over the past several months in patients with covid- in some countries. case studies have reported benefit in severely ill patients with covid- . , , however, the clinical and antiviral efficacy of remdesivir in covid- remains to be established. here, we report the results of a placebocontrolled randomised trial of remdesivir in patients with severe covid- . this was an investigator-initiated, individually randomised, placebo-controlled, double-blind trial to assess the effectiveness and safety of intravenous remdesivir in adults (aged ≥ years) admitted to hospital with severe covid- . the trial was done at ten hospitals in wuhan, hubei, china). ethical approval was obtained from the institutional review boards of each participating hospital. written informed consent was obtained from all patients, or their legal representative if they were unable to provide consent. the trial was done in accor dance with the principles of the declaration of helsinki and the international conference on harmonization-good clinical practice guidelines. the protocol is avail able online. eligible patients were men and non-pregnant women with covid- who were aged at least years and were rt-pcr positive for sars-cov- , had pneumonia evidence before this study we searched pubmed, up to april , , for published clinical trials assessing the effect of remdesivir among patients with laboratory-confirmed coronavirus disease . the search terms used were ("covid- " or " -ncov" or "sars-cov- ") and "remdesivir" and ("clinical trial" or "randomized controlled trial"). we identified no published clinical trials of the effect of remdesivir in patients with covid- . our study is the first randomised, double-blind, placebocontrolled clinical trial assessing the effect of intravenous remdesivir in adults admitted to hospital with severe covid- . the study was terminated before attaining the prespecified sample size. in the intention-to-treat population, the primary endpoint of time to clinical improvement was not significantly different between groups, but was numerically shorter in the remdesivir group than the control group, particularly in those treated within days of symptom onset. the duration of invasive mechanical ventilation, although also not significantly different between groups, was numerically shorter in remdesivir recipients than placebo recipients. no statistically significant benefits were observed for remdesivir treatment beyond those of standard of care treatment. our trial did not attain the predetermined sample size because the outbreak of covid- was brought under control in china. future studies of remdesivir, including earlier treatment in patients with covid- and higher-dose regimens or in combination with other antivirals or sars-cov- neutralising antibodies in those with severe covid- are needed to better understand its potential effectiveness. for the trial protocol see https://www.researchsquare. com/article/rs- /v confirmed by chest imaging, had oxygen saturation of % or lower on room air or a ratio of arterial oxygen partial pressure to fractional inspired oxygen of mm hg or less, and were within days of symptom onset. eligible patients of child-bearing age (men and women) agreed to take effective contraceptive measures (including hormonal contraception, barrier methods, or abstinence) during the study period and for at least days after the last study drug administration. exclusion criteria included pregnancy or breast feeding; hepatic cirrhosis; alanine aminotransferase or aspartate aminotransferase more than five times the upper limit of normal; known severe renal impairment (estimated glomerular filtration rate < ml/min per · m²) or receipt of continuous renal replacement therapy, haemodialysis, or peritoneal dialysis; possibility of transfer to a non-study hospital within h; and enrolment into an investigational treatment study for covid- in the days before screening. the use of other treatments, including lopinavir-ritonavir, was permitted. eligible patients were randomly assigned ( : ) to either the remdesivir group or the placebo group. randomisation was stratified according to the level of respiratory support as follows: ( ) no oxygen support or oxygen support with nasal duct or mask; or ( ) high-flow oxygen, non-invasive ventilation, invasive ventilation, or extracorporeal membrane oxygenation. the permuted block ( patients per block) randomisation sequence, including stratification, was prepared by a statistician not involved in the trial using sas software, version . . eligible patients were allocated to receive medication in individually numbered packs, according to the sequential order of the randomisation centre (jin yin-tan hospital central pharmacy). envelopes were prepared for emergency unmasking. patients received either intravenous remdesivir ( mg on day followed by mg on days - in single daily infusions) or the same volume of placebo infusions for a total of days (both provided by gilead sciences, foster city, ca, usa). patients were assessed once daily by trained nurses using diary cards that captured data on a six-category ordinal scale and safety from day to or death. other clinical data were recorded using the who-international severe acute respiratory and emerging infections consortium (isaric) case record form. the safety assessment included daily monitoring for adverse events, clinical laboratory testing (days , , , and ), -lead electrocardiogram (days and ), and daily vital signs measurements. clinical data were recorded on paper case record forms and then double entered into an electronic database and validated by trial staff. naso pharyngeal or oropharyngeal swabs, expectorated sputa as available, and faecal or anal swab specimens were collected on days , , , , , , , and for viral rna detection and quantification. the trial was monitored by a contract research organisation (hangzhou tigermed consulting). virological testing was done at the teddy clinical research laboratory (tigermed-di'an, hangzhou, china) using quantitative real-time rt-pcr. rna was extracted from clinical samples with the magna pure system (roche, rotkreuz, switzerland), detected and quantified by cobas z qpcr (roche), using lightmix modular sars-cov- assays (tib mobiol, berlin, germany). at baseline, the upper (nasopharyngeal or oropharyngeal swabs) and lower respiratory tract specimens were tested for detection of e-gene, rna-dependent rna polymerase gene, and n-gene, then samples on the subsequent visits were quantitatively and qualitative assessed for e-gene. the primary clinical endpoint was time to clinical improvement within days after randomisation. clinical improvement was defined as a two-point reduction in patients' admission status on a six-point ordinal scale, or live discharge from the hospital, whichever came first. the six-point scale was as follows: death= ; hospital admission for extracorporeal membrane oxygenation or mechanical ventilation= ; hospital admission for noninvasive ventilation or high-flow oxygen therapy= ; hos-pital admission for oxygen therapy (but not requiring high-flow or non-invasive ventilation)= ; hospital admission but not requiring oxygen therapy= ; and discharged or having reached discharge criteria (defined as clinical recovery-ie, normalisation of pyrexia, respiratory rate < breaths per minute, saturation of peripheral oxygen > % on room air, and relief of cough, all maintained for at least h)= . the six-point scale was modified from the seven-point scale used in our previous covid- lopinavir-ritonavir rct by combining the two outpatient strata into one. secondary outcomes were the proportions of patients in each category of the six-point scale at day , , and after randomisation; all-cause mortality at day ; frequency of invasive mechanical ventilation; duration of oxygen therapy; duration of hospital admis sion; and proportion of patients with nosocomial infection. virological measures included the proportions of patients with viral rna detected and viral rna load (measured by quantitative rt-pcr). safety outcomes included treatment-emergent adverse events, serious adverse events, and premature discontinuations of study drug. the original design required a total of events across both groups, which would provide % power under a one-sided type i error of · % if the hazard ratio (hr) comparing remdesivir to placebo is · , corresponding to a change in time to clinical improvement of days assuming that time to clinical improvement is days on placebo. one interim analysis using triangular boundaries and a : allocation ratio between remdesivir and placebo had been accounted for in the original design. assuming an % event rate within days across both groups and a dropout rate of % implies that about patients should be recruited for this trial ( on placebo and on remdesivir). the possibility for an interim analysis after enrolment of about patients was included in the design if requested by the independent data safety and monitoring board. the primary efficacy analysis was done on an intentionto-treat (itt) basis with all randomly assigned patients. time to clinical improvement was assessed after all patients had reached day ; no clinical improvement at day or death before day were considered as right censored at day . time to clinical improvement was portrayed by kaplan-meier plot and compared with a logrank test. the hr and % ci for clinical improvement and hr with % ci for clinical deterioration were calculated by cox proportional hazards model. other analyses include subgroup analyses for those receiving treatment days or less vs more than days after symptom onset, time to clinical deterioration (defined as one category increase or death), and for viral rna load at entry. the differences in continuous variables between the groups was calculated using hodges-lehmann between feb , , and march , , patients were screened, of whom were eligible (figure ). patients were assigned to receive remdesivir and to receive placebo; one patient in the placebo group withdrew their previously written informed consent after randomisation, so and patients were included in the itt population. no patients were enrolled after march , because of the control of the outbreak in wuhan and on the basis of the termination criteria specified in the protocol, the data safety and monitoring board recommended that the study be terminated and data analysed on march . at this stage, the interim analysis was abandoned. when all the other assumptions stayed the same, with the actual enrolment of participants, the statistical power was reduced from % to %. three patients in the remdesivir group did not start their assigned treatment so were not included in safety analyses (figure ). the median age of study patients was years (iqr - ); sex distribution was ( %) men versus ( %) women in the remdesivir group and ( %) versus ( %) in the placebo group (table ). the most common comorbidity was hypertension, followed by diabetes and coronary heart disease. lopinavir-ritonavir was co-administered in ( %) patients at baseline. most patients were in category of the six-point ordinal scale of clinical status at baseline. some imbalances existed at enrolment between the groups, including more patients with hypertension, diabetes, or coronary artery disease in the remdesivir group than the placebo group. more patients in the control group than in the remdesivir group had been symptomatic for days or less at the time of starting remdesivir or placebo treatment, and a higher proportion of remdesivir recipients had a respiratory rate of more than breaths per min. no other major differences in symptoms, signs, laboratory results, disease severity, or treatments were observed between groups at baseline. median time from symptom onset to starting study treatment was days (iqr - ). no important differences were apparent between the groups in other treatments received (including lopinavir-rito navir or corticosteroids; time from symptom onset to corticosteroids therapy, days ( - ) ( - ) duration of corticosteroids therapy, days ( - ) ( - ) data are median (iqr) or n (%). *three patients did not start treatment so are not included in time from symptom onset to start of study treatment subgroup analyses. in patients with use of remdesivir within days after symptom onset, -day mortality was not significantly different between the groups, although numerically higher in the placebo group; by contrast, in the group of patients with late use, remdesivir patients had numerically higher -day mortality, although there was no significant difference. clinical improvement rates at days and day were also not significantly different between the groups, but numerically higher in the remdesivir group than the placebo group. for patients assigned to the remdesivir group, duration of invasive mechanical ventilation was not significantly different, but numerically shorter than in those assigned to the control group; however, the number of patients with invasive mechanical ventilation was small. no significant differences were observed between the two groups in length of oxygen support, hospital length of stay, days from randomisation to discharge, days from randomisation to death and distribution of six-category scale at day , day , and day (table ; appendix p ). of patients ( in the remdesivir group and in the placebo group) who were rt-pcr positive at enrolment, ( %) of the with data available had undetec table viral rna on the nasopharyngeal and oropharyngeal swab taken at base line. the mean baseline viral load of nasopharyngeal and oropharyngeal swabs was · log copies per ml (se · ) in the remdesivir group and · log copies per ml ( · ) in the control group (table ). viral load decreased over time similarly in both groups (figure a). no differences in viral load were observed when stratified by interval from symptom onset to start of study treatment (appendix p ). in the subset of patients from whom expectorated sputa could be obtained ( patients), the mean viral rna load at enrolment was nearly -log higher in the remdesivir group than the placebo group at enrolment (figure b). when adjusted for baseline sputum viral load at enrolment, the remdesivir group showed no significant difference at day from placebo, but a slightly more rapid decline in load (p= · ). the cumulative rate of undetectable viral rna of nasopharyngeal and oropharyngeal swabs by day was ( %) of patients, and the negative proportion was similar among patients receiving remdesivir and those receiving placebo (appendix p ). adverse events were reported in ( %) of patients in the remdesivir group and ( %) of in the control group (table ). the most common adverse events in the remdesivir group were constipation, hypoalbuminaemia, hypokalaemia, anaemia, thrombocytopenia, and increased total bilirubin; and in the placebo group, the most common were hypoalbuminaemia, constipation, anaemia, hypokalaemia, increased aspartate aminotransferase, increased blood lipids, and increased total bilirubin. ( %) serious adverse events were reported in the remdesivir group and ( %) were reported in the control group. more patients in the remdesivir group than the placebo group discontinued the study drug because of adverse events or serious adverse events ( [ %] in the remdesivir group vs four [ %] in the placebo group), among whom seven ( %) were due to respiratory failure or acute respiratory distress syndrome in the remdesivir group. all deaths during the observation period were judged by the site investigators to be unrelated to the intervention). our trial found that intravenous remdesivir did not significantly improve the time to clinical improvement, mortality, or time to clearance of virus in patients with serious covid- compared with placebo. compared data are mean (se). results less than the lower limit of quantification of the pcr assay and greater than the limit of qualitative detection are imputed with half of actual value; results of patients with viral-negative rna are imputed with log copies per ml. with a previous study of compassionate use of remdesivir, our study population was less ill (eg, at the time of enrolment, · % were on invasive mechanical ventilation or extracorporeal membrane oxygenation vs % in the previous study) and was treated somewhat earlier in their disease course (median days vs days). such differences might be expected to favour remdesivir, providing greater effects in our study population, but our results did not meet this expectation. however, our study did not reach its target enrolment because the stringent public health measures used in wuhan led to marked reductions in new patient presentations in mid-march, and restrictions on hospital bed availability resulted in most patients being enrolled later in the course of disease. consequently, we could not adequately assess whether earlier remdesivir treatment might have provided clinical benefit. however, among patients who were treated within days of symptom onset, remdesivir was not a significant factor but was associated with a numerical reduction of days in median time to clinical improvement. ongoing con trolled clinical trials are expected to confirm or refute our findings. in one murine model of sars, remdesivir treatment starting at days after infection, after virus replication and lung airway epithelial damage had already peaked, significantly reduced sars-cov- lung titres but did not decrease disease severity or mortality. a need for early treatment has been found in non-human primate models of sars and mers in which virus replication is very short-lived and lung pathology appears to develop more rapidly than in human infections. , such findings argue for testing of remdesivir earlier in covid- . remdesivir did not result in significant reductions in sars-cov- rna loads or detectability in upper respiratory tract or sputum specimens in this study despite showing strong antiviral effects in preclinical models of infection with coronaviruses. in african green monkey kidney vero e cells, remdesivir inhibited sars-cov- with a % effective concentration (ec ) of · µg/ml and an ec of · µg/ml. in human nasal and bronchial airway epithelial cells, a fixed µm ( · µg/ml) concentration reduced estimated intracellular viral titres over · log % tissue culture infective dose per ml at h. in human airway epithelial cells, the ec for remdesivir was · µg/ml for sars-cov and · µg/ml for mers-cov. in a murine model of mers, subcutaneous remdesivir showed significant antiviral and clinical effects with a dose regimen that maintained plasma concentrations greater than µm ( · µg/ml) throughout the dosing interval. in rhesus macaques, a mg/kg dose, reported to be roughly equivalent to -mg daily dosing in humans, was effective for treatment of mers-cov infection and reduced pulmonary virus replication when started at h after infection. healthy adult volunteers receiving doses similar to our trial ( mg on day , mg on days - ) had mean peak plasma concentrations of · µg/ml (percentage coefficient of variation · ) on day and · µg/ml ( · ) on day . doses of mg/day for days have been adequately tolerated in healthy adults, and a daily dose regimen of mg for days followed by mg for days appeared to be generally well tolerated in one patient with ebola meningoencephalitis. however, the pharmacokinetics of remdesivir in severely ill patients, and particularly the concentrations of the active nucleotide metabolite (gs- ) triphosphate in respiratory tract cells of treated patients, are unknown. studies of higher-dose regimens for which there are safety data (eg, - mg daily doses) warrant consid eration in severe covid- . our study found that remdesivir was adequately tolerated and no new safety concerns were identified. the overall proportion of patients with serious adverse events tended to be lower in remdesivir recipients than placebo recipients. however, a higher proportion of remdesivir recipients than placebo recipients had dosing prematurely stopped by the investigators because of adverse events including gastrointestinal symptoms (anorexia, nausea, and vomiting), aminotransferase or bilirubin increases, and worsened cardiopulmonary status. limitations of our study include insufficient power to detect assumed differences in clinical outcomes, initiation of treatment quite late in covid- , and the absence of data on infectious virus recovery or on possible emergence of reduced susceptibility to remdesivir. of note, in non-human primates, the inhibitory effects of remdesivir on infectious sars-cov- recovery in bronchoalveolar lavages were much greater than in controls, but viral rna detection in upper and lower respiratory tract specimens were not consistently de creased versus controls. coronaviruses partially resistant to inhibition by remdesivir (about six-times increased ec ) have been obtained after serial in vitro passage, but these viruses remain susceptible to higher remdesivir concentrations and show impaired fitness. the frequent use of corticosteroids in our patient group might have promoted viral replication, as observed in sars and mers, although these studies only reported pro longation of the detection of viral rna, not infectious virus. furthermore, we have no answer to whether longer treatment course and higher dose of remdesivir would be beneficial in patients with severe covid- . in summary, we found that this dose regimen of intravenous remdesivir was adequately tolerated but did not provide significant clinical or antiviral effects in seriously ill patients with covid- . however, we could not exclude clinically meaningful differences and saw numerical reductions in some clinical parameters. ongoing studies with larger sample sizes will continue to inform our understanding of the effect of remdesivir on covid- . furthermore, strategies to enhance the antiviral potency of remdesivir (eg, higher-dose regimens, combination with other antivirals, or sars-cov- neutralising antibodies) and to mitigate immuno pathological host responses contributing to covid- severity (eg, inhibitors of il- , il- , or tnfα) require rigorous study in patients with severe covid- . bc, cw, and yew had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. cw and bc decided to publish the paper. bc, cw, yew, pwh, tj, and fgh provided input on the trial design. bc, cw, yew, fgh, and pwh were responsible for acquisition, analysis, and interpretation of data. yew, fgh, pwh, and gf drafted the manuscript. bc, cw, pwh, fgh, gf, tj, and xg critically revised the manuscript. yew contributed to statistical analysis. gf gave valuable suggestions for data analysis. all authors contributed to conducting the trial. fgh has served as non-compensated consultant to gilead sciences on its respiratory antiviral programme, outside the submitted work. all other authors declare no competing interests. after approval from the human genetic resources administration of china, this trial data can be shared with qualifying researchers who submit a proposal with a valuable research question. a contract should be signed. characteristics of and important lessons from the coronavirus disease (covid- ) outbreak in china: summary of a report of cases from the chinese center for disease control and prevention epidemiological and clinical characteristics of cases of novel coronavirus pneumonia in wuhan, china: a descriptive study clinical course and risk factors for mortality of adult inpatients with covid- in wuhan, china: a retrospective cohort study covid- in critically ill patients in the seattle region-case series remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus ( -ncov) in vitro hydroxychloroquine, a less toxic derivative of chloroquine, is effective in inhibiting sars-cov- infection in vitro hydroxychloroquine in patients with covid- : an open-label, randomized, controlled trial favipiravir versus arbidol for covid- : a randomized clinical trial treatment of critically ill patients with covid- with convalescent plasma a trial of lopinavir-ritonavir in adults hospitalized with severe covid- gs- and its parent nucleoside analog inhibit filo-, pneumo-, and paramyxoviruses broad-spectrum antiviral gs- inhibits both epidemic and zoonotic coronaviruses therapeutic efficacy of the small molecule gs- against ebola virus in rhesus monkeys broad spectrum antiviral remdesivir inhibits human endemic and zoonotic deltacoronaviruses with a highly divergent rna dependent rna polymerase comparative therapeutic efficacy of remdesivir and combination lopinavir, ritonavir, and interferon beta against mers-cov prophylactic and therapeutic remdesivir (gs- ) treatment in the rhesus macaque model of mers-cov infection characterization and treatment of sars-cov- in nasal and bronchial human airway epithelia clinical benefit of remdesivir in rhesus macaques infected with sars-cov- a randomized, controlled trial of ebola virus disease therapeutics compassionate use of remdesivir for patients with severe covid- first case of novel coronavirus in the united states group sequential clinical trials with triangular continuation regions gilead sciences. investigator's brochure of remdesivir late ebola virus relapse causing meningoencephalitis: a case report coronavirus susceptibility to the antiviral remdesivir (gs- ) is mediated by the viral polymerase and the proofreading exoribonuclease effects of early corticosteroid treatment on plasma sars-associated coronavirus rna concentrations in adult patients corticosteroid therapy for critically ill patients with middle east respiratory syndrome we thank gilead sciences for providing the study drugs and huyen cao and anu osinusi for advice regarding safe use of remdesivir. we thank joe yao and ella lin for statistical consultation. we also thank members of the international data safety monitoring board (jieming qu key: cord- -tgn kk authors: kavanagh, matthew m; katz, ingrid t; holmes, charles b title: reckoning with mortality: global health, hiv, and the politics of data date: - - journal: lancet doi: . /s - ( ) - sha: doc_id: cord_uid: tgn kk nan example, the institute for health metrics and evaluation's global burden of disease studies. these estimates allow aid agencies, such as the us president's emergency plan for aids relief (pepfar) and the global fund, to justify their financing, and national politicians in both donor governments and implementing governments to take (often deservedly) credit for any progress. however, these estimates do little to help local leaders, programme managers, and clinicians, all of whom exercise far less power over budgets, to assess the effectiveness of hiv services. mature hiv programmes face the complex task of accelerating enrolment while simultaneously improving the quality of services and addressing longterm retention of people who start treatment when still asymptomatic. monitoring systems could track actual deaths and their causes, feeding these data back for use throughout the health system, but these systems have not been prioritised. the existing priorities perpetuate the long-standing challenge in global health of missing mortality data for programmatic and research purposes. , for example, south africa's success in establishing a system for registering deaths makes it the only country in sub-saharan africa with a classification higher than very low in vital registration capacity. the absence of data on actual mortality at the programme and clinic level, whether all-cause mortality or aids-related mortality, has undermined the aids response on several fronts. most fundamentally, it has led to death being undervalued as an outcome in hiv programmes. many clinics and programmes track in this context, a broad set of patients have for years been categorised as lost to follow-up, conflating all individuals who transfer to another clinic or disengage from care and stop treatment with individuals who have actually died. this amalgamation of different groups is a problem not just in hiv but in multiple efforts to fight disease, from tuberculosis to cardiovascular disease and diabetes. , one study that traced a sample of people lost to followup in uganda, kenya, and tanzania found that % of these individuals had actually died, three times more than clinic-level data suggested. in another sample of people who initiated antiretroviral therapy in african countries, about % had died within years, · times the rate shown in clinic records. although distinguishing aids mortality from non-aids mortality is difficult in lowresource settings, tracking all-cause mortality among people living with hiv at a granular level will yield actionable insights, even as greater diagnostic capacity is built. these measures can also support integration efforts by increasing awareness of the numerous so-called silent deaths due to non-hiv causes, such as cardiovascular disease. one of the most important implications of the paucity of data of local mortality is that programmes do not sufficiently prioritise interventions for people with advanced disease. studies in south africa, kenya, zambia, and the democratic republic of the congo have shown that most patients with hiv admitted to hospital have already been on antiretroviral therapy (often for years) but they either stop treatment or are on a treatment regimen that is not effectively suppressing the virus. - a high proportion of patients die because of hiv-related illnesses that could have been prevented. a set of evidence-based clinical interven tions has been recommen ded by who to prevent this mortality, including point-of-care cryptococcal screening and tuberculosis urine lipoarabinomannan screening, along with prophylactic and preventive treatment. however, uptake has been slow and insufficient in a context of scarce resources. data on localised and specific mortality could provide a basis for programme managers to target resources to clinics, regions, or populations where these interventions are most needed. without granular mortality data, comparisons between different sites, regions, and subpopulations cannot be made. a study across four provinces in zambia, for example, found that some clinics had mortality rates greater than ten times those of the best performing clinics; a degree of heterogeneity that could be related to clinical, structural, or other factors. health leaders who have access to reliable mortality information can identify and learn from successful programmes and apply these findings to programmes that underperform. generating information to be used at the low levels of the health-care system, by clinic managers, district-level public health officials, and local community groups, has not been a political priority. generating this kind of information is also not simple. medical record systems in low-income and middle-income countries remain weak. many deaths among people living with hiv occur outside the health-care system. yet action is even more urgent in situations where deaths are concentrated among the individuals who are hardest to reach. we see at least three opportunities to address these challenges and enable timely mortality tracking, alongside efforts to prevent unnecessary deaths. first, progress in countries as diverse as south africa, malaysia, nicaragua, and fiji shows that developing more robust vital registries is possible within a few years and with relatively small amounts of funding. in south africa, in particular, tracking the mortality of young people using systems at the local level helped monitor the effectiveness of hiv programmes. low-cost efforts to create sample vital registration systems with verbal autopsy also show promise. importantly, these efforts have the advantage of supporting all health programmes. hiv funders, including pepfar and the global fund, should partner with national governments and health funders, such as the uk department for international development and world bank, to develop and strengthen vital registries, building on momentum from who, unicef, and others. second, robust patient-tracing activities should be incorporated as core objectives of all hiv programmes and funded accordingly. actual mortality rates should be key programme indicators, made easier by investments in vital registration. pepfar took the bold step, in , of requiring the programmes it funds to report on hiv mortality. hopefully, this step will improve patient outcomes by incentivising effective interventions for advanced hiv disease and support for people who have stopped treatment to re-enter care. third, we can move towards a variety of outcomeoriented global health programmes beyond hiv, for which measures of success move from the number of patients receiving services to explicit reductions in mortality rates. some maternal health efforts have shown it is possible to uncover and address the causes of maternal deaths, but many have struggled to have a widespread effect. these approaches face similar challenges to hiv with regard to data limitations, adequate scaling, sufficient resources, and a high number of deaths outside facilities. other compelling examples, such as the public-private saving mothers giving life programme, show how focusing on maternal mortality rates and leveraging systems developed for the hiv response could improve facilities and increase demand. initiated by the obama administration, the programme helped decrease maternal mortality by % in regions of uganda, and % in regions of zambia before it was discontinued by the trump administration. these programmes should be revived and expanded. broader global health efforts can learn from the hiv experience. mortality estimates based on aggregate national mod elling can be influential in drawing political attention to these issues, and in encouraging collective action and making high-level decisions on the allocation of resources. however, as effective programmes are scaled up, mortality is likely to become more localised, heterogeneous, and less susceptible to single interventions. from emerging infectious diseases to cancer and mental health diseases, this path is likely to be similar. as efforts to address non-communicable diseases in low-income and middle-income countries gain momentum, they are likely to include provision of long-term biomedical interventions such as anti-hypertensives for high blood pressure and oral hypoglycaemic medi cations for diabetes. tracking actual mortality and building the necessary capacity to identify the causes of death will be key for programmes to fully account for the progress that is made and motivate filling gaps in the quality of services. making the shift to reporting on and addressing actual mortality will require a political reorientation by funders towards prioritising information that might be less useful to them than high-level modelled estimates but essential for the people designing and implementing frontline programmes. the hiv response could lead this change by committing resources as part of an effort to regain the momentum against preventable deaths. this commitment will require a collective effort to mobilise the political will needed to improve and empower decisionmaking and a renewed focus on what ultimately matters most to the individuals in the pandemic's path-avoiding unnecessary deaths. global aids update: communities at the centre institute for health metrics and evaluation. global burden of disease compare beyond precision: embracing the politics of global health numbers generation of political priority for global health initiatives: a framework and case study of maternal mortality metric partnerships: global burden of disease estimates within the world bank, the world health organisation, and the institute for health metrics and evaluation counting the dead and what they died from: an assessment of the global status of cause of death data reliable direct measurement of causes of death in low-and middle-income countries a global assessment of civil registration and vital statistics systems: monitoring data quality and progress improved retention rates with low-cost interventions in hypertension and diabetes management in a rural african environment of nurse-led care: a cluster-randomised trial loss-to-follow-up on multidrug resistant tuberculosis treatment in gujarat, india: the when and who of it estimation of mortality among hiv-infected people on antiretroviral treatment in east africa: a sampling based approach in an observational, multisite, cohort study retention and mortality on antiretroviral therapy in sub-saharan africa: collaborative analyses of hiv treatment programmes high proportions of patients with advanced hiv are antiretroviral therapy experienced: hospitalization outcomes from sub-saharan african sites hiv-related medical admissions to a south african district hospital remain frequent despite effective antiretroviral therapy scale-up care continuum and postdischarge outcomes among hiv-infected adults admitted to the hospital in zambia guidelines for managing advanced hiv disease and rapid initiation of antiretroviral therapy. geneva: world health organization estimated mortality on hiv treatment among active patients and patients lost to follow-up in provinces of zambia: findings from a multistage samplingbased survey the future for women and children: unicef and who joint statement on strengthening civil registration and vital statistics (crvs) president's emergency plan for aids relief. monitoring, evaluation, and reporting indicator reference guide maternal death surveillance and response: a tall order for effectiveness in resource-poor settings impact of the saving mothers, giving life approach on decreasing maternal and perinatal deaths in uganda and zambia all authors contributed to conceptualising, drafting, and editing the manuscript. mmk received a grant for a joint policy mapping project with unaids. all other authors declare no competing interests. key: cord- -vwxbo b authors: taylor, allyn l; habibi, roojin; burci, gian luca; dagron, stephanie; eccleston-turner, mark; gostin, lawrence o; meier, benjamin mason; phelan, alexandra; villarreal, pedro a; yamin, alicia ely; chirwa, danwood; forman, lisa; ooms, gorik; sekalala, sharifah; hoffman, steven j title: solidarity in the wake of covid- : reimagining the international health regulations date: - - journal: lancet doi: . /s - ( ) - sha: doc_id: cord_uid: vwxbo b nan amid frenzied national responses to covid- , the world could soon reach a critical juncture to revisit and strengthen the international health regulations (ihr), the multilateral instrument that governs how states and who collectively address the global spread of disease. , in many countries, ihr obligations that are vital to an effective pandemic response remain unfulfilled, and the instrument has been largely sidelined in the covid- pandemic, the largest global health crisis in a century. it is time to reimagine the ihr as an instrument that will compel global solidarity and national action against the threat of emerging and re-emerging pathogens. we call on state parties to reform the ihr to improve supervision, international assistance, dispute resolution, and overall textual clarity. first, the covid- pandemic highlights longstanding challenges in the identification of a public health emergency of international concern (pheic). the ihr obliges states to notify who of any event that may constitute a pheic within h after public health authorities' assessment. evidence indicates that some public health authorities in wuhan, china, suspected what later became known as severe acute respiratory syndrome coronavirus for several weeks before who was privy to the information. without legal authority to independently visit china and review the outbreak situation, who faced a barrier in mounting a cogent global response. in a reimagined ihr, states should allow for information to be received from non-state actors without being subject to verification from the state in question, as currently required by the ihr. moreover, national accountability should be strengthened by mandating independent experts to conduct missions to states so that they can review potential outbreak situations. arms control treaties bear the strongest examples of such inspection mechanisms, but they have also been wielded in other realms of global health, principally the international drug control regime. the concrete links between infectious disease control and global security provide a compelling rationale for an inspection mechanism that encourages states to be more forthright and accountable in reporting a potential pheic. relatedly, the process for declaring a pheic must be revisited. in a reimagined ihr, states should call for transparency in the deliberations that lead to a pheic, by publishing, for example, the transcript of discussion that led to the declaration of a pheic. transparency would enhance accountability in the ihr process. furthermore, states should consider replacing the rigid binary pheic architecture, whereby the decision is either no pheic or a pheic, with an incremental mechanism that would enable intermediate stages for ihr-based alerts and guidance. this change would enable greater flexibility and global coordination in responding to disease outbreaks as they unfold. second, covid- has shown that all states must invest more domestic resources in their public health systems. following more than a decade under the revised ihr, only a third of countries meet the core capacities of public health systems required therein, impacting countries' abilities to prevent, detect, and respond to disease outbreaks and putting "the whole world at risk". however, even in states where public health core capacities are deemed strong, public health responses to covid- are woefully inadequate. strengthening public health core capacities in all countries demands the concretisation of global solidarity and international support in our shared vulnerability to pathogens. states should consider bolstering the ihr provisions for international assistance, including incorporating a financial mechanism to assist lowincome countries in building and sustaining required capacities. to ensure accountability for national capacity building, states should integrate an effective reporting mechanism to monitor implementation of ihr obligations. robust reporting procedures generally require states to submit periodic national reports on the measures adopted, progress made, and problems encountered in the implementation of a treaty and, crucially, to incorporate some type of independent review. periodic reporting procedures assist states in identifying and alleviating obstacles they face when implementing commitments, without criticising their performance. international monitoring is crucial for treaty implementation in a wide range of fields and can be imagined as a key mechanism to catalyse cooperation in a post-covid- world. the absence of any provision for such monitoring in the ihr hampers its effectiveness and relevance. third, the covid- pandemic confirms how disruptive health measures can be for trade, transport, and economic activities. [ ] [ ] [ ] disputes over the legality of such health measures are likely, and agreed mechanisms to settle them would prevent political tensions from becoming disruptions. some disputes lend themselves to longer judicial processes, but many would benefit from prompt and practical mechanisms of resolution. the ihr provides a range of options, but these have never been publicly used. multilateral dispute resolution processes, including consultation forums among concerned states and an active good offices role by the who director-general preceding the dispute resolution process, could provide pragmatic solutions. fundamentally, states must tackle the overarching issue of ambiguity in the text of the regulations in any future ihr reform process. the widespread lack of clarity with respect to key state obligations in the current ihr undermines compliance by producing a "zone of ambiguity within which it is difficult to say with precision what is permitted and what forbidden". there will soon come a time when negotiators will meet to reimagine the ihr or devise a new legal instrument to promote global cooperation to address infectious disease outbreaks and other global health threats. the challenge should be met head on, not squandered or hidden behind a veil of ambiguity so that a strengthened ihr is better equipped to respond to future global health challenges and acts as an instrument for global solidarity. alt was a legal adviser at who and a consultant to who on global health law matters. glb reports personal fees from who regional office for europe for consultancy on governance and procedural questions; the fees relate to a consultancy on the governance of the office and the procedures of the regional committee. sd is a member of the who research ethics review committee. me-t previously worked as a consultant to who on unrelated matters. ap reports grants and personal fees as past and current consultant to who on global and public health law matters, including the ihr. graduate institute of international and development studies who director-general's opening remarks at the world health assembly. world health organization who. international health regulations, wha . , nd edn. geneva: world health organization clinical features of patients infected with novel coronavirus in wuhan, china addressing the global tragedy of needless pain: rethinking the united nations single convention on narcotic drugs security council resolution transparency in ihr emergency committee decision making: the case for reform interim report on who's response to covid- global preparedness monitoring board. a world at risk: annual report on global preparedness for health emergencies rethinking pandemic preparation: global health security index (ghsi) is predictive of covid- burden, but in the opposite direction in: oxford handbook of united nations treaties trade set to plunge as covid- pandemic upends global economy global economic prospects effects of novel coronavirus (covid- ) on civil aviation: economic impact analysis the new sovereignty key: cord- -o ezn dd authors: wang, lei-yun; cui, jia-jia; ouyang, qian-ying; zhan, yan; guo, cheng-xian; yin, ji-ye title: remdesivir and covid- date: - - journal: lancet doi: . /s - ( ) - sha: doc_id: cord_uid: o ezn dd nan frequency of slco b (rs ) showed the opposite result (appendix). meanwhile, we also collected sars-cov- samples from china and sars-cov- samples from the usa using an online database. the frequency of potential functional variations such as p.p l (c. c>t) in polyprotein ab, which is the target of remdesivir, were largely different in the genomes from the usa ( · %) and china ( · %). these variations could generate the efficacy discrepancy of remdesivir among these clinical trials. similar to remdesivir, ethnic diversity was also found in pharmacogenes related to other drugs, such as chloroquine, in covid- treatment. in summary, pharmacogenomic studies for covid- therapy seem to be needed urgently. the panel on antiretroviral guidelines for adults and adolescents with hiv and the american association for the study of liver diseases guidelines for hepatitis c virus treatment suggest that combination therapy for severe acute respiratory syn drome coronavirus infection will outperform single drugs. yeming wang and colleagues reported that the hazard of -day clinical improvement for patients with severe covid- randomly assigned to remdesivir was · times ( % ci · to · ) the hazard of patients randomly assigned to placebo, but the -day mortality in both these groups was similar. relatedly, cao and colleagues reported that the hazard of -day clinical improvement for patients with severe covid- randomly assigned to lopinavir-ritonavir was · times ( % ci · to · ) the hazard among patients randomly assigned to standard care, and the -day mortality was reduced by % ( % ci - to ). nearly % of patients in the wang and colleagues trial were also receiving lopinavir-ritonavir, but their results are not stratified by lopinavirritonavir status. reporting estimates stratified by concomitant lopinavirritonavir use would help guide the design of future (factorial) trials that investigate the joint effects of these two therapies, even if imprecise. also, reporting the proportion of patients clinically improved at days is more interpretable than the hazard ratio. additionally, wang and colleagues report that the effect of remdesivir on clinical improvement appeared stronger among patients who started treatment within days of symptom onset than among those who started later. cao and colleagues reported similar strengthening of the lopinavirritonavir treatment effect among patients who started treatment within days of symptom onset. as in hiv, timing of treatment initiation for covid- appears to be of crucial importance in the design of future research. in a chinese clinical trial by yeming wang and colleagues, remdesivird did not show significant benefits for patients with severe covid- . shortly after their study was published, remdesivir was authorised in the usa by the us food & drug administration and approved in japan for patients with severe covid- on the basis of preliminary phase trial results. we find it puzzling that the discrepancy of results between china and the usa is merely justified by different study designs. genetic factors can influence drugs' efficacy and toxicity. therefore, it is reasonable to seek answers from the genetic backgrounds of patients with covid- and of severe acute respiratory syndrome coronavirus (sars-cov- ) in china and the usa. from the gnomad database, we collected: genomes from east asia that represented chinese people; and genomes from europeans, from latinx, and from african americans, which represented the three majority ethnicities in the usa. genetic diversity was found in seven pharmacogenes that mainly related to pharmacokinetics and pharmacodynamics of remdesivir. notably, the mutation frequency of cyp d (rs ) in east asia ( · %) was much greater than that of the american ethnicities ( · - · %), whereas the mutation only a limited number of new-onset severe patients. a detailed recruitment process has been reported elsewhere. the suggestion made by jessie k edwards and colleagues to report the effect of remdesivir stratified by lopinavir-ritonavir is important, although the potential effect of lopinavir-ritonavir was not confirmed in covid- patients. evaluating whether an interaction exists between lopinavir-ritonavir and remdesivir is still important and can also provide evidence for the feasibility of factorial trial of these two drugs. the result from our trial showed that there was no statis tically significant interaction between lopinavir-ritonavir and remdesivir on time to clinical improvement (p= · ). we appreciate the possible explanation raised by lei-yun wang and colleagues that the genetic backgrounds of patients might be one of the reasons for discrepant results between the chinese and american remdesivir clinical trials. , , . the relationship between seven pharmacogenes and the plasma concentration of remdesvir in two populations should be confirmed. whether the different strains of severe acute respiratory syndrome coronavirus between china and the usa contribute to the discrepant effect of remdesivir also needs to be confirmed. mccreary and angus speculate that differences in study design could be the reason to explain the variation in results from the trials of remdesivir. they also provide several valuable questions about the variable effects of remdesivir in different trials. although the conclusions between the three trials have discrepancies, , , we still want to emphasise that the main findings from remdesivir trials showed similar but limited beneficial effect of remdesivir in patients with covid- . we declare no competing interests. remdesivir for the treatment of covid- -a preliminary report the mutational constraint spectrum quantified from variation in humans drugbank . : a major update to the drugbank database for the novel coronavirus resource we thank the clinicians and researchers around the world for their comprehensive interpretation of the results of our randomised controlled trial of remdesivir for covid- . they shared valuable thoughts from different perspectives according to related evidence from in vitro and animal models, and pharmacogenomic studies. a suggestion was made for subgroup analyses by concomitant lopinavirritonavir use. concerns for not reaching the predetermined sample size in our study were also expressed. these comments are appreciated and helpful for future conduct and interpretation of covid- therapy studies.matthew glaus and serena von ruden point out that the therapeutic effect of remdesivir might be lost when treat ment initiation was delayed, based on results from animal studies. , we certainly agree that initiating remdesivir at an earlier stage might contribute to better clinical benefits. however, it is challenging to initiate early antiviral therapy due to possible delays in screening and diagnosis of covid- . in our trial, we set days from symptom onset as one of the inclusion criteria. alicia dennis questioned the fact that our trial was terminated by march , , due to reasons we have stated and further commented that ongoing study recruitment would probably have been possible. although the number of confirmed covid- patients at the time was still large in wuhan, china, there were samira asma and colleagues show the complexity of the global monitoring of health-related sustainable develop ment goals (sdgs) and argue for convergence, harmonisation, and strong data science. however, many offspring of sdg monitoring systems have emerged beyond the monitoring of un sdg indicators, either at supra-national level