key: cord-290314-ldv9hsv1 authors: cortis, dominic title: on determining the age distribution of covid-19 pandemic date: 2020-05-15 journal: front public health doi: 10.3389/fpubh.2020.00202 sha: doc_id: 290314 cord_uid: ldv9hsv1 pandemics tend to have higher occurrence (morbidity) in younger individuals but higher mortality for the elderly. the higher rate of mortality of covid-19 in elderly individuals has been discussed in many reports. however, this pandemic is a double-edged sword as this comment shows higher morbidity rates in elderly as well. this is shown by comparing the age distribution of cases in china and south korea to the relative populations. in every case, the relative number of elderly contracting the virus is far higher than the proportion of elderly in the population. this is unlike past pandemics and shows that aging populations are at an even higher risk than the perceived age dependent rates may imply. the crude death rate for covid-19 cases reports has ranged significantly. for example, guan et al. (1) reports a death rate of 1.4% while baud et al. (2) reports 5.7%. the largest study published to date (44,672 cases) reports a death rate of 2.3% (3) . there are a considerable number of factors that affect the crude rate. the numerator can be affected by the fact that any current statistics would be based on the number of deaths to date as a fraction to the number of confirmed cases-with some of the latter ending in death at a later stage (2) . the denominator can be affected by the number of tests conducted and the age distribution. a higher number of tests conducted is likely to include a higher proportion of asymptomatic people or people with mild symptoms that may have been missed, hence lowering the crude rate. a higher strain on the health system may lead to a lower proportion of asymptomatic people or people with mild to moderate symptoms being tested as well as a higher proportion of deaths on clinical cases due to lack of resources, affecting both the numerator and denominator. these factors are inter-related. for example, younger individuals tend to have a higher proportion of asymptomatic people or people with mild symptoms who are likely to be missing from any statistics in extreme scenarios. moreover, the final crude rate is not only dependent on the age specific mortality rates but also the distribution of ages for covid-19 positive cases. this comment discusses the distribution of confirmed covid-19 cases in relation to the population distribution for three studies. the three studies selected are zhang (3), guan et al. (1) , and korea centers for disease control and prevention (4). the first two are based in china at a point were most covid-19 cases would have emerged and be concluded by now. the last report would be able to provide a comparison on the age distribution for cases in the country with one of the highest proportion of tests performed per million people 1 . national office statistics tend to group age distribution in three cohorts: less than 15 years old (youths), 15 to 64 years old (working population), and above 65 years old (elderly). the distribution of expected cases based on standard population statistics is compared to the same distribution for observed covid-19 cases together with the old age dependency ratio (oadr) being the ratio of elderly to working population for each study. korean national office statistics (5) also show an additional grouping (being 3.2% of total) marked as foreigners. for simplication, 80% of foreigners are set in the working population cohort and 10% are set in each of the other two cohorts. zhang (3) and korean centers for disease control and prevention (4) report covid-19 positive cases and deaths in 10-year ranges. the age ranges 10-20 and 60-70 are assumed to be uniformly distributed and hence half of the frequencies for each (10-20 and 60-70) are included in the working population cohort. zhang (3) the table below summarizes the results obtained comparing the distribution of ages for the three major cohorts. the percentage of youths with confirmed covid-19 cases is far lower than the standard population percentage, even in south korea where a larger proportion of tests were held. the proportion of covid-19 confirmed cases for youths is lower in china (1.55%, 0.89%) than south korea (4.04%) as individuals with mild symptoms would have not been tested as in south korea. the reduction in youths with clinically apparent covid-19 cases does not result in a proportional increase for all other age groups but is more weighted to older individuals. this is shown by a higher old age dependency ratio for the actual cases in every scenario. one must consider that for the scenario generated by guan et al. (1) the ratio of older individuals may have only increased 3.38% in absolute terms but this is a 28.77% growth in relative terms. this is a brief report set in a scenario that is updating on a daily basis. the statistics used may not be complete. for example, wuhan has recently revised its covid-19 death toll upwards by 50% (7) and mortality statistics across many countries show excess number of deaths than reported (8, 9) . this leads to many limitations, including the robustness of the results. the aim of this comment is to generate ideas around future possible research and early indications of risk. another limitation is that countries, or even regions within the same country, may have had different approaches. in a stressed scenario, the public healthcare system would only be recording extreme cases, which tend to be elderly individuals with respect to covid-19. that may mean that the skewness toward elderly may be biased. however, it also proves that, if there is a skewness, it leans toward having covid-19 manifest itself relatively more in elderly. these observations add to the ongoing discussion that the virus is highly contagious for elderly individuals, not only due to a higher rate of mortality 2 , but also due a higher proportion of cases. in essence, aging populations may be at increased risk from a 2-fold effect. if a population has a higher proportion of elderly, the proportion of confirmed covid-19 cases would be higher, accentuated further if no normal tests are made. this is substantially different than what is typically reported for influenza (10) or other pandemics (11) which tend to have higher morbidity for younger individuals. for example, lemaitre and carrat (12) show that the relative ratios of morbidities were much higher for younger individuals than older ones in usa and france for the pandemics in the late 1970s (h1n1), late 1980s (h3n2) and in 2009 (h1n1). it is therefore ideal that age specific mortality rates together with age specific count of cases are reported rather than crude rates and total counts of positive cases. the three studies sampled have an estimated oadr of lower than 21%. in each of the three scenarios above, the relative growth in the elderly cohort ranges from 18.56% (kcdc) to 79.27% (zhang) in relative terms. the oadr in korea and china is lower than any european country except for north macedonia (20.2%), andorra (18.7%), armenia (17.6%), turkey (12.9%), and azerbaijan (9.6%). the european union area has an average old-age dependency ratio of 31.0% while italy has the highest rate at 35.7% (13) . therefore, the frequency of the pandemic in italy can be partially described by its relatively older population. other countries at increased risk due to high oadr are japan, finland, portugal greece, germany bulgaria, france, and sweden (14) . age distributions can also partially explain why some countries such as turkey have a low covid-19 mortality rate despite the high number of cases. as some countries are at different stages of the pandemic, further evaluation of the age distribution by morbidity would be of interest to prepare for future strains of covid-19 or a possible second wave. the author confirms being the sole contributor of this work and has approved it for publication. clinical characteristics of coronavirus disease 2019 in china real estimates of mortality following covid-19 infection analysis of epidemiological characteristics of new coronavirus pneumonia the updates on covid-19 in korea as of 29 april wuhan revises coronavirus death toll up by 50 percent global coronavirus death toll could be 60% higher than reported available online at influenza and the winter increase in mortality in the united states, 1959-1999 pandemic versus epidemic influenza mortality: a pattern of changing age distribution comparative age distribution of influenza morbidity and mortality during seasonal influenza epidemics and the 2009 h1n1 pandemic cities -the young and the old age dependency ratio, old (% of working-age population). (n.d.) the author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.the reviewer mf declared a past co-authorship with the author dc.copyright © 2020 cortis. this is an open-access article distributed under the terms of the creative commons attribution license (cc by). the use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. no use, distribution or reproduction is permitted which does not comply with these terms. key: cord-294863-5qf5dqdg authors: ricci, fabrizio; izzicupo, pascal; moscucci, federica; sciomer, susanna; maffei, silvia; di baldassarre, angela; mattioli, anna vittoria; gallina, sabina title: recommendations for physical inactivity and sedentary behavior during the coronavirus disease (covid-19) pandemic date: 2020-05-12 journal: front public health doi: 10.3389/fpubh.2020.00199 sha: doc_id: 294863 cord_uid: 5qf5dqdg nan since the escalation of coronavirus disease 2019 (covid-19) pandemic, over a billion people across the world have faced restrictions due to varying degrees of confinement, and in the absence of a vaccine against sars-cov-2, massive public health interventions have been implemented to contain the outbreak. the lockdown set up in many countries to combat the covid-19 epidemic entails unprecedented disruption of lives and work, determining specific risks related to mental and physical health in the general population, especially among those who stopped working during the current outbreak (1) . the implementation of confinement policies to contain covid-19 could be a catalyst for concealed mental and physical health conditions, further enhancing the effects of psychosocial risk factors, including stress, social isolation, and negative emotions that may act as barriers against behavioral changes toward an active lifestyle and negatively impact on global health, well-being and quality of life, ultimately resulting in result in a range of chronic health conditions (2, 3). the world health organization (who) classified physical inactivity as the fourth leading risk factor accounting for 6% of global mortality, following hypertension (13%), smoking (9%) and diabetes (6%). the relationship between physical inactivity and obesity trends was quite evident since 1953 when the london busmen study showed that bus drivers who mainly sat during work presented with larger waist circumferences, higher levels of adiposity and increased risk of coronary events than bus conductors, who walked the aisles and climbed the stairs of double-decker buses (4). physical inactivity levels are rising in many countries with significant implications for the prevalence of non-communicable diseases and the general health of the population worldwide. the who recommends that adults accumulate at least 150 min of moderate to vigorous-intensity physical activity (mvpa) or 75 min of vigorous-intensity physical activity (vpa) throughout the week, cumulated in bouts lasting ≥10 min. this volume of physical activity (pa) is associated with a lower risk of cardiovascular (cv) morbidity and mortality and a number of other healthcare benefits (5). unfortunately, attained levels of daily pa are largely insufficient, especially in western countries. recent evidence suggests that sedentary behavior (sb) is independently associated with traditional cv risk factors and increased cv morbidity and global mortality, regardless of pa volume (6). sb is defined as any waking behavior characterized by an energy expenditure ≤1.5 metabolic equivalents, while in a sitting, reclining or lying posture. typical sb includes "screen time" (tv viewing, videogame playing, computer use), car-driving, and reading. importantly, in a dose-response metaanalysis of 34 studies, including 1,331,468 community-dwelling participants, total sitting time volumes >8 h and 6 h/day were associated with increased risk of all-cause death and cv death, respectively, in pa adjusted analyses (7). for tv viewing time, an increased risk for all-cause and cv mortality was strongest above levels of 3-4 h/day, regardless of pa level (7). thus, physical inactivity and sb should be considered as separate entities with their unique determinants and health consequences, but with synergistic harmful effects on cv health (8) . while containing the spreading of the contagion as quickly as possible is the urgent public health priority, there have been few public health guidelines for the public as to what people can or should do in terms of maintaining their daily exercise or pa routines (9, 10) . safeguarding psycho-physical health in a lockdown situation is paramount, and special attention should be paid to elderly and pediatric populations. with advancing age, it becomes more difficult to reverse the effects of deconditioning of the musculoskeletal system. children and adolescents have higher pa needs than adults, and these are more difficult to achieve during the quarantine period, also due to the influence of home environment (11) . both physical and social environmental factors operating within the home space are indeed important influences on sb and pa, especially for the pediatric population (12) . regarding adolescents, another point that warrants careful vigilance concerns the risks associated with increased total screen time, including the total hours spent on computer, tv and video gaming. who just released guidance intended for people in selfquarantine without any symptoms or diagnosis of acute respiratory illness, containing a set of practical advice on how to stay active and reduce sb while at home. who further highlights how standard recommendations of 150 min of mvpa or 75 min of vpa per week, or a combination of both, can still be achieved even at home, with no special equipment and with limited space. there is a robust health rationale for staying active at home in the current precarious environment, for all age groups. the following are general recommendations, unless otherwise specified. you can meet weekly recommendations performing short bouts of pa, including taking the stairs, performing domestic chores, such as cleaning and gardening, or funniest activities such as dancing. walk and stand up take every chance to walk and stand up, like walking during a call, or taking a breath of fresh air, even just at the window. try not to sit continuously for more than 1 h, but rather to take a 1-2 min break every 30 min. alternatively, consider active breaks every 2 h of sb or distribute periods ≥10 min of continuous aerobic activity throughout the day. light-intensity activities like mobilizing the muscular masses and the joints are fine. older people can perform them even in sitting or semi-lying position. follow online exercise classes, play with children, help the elderlies to stay active take the advantage of free, virtual exercise classes on the web, devote more time to playing with children and encourage seniors to stay safe and active choosing suitable exercises for endurance, strength, balance, and flexibility. avoid screen time while playing with children in favor of funny activities and active playing. for children and teens, it is advisable to play with sports or fitness video games with motion sensor controls. performing light-intensity activities while assisting older people protects you from sedentariness. active play rather than screen time helps you and your children to avoid snacking. be regular have regular times for main meals, sleep, and wake-up calls. your sleep should be of sufficient duration and good quality. prioritize continuity and regularity rather than the intensity of the pa and gradually increase frequency, duration, and intensity. activity trackers and smartphone apps can help in monitoring your progress. in case of poor experience and poor physical fitness, be careful. specific recommendations and tips for children, adults, and elderly are further detailed in figure 1 . while recognizing the importance of confinement policies set up to contain covid-19 pandemic, we firmly recommend the relevance of home-based programs for figure 1 | physical activity, sedentary behavior, sleep recommendations, and tips for covid-19 quarantine period. blue, adults; gray, older people; orange, preschooler; yellow, school-aged children and adolescents; bold, international guidelines and recommendations; italic, tips for quarantine period; pa, physical activity; sb, sedentary behavior; lpa, light-intensity physical activity; mpa, moderate-intensity physical activity; vpa, vigorous-intensity physical activity; mvpa, moderate to vigorous-intensity physical activity. in the central portion of the figure we reported recommended hours of sleep by age group. *perform strengthening activities in non-consecutive days. +, ++, + + +: relative importance of pa/exercise type for each age category. dumbbell: muscle and bone strengthening activities; running: aerobic activities; monopodalic standing: balance exercise; bending: flexibility. disruption physical inactivity and sedentary behavior as a critical behavioral strategy for the prevention of global health and consequences of psychosocial stress during the current lockdown. fr and pi drafted the manuscript. all co-authors provided critical revision for important intellectual content. unprecedented disruption of lives and work: health, distress and life satisfaction of working adults in china one month into the covid-19 outbreak sanchis-gomar f. health risks and potential remedies during prolonged lockdowns for coronavirus disease 2019 (covid-19) physical inactivity and cardiovascular disease at the time of coronavirus disease 2019 (covid-19) mortality, and incident type 2 diabetes: a systematic review and dose response meta-analysis relationship of sedentary behavior and physical activity to incident cardiovascular disease: results from the women's health initiative coronavirus disease (covid-19): the need to maintain regular physical activity while taking precautions a tale of two pandemics: how will covid-19 and global trends in physical inactivity and sedentary behavior affect one another? prog cardiovasc dis associations between the home physical environment and children's home-based physical activity and sitting socio-cultural determinants of physical activity across the life course: a 'determinants of diet and physical activity' (dedipac) umbrella systematic literature review the authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.copyright © 2020 ricci, izzicupo, moscucci, sciomer, maffei, di baldassarre, mattioli and gallina. this is an open-access article distributed under the terms of the creative commons attribution license (cc by). the use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. no use, distribution or reproduction is permitted which does not comply with these terms. key: cord-253367-n6c07x9q authors: ussai, silvia; armocida, benedetta; formenti, beatrice; palestra, francesca; calvi, marzia; missoni, eduardo title: hazard prevention, death and dignity during covid-19 pandemic in italy date: 2020-09-18 journal: front public health doi: 10.3389/fpubh.2020.00509 sha: doc_id: 253367 cord_uid: n6c07x9q on 9 march 2020, italy passed the prime minister's decree n. 648, establishing urgent measures to contain the transmission of covid-19 and prevent biological hazards, including very restrictive interventions on public holy masses and funerals. italy banned burial procedures based (i) on the recent acknowledgment about the virus environmental stability as well as (ii) its national civil contingency plan. hence, only the cremation process is admitted for covid-19 deaths. viewing of the body is permitted only for mourners, which are allowed to perform the prayer at the closing of the coffin and the prayer at the tomb (cf. rite of succession, first part n. 3 and n. 5). the dead cannot be buried in their personal clothes; however, priests have been authorized to put the family clothes on top of the corpse, as if they were dressed. burying personal items is also illegal. the dignity of the dead, their cultural and religious traditions, and their families should be always respected and protected. among all the threats, covid-19 epidemic in italy revealed the fragility of human beings under enforced isolation and, for the first time, the painful deprivation of families to accompany their loved ones to the last farewell. ethics poses new challenges in times of epidemics. on 9 march 2020, italy passed the prime minister's decree n. 648, establishing urgent measures to contain the transmission of covid-19 and prevent biological hazards, including very restrictive interventions on public holy masses and funerals. italy banned burial procedures based (i) on the recent acknowledgment about the virus environmental stability as well as (ii) its national civil contingency plan. hence, only the cremation process is admitted for covid-19 deaths. viewing of the body is permitted only for mourners, which are allowed to perform the prayer at the closing of the coffin and the prayer at the tomb (cf. rite of succession, first part n. 3 and n. 5). the dead cannot be buried in their personal clothes; however, priests have been authorized to put the family clothes on top of the corpse, as if they were dressed. burying personal items is also illegal. the dignity of the dead, their cultural and religious traditions, and their families should be always respected and protected. among all the threats, covid-19 epidemic in italy revealed the fragility of human beings under enforced isolation and, for the first time, the painful deprivation of families to accompany their loved ones to the last farewell. ethics poses new challenges in times of epidemics. on march 24, 2020, the world health organization (who) released its guideline on "infection prevention and control for the safe management of a dead body in the context of covid-19" (1) . the document offers the most updated recommendations on the safe and dignified burial procedures of deceased persons with suspected or confirmed covid-19. these include, among others: (1) the lack of evidence-which does not mean that we may exclude the possibility of future evidence emerging-of human transmission to subjects having become infected from exposure to the bodies of persons who died with/for covid-19. this, in contrast with ebola or marburg diseases, where dead bodies are known to be associated with contagion; (2) the option for decedents with confirmed or suspected covid-19 to be buried or cremated; (3) respect of customs, with family's chance to view the body after it has been prepared for burials, using standard precautions at all times including hand hygiene; (4) body wrapping in cloth and deceased transfer as soon as possible to the mortuary area. who recommendations are released in the form of interim guidance, subjected to revision as new evidence becomes available. national healthcare authorities are fully empowered in leading local actions according to the context and customs. italian government adopted the highest level of precautions given its exceptional number of deaths (34.561, 20 june 2020) and the limited knowledge on this novel virus. on 9 march 2020, italy passed the prime minister's decree n. 648 (2) , establishing urgent measures to contain the transmission of covid-19 and prevent biological hazards, including very restrictive interventions on public holy masses and funerals. in coordination with the measures launched by the italian authorities, the italian conference of bishops (conferenza episcopale italiana) issued a statement describing actions taken by the vatican to limit the spread of covid-19 (3) . severe measures that entail stringent restrictions on freedom of movement and association affecting the right to decent burials can be hugely distressing for families, exacerbating their grief. when balanced against public health interests, a basic rule is that governments should employ the least restrictive means necessary to protect public health. during the emergency phase, italy banned burial procedures based (i) on the recent acknowledgment about the virus environmental stability (4) as well as (ii) its national civil contingency plan. hence, only the cremation process was admitted for covid-19 deaths. the visit to the body was equally forbidden by the health authority. therefore, in addition to the funeral ceremonies, any prayer at the closing of the coffin was suspended as well. viewing of the body was permitted only for mourners, which were allowed to perform the prayer at the closing of the coffin and the prayer at the tomb (cf. rite of succession, first part n. 3 and n. 5). the dead could not be buried in their personal clothes; however, priests have been authorized to put the family clothes on top of the corpse, as if they were dressed. burying personal items was also illegal. funeral gatherings were not permitted and family members of sars-cov-2 victims were either denied to participate at the burial as they themselves were, most of time, under quarantine. in order to minimize delays between time of death and cremation, deceased were taken straight to the cemetery where a brief rite of burial was celebrated. all the masses in suffrage of the deceased with the family have been postponed after the emergency. italy's mortuary industry has been overwhelmed as the number of dead kept rising. in bergamo, a city in lombardy region with the highest number of covid-19 cases in italy, the capacity to manage dead bodies exceeded. the time frame set by law from the death to the burial was up to 48 h. however, due to the unprecedented amount of deaths, certain areas experienced a 30 min turnover procedure because of the pressure created by the number of corpses, as caskets have been piling up in churches instead of the local cemeteries, which were full. the military stepped in to move about 70 coffins to other provinces and regions for timely burial procedures (5) . the cremation followed the standard procedure foreseen for biological hazard risk. for instance, in order to increase the capacity of each burial facility and in compliance with all hygiene requirements, safety and environmental regulations, alternative technical solutions have been allowed for each cremation to shorten the burial execution time, for example by accelerating the ignition of the coffin. the use of easily inflammable wooden coffins has been encouraged in cremation and only the use of a zinc inner bonnet was permitted. in case of massive transportation of crematorium coffins, these have been carried out with a closed truck, also military, to be disinfected properly after use, preferably internally covered with waterproof material easily washable. furthermore, in the cemetery register it was mandatory to indicate that the coffin was packed for the burial of the deceased with a contagious infectious disease by affixing the code "y" (6) . currently, the recovery phase is easing restrictions on funeral and burial procedures. family members (up to 15 people) can participate in the holy mass; any physical contact between the participants must be avoided. the funeral should preferably take place outdoors and it is mandatory the use of personal protective equipment (ppe) as well as the strict observance of the interpersonal safety distance of at least 1 m (7). on march 31, 2020 the italian government proclaimed a national day of mourning, inviting all public institutions to expose the italian flag at half-mast "as a sign of mourning for the victims of the coronavirus, of proximity to their families and of national participation in the condolences to the most affected communities." authors acknowledge that in the absence of any pharmaceutical intervention, the only strategy against covid-19 was to reduce mixing of susceptible and infectious people through early ascertainment of cases or reduction of contact. although biologic hazard prevention actions (including death management) have been praised by who, the possibility of imposing severe restrictions on death during covid-19 as adopted by the italian government raises important questions. the population requires and deserves assurance that the decision to enact these measures affecting vital cultural practices as faith-based services has been informed by the best attainable evidence. it is therefore relevant that policy makers maintain the public's trust through use of rigorous scientific assessment of risk and effectiveness. yet, burial restrictions in italy have been imposed without any individualized risk assessment. difficult questions will then arise, though. for example, was complete funeral ban necessary, or might the final goodbye be still said by families while practicing physical distancing? the dignity of the dead, their cultural and religious traditions, and their families should be always respected and protected. among all the threats, covid-19 epidemic in italy revealed the fragility of human beings under enforced isolation and, for the first time, the painful deprivation of families to accompany their loved ones to the last farewell. infection prevention and control for dead body management in the context of covid-19: interim guidance ulteriori interventi urgenti di protezione civile in relazione all'emergenza relativa al rischio sanitario connesso all'insorgenza di patologie derivanti da agenti virali trasmissibili. (ordinanza n. 648) -serie generale decreto "coronavirus": la posizione della cei persistence of coronaviruses on inanimate surfaces and their inactivation with biocidal agents altro giorno di lutto per bergamo: 70 bare sui camion dei militari oggetto: indicazioni emergenziali connesse ad epidemia covid-19 ministry of health publicly available datasets were analyzed in this study. this data can be found here: http://www.protezionecivile. gov.it. all persons listed as authors have contributed to preparing the manuscript and their authorship meets the international committee of medical journal editors (icmje) criteria. the authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.copyright © 2020 ussai, armocida, formenti, palestra, calvi and missoni. this is an open-access article distributed under the terms of the creative commons attribution license (cc by). the use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. no use, distribution or reproduction is permitted which does not comply with these terms. key: cord-254043-1slz1dvr authors: jamil, tahira; alam, intikhab; gojobori, takashi; duarte, carlos m. title: no evidence for temperature-dependence of the covid-19 epidemic date: 2020-08-26 journal: front public health doi: 10.3389/fpubh.2020.00436 sha: doc_id: 254043 cord_uid: 1slz1dvr the pandemic of the covid-19 extended from china across the north-temperate zone, and more recently to the tropics and southern hemisphere. the hypothesis that covid-19 spread is temperature-dependent was tested based on data derived from nations across the world and provinces in china. no evidence of a pattern between spread rates and ambient temperature was found, suggesting that the sars-cov-2 is unlikely to behave as a seasonal respiratory virus. on 30th january the who declared the novel coronavirus (covid-19) outbreak a public health emergency of international concern (http://www.euro.who.int/en/home). the epidemic spread gradually from wuhan province in china, to other asian nations, the middle east and europe. by early march the epidemic was mostly concentrated in territories extending between 30 and 50 • n (1), now in late winter, leading to the suggestion, echoed by the global media, that the epidemic is likely to be temperature-dependent. this supported speculation of possible decline in severity with the onset of warmer spring and summer temperatures in north-temperate latitudes (1, 2) , comparable to many viruses affecting human respiratory systems, including sars (3, 4) . however, recent (updated up to may 31, 2020; cf. methods) data revealed the spread of the epidemic across territories experiencing warm temperatures in the tropics (e.g., indonesia, singapore, brazil) and southern hemisphere as well (e.g., australia, argentina). the current distribution of the epidemic challenges, therefore, the inference that sars-cov-2 may behave as a seasonal respiratory virus based on previous statistical analyses from earlier realized distributions. here we examine the relationship between the apparent exponential rate of sars-cov-2 spread (γ ) and the effective reproductive number (rt) of infection and the average daily temperature (t avg ) across nations and chinese provinces where epidemics, with at least 1,000 cases reported, have been reported (data updated up to 31 may, 2020). the novel coronavirus (covid-19) daily data are confirmed cases for affected countries and provinces of china reported between 31st december 2019 and 31st may 2020. the data was collected from the reports released by who, european centre for disease prevention and control (ecdc), and john hopkin cssa. data include confirmed and a cumulative total of covid-19 cases in affected countries/provinces. the average temperatures of all the affected countries were collected from https://www.timeanddate.com/weather/. the monthly mean temperature of february to may 2020 of capital cities for the various nations were used as reference temperatures for the country. to avoid the estimates to be biased by confinement measurements rather than displaying the epidemic spread, we calculated the exponential rate and effective reproduction number (rt) of epidemic spread for the period of exponential growth in number of cases, which was defined as that showing a linear slope when plotting number of cases vs. time. we analyzed the data where the covid-19 incident has at least a 10-day growth period, and the total number of cases was at least 1,000. hence, we fitted the exponential model to each country and each province of china and calculated exponential rate parameters for the countries where n is the cumulative number of diagnosed persons and days is the number of days and γ is the exponential rate (100 x γ = % increase per day). to calculate the effect of temperature on the exponential rate parameter, we first regressed the exponential rate parameters retrieved from the exponential model on t avg and t 2 avg γ ∼ t avg + t 2 avg if the squared term is significant, it provides evidence of non-linearity. the thermal performance of covid-19 was characterized by fitting spread rate estimate or growth parameter (γ ) and temperature to the gaussian function; t avg is the average temperature (in • c) that best encompasses the growth period of covid-19 cases since its 100 incidences in a country/region of china. where, amplitude (a) is the coefficient related to maximum of spread rate of countries, the optimum (opt) on the temperature gradient is where the maximum of spread rate is attained and the tolerance (tol) gives the width of the response curve. this model has non-linear form, and the model parameters opt and tol occur non-linearly in the model function. parameter of thermal performance curve was estimated by fitting gaussian model to the growth rate and temperature of infected countries. the initial values for the gaussian parameters opt, tol, and a were obtained directly using maximum-likelihood polynomial regression for the gaussian function. estimated the effective reproductive number (rt), the average number of infections at time t, per infected case over the course of their infection for covid-19 for provinces of china and other countries using a discrete γ distribution with a mean of 4.8 days and a standard deviation of 3.5 days for the serial interval distribution. all analyses were performed using r statistical computing software. the data set is available from jamil et al. (5) . our results show that evidence for a temperature-dependence of the transmission reported in previous papers was likely to be spurious, reflecting the pathways of spread, and that there is no evidence for thermal dependence of the transmission across the 1-34 • c t avg range across the affected regions. this suggests little basis to expect evidence for the virus to behave as a seasonal respiratory virus. epidemiological data consisting in the rate of increase in accumulated diagnosed cases among nations (global) shows γ ranging from 3.4% day −1 to 25.8% day −1 (figure s1) , with an average of 12.06 ± 0.45 % day −1 (figure 1, figure s1 ), and apparent rt of 1.4 ± 0.02 (figure 1) . surprisingly, γ and rt across chinese provinces (mean ± se = 10.17 ± 0.96 % day −1 and 1.17 ± 0.04) were below those of other nations (mean ± se = 12.06 ± 0.45 % day −1 and 1.4 ± 0.02), possibly because much faster confinement of the chinese population did not allow for the potential exponential rates under uncontrolled conditions to be realized. the broad variability in realized γ and rt between nations (global) and provinces (china) largely reflects differences in detection likelihood along with the timing and rigor of adoption of confinement measures. the relationship between γ and rt and t avg shows no evidence for a reduced spread rate with warming (figure 1) , unlike analyses based on previous data. a number of nations with t avg > 20 • c, including subtropical and tropical (brazil, qatar, saudi arabia, uae, india, and indonesia), and southern-hemisphere (peru, chile, argentina) nations (figure 2) , support γ and rt above the median values of 11.3% day −1 and 1.38, respectively (figure 1) . however, the same analysis conducted on earlier data of 15th march, did provide some evidence for low γ and rt for t avg > 20 • c (figure s2 ). our updated results (figure 1 ) and same analysis conducted on 27th march and 31st may (figures s3, s4) show, however, that this apparent temperature-dependence was confounded with a prevailing zonal pattern of spread across the north-temperate zone, possibly reflecting the main patterns of human mobility, which delayed arrival of the epidemics to the southern hemisphere and the tropics. the results suggest that, contrary to prior assessments, the spread rate of the covid-19 pandemic is temperature-independent, suggesting that there is little hope for relief as temperatures in the northern hemisphere increase, and that poor nations with weak health systems in tropical regions, such as african, are at great figure 1 | the relationship between the apparent exponential rate of sars-cov-2 spread (γ ) and the effective reproductive number (rt) and the average daily temperature (t avg ) across nations and chinese provinces for the period of exponential growth in number of cases of covid-19 (data last accessed june 1, 2020, figure s1 ). green symbols represent provinces in china while red symbols represent other nations. frontiers in public health | www.frontiersin.org figure 2 | spatial distribution of the apparent exponential rate of sars-cov-2 spread (γ ) and the effective reproductive number (rt) and the average daily temperature (t avg ) across nations (data last accessed june 1, 2020). risk. analysis based on studies in china reported contrasting relationship between spread rate and temperature, ranging from positive relationship reported for wuhan, china (6), for chinese cities with very low (< 3 • c) ambient temperatures (7) , or positive (8) or negative (9) relationships for provinces across china, and lack of relationship between spread rates and temperature across cities in china (10) . we believe that the conflicting nature of these results may derived, as shown for our analysis at the global scale prior to may 15, from confounding factors, including the spread across provinces in china as well as confinement policies. in contrast to these analyses for china, based on the analysis of single time periods and including provinces and cities with very low number of cases, where calculations involve significant uncertainty, we repeated our analysis across time period spanning 3 months, as well as an analysis based on the initial exponential spread, before confinement measures flattened the spread rate. indeed, our analysis, including provinces across china, unveiled the risk of such spurious relationships, such as that obtained using global data until 15 march, 2020, due to confounding factors associated with the routes of spread of the epidemic. similar partial evidence for a decrease in spread rates with increasing temperature for barcelona. spain (11) , is likely to have also confounded the relationship between temperature and spread rates with the effects of confinement policies that reduced spread rates in that city as temperature increased during the study period. hence, our findings at the global scale, and consolidated across multiple time periods following the pandemic state, reject the hypothesis of a relationship between covid-19 spread rates and ambient temperature, consistent with those of recent studies that also reported no evidence for an association of epidemic growth with temperature using different approaches and data (12) . many countries have employed strong lockdown and mandated school closures and restrictions of mass gatherings, social distancing to slow the growth of covid-19 pandemic, which have successfully contained the spread on most cases. our results suggest that release plans from confinement should not assume that spread rates will decrease with warm summer temperatures. data sources: the data on covid-19 is available publicly across many sources; where downloadable data files are updated daily few are listed below; world health organization(https://www.who.int/emergencies/ diseases/novel-coronavirus-2019/situation-reports/ cd and tj conceived, designed the research, and wrote the first draft. tj conducted the analysis. all authors contributed to improving the paper and approved the submission. this research was supported by funding provided by the king abdullah university of science and technology to the cbrc. the supplementary material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fpubh. 2020.00436/full#supplementary-material figure s1 | the apparent average (± se) exponential rate of sars-cov-2 spread (γ ), the average (and 95% confidence limits) of effective reproductive number of infection (rt) and the average daily temperature (t avg ) total case and number of days of the exponential growth period across nations and chinese provinces where epidemics have been reported (data updated through may 31, 2020). figure s2 | the relationship between the apparent exponential rate of sars-cov-2 spread (γ ) and the effective reproductive number of infection (rt) and the average daily temperature (t avg ) across nations and chinese provinces where > 100 cases of covid-19 have been reported, as of figure 1 , but with data updated only until 15th march. the gaussian function with temperature provided a significant fit for γ with temperature. figure s3 | the relationship between the apparent exponential rate of sars-cov-2 spread (γ ) and the effective reproductive number of infection (rt) and the average daily temperature (t avg ) across nations and chinese provinces where > 100 cases of covid-19 have been reported, as of figure 1 , but with all data updated only until 27th march. figure s4 | the relationship between the apparent exponential rate of sars-cov-2 spread (γ ) and the effective reproductive number of infection (rt) and the average daily temperature (t avg ) across nations and chinese provinces, as of figure 1 , but with all data updated until 31st may. temperature, humidity, and latitude analysis to estimate potential spread and seasonality of coronavirus disease 2019 (covid-19) temperature significant change covid-19 transmission in 429 cities. medrxiv an initial investigation of the association between the sars outbreak and weather: with the view of the environmental temperature and its variation epidemiology and clinical presentations of the four human coronaviruses 229e, hku1, nl63, and oc43 detected over 3 years using a novel multiplex real-time pcr method global data set on spread of covid-19 and ambient temperature effects of temperature variation and humidity on the death of covid-19 in wuhan association between ambient temperature and covid-19 infection in 122 cities from china impact of temperature on the dynamics of the covid-19 outbreak in china covid-19 transmission in mainland china is associated with temperature and humidity: a time-series analysis no association of covid-19 transmission with temperature or uv radiation in chinese cities is temperature reducing the transmission of covid-19? impact of climate and public health interventions on the covid-19 pandemic: a prospective cohort study the authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.copyright © 2020 jamil, alam, gojobori and duarte. this is an open-access article distributed under the terms of the creative commons attribution license (cc by). the use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. no use, distribution or reproduction is permitted which does not comply with these terms. key: cord-342517-bzmhjvr5 authors: rassouli, maryam; ashrafizadeh, hadis; shirinabadi farahani, azam; akbari, mohammad esmaeil title: covid-19 management in iran as one of the most affected countries in the world: advantages and weaknesses date: 2020-09-15 journal: front public health doi: 10.3389/fpubh.2020.00510 sha: doc_id: 342517 cord_uid: bzmhjvr5 covid-19 management is a hot topic due to its extensive spread across the world and the declaration of pandemic status. how a crisis is managed in each country is influenced by several factors, and various strategies are applied in accordance with these factors in order to manage the crisis. due to the rapid spread and increasing trend of the crisis and the fact that almost more than half of the countries are engaged in this pandemic, it is impossible to apply trial-and-error based strategies. one of the best strategies is to use the experiences of other countries in dealing with covid-19. this report explores the advantages and weaknesses of the islamic republic of iran in the management of this crisis in regard with political economic and cultural issues, health service coverage, and the transparency of information that can be used as a model for other countries around the world. the islamic republic of iran, as the second country to declare two deaths due to coronavirus, within 50 days after china on february 18, 2020 (1), is still one of the countries to deal with most cases of covid-19 infection and the subsequent deaths (2) . obviously, managing the disease, which is considered a pandemic according to the world health organization (3) , requires specific strategies that may vary due to different factors in each country, which may either lead to effectively dealing with the disease or cause challenges. considering the fact that using global experience, especially in times of crisis, is one of the best crisis management mechanisms, a review of the strengths and weaknesses of the islamic republic of iran in the covid-19 management covering the political-economic aspects, health services coverage, cultural aspect, and the transparency of information can be used as a model by other involved countries, while at the same time benefiting from the strategies of countries with similar experiences. health is not only a biological, but also a political, social, cultural, and economic issue. "health is a political issue" has been a point of consensus for a long time (4) . therefore, the ability of countries to manage covid-19 is strongly influenced by their political-economic conditions which can be considered both an advantage and a threat. thus, it can be said that sanctions as a political-economic factor, more than any other factor, have challenged iran's ability to cope with covid-19. covid-19 spreads in iran at the same time as the most severe sanctions are imposed on iran. although over the past four decades various sanctions have always been imposed on iran, since may 2019, the unilateral us sanctions against iran have been increased significantly (5) . the iranian health system has been directly and indirectly impacted by these sanctions, although it is one of the most prominent health systems in the eastern mediterranean region (6) . although it is believed that sanctions are imposed on the physical weapons of war and do not include medicines and medical equipment, due to difficulties in commercial and financial exchanges with most countries, some essential medicines and laboratory equipment especially diagnostic, medical, and protection kits are not sufficiently available. in addition, numerous sanctions in the field of publishing research articles impede the international community's awareness of the consequences of such sanctions. on the other hand, as an advantage, the influential presence of effective and socially acceptable positions such as the iranian supreme leader as the highest religious authority and commander-in-chief can be named which helped in facing many unbearable challenges rooted in the beliefs, the culture and the religion of iranian people, by taking measures such as ordering the general staff of the armed forces to assist with the implementation of the regulations made by the supreme national security council, thanking the medical community on many occasions, advising on the implementation and acceptance of the by-laws of coronavirus committee, and issuing the closures of sacred shrines and the suspension of friday prayer (7) . in regard to the second dimension, the health system capacity and service coverage of iran have a suitable condition with 65 schools/universities of medical sciences integrated with health services as the unique country in the world is responsible for covering the whole people's needs. in iran, where measures have been taken regarding the primary health care (phc) since 5 years before the alma-ata declaration (1978) the use of the network system is considered as one of the main mechanisms of coping with covid-19 in a ratified the health system. however, upon the prevalence of covid-19 in the country, much potential was ignored, one of which was the capacity of the phc system with ∼21,500 centers in rural areas and ∼8,000 health centers in the governmental sector. however, after a while, part of the outpatient management protocol was assigned to this extensive network for home-to-home screening and the information on the health status of all iranians was registered in a system. therefore, it is possible to follow up on individuals by having access to the patients' contacts and other information (8) . in addition, not assigning epidemiologists at the right time to determine indicators such as fatality and mortality was among the weaknesses that disturbed predictions for estimating care and diagnostic needs. although many research centers in the country have begun to develop high-sensitivity and specificity diagnostic kits and these experiments are carried out in 50 laboratories, it is still not possible to perform tests on all potential cases. on the other hand, the dissemination of viruses firstly began in the central regions of the country and then intensively spread to other regions (9). the sudden increase in the number of cases led to a shortage of hospital beds in the referral hospitals initially dedicated to these patients, although there are ∼130,000 private and public hospital beds in iran. this shortage, which has been a concern of the authorities in all provinces, has led to the establishment of care centers after the early discharge of patients from referral hospitals or outpatient admission prior to hospital admission. although the establishment of these centers took place in the middle of march, with the launch of command headquarters, it was attempted to refer patients to these centers after the acute period of the disease was passed if they could not be discharged to home, or to become a center for mild patients. an interesting point in the management of these centers is the combination of military staff and volunteer or hospital personnel that may be somewhat different from international standards as these centers should apparently be managed by military forces to prevent hospital personnel from being separated from their workplace. on the contrary to the above weaknesses, the diagnosis, treatment, and follow-up of symptomatic and infected patients have been free from the very beginning. a variety of therapeutic and diagnostic protocols have been developed in the form of clinical trials. in this regard, coronavirus molecular diagnostic network and anti-coronavirus scientific committee consisting of faculty members of the iranian universities of medical sciences, and specialists, and experts in various fields with the aim of collaborating with the ministry of health and medical education (mohme). the launch of mohme online patient screening system for screening more than 75 million people so far and controlling the outbreak was among the effective measures taken to reduce referrals to health centers and reduce the risk of infection in healthy people, of which 146,000 were discovered and referred to health centers (10) . as the third dimension, culture has always been considered one of the effective factors on health (11), the importance of which is particularly clear in the covid-19 pandemic. the iranian new year's celebration (march 21th) is thousands of years old symbolizing renewal in all aspects for iranians. therefore, all people prepare for nowruz from the middle of february which is apparent from the high traffic and crowds of people walking in the streets and all parts of cities. on the other hand, the nearly 15-day holiday of nowruz is a time for iranians to make many trips. thus, the concurrency of covid-19 pandemic with these days, which happened similarly in china, led to possibly the highest rate of interpersonal contact in the community, and the city-to-city spread of the disease by nowruz travelers. although there is a lack of cooperation and attention to the health guidelines by some people, the cooperation of many other members of the community is exemplary. the adherence to the slogan "we stay at home" and avoiding social interactions, performing volunteer activities such as the disinfection of public areas, the voluntary presence at patients' bedside, gooddoers' helping provide and produce protective equipment such as scrubs and masks, changing factory production lines to manufacture and prepare disinfectants, gloves, etc., landlords' not receiving rental fees, and obeying the supreme leader's orders not to visit sacred shrines and sanctuaries are examples of the culture of sacrifice among iranian (12) . the last point is that the information provided by iranian authorities is always regarded as the most reliable information unless, for some reason, this transparency is compromised. despite the daily reports of the number of the infected, recovered cases and deaths by the mohme, the negative propaganda in foreign media and cyberspace has been able to effectively worsen the community's attitude toward the iranian management. this negative wave targets a wide range of issues from the number of deaths reported by the authorities to the news of digging mass graves for the victims and even suggests iran as the center for spreading the disease through its international airports, even in cities with no airports. everything considered, while disturbing public opinion, this will lead to distrust toward iran's effectiveness in dealing with the outbreak in this country (13) . overall, what has helped iran control the disease so far can be summarized in several factors: the managerial concept all governance, although delayed, was strongly implemented were religious leaders along with military forces and civil volunteers accompanied the mohme. on the other hand, the powerful phc infrastructure and therapeutic, care, and specialized workforce which is appropriately distributed, due to the spread of the universities of medical sciences all across the country, have played important roles in disease management. despite the actions taken to create an atmosphere of distrust, the honesty of the authorities even in regard to the shortage of resources and equipment is considered an advantage in iran. and finally, given iran's specific circumstances, the focus should be put on domestic production, rather than importing equipment, to soon change the country into an exporter of health goods. in regard with the weaknesses of the system in dealing with the disease, due to the shortage of diagnostic kits at the onset of the disease in the country and its impact on the infected cases and subsequent deaths, some contradictory statistics have been presented which have led to the misinterpretation of the statistics and influenced planning for hospital beds, and hospitalization and patient care facilities. the shortage of data, the epidemiologists' lack of engagement in investigating the disease trend, and presenting different scenarios have also contributed to this matter. the lack of personal protective equipment for the frontline staff and people is also a challenge for the health system that has resulted in the death of a number of physicians and nurses. furthermore, the lack of advanced equipment for the care of critically ill patients in intensive care units, as a result of sanctions, is what requires to be managed. in summary regarding the detection of new cases and rapid responses health authorities did the best by supporting people but tracing the cases were not in an appropriate status, they asked them to stay home by family responsibility, but it did not work in some cases and the infected cases were in touch with the public. we did not use the temporary care centers as a part of the phc facility, social distancing was were supported by other stakeholders not managing by health managers, which may not be promising effective in the future. ultimately, it is certain that the covid-19 pandemic will end as did all previous ones, although it obviously will not be the last. therefore, the lessons learned from managing it in each country and sharing it with other countries can help prepare the world to deal with future pandemics. all datasets presented in this study are included in the article/supplementary material. modeling and prediction of the 2019 coronavirus disease spreading in china incorporating human migration data. medrxiv coronavirus cases prevention ucfdca health is a political issue covid-19 battle during the toughest sanctions against iran the eastern mediterranean region: a decade of challenges and achievements thanks to the supreme leader for the efforts of physicians and nurses in the fight against the corona virus health information system in primary health care: the challenges and barriers from local providers' perspective of an area in iran daily statistics of covid-19 in iran people's screening system culture, behavior and health university-industry cooperation, a mechanism to deal with the corona virus estimation of covid-2019 burden and potential for international dissemination of infection from iran. medrxiv all authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication. the authors would like to appreciate the managers of the shahid beheshti university of medical science for their support. key: cord-259619-sco0d5cc authors: ludvigsson, johnny; von herrath, matthias g.; mallone, roberto; buschard, karsten; cilio, corrado; craig, maria; ilonen, jorma; leslie, david; mcgeoch, julie e. m.; schneider, darius; skyler, jay s.; flodström tullberg, malin; hober, didier title: corona pandemic: assisted isolation and care to protect vulnerable populations may allow us to shorten the universal lock-down and gradually re-open society date: 2020-09-30 journal: front public health doi: 10.3389/fpubh.2020.562901 sha: doc_id: 259619 cord_uid: sco0d5cc nan severe acute respiratory syndrome coronavirus-2 (sars-cov-2), the virus that causes coronavirus disease 2019 (covid19) , has emerged as a major threat to mankind. the proportion of those dying from covid-19 is highest in the elderly population and those with pre-existing co-morbidities (such as severe obesity, hypertension, diabetes, cancer, chronic respiratory, renal, or cardiovascular disease) (1) (2) (3) (4) . as individuals can spread the virus rapidly without exhibiting any symptoms, multiple countries have taken steps to shut down schools, universities, whole companies and businesses, and entire villages, towns, and countries have been isolated. these drastic measures will have enormous economic, public health, and psychological consequences (5) (6) (7) (8) (9) . it is likely that we are significantly underestimating the prevalence of covid-19. the proportion of asymptomatic infected individuals has been estimated between 17.9% (10) and 51% (11) , but could be as high as 80% (12) . it has not been established whether transmission can occur before symptoms appear, but the virus has been detected in the stool of an asymptomatic child (13) and there are indications of transmission from asymptomatic carriers (14) . in some countries, it may be too late to sufficiently "flatten the curve" (15) based on a universal lock-down strategy. coercive measures could be counterproductive and erode public trust and cooperation (16) . moreover, it is of great concern that large-scale lock-down of society has many additional negative impacts. it is of critical importance therefore that more refined strategies are considered, which may help containing the pandemic whilst minimizing significant societal disruption, and help allocate resources in the most effective ways. others have pointed out that, despite the breadth and allure of travel bans and mandatory quarantine, an effective response to sars-cov-2 requires newer, more creative legal tools but without clear recommendations on how to achieve this (17) . while certain countries start to re-open their societies and borders, most remain on lockdown measures to different extents. we suggest here that more selective assisted isolation of vulnerable populations would reduce the predictable increase in hospital admissions and more rapidly alleviate the fallout from total lockdown measures. sars-cov-2 infection rarely leads to symptoms in people below 20 years of age (18) and usually causes mild symptoms in people up to the age of 50 years (19) . additional risk factors (2, 4, 20) negatively impact the outcome, and may potentially include high dose exposure in health care settings. even though covid19 sometimes leads to need for treatment at intensive care units (icu) also for younger individuals, the virus appears most dangerous for a selected group of the most vulnerable people. in several countries, the average age of the deceased patients is around or above 80 years. we must consider diverting our major efforts to protect the vulnerable-elderly and patients with preexisting comorbidities-by providing safe and assisted isolation and care; not least now that lockdown rules start to be relaxed. the vulnerable have to receive the necessary support to stay home, isolated, until it is safe again for them to return to normal life with social and physical contacts. 1. identify and provide uninfected caregivers who do not spread the virus. preferentially and ideally, these people will already have had covid19 and have cleared the infection. with blood tests that measure antibodies against sars-cov-2 (21) we now have the tool to identify a majority of individuals that have had and cleared the infection. in some individuals the sars-cov-2 antibody response may be too be too low to be detected and before tests assessing t cell immunity become available for routine use all subjects with negative tests must be assured to be non-immune and tested by rna-based tests that can detect sars-co-v-2 rna in respiratory specimens. these tests must be performed routinely and regularly in people who assist isolated people. the ability to test large numbers of individuals, rapidly, repeatedly and effectively, for the presence of the virus, and for the existence of immunity is a cornerstone of this strategy. certification of tests should be fast-tracked, as time is of essence here. 2. educate caregivers on how to avoid spreading the virus, including hygiene rules and provision of personal protective equipment, including respiratory protective and risk mitigation measures. 3. establish programs for home delivery of food, medications, and other essential items, to avoid unnecessary exposure, especially of the vulnerable populations. clear protocols for handling and cleaning the delivered goods must also be established. 4. provide shelter for those infected, isolating them from family members, and to those who are already in the proximity of infected family members to avoid transmission from asymptomatic family members to vulnerable ones. 5. in parallel, isolation of individuals with symptoms, diagnosed cases, and their contacts should continue (22) . these measures are per se not easy to accomplish but might be more efficient than the universal lockdown that is being pursued in different countries to different degrees. how can we most safely and rapidly revert to "normal"? here, we face two main options and some potentially risky and tough choices. a. the prolonged complete lockdown is not sustainable for an extended period of time due to its drastic and increasing economic and societal fallouts. -even if successful, universal curfews would have to be implemented over many months, with unforeseeable consequences on society in many ways. still, there are then billions of virus-naïve people who could potentially support new outbreaks. -the economic collapse with mass unemployment will have deleterious effects on health, including increasing mortality also in younger age groups. as an example, the much less severe economic turbulence of 2009 was calculated to cause the death of 260,000 individuals just by cancer (5), and the negative effects on health in the developing countries was very large (6). -in addition, these measures will, over time, destabilize society, not only through tremendous economic losses, but also through the risk of increasing social unrest and the psychological consequences of social isolation (7, 9) . selective damage to people with vulnerable job categories, particularly in countries without adequate social network safety, will put them in desperate situations and soon left without options (8). -lastly, one could argue that a functioning economy and intact supply chains will better enable us to protect the more vulnerable and limit severe outcomes. we will then have enough hospital/icu beds to take care of those who will need them. b. protect the vulnerable and then progressively ease overall restrictions. we must carefully consider and follow the emerging epidemiological data, especially the number of infections with severe outcome in younger individuals and those without preexisting conditions, before coming to premature conclusions. however: -the intensification of measures to protect the vulnerable must be implemented in priority. -once these measures established, day-care centers, schools, and colleges could re-open, to care for young children whose parents are unable to provide full-time care due to essential professions to prevent them from being cared for by grandparents, who need protection, not exposure. -in the meantime, the general population of less vulnerable and mostly younger people should still respect physical distancing and hand hygiene standards. this includes having sufficient sanitizers provided in public places, e.g., in stores at checkout lines, or public transport. anyone in this group who exhibits any potential covid-19 symptoms should immediately follow the recommended self-isolation procedures and not return to society until after having been symptom-free for 2 days. otherwise, they should live near normally, work, go to school, go to shops, and consume to prevent economic downturns. -economic support from governments and banks should be provided, especially for those industries/small businesses that experience a shortfall or have been forced to close down (i.e., travel, hotels, restaurants, cruises, artists, concert halls, etc.), because the vulnerable must stay isolated. urgent funding is also required for hospitals, laboratories, and researchers to enable the fastest possible development of diagnostic assays and new therapies. -gradually then, a substantial proportion of the less endangered population will become infected by sars-cov-2 and develop immunity, leading to a gradual end of the epidemic (something that might already be happening in hotspots). more universal testing for active virus and anti-viral antibodies could then be used to determine when it would be time to advise the vulnerable to resume a regular and normal life again. we hypothesize that such a wellcontrolled shorter bubble could work in our favor, allowing resumption of societal functioning and resource generation until clinically proven treatment options for the critically ill and vaccines become available. there have been several pandemics in recent decades such as the asian flew, the honkong flew, the swine flew, etc., with great losses of lives, but without the dramatic influence on societies as the present pandemic. the approach to contrast the covid19 (or sars-cov-2) pandemic varies greatly among countries. intensive testing coupled with tracking and isolation has at least so far indeed bent the curve so far in south korea and new zealand, possibly, also in singapore, hong kong, and china (the latter with rather drastic containment measures). however, these measures have isolated subjects at risk, but have not increased immunization of the population with so called herd immunity through the transient infection of the less vulnerable. hence, they still leave plenty of risk for re-emerging outbreaks, as increasingly reported. the strategy we propose is more sustainable in the long term, protecting the vulnerable population while we wait for herd immunity to be established, either through natural infection among the lower-risk population or a vaccine. otherwise, society would be forced to remain closed, or return to lockdown. sweden has used a policy rather similar to our recommendations to protect vulnerable groups, without a frontiers in public health | www.frontiersin.org total lock-down of the society. day-care centers and schools, shops, and even restaurants have remained open, while maintaining hygiene and physical distancing recommendations to slow down spreading of the disease. the covid-19 curve has been flattened enough to maintain 20-30% of icu capacity available (23) . difficulties to keep elderly completely isolated has caused loss of many lives, but mainly among people >80 years (median age 84 years for those who have died) with co-morbidities and limited life expectancy. yet, the death rate has remained similar or sometimes even lower than in several other european countries hit by the epidemic at the same time (figure 1 ). all curves tend to a slower rate over 8 months irrespective of the degree of lockdown measures implemented. one explanation for the rather similar death rates caused by the pandemic could be that in every country there are many undocumented mild cases that spread the disease and overall a degree of herd immunity is developing. australia, due to strict lockdown now has an increase, and the numbers of new cases with covid19 are increasing in several european countries with previous strict lock-down. although some economic depression has been unavoidable because of both decreased consumption and the dependence on global economy, according to the european union the economy is expected to be less negatively impacted in sweden than in countries with total lock-down measures. in conclusion, we here offer some considerations on possible paths to ease out of restrictions with a focus on protecting the vulnerable, decreasing the load on hospital, health force and caregivers, and promoting immunity in the population to reduce the risk of future epidemics. politicians will have to face the natural unease accompanied with releasing restrictions under such measured conditions. still, it is key to balance restrictions with the stage of the epidemic in certain areas and with the long-term impacts that broad and severe restrictions will have. once we emerge from the acute phase of this tragedy, we will have to divert much of our resources to preventive measures to avert future impacts of emerging viral and bacterial infections. jl and mvh wrote the first draft. dh, ds, and mf added some references. all authors revised the manuscript and approved the final version. coronavirus disease 2019 (covid-19) and cardiovascular disease clinical course and risk factors for mortality of adult inpatients with covid-19 in wuhan, china: a retrospective cohort study cardiovascular considerations for patients, health care workers, and health systems during the coronavirus disease 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transmission dynamics of the covid-19 outbreak and effectiveness of government interventions: a data-driven analysis us emergency legal responses to novel coronavirus balancing public health and civil liberties covid-19 -the law and limits of quarantine systematic review of covid-19 in children show milder cases and a better prognosis than adults transmission potential and severity of covid-19 in south korea clinical characteristics of novel coronavirus cases in tertiary hospitals in hubei province a serological assay to detect sars-cov-2 seroconversion in humans feasibility of controlling covid-19 outbreaks by isolation of cases and contacts the swedish intensive care register we are grateful to the more than hundred scientists who have participated in the discussion leading to this paper. the authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.copyright © 2020 ludvigsson, von herrath, mallone, buschard, cilio, craig, ilonen, leslie, mcgeoch, schneider, skyler, flodström tullberg and hober. this is an openaccess article distributed under the terms of the creative commons attribution license (cc by). the use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. no use, distribution or reproduction is permitted which does not comply with these terms. key: cord-315609-naqo1m0r authors: prayuenyong, pattarawadee; kasbekar, anand v.; baguley, david m. title: clinical implications of chloroquine and hydroxychloroquine ototoxicity for covid-19 treatment: a mini-review date: 2020-05-29 journal: front public health doi: 10.3389/fpubh.2020.00252 sha: doc_id: 315609 cord_uid: naqo1m0r at this time of the covid-19 pandemic, potentially effective treatments are currently under urgent investigation. benefits of chloroquine and hydroxychloroquine for the treatment of covid-19 infection have been proposed and clinical trials are underway. chloroquine and hydroxychloroquine, typically used for the treatment of malaria and autoimmune diseases, have been considered for off-label use in several countries. in the literature, there are reports of ototoxic effects of the drugs causing damage to the inner ear structures, which then result in hearing loss, tinnitus, and/or imbalance. this mini-review represents a summary of the findings from a systematic search regarding ototoxicity of chloroquine and hydroxychloroquine in the published literature. the characteristics of sensorineural hearing loss and/or tinnitus after chloroquine or hydroxychloroquine treatment can be temporary but reports of persistent auditory and vestibular dysfunction exist. these are not frequent, but the impact can be substantial. additionally, abnormal cochleovestibular development in the newborn was also reported after chloroquine treatment in pregnant women. the suggested dose of chloroquine for covid-19 infection is considerably higher than the usual dosage for malaria treatment; therefore, it is plausible that the ototoxic effects will be greater. there are potential implications from this review for survivors of covid-19 treated with chloroquine or hydroxychloroquine. patient reports of hearing loss, tinnitus, or imbalance should be noted. those with troublesome hearing loss, tinnitus and/or imbalance are encouraged to be referred for hearing evaluation and interventions once they are stable. clinical trials of chloroquine or hydroxychloroquine should also consider including audiological monitoring in the protocol. at this time of the covid-19 global pandemic, potentially effective treatments are currently under urgent investigation. currently, there is no evidence from randomized clinical trials that any specific therapy improves outcomes in patients with covid19 (1). chloroquine and hydroxychloroquine are considered to be promising repurposed drugs against covid-19, based on pathophysiological considerations and in vitro results (2, 3). these drugs have received particular attention as they are widely available and inexpensive. chloroquine and hydroxychloroquine, quinine-related compounds, have been used for the treatment of malaria and chronic inflammatory diseases such as systemic lupus erythematosus and rheumatoid arthritis. the anti-viral and anti-inflammatory properties may account for the efficacy in treating patients with covid-19 infection (4). there have been reports that patients who received chloroquine or hydroxychloroquine had faster virological clearance (5, 6) , however there are some limitations of the studies such as small sample size and questionable methodology. there is no high-quality evidence of potential benefit of these drugs at the moment. presently, there are over 80 registered ongoing trials worldwide examining the role of chloroquine and hydroxychloroquine in covid-19 treatment (7) . clinical practice guidelines have considered chloroquine and hydroxychloroquine for off-label and compassionate therapies against moderate to severe cases of covid-19 in several countries including china, korea, usa, france, italy, and belgium (8) . there is currently also a massive global demand for chloroquine and hydroxychloroquine as people around the world are self-medicating after health professionals and politicians have endorsed the drugs. chloroquine and hydroxychloroquine are also freely available in the uk and other countries without prescription. some potential side effects of chloroquine and hydroxychloroquine are cardiac arrhythmias, retinopathy, and muscle weakness (4). the clinical and research literature also contains reports of ototoxic effects after chloroquine and hydroxychloroquine treatment. ototoxicity refers to drug-related injury causing damage to the inner ear structures, which then result in hearing loss and/or tinnitus (the subjective perception of sound such as ringing, hissing, or buzzing, without an external source), and/or imbalance (9) . permanent hearing loss can adversely affect cognitive health (10) and mental well-being (11) . troublesome tinnitus is associated with insomnia, poor concentration, anxiety and depression (12) . the mechanisms of chloroquine associated hearing loss include cochlear outer hair cell dysfunction, and inhibition of post synaptic sodium channel function in cochlear spiral ganglion cells (13) . additionally, some alterations in central auditory function, which may trigger tinnitus, have been observed after quinine administration (13) . this mini-review represents a summary of the findings from a literature search regarding ototoxicity of the drugs in the published literature as well as the discussion of potential implications for survivors of covid-19 so treated. a systematic literature search on medline and embase platforms was undertaken on 26th march 2020, updated on 23rd april 2020. the search strategy combined mesh terms and keywords of chloroquine or hydroxychloroquine, ototoxicity, hearing loss, hearing, tinnitus. english language publications containing relevant data to this review were included. data extraction items included year, study design, sample size, and audiological outcomes. data were collated in the table and then summarized by narrative synthesis. recommendations from audiological professional perspectives were then made. eleven publications, reporting topics associated with ototoxic effects of chloroquine, were identified and are summarized in table 1 . the year of publication ranged from 1954 to 2015. there were 7 case reports, 2 observational studies, 1 case control study, and 1 review article. the sample size of the study participants varied from 1 to 74. ten patients (8 adults and 2 children) in 6 publications had either abnormal audiogram or reported hearing loss after chloroquine treatment. three out of ten cases had temporary sensorineural hearing loss after chloroquine treatment that improved after cessation of the medication (14, 19) . a prospective observational study in 2015 concluded that ototoxic effects of chloroquine at regular doses for malaria treatment (1.2 g daily for 3 days) were fully reversible (14) . sensorineural hearing loss after chloroquine in a 6-year old girl was partially reversible after prednisolone administration (19) . however, permanent severe sensorineural hearing loss has also been reported in 2 cases (17, 20) . additionally, reversible chloroquine-induced cochlear injury was detectable by brainstem audiometry in 13 out of 70 patients despite normal pure tone audiogram results (18) . tinnitus has also been reported concurrently with persistent hearing loss in 1 case (20) . imbalance was reported in 3 cases (14, 19, 20) . while there was no difference in hearing thresholds between children who were and were not exposed to chloroquine during gestation (16) , there were 3 case reports of intrauterine effects of chloroquine associated with abnormal cochleovestibular development in newborns (21, 22) . six case reports, describing ototoxic effects associated with hydroxychloroquine, were identified and are displayed in table 2 . publication year ranged from 1998 to 2018. sensorineural hearing loss was identified after hydroxychloroquine treatment in five adults and two children. the sensorineural hearing loss was found to be either reversible (25, 28) or irreversible (24, 29) . the onset of hearing loss after hydroxychloroquine treatment varied from 1 month (25) to several years (29) . tinnitus was also reported concomitantly with hearing loss in 2 cases (24, 28) . the manifestation of sensorineural hearing loss and/or tinnitus and/or imbalance after chloroquine and hydroxychloroquine can be either temporary or permanent. most of the studies on this topic were case series or case reports with only a few observational studies. information from a definitive large study with good methodology is still lacking. ototoxicity after chloroquine use tends to be more sudden, while assessment of short term chloroquine-induced ototoxicity in malaria patients (14) subramaniam and vaswani (14) prospective observational study 30 (aged 14-58 years old) 1200 mg loading load then 600 mg oral every 12 hours for 2 days -2 subjects showed a change in hearing thresholds on high frequency audiometry (8) (9) (10) (11) (12) . pure tone audiometry showed bilateral mild sensorineural hearing loss at 12 khz in 1 subject, and bilateral mild to moderate sensorineural hearing loss at 8 khz in another. the otoacoustic emission (oae) and auditory brainstem response (abr) findings were also abnormal in these 2 subjects. a 1 month follow-up pure tone audiogram was normal. -1 subject showed vestibular side effects in the form of 'giddiness' and nystagmus which spontaneously resolved on completion of therapy. chloroquine ototoxicity (15) bortoli and santiago m (15) review ---some reports have described sensorineural hearing loss, tinnitus, sense of imbalance after prolonged high dose of chloroquine. -the reversibility of chloroquine ototoxicity has been debatable. chloroquine gestational use in systemic lupus erythematosus: assessing the risk of child ototoxicity by pure tone audiometry (16) borba et al. (16) case-control study 19 (mean age of mothers was 27 years old) 250 mg daily -there was no difference in hearing thresholds by pure tone audiometry of children between chloroquine exposure and non-exposure groups during the gestation. the mean hearing thresholds (pure tone audiometry) at low frequencies of exposure and non-exposure groups were similar (11.4 ± 4.5 vs. 11.9 ± 3.0 db; p = 0.66). the mean hearing threshold at high frequencies of exposure and non-exposure groups were not significantly different (8.5 ± 5.0 vs. 7.4 ± 3.6 db; p = 0.55). chloroquine ototoxicity: an idiosyncratic phenomenon (17) hadi et al. (17) case report of a 2.5-year-old boy 1 no information -abnormal gait a few hours after single chloroquine intramuscular injection. severe hearing loss on the 2nd day. 10 days later, he was treated with steroid and plasma expander. he still had permanent severe hearing loss at 3-5 years follow up. no testing technique information given. alterations of auditory evoked potentials during the course of chloroquine treatment (18) bernard (18) observational study 74 no information -there was no hearing change by pure tone audiogram. -there were abnormal results of brainstem audiometry (auditory brainstem audiometry) in 13 patients which resolved after chloroquine discontinuation. chloroquine ototoxicity-a reversible phenomenon? (19) mukherjee (19) case report of a 6-year-old girl 1 250 mg intramuscular injection daily for 7 days -she complained of hearing loss, and had abnormal gait after chloroquine injection for malaria. pure tone audiometry indicated severe unilateral sensorineural hearing loss, which was worse at mid frequencies (mean hearing threshold at mid frequencies = 80 db) -patient hearing improved after prednisolone administration, and pure tone audiometry indicated the mean hearing threshold at mid frequencies was 35 db bilaterally. ototoxicity of chloroquine phosphate: a case report (20) dwivedi and mehra (20) case report of a 52-year-old man 1 1,000 mg loading load -the patient had bilateral permanent deafness, severe vomiting, vertigo, blurring of vision and tinnitus at 1.5 hour after taking a single dose of 1g of chloroquine. pure tone audiometry indicated hearing thresholds of more than 90 db in both ears. obiako (personal communication) case report 4 no information -there were 4 cases of sensorineural deafness following chloroquine phosphate injections. no testing technique information given. ototoxicity of chloroquine (21) matz and naunton (21) case report 1 no information -there was a complete absence of inner and outer hair cells throughout the length of the cochlea in a deaf child whose mother took chloroquine during pregnancy. no testing technique information given. the ototoxicity of chloroquine phosphate (22) hart and naunton (22) case report 2 no information -there were 2 cases of severe bilateral cochleovestibular paresis whose mothers were treated with chloroquine during her pregnancy.no testing technique information given. dewar and mann (23) case report 1 no information -the patient had irreversible sensorineural deafness, after being treated with chloroquine for 7 months. no testing technique information given. frontiers in public health | www.frontiersin.org (27) coutinho and duarte (27) case report of a 7-year-old girl 1 200 mg daily -patient had unilateral slowly progressive hearing loss after 2 years of hydroxychloroquine use. pure tone audiometry indicated moderate to severe sensorineural hearing loss (mean hearing threshold 65 db). the auditory brainstem response (abr) test showed absence of response at 90 db in the right ear. hydroxychloroquine ototoxicity in a patient with rheumatoid arthritis (28) seckin et al. (28) case report of a 34-year-old woman 1 400 mg daily -patient complained of hearing loss and tinnitus after 5 months of hydroxychloroquine use. pure tone audiometry indicated bilateral mild sensorineural hearing loss. after discontinuation of hydroxychloroquine, patient symptoms improved and the follow-up audiogram was normal. otoxicity due to hydroxychloroquine: report of two cases (29) johansen and gran (29) case report of a 44-year-old woman and a 44-year-old man 2 no information -patients had irreversible sensorineural hearing loss after several years of hydroxychloroquine use. no testing technique information given. frontiers in public health | www.frontiersin.org hydroxychloroquine is more likely to cause ototoxicity after prolonged use. this could be due to different drug efficacy and equivalent dosage. furthermore, hearing loss in these patients could be associated with other possible causes rather than chloroquine and hydroxychloroquine including autoimmune disease e.g., systemic lupus erythematosus (30) , sudden sensorineural hearing loss or presbycusis. the suggested dose of chloroquine for patients diagnosed with covid-19 infection (1 g daily for 10 days) is substantially higher compared with the usual dosage of chloroquine for malaria treatment (1 g daily for 3 days) (5). there is no information regarding the ototoxic effect of chloroquine at this higher dose. patients with chronic inflammatory diseases were treated with a usual dose of hydroxychloroquine 400 mg daily for long durations (months or years). a suggested dose of hydroxychloroquine for covid-19 infection is an initial loading dose of 800 mg followed by 400 mg daily for 4 days based on the in vitro model (2), and 600 mg daily for 10 days from a french study (6) . in general, the recommended dosage of hydroxychloroquine in covid-19 patients is slightly higher but in a shorter duration compared to that in autoimmune disease. the ototoxic effects of these regimens are unknown. due to the potentially substantial number of the world's population who may take chloroquine or hydroxychloroquine, there is the prospect of a significant number of people being affected with ototoxic side effects. it is therefore vital to build awareness about the presentation and impact of the symptoms of drug-induced ototoxicity. patient reports of hearing loss, tinnitus, or imbalance should be noted. those with troublesome hearing loss or tinnitus are encouraged to be referred for hearing evaluation, including extended high frequencies audiometry at 8-16 khz where possible, once they are stable. available options of audiological interventions for those with bothersome hearing impairment or tinnitus are counseling, hearing aids, and tinnitus therapy. the possibility of exacerbation of pre-existing hearing loss and/or tinnitus should be considered. synergistic adverse auditory effects when other ototoxic medication is administered with chloroquine or hydroxychloroquine, such as aminoglycoside antibiotics and azithromycin, is a further risk (9) . severe cases of covid-19 can also progress to respiratory distress and hypoxia (31) . hypoxia is known to have deleterious effects on the stria vascularis of the cochlea organ including alterations to cochlear potentials and histologic changes (32) . therefore, it is certainly possible that the combined effects of hypoxia and administration of chloroquine or hydroxychloroquine on hearing could be worse than either one alone. clinical trials of chloroquine or hydroxychloroquine should also consider including audiological monitoring in the protocol. ideally, a hearing test should be conducted both before and after drug administration to examine drug-induced hearing change. common methods for audiological evaluation include pure tone audiometry, otoacoustic emission (oae), and tinnitus questionnaire. however, conventional methods and setting of hearing evaluation is impractical based on the infectious nature of covid-19 and the urgency of drug administration. selfmonitoring by validated smartphone-based apps for hearing assessments in addition to self-report of symptoms is an approach of interest in this situation. although chloroquine and hydroxychloroquine are generally considered safe in pregnant women, the use of chloroquine during pregnancy in the first trimester should be contemplated with particular caution since there are reports of abnormal cochleovestibular development in newborns. hydroxychloroquine has a safer clinical profile in pregnancy, thus is a more suitable option than chloroquine (33) . recent publications have brought attention to the possible benefit of chloroquine and hydroxychloroquine in covid-19 treatment. it is important to build awareness about the possibility of ototoxicity in survivors of covid-19 treated with these drugs. patient reports of hearing loss, tinnitus, or imbalance should be noted. those with troublesome hearing loss or tinnitus are encouraged to be referred for hearing evaluation and interventions once they are stable. clinical trials of chloroquine or hydroxychloroquine should also consider including audiological monitoring in the protocol. hydroxychloroquine and azithromycin as a treatment of covid-19: results of an open-label non-randomized clinical trial chloroquine and hydroxychloroquine in covid-19 expert consensus on chloroquine phosphate for the treatment of novel coronavirus pneumonia. zhonghua jie he he hu xi za zh pharmacological drugs inducing ototoxicity, vestibular symptoms and tinnitus: a reasoned and updated guide hearing loss as a risk factor for dementia: a systematic review hearing loss and depression in older adults: a systematic review and meta-analysis problems and life effects experienced by tinnitus research study volunteers: an exploratory study using the icf classification clinical and research perspectives assessment of short term chloroquine-induced ototoxicity in malaria patients chloroquine ototoxicity chloroquine gestational use in systemic lupus erythematosus: assessing the risk of child ototoxicity by pure tone audiometry chloroquine ototoxicity: an idiosyncratic phenomenon alterations of auditory evoked potentials during the course of chloroquine treatment chloroquine ototoxicity-a reversible phenomenon? ototoxicity of chloroquine phosphate. a case report ototoxicity of chloroquine the ototoxicity of chloroquine phosphate chloroquine in lupus erythematosus hydroxychloroquine ototoxicity in a patient with systemic lupus erythematosus a case report of hearing loss post use of hydroxychloroquine in a hiv-infected patient hydroxychloroquine-induced ototoxicity in a child with systemic lupus erythematosus hydroxychloroquine ototoxicity in a child with idiopathic pulmonary haemosiderosis hydroxychloroquine ototoxicity in a patient with rheumatoid arthritis ototoxicity due to hydroxychloroquine: report of two cases hearing loss in patients with systemic lupus erythematosus an overview of coronaviruses including the sars-2 coronavirus -molecular biology, epidemiology and clinical implications effects of hypoxia on cochlear blood flow in mice evaluated using doppler optical microangiography covid-19: a recommendation to examine the effect of hydroxychloroquine in preventing infection and progression all authors planned and structured the paper. pp undertook the review and wrote the first draft. db, pp, and ak jointly revised the manuscript. pp and db receive support from the uk national institute for health research (nihr), but their views are their own and do not reflect those of nihr nor the uk department of health and social care. key: cord-309663-h06876ok authors: olea-popelka, francisco; fujiwara, paula i. title: building a multi-institutional and interdisciplinary team to develop a zoonotic tuberculosis roadmap date: 2018-06-12 journal: front public health doi: 10.3389/fpubh.2018.00167 sha: doc_id: 309663 cord_uid: h06876ok tuberculosis (tb), as the major infectious disease in the world, has devastating consequences for not only humans, but also cattle and several wildlife species. this disease presents additional challenges to human and veterinary health authorities given the zoonotic nature of the pathogens responsible for the disease across species. one of the main public health challenges regarding zoonotic tb (ztb) caused by mycobacterium bovis is that the true incidence of this type of tb in humans is not known and is likely to be underestimated. to effectively address challenges posed by ztb, an integrated one health approach is needed. in this manuscript, we describe the rationale, major steps, timeline, stakeholders, and important events that led to the assembling of a true integrated multi-institutional and interdisciplinary team that accomplished the ambitious goal of developing a ztb roadmap, published in october, 2017. it outlines key activities to address the global challenges regarding the prevention, surveillance, diagnosis, and treatment of ztb. we discuss and emphasize the importance of integrated approaches to be able to accomplish the short (year 2020) and medium term (year 2025) goals outlined in the ztb roadmap. worldwide, there is consensus that solutions to complex issues need the participation and involvement of different stakeholders. recent outbreaks of emerging and re-emerging zoonoses [i.e., zika, ebola, middle east respiratory syndrome (mers), avian and swine influenza] (1) have heightened the public's awareness about the close and complex interrelationship between the health of humans, wildlife species, and domestic animals. tuberculosis (tb), is one such disease that continues to have devastating consequences for not only humans, but also cattle and several wildlife species (2) (3) (4) (5) . caused by bacteria belonging to the mycobacterium tuberculosis complex (mtbc), tb presents additional challenges to human and veterinary health authorities given the zoonotic nature of the pathogens responsible for the disease and the ability of mtbc agents to be shared across species (4, 5) . tb in humans is caused primarily by mycobacterium tuberculosis (m. tb); worldwide, it is the leading cause of death in humans by an infectious disease (2) . bovine tb caused by mycobacterium bovis (m. bovis) is widely distributed around the world (3, 6) and continues to cause considerable economic losses to farmers and countries due to the reduced production of affected animals, culling of animals from herds (or entire herd depopulation in some cases), and the elimination of affected (or all) parts of animal carcasses at slaughter (7) . m. bovis can also infect and cause tb in humans (zoonotic tuberculosis (ztb) (8) (9) (10) (11) . the world health organization (who) estimated that "in 2016 there were 147,000 new cases of ztb and 12,500 deaths due to this type of tb" (2) . furthermore, m. bovis has the ability to cause tb and cause death in several wildlife species (4, 5) . one of the main public health challenges regarding ztb is that its true incidence in humans is not known and is likely to be underestimated due to the lack of systematic surveillance for m. bovis as a causal agent of tb in people in all low-income, high tb burden countries where bovine tb is endemic, and the inability of laboratory procedures most commonly used to diagnose human tb to identify and differentiate m. bovis from m. tb (12) . to effectively address challenges posed by ztb (and other diseases at the "animal-human" interface), a crosssectorial and multidisciplinary one health approach linking animal, human, and environmental health is required. in this manuscript, we describe the rationale, major steps, timeline, stakeholders, and important events that lead to the assembling of a true integrated multi-institutional and interdisciplinary team that worked toward and accomplished the ambitious goal of developing a ztb roadmap that was published in english, spanish, and french (13) (14) (15) to address the global challenges regarding the prevention, surveillance, diagnosis, and treatment of zoonotic tb (ztb), globally. we discuss and emphasize the importance of integrated approaches to be able to accomplish the short (year 2020) and medium term (year 2025) goals outlined in the ztb roadmap. the international union against tuberculosis and lung disease (the union) is an international scientific organization that works with partners, including governments, academia, and civil society, to fight tb, tobacco use and other lung diseases in low-and middle-income countries, through technical assistance, training, and research. through its volunteer members, it houses scientific sections that promote areas of specific interest. the union's ztb sub-section is a global network of physicians, veterinarians, researchers, economists and social anthropologists that works to understand the dynamics of ztb, create global awareness, and facilitate multi-institutional collaboration to address the challenges posed by it. efforts conducted by the ztb sub-section has led to a continuous and stable increase in the number of activities, attention, and attendees to ztb-related activities at the annual union world conference on lung health. for example, at the 2010 conference in berlin, germany, there was only one ztb session (symposium) attended by less than 10 people. over the last seven years, the ztb activities at the annual conference have increased to two scientific symposia, one poster session, one meet the expert session, press releases, and a keynote talk on ztb at the plenary session in south africa during the 2015 conference. during the last conference in guadalajara, mexico in october 2017, an audience of approximately 75 professionals from different disciplines attended each of the two ztb scientific symposia. prior to the union's initial activities to create global awareness of ztb, in 2010, the who, oie and fao pioneered one health approaches under a tripartite partnership, which shares responsibilities and jointly develop and implement integrated strategies for addressing health risks at the human animal-ecosystem interface (12) . the combined involvement and commitment of these three institutions has been crucial to successfully develop a ztb roadmap since these institutions jointly: (1) provide global leadership for tb prevention, care and control (who); (2) is responsible for improving animal health and welfare (oie); and (3) work toward improving food security, nutrition and agricultural productivity and reduce rural poverty (fao). in march 2014, the ztb sub-section created a working group to raise awareness of the public health risk posed by ztb. this working group included participants from key parties including the: one of the accomplishments of this working group was the publication of a manuscript (10) calling for a call to action in the lancet infectious disease journal. a constellation of events has occurred to bring ztb to the awareness of scientists, policymakers, government officials and the general public. in may 2014, the world health assembly, who's yearly gathering of the world's ministers of health, approved the new post-2015 global tb strategy. the strategy aims to end, rather than merely control, the global tb epidemic, with targets to reduce tb deaths by 95% and to reduce new cases by 90% between 2015 and 2035, and to ensure that no family is burdened with catastrophic expenses due to tb. it set interim milestones for 2020, 2025, and 2030 (16) . thus, finding and treating every case of tb, whether caused by m. tb or m. bovis, will count toward the achievement of this ambitious goal. for this reason, as countries move toward detecting the 3 million tb cases estimated to be missed annually, and in light of the endorsed who "end tb" strategy, the tripartite, the union and the key organizations concerned with human and animal health, agriculture and tb joined forces to develop a zoonotic tb road map outlining medium-and long-term milestones to globally address the prevention, surveillance, diagnostic, and treatment challenges faced by persons with ztb. in september 2015, the united nations declared the end of the millennium development goals and used them as the foundation for the sustainable development goals (sdgs) (17) for 2015-2030, encompassing 17 broad and comprehensive topic areas, ranging from elimination of poverty and hunger, improved education and gender equality, to clean water and energy, action on climate and improvement of life under water and on land. the third sdg addresses global health, with tb highlighted as one of the priorities, thus presenting a key opportunity to improve the health of communities affected by ztb. the stop tb partnership, the global advocacy organization for tb, published the 4th edition of its global plan to end tb, 2016-2020 entitled "the paradigm shift" (18) . this is a costed plan that includes actions needed to decrease tb, and is in full support of who's end tb strategy. the global plan has set its 90-(90)-90 targets, which are to: identify 90% of all tb cases; concentrate on identifying 90% of those in key populations; and ensure 90% obtain appropriate treatment until cure. for the first time in this document, communities and people at risk of contracting ztb were included as a key population. a meeting co-organized by who and the union, with contributions from leading international organizations for human and animal health, academic institutions, and nongovernmental organizations took place at who in geneva. there, the first steps toward formally conceptualizing a roadmap for ztb began, in which ten priorities were identified to be presented to who's global tb programme's strategic technical advisory group (stag) for tb in june 2016. in addition to the 10 institutions initially working on increasing global awareness of ztb, the following institutions joined the efforts at this specific meeting: -swiss tropical and public health institute, switzerland -animal and plant health agency (apha), united kingdom -university of ibadan, nigeria -the global research alliance for bovine tuberculosis (grabtb) the involvement and participation of grabtb was an important addition and played a strategic role in partnering with colleagues focusing in improve the understanding and control of bovine tb and developing novel and improved tools to control the disease at its bovine source (13) . grabtb was established in 2014 and as part of its strategic goals, the alliance seeks not only to enhance collaboration within its members and institutions, but also with the broader human and animal tb research community. the 10 priorities proposed for the ztb roadmap were endorsed by the stag, and a working group was created and tasked to produce and publish a ztb road map during 2017. at the stag meeting, a former ztb survivor, from the masaai community in kenya shared with the scientific community the challenges she faced while suffering from this disease, which included: initial misdiagnosis, development of extrapulmonary (abdominal) tb, antimicrobial resistance to anti-tb drugs additional to the inherent resistance m. bovis has against pyrazinamide, and the need for longer (12 months) antimicrobial treatment, compared to the standard of 6 months. during the 47th union world conference on lung health in liverpool, england, a british veterinarian and former ztb patient/survivor also shared his experience and challenges of initial misdiagnosis, extrapulmonary (pleural) tb, drug resistance to isoniazid in addition to pyrazinamide, and the longer treatment required while battling ztb in the year 2013. these patients' testimonies further emphasized that ztb is not a disease from the past, and highlighted the challenges faced by certain communities at higher risk of contracting ztb. both patients emphasized the need of more awareness among the medical community to better diagnose and treat ztb patients, and thus prevent the additional complications they had to endure. the heads of state comprising the g20 forum declared that "shaping an interconnected world, calls for a one health approach to tackling the spread of antimicrobial resistance and highlighted the need to foster research and development for tb" (19) . the roadmap for ztb was published and launched at the union world conference for lung health in guadalajara, mexico. the roadmap is the product of efforts of the tripartite partnership on zoonotic diseases comprising who, oie, and fao and the union, and is available in english, french, and spanish (13) . the role of media over the past 3 years, all efforts, activities, and events related to ztb were highlighted by a considerable number of local, regional, national, and global media sources including central news network (cnn), the british broadcasting corporation (bbc), and le monde newspaper in france, to name a few. the zoonotic tb roadmap (13) outlines 10 priorities to address the existing challenges posed by ztb, divided into three major core themes: (1) improve the scientific evidence, (2) reduce transmission at the animal-human interface, and (3) strengthen intersectoral and collaborative approaches. "identify opportunities for community-tailored interventions that jointly address human and animal health interventions that jointly address human and animal health can increase health and economic benefits for communities. sharing of human resources, equipment and transport across sectors can reduce operational costs. this increased cost-effectiveness is especially relevant given the public funding constraints that often exist in settings where people are most at risk of zoonotic tb. for example, outreach childhood immunization campaigns or other existing livestock vaccination or testing programmes conducted in rural communities could be used to concurrently deliver educational and behavior change messages about food safety, to test livestock for bovine tb or, potentially in the future, to implement livestock vaccination campaigns against bovine tb. interventions must be tailored to the cultural and socioeconomic characteristics of each setting. community-driven participatory initiatives are key to achieving sustainability." table 1 | timeline for action and milestones to be achieved in the short (2020) and medium term (2025) outlines in the ztb roadmap (13) . reduce transmission at the animal-human interface although the publication of the ztb roadmap represents an unprecedented and historical accomplishment in the fight against global tb (20) , there is still much work to be conducted in order to implement the actions needed to improve the prevention, diagnosis, control and treatment of ztb. table 1 is an excerpt from the ztb roadmap in which the short (year 2020) and medium term (year 2025) milestones to be accomplished are outlined under the three core themes of the roadmap. one of the key elements toward accomplishing these goals is that the unique cultural and socioeconomic factors that shape the relationship between people, livestock, and wildlife species in different ecosystems must be taken into account, while including the at-risk communities in future efforts to reduce the risk of zoonotic transmission of m. bovis across species. these efforts not only need to focus on preventing transmission from livestock (mostly cattle) to humans, but also, and in parallel, to reduce the prevalence of the disease in both domestic and wildlife species. the availability of improved diagnostic tools for ztb in different species, as well as the implementation of disease monitoring, surveillance, and prevention strategies in livestock and wildlife species will be a crucial and much needed component to be able to implement comprehensive programs that will account for the complexities ztb poses due to its zoonotic nature. finally, including vaccination of wildlife (where feasible), not only has the potential for reducing the burden of disease, but also could play an important role in conservation efforts, especially among endangered and protected species. implementing an integrated approach to develop the ztb road map did not come without the inherent challenges of multidisciplinary and multi-institutional projects. that said, the accomplishment of this milestone in the fight against tb was the vision of a world free of tb, no matter what its source, the strong support of who and the stop tb partnership, a motivated core group that drove the process by providing clear goals and timelines, being inclusive by inviting all interested parties, and fostering a strong commitment to work together from colleagues and institutions both from the human and animal sectors that previously were working in isolation. this collaboration has opened new doors and opportunities as the world fights to end tb. all authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication. the national institute for occupational safety and health (niosh): emerging infectious diseases world health organization report of the meeting of the oie ad hoc group on tuberculosis, annex 8 of the oie scientific commission for animal diseases report -september one health in the shrinking world: experiences with tuberculosis at the human-livestock-wildlife interface evidence of increasing intra and inter-species transmission of mycobacterium bovis in south africa: are we losing the battle? available online at mycobacterium bovis infection and control in domestic livestock zoonotic tuberculosis due to mycobacterium bovis in developing countries zoonotic mycobacterium bovis-induced tuberculosis in humans current knowledge and pending challenges in zoonosis caused by mycobacterium bovis: a review zoonotic tuberculosis in human beings caused by mycobacterium bovis -a call for action why has zoonotic tuberculosis not received much attention? world health organization, world organisation for animal health, food and agricultural organization of the united nations world health organization, world organisation for animal health, food and agricultural organization of the united nations, the international union against tb and lung disease. hoja de ruta contra la tuberculosis zoonotica world health organization, world organisation for animal health, food and agricultural organization of the united nations, the international union against tb and lung disease available online at united national sustainable development goals (sdgs) global plan to end tb: the paradigm shift g20 leaders declaration: shaping an interconnected world a roadmap for zoonotic tuberculosis: a one health approach to ending tuberculosis in addition to the institutions listed on the manuscript the authors wish to acknowledge the work of additional institutions that contributed to the development of the ztb roadmap: servicio key: cord-333460-4ui8i9u5 authors: li, qing; chen, jinglong; xu, gang; zhao, jun; yu, xiaoqi; wang, shuangyan; liu, lei; liu, feng title: the psychological health status of healthcare workers during the covid-19 outbreak: a cross-sectional survey study in guangdong, china date: 2020-09-18 journal: front public health doi: 10.3389/fpubh.2020.562885 sha: doc_id: 333460 cord_uid: 4ui8i9u5 background: the sudden outbreak of covid-19 has caused mental stress on healthcare workers (hcw). this study aimed to assess their psychological health status at the peak of covid-19 and to identify some coping strategies. methods: a cross-sectional survey study was conducted during the outbreak of covid-19. the survey was completed by 908/924 hcw (response rate 98.27%) in government-designated hospitals in guangdong, china. a quality of life (qol) scale, the zung self-rating anxiety scale (sas), and the zung self-rating depression scale (sds) were used to evaluate their psychological status. logistic regression models were used to identify the occupational factors related to anxiety or depression. results: a total of 221 (24.34%) respondents had varying levels of anxiety, and 299 (32.93%) of them had depression. the mean sas (42.9) and sds (47.8) scores of hcw indicated that they were in the normal range for both anxiety and depression. contact with covid-19 cases or suspected cases, worry about suffering from covid-19, worry about their family, and dismission during the covid-19 period were significant work-related contributing factors to the psychological health problems of hcw (all p<0.01). conclusions: the overall psychological health status of hcw in guangdong, china, during the outbreak of covid-19 was not overly poor. updating and strengthening training in disease information, the provision of adequate medical supplies, and care about the life and health of medical staff and their family members may reduce their mental stress. in december 2019, the outbreak of pneumonia caused by the 2019 novel coronavirus (2019-ncov) in wuhan, hubei province, china (1, 2) , was quickly spread by the largest human migration in the world, the spring festival travel rush. by the time of this submission, it had become a serious infectious disease that has spread throughout the world. the world health organization (who) named the infection covid-19 in february 2020. in china, provinces successfully began the first-level response to major public health emergencies on january 23, 2020. guangdong, where the author is located, is one of the most populous provinces in china due to its hyper active economy and booming industry that attracts migrant workers. it is also the province with the largest number of cases after hubei reported during our study period, and huge migration may bring serious outbreaks. previous studies have shown that doctors, nurses, and other staff in hospitals suffer from psychological problems during an epidemic of an infectious disease. during the outbreaks of the 2003 severe acute respiratory syndrome (sars) and 2015 middle east respiratory syndrome (mers), psychological problems, including anxiety, depression, and sleep disorders, were very common in medical workers in taiwan, hong kong, singapore, korea, and canada (3) (4) (5) (6) (7) (8) (9) (10) (11) (12) (13) . similar to sars and mers, front-line healthcare workers (hcw) may be in direct contact with and have to care for patients and suspected cases of covid-19; they are therefore at a particularly high risk of infection. in the battle against covid-19, more than 3,000 doctors and nurses have been infected, and a dozen have died. hcw also face pressure from overwork, lack of supplies, negative emotions of patients, and concerns about their families. these factors may cause many psychological stress (14, 15) . to date, there have been few known systematic studies targeting this topic. the aim of our study was to assess the psychological status of hcw in guangdong province, china, and to identify coping strategies during the outbreak of covid-19. this study was a cross-sectional survey study. it was approved by the ethics committee of the guangzhou first people's hospital (k-2020-055-01). considering the high infectivity of covid-19, the popularity of wechat in china, and the feasibility of electronic questionnaires, a professional online questionnaire platform powered by www.wjx.cn was used in answering the paperless survey. we started the survey on february 3 for the medical institutions that resumed their work after the spring festival. at that time, 10 days had passed since the chinese government officially declared a state of emergency on january 23. the research objects of this study were doctors, nurses, and other staff in the government-designated hospitals in guangdong including guangzhou first people's hospital, guangzhou eighth people's hospital (infectious disease hospital), and 10 other hospitals. non-medical staff were defined as a control group. persons with previous mental illness were excluded. february 24 was used as the cut-off point because the major public health emergency was adjusted to the second level on that day. the study was conducted at the peak of the covid-19 outbreak. all respondents completed the survey anonymously. they were required to complete questionnaires on quality of life (qol) and psychological comorbidities. each item had to be answered before it could be submitted. a mobile internet protocol address was limited to only one response to avoid duplication. a professional psychologist participated in the whole process of this research and assisted in evaluating the psychological state of the respondents. the results were used for analysis. the questionnaire consisted of three sections and started with informed consent. all participants provided informed consent before proceeding with the subsequent investigations. the first section recorded the participants' sociodemographic variables and personal information, including age, gender, marital status, education, occupation, working hours, financial status, income satisfaction, and essential sleep conditions. we defined the front-line doctors and nurses in the fever clinic, emergency department, and intensive care unit as high-risk medical staff, while others were low risk. the second section collected information about covid-19. because covid-19 is a new disease, we could not find a validated instrument for it. we referred to studies on sars and mers and then designed several items, such as exposure to covid-19, training for the disease, and stigma. two established methods were used in the third section. anxiety and depression were the most prevalent mental illnesses. symptoms of anxiety and depression in the past week were assessed by the zung self-rating anxiety scale (sas) (16) and the zung self-rating depression scale (sds) (17) , which have been well-validated (18) . both sas and sds use 20-items likert scales with four potential answers ranging from one (little of the time) to four (most of the time). the raw scores are transformed into index scores (range 25-100) (sas index score: < 50 = normal, 50-59 = mild anxiety, 60-69 = moderate anxiety, ≥70 = severe anxiety; sds index score: < 53 = normal, 53-62 = mild depression, 63-72 = moderate depression, ≥73 = severe depression). descriptive statistics were performed on demographic factors, health factors, economic factors, work factors, and sas and sds scores. differences in sas and sds scores for occupation were accessed with analysis of variance (anova). then we compared the morbidities of anxiety and depression between two different occupational groups using the chi-squared test. multivariate logistic regression models (unadjusted and adjusted) were used to examine the relationships between covid-19 work-related factors and anxiety and depression. we defined cases with anxiety when the sas score was over 50 and defined cases with depression when the sds score was over 53. in all models, we separately included the following factors: occupation, working years, contact with covid-19 cases, worry about suffering from covid-19, worry about their family suffering from covid-19, worry about stigma due to covid-19-related jobs, and dismission intention during the covid-19 period. for each model, we adjusted for age, gender, education, marital status, monthly income, and history of basic illness. we defined statistical significance as p < 0.05 for a two-tailed test, and all statistical analyses were conducted using r v3.42 (r foundation for statistical computing, vienna, austria). a total of 924 surveys of hcw were collected, 908 (response rate 98.27%) of which were completed correctly. sixteen respondents (1.73%) were excluded due to significant data errors in the age, height, and weight items. and 369 questionnaires of the controls were completed at the same time. the sociodemographic characteristics and other information for covid-19 of healthcare workers and controls are given in table 1 . the results showed that there was no significant difference between hcw and the controls in terms of age, gender, marital status, and history of basic illness. in total, 67.7% of the hcw respondents had direct contact with covid-19 patients or suspected cases at work. a total of 25.88 and 41.08% of the hcw respondents worried about themselves or their family members being infected by covid-19, respectively. only 6 (0.66%) hcw respondents had feelings of social discrimination. a total of 16.19% of the hcw respondents showed the intention to take leave or resign from their job. compared with the controls, hcw has a significantly higher morbidity of both anxiety and depression. among them, 221 (24.34%) hcw participants had varying levels of anxiety with a mean sas score of 42.9, and 299 (32.93%) of them had depression. the mean sds score was 47.8. sas and sds scores in different occupational groups and morbidity of anxiety and depression are shown in table 2 . the chi-squared test showed that the morbidity of anxiety was increased significantly in clinicians at high risk than at low risk (χ 2 = 8.895, df = 1, p = 0.003). there was an increase in morbidity of both anxiety and depression in nurses at high risk compared with nurses at low risk (anxiety: the determining factors of anxiety and depression are shown in tables 3, 4. in table 3 previous studies have shown that 23.9-68.8% of hcw suffered from mental health problems in china due to the high workload, promotion pressure, deteriorating doctor-patient relationships, medical disputes, and even violence (19) (20) (21) (22) . on this basis, the outbreak of covid-19 undoubtedly increased the psychological pressure of hcw, who were the soldiers in this battle. our study found that the anxiety and depression rates of hcw during the peak of the covid-19 epidemic were 24.34 and 32.93%, respectively. staff in low risk positions had a lower rate of psychological problems than doctors and nurses who worked in positions with a high risk of covid-19 exposure, such as fever clinics, emergency departments, and intensive care units, especially nurses. compared with doctors, nurses had more opportunities to have contact with cases, which increased the risk of infection. however, surprisingly, the mean scores of the sas (42.9) and sds (47.8) of hcw indicated that they were in the normal range for both anxiety and depression, which seemed to differ from the results of previous studies on sars and mers (3) (4) (5) (6) (7) (8) (9) (10) (11) (12) (13) . we performed stratification analysis by occupational exposure risk or patient contact history but obtained similar results. reviewing the past few months in china during covid-19, whether it was wuhan in the peak of the epidemic, or in harbin, heilongjiang province, where the hospital infection outbreak happened recently, covid-19 mainly attacked theoretically low risk hcw (medical staff in departments for ophthalmology, surgery, neurology, and caregivers) (23) . critical illness medical staff were also in this category. in harbin, epidemiological studies further confirmed that the lack of sufficient vigilance and personal protection in hcw was the main reason for the hospital infection. this could suggest that there is no real low risk area during covid-19. our study was conducted after the notification of high infection in low risk departments in wuhan. guangdong was the most seriously affected area except hubei at that time. but the anxiety and depression of hcw in low risk departments were still significantly lower than those in high risk departments. this situation was most likely due to insufficient vigilance. anxiety helps us anticipate and assess potential danger in ambiguous situations (24, 25) . combined with the results of our study, it is possible that our awareness of disease prevention and self-protection can be strengthened by some psychological pressure during covid-19. on the contrary, it may increase the chance of infection due to lack of tension or negligence of the disease. this is the population that should be concerned and their knowledge of disease and personal protection should be enhanced. our aim was to identify the determinative factors of the impact of covid-19 on hcw's psychological status. a review of previous literature suggests that many factors can also affect the mental health of hcw in non-epidemic situations (19) (20) (21) (22) . further adjusted logistic regression showed that there was no significant correlation between the exposure risk and occupation, working years, and stigma and the psychological status of hcw during the outbreak of covid-19. however, concerns about selfinfection and family health were statistical factors that were all positively related to both anxiety and depression according to the sas and sds scores. we will attempt to determine reasons for this result. similar to sars and mers, covid-19 can be spread by respiratory droplets and direct contact, with urine, stool, and saliva being potential routes (26) (27) (28) (29) . although an early study evaluated its r0 = 2.2 (1), other studies found the average r0 to be 3.28, even reaching 6.47 (26) (27) (28) (29) . compared with sars (r0 = 3.6), the contagious power of covid-19 is much higher (27) . hcw who face such a highly contagious disease with an incubation period, especially nurses at high risk (40.83%, 69/169), show serious concern about their possibility of infection. a total of 41.12% of the respondents worried about their families due to both the lack of care and the high risk of infection caused by the hcw themselves. however, the statistical results showed that the experience of contact with patients or suspected cases was a positive factor for both anxiety and depression. our investigation showed that all the respondents, even administrative staff, received different levels of medical knowledge and protection training about this infectious disease. apart from the brief panic at the beginning, 99.01% of them believed that the available protective measures were adequate at this moment. this may be due to the improvement of china's disease control system and the development of awareness of infectious disease prevention and control after the experience of sars (30) . the more people are prepared for covid-19, the more confident they can be. during sars and mers, 20-49% of hcw experienced social stigmatization because of their jobs (3, 5, 7, 10, 12) . however, in our study, it seemed that hcw did not worry about stigma (99.34%). this may be related to the development of social media, information disclosure, and the government's positive publicity. accurate and timely covid-19 information was provided to the public to reduce uncertainty and minimize stigmatization of hcw. this suggestion was mentioned in ya mei bai's article and now seems to be effective (3) , and hcw are hailed as heroes in harm's way (31). the public has shown more respect for medical staff, which may reduce the stress of hcw. we found that 16.19% of the respondents, mainly caregivers (66.03%, 70/106), had the intention to resign or take leave, while only a few doctors and nurses had this intention. this was a statistically significant factor associated with anxiety among hcw. among the caregivers, 91.51% were married females. this has been seen as an escape in some studies (3, 5, 11) . this may be due to a lower education level (77.35% did not receive a college education) and family identity as a mother, which has caused a shortage of caregivers in many hospitals. a similar conclusion was mentioned by chenyu zhou in her research on chinese medical staff (20) . in addition, our investigation showed that 58.92% of hcw worked more than 8 h a day, 25.33% of them were dissatisfied with their current income, and 23.12% of them had sleeping problems and needed hypnotics. previous studies have shown that these factors were related to the mental health of medical staff in usual jobs. this may be a long-term problem rather than a current one that is specific to the covid-19 epidemic. after the guideline of psychological crisis intervention for 2019-ncov pneumonia was released by the national health commission of china on january 27, it seemed that some measures had been taken (32, 33) . our study finds that there was some effect. the psychological health of hcw was better than expected. the limitations of our study are as follows. firstly, the study was completed on mobile devices, and the sampling was voluntary. therefore, the possibility of selection bias should be considered. secondly, we could not cover all potential risk factors in this investigation. thirdly, the objects of this study were hcw in guangdong province, and this sample cannot represent the mental status of hcw in hubei, the center of the epidemic, who might suffer from more serious psychological problems. although some hcw in guangdong, china, had psychological problems during the outbreak of covid-19 especially the firstline doctors and nurses, the findings of the present study indicated that their overall psychological health status was not too poor. it is possible that our awareness of disease prevention and 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number of covid-19 is higher compared to sars coronavirus predicition modeling with data fusion and prevention strategy analysis for the cpvid-19 outbreak (chinese) the epidemiological characteristics of an outbreak of 2019 novel coronavirus disease (covid-19) in china (chinese) applying the lessons of sars to pandemic influenza: an evidence-based approach to mitigating the stress experienced by healthcare workers wang yi delivers a speech at the 56th munich security conference the guideline of psychological crisis intervention for 2019-ncov pneumonia. national health commission of china (chinese) the studies involving human participants were reviewed and approved by the ethics committee of the guangzhou first people's hospital (k-2020-055-01). written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements. all authors have read through the manuscript and approve for submission. as the corresponding author, i have had full access to all aspects of the research and writing process, and i assume final responsibility for the contents of the paper. the authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.copyright © 2020 li, chen, xu, zhao, yu, wang, liu and liu. this is an open-access article distributed under the terms of the creative commons attribution license (cc by). the use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. no use, distribution or reproduction is permitted which does not comply with these terms. key: cord-301052-qdhkwa4s authors: al-tammemi, ala'a b. title: the battle against covid-19 in jordan: an early overview of the jordanian experience date: 2020-05-07 journal: front public health doi: 10.3389/fpubh.2020.00188 sha: doc_id: 301052 cord_uid: qdhkwa4s since the initial spark of the covid-19 outbreak in december 2019, which was later declared by the world health organization (who) to be a global pandemic, all affected countries are implementing various preventive and control measures to mitigate the spread of the disease. the newly emerging virus brings with it uncertainty—not only regarding its behavior and transmission dynamics but also regarding the current lack of approved antiviral therapy or vaccines—and this represents a major challenge for decision makers at various levels and sectors. this article aims to provide an early overview of the covid-19 battle within the jordanian context, including general reflections and conclusions on the value of collaborative efforts in crises management. it has been over five decades since the first discovery of human coronaviruses (1) . a series of outbreaks and epidemics of respiratory illnesses have been attributed to various types of these viruses, such as severe acute respiratory syndrome (sars) and middle east respiratory syndrome (mers), which were caused by sars-cov and mers-cov, respectively, in addition to the current coronavirus disease 2019 (covid-19) (1, 2) . covid-19 is caused by novel sars-cov-2, which, to a certain degree, possesses genomic similarities to mers-cov and sars-cov (2, 3) . these coronaviruses are transmitted from their animal origins to humans through an intermediate host, such as camels in the case of mers and civet cats in the case of sars (1, 4) . unfortunately, the intermediate host that is responsible for the interspecies (animal to human) transmission of the novel sars-cov-2 is still under debate (2) ; pangolins could be a potential candidate (4) , however, it is still debatable whether the primary origin of the novel sars-cov-2 stems from bats or pangolins (2) . in late december 2019, pneumonia of an unknown cause was reported in wuhan city, china, and, from this point of origin, the outbreak has spread extensively to a global scale (3) . on the 30th of january 2020, the who declared the outbreak of covid-19 as a global public health emergency, and, upon the exponential increase in the number of cases and countries affected by the disease, covid-19 was then declared as a pandemic on the 11th of march 2020 (4) (5) (6) . the symptoms of covid-19 mostly appear within 2-14 days of acquiring the virus, and a different range of symptoms and severity can affect patients, including fever, dry cough, dyspnea, sore throat, nausea, vomiting, diarrhea, myalgia, and fatigue (5, 7, 8) . although most covid-19 patients develop a mild degree of symptoms and exhibit spontaneous recovery, there is still a proportion of patients, especially older age groups with underlying comorbidities, that are at higher risk of developing a more severe illness that is associated with complications (5, 7). as of the 16th of april 2020, 2:00 cest, the who announced that 213 countries and territories have been affected by the covid-19 with 1 995 983 confirmed cases and 131 037 confirmed deaths due to this disease (9) . covid-19 has high transmissibility (10) . the mechanism of the viral spread in covid-19 still has some degree of uncertainty (5) . however, human to human transmission is reported to occur via respiratory droplets and aerosols that result from infected persons as well as via direct contact with contaminated objects (3, 10) . various preventive and control measures at different levels have been implemented in different countries around the world in order to combat the spread of covid-19. among these measures, on an individual level, are maintaining a social distance of at least 3 feet between individuals, washing hands frequently, using hand sanitizers, practicing coughing and sneezing etiquette, avoiding handshaking and kissing, avoiding direct contact with ill persons, especially those who exhibit symptoms of respiratory infections, and wearing face masks in certain situations (3, 5, (10) (11) (12) . as of the date of writing this article, most covid-19 patients receive symptomatic and supportive treatment, but there is no definite antiviral therapy for covid-19 yet (3, 10) . the scientific community is currently working vigorously to develop an effective antiviral therapy as well as a vaccine for covid-19 (3, 5, 10, 13) . jordan is located in the eastern mediterranean region with an estimated population of around 10.6 million inhabitants and a total area of 89,342 square kilometers (14, 15) . jordan shares borders with iraq, israel and the occupied palestinian territory, saudi arabia, as well as syria (15). the world bank currently classifies jordan as an upper middle-income country with a gross national income (gni) of 9,430 international dollars per capita in 2018 (16) . since the beginning of the covid-19 outbreak, the jordanian government has followed the recommendations and updates provided by the who. a series of preventive and control strategies at the local and national levels have been implemented in order to limit the spread of covid-19 inside jordan. the fight against covid-19 in jordan is led by the government through a collaborative multi-disciplinary team at the highest levels at the national center for security and crises management (ncscm) (17, 18) . this crisis task force is comprised of expert decision makers from different ministries, sectors, and organizations in order to reach for and provide the best evidence-based recommendations for implementation (18). decisions regarding different life perspectives are cautiously and continuously updated and disseminated to the public through official authorities. in addition, teams of experts in epidemiological surveillance are currently working across the country to tackle cases and provide random viral testing and surveillance (12) . furthermore, the number of confirmed cases, recoveries, and deaths are publicly announced to the population each day through official reports by the government. keeping up with the advancements in digital health, a covid-19 website provided in the arabic language has been created by a collaborative efforts between the ministry of health and the ministry of digital economy and entrepreneurship, and it aims to spread awareness, knowledge, statistics, and recommendations to the public (12) . besides, a collaboration between the jordanian government and facebook was developed to spread awareness about covid-19 to jordanians who access facebook, as it is one of the most commonly used social networking sites among jordanians (12) . jordan is considered a touristic country and a main connection point for many flights and trips within the region, and this, along with the noticeable increase in number of covid-19 cases globally, has meant that the government has started to implement (periodically revised) strict rules and measures relating to travel, education, religious and social events, as well as working within various industries (17) . the primary step in preventing and controlling the spread of covid-19 in jordan started at the country's entry ports through temperature screening of incoming travelers as well as enforcing a quarantine to those who came from countries with high covid-19 spread (12, 17) . the turning point in the country's preventive and control measures was dated as the 17th of march 2020 upon declaring the national defense law in order to mitigate the spread of covid-19 in jordan. on the 20th of march 2020, a decision for a nationwide curfew was declared with strict rules on individuals' mobility and extreme fines for violations (17) . during the curfew, decisions are announced regularly, and the degree of restricting individuals' mobility varies during the week with oscillation between roundthe-clock and partial curfew (17) . the country's preventive and control measures are briefly highlighted and discussed in the following section. the decisions about international travel have progressed through many stages that accompanied the growth in the number of covid-19 cases globally, especially in countries that have been struck severely by the disease. these measures started with banning the entry of incoming non-jordanian travelers from specific countries, including china, south korea, italy, and iran, with exceptions given to jordanian nationals who were allowed to enter jordan with an obligatory 14 days of quarantine at specified facilities provided that were regulated by the government (12, 17) . later on, more countries have been added to the ban and restriction list (12, 17) . the most extreme measure was in announcing a total country lockdown starting effectively from the 17th of march 2020 until further notice; the only exception was in cases of commercial cargo movements (17) . the jordanian population is characterized by high levels of sociability and social events that occur on a daily basis with handshaking as a traditional and essential form of greeting. keeping that in mind, these societal characteristics make it somehow challenging to control a disease with high transmissibility like covid-19. strict measures that aim to restrict these events and limit the possibility to communicate the disease within the society have been implemented (12, 17) . these measures included strict rules that banned all the following until further notice: social events and public gatherings, such as weddings and funerals, prayer's attendance at all mosques and churches, and social visits to hospitals and prisons (17) . in addition, all sports facilities, cinemas, and youth centers were banned, as was shisha (hookah) at cafes and restaurants, and restaurants and cafes were obligated to keep enough social distance between seats (12, 17) . surprisingly, these measures were intensified on the 17th of march 2020 to include a strict ban on public gatherings of more than 10 persons, ban on inter-city travel and all public transportation, and closing all malls and commercial centers (12, 17) . then, on the 20th of march 2020, a country curfew was declared with a strict ban on individuals' mobility (17) . since declaring the curfew, the jordanian government has actively worked to ensure compliance with rules and directions of the curfew and has taken multiple measures to facilitate and ease the movement of individuals for the acquisition of supplies for basic needs during total and partial curfew times (17) . various efforts by different authorities have been made to reduce the stress and increase the societal adaptability to the curfew. many decisions that control different industries in jordan have been made in order to protect the employees and their families. although governmental and private institutions continued to work as usual until the middle of march, a critical decision was announced on the 17th of march 2020 that suspended all work duties at public and private sectors, with the closure of all industrial activities until further notice excluding vital industries, such as healthcare, energy, food, as well as the crisis task force (17) . in addition, electronic platforms were created to gather information about vulnerable workers and families in order to support them financially through official channels (17) . healthcare institutions and healthcare workers were exempted from the curfew rules in order to keep healthcare facilities functioning and ready for patients, taking into consideration the careful use of personal protective measures (12, 17) . all academic institutions at all levels were closed effective of the 15th of march 2020 and until further notice. accordingly, all teaching and learning activities moved toward distance learning platforms (17) . the statistics about covid-19 in jordan are publicly announced by government officials and are available on a specific covid-19 website created for this purpose, though the publicly announced statistics do not include any sensitive information about the patients (12) . the first confirmed case of covid-19 was registered in jordan on the 2nd of march 2020: a young jordanian male who was on a trip to italy. upon confirming the first case, the national measures were scaled up in order to limit and tackle the spread of covid-19 effectively. as of the 16th of april 2020, there have been 402 confirmed cases of covid-19 and seven deaths attributed to the disease (12, 17) . in addition, most of confirmed cases were jordanian nationals. the seven deaths occurred in the period between the 28th of march and the 9th of april 2020 for people of older age groups with underlying comorbidities as per the government officials (12) . more details about these statistics are provided in charts 1, 2. in the previous decades, many emerging respiratory viruses and respiratory diseases have posed a threat to humans globally (19) . it is important to focus on the value of having a national preparedness plan in response to emerging communicable diseases. in addition, lessons should be learned from the previous outbreaks and pandemics (20) . the covid-19 pandemic is an emerging public health issue that threatens human life and is an unpredictable situation with many uncertainties, thus exhibiting the main characteristics of a "crisis" (21, 22) . crises management is challenging to both policy makers as well as decision makers; an improper and incomplete response can lead to devastating outcomes (22) . this article has provided a brief overview of the ongoing jordanian experience and response in combating covid-19. the measures that were implemented by the government aimed particularly to mitigate the spread of the disease and to increase the societal awareness about this pandemic. from the previous charts, spikes in the number of new cases were noticed during the last week of march and the first week of april even though the country's lockdown and curfew preceded these spikes. this raises concerns about the behavior of sars-cov-2 and transmission dynamics. proper communication and information dissemination are essential in crises management (22) . the jordanian government has implemented various measures that are aimed at providing the public with essential information and directions by reaching different age groups across the country through media channels, such as television, internet, and covid-19 emergency hotlines, as well as through the armed and security forces who provided support and assistance for the public. google tm has created a platform that collects and aggregates anonymous data on trends of individuals' mobility within the community across different countries using data from google maps, aiming to support health officials and policy makers during this pandemic (23). as of the 11th of april 2020, google mobility charts showed that individuals' mobility in jordan has been effectively reduced during the curfew. interestingly, the mobility around highly crowded spots was reduced: retail and recreation centers have seen a reduction by 93% compared to the baseline, grocery stores have seen a reduction by 89% compared to the baseline, and workplaces have seen a reduction by 81% compared to the baseline (23). the data from these mobility charts show that the governmental restrictions on individual's movements were effective and successful despite the few hundreds of violations that happened at the beginning of the curfew (24) . the psychological impacts associated with curfew and lockdown are also challenging to the society and the government. the extent of societal adaptability to this sudden change in lifestyles could be determined by the level of awareness among individuals and the degree of the governmental restrictions (25) . despite the limited number of violations that happened during the curfew, the jordanian public showed high levels of commitment and awareness, as reflected by the slow pace of covid-19 spread inside the country, and this implies that majority of the public have adopted the recommended preventive and control measures successfully. different societal responsibilities, including social distancing, frequent hand washing and sanitization, as well as complying with the recommendations from health authorities, will all result in a more effective national response to limit the spread of the disease, especially upon the release of the current lockdown and curfew in jordan. the main goal of the lockdown and curfew strategy is preventing the exponential rise in the number of infected persons within a short period to avoid overwhelming the healthcare facilities (26) . however, the process of returning to normal life after releasing the lockdown and curfew is also challenging to both decision makers and the society. early reduction and easing up of governmental interventions and restrictions might lead to adverse impacts in causing a subsequent strike of covid-19 (27) . looking at the fact that effective antiviral medications and vaccines are still lacking, the jordanian decision makers should not ignore the possible scenario of a serious subsequent strike with covid-19 cases after ending the current lockdown and curfew considering the slow pace of covid-19 spread and the undeveloped population-scale immunity. thus, plans for managing a possible "second wave" of infections must be incorporated into the lockdown and curfew exit strategy (26) , and this should be supported by simulations of the effects of different public health measures to predict future scenarios (27) . bearing that in mind, the jordanian public have a tremendous responsibility in terms of adapting to the covid-19 preventive measures and implementing them as a new normal lifestyle, especially in the period following the lockdown and curfew. furthermore, the jordanian preparedness and response strategy can benefit from the ongoing global experiences and scenarios regarding the covid-19 pandemic. although jordan was among the first countries to implement highly strict preventive and control measures, there are always opportunities to learn from the global experience to improve the current national strategy. at this early stage and the uncertain future scenarios, it is difficult to critically compare the effectiveness of various covid-19 response strategies at different contexts despite the fact that the numbers of covid-19 cases and deaths in jordan are much lower than in most of the neighboring countries. however, during and after the battle of covid-19, countries, including jordan, must take more serious steps to strengthen and improve their healthcare system capacity in order to be well-prepared for such crises in the future (28, 29) . having a sufficient reservoir of medical devices and personal protective equipment as well as a backup of highly trained healthcare staff for critical units will be of great assistance and support to keep going during pandemics. as a country of limited resources, the covid-19 pandemic is expected to have a noticeable negative impact on the jordanian economy due to the ongoing country's lockdown and curfew. in response to that, an emergency response fund, with generous contributions from different components of the jordanian public, has been created in order to reduce the economic impacts of this crisis (12, 17) . recently, the government also began to relax some restrictions by allowing certain commercial sectors to return to work under specific regulations (17) . however, the individuals' commitment to and compliance with the preventive measures are critical during these relaxations. besides, it is beneficial to carry out economic studies to develop some insight into the current economic status as well as the period that will follow the release of the lockdown and curfew. in conclusion, the jordanian way of combating the covid-19 pandemic is promising despite the uncertain future predictions and scenarios. in addition, the jordanian crises management task force provides an example of how important the collaborative efforts in providing critical decisions are. adopting and implementing the technical guidelines in emergency health situations provided by the who is also crucial (30) . moreover, maintaining high levels of awareness and commitment within the jordanian society, strengthening the government-society partnerships, having a well-formulated national preparedness and response strategy with effective leadership, as well as implementing internationally standardized guidelines in crises management are all essential to success and progress during critical situations like the covid-19 pandemic. the numbers of covid-19 cases and deaths that were used to develop the charts for this study can be found on [https://corona. moh.gov.jo/]. the author confirms being the sole contributor of this work and has approved it for publication. the author acknowledges with gratitude the generous sisgp scholarship provided to him by the swedish institute (si) for his current postgraduate study in public health. insights into the recent 2019 novel coronavirus (sars-cov-2) in light of past human coronavirus outbreaks probable pangolin origin of sars-cov-2 associated with the covid-19 outbreak severe acute respiratory syndrome coronavirus 2 (sars-cov-2) and coronavirus disease-2019 (covid-19): the epidemic and the challenges sarscov-2 and coronavirus disease 2019: what we know so far world health organization declares global emergency: a review of the 2019 novel coronavirus (covid-19) world health organization. who europe coronavirus disease (covid-19) outbreak -who announces covid-19 outbreak a pandemic available online at novel coronavirus (2019-ncov) outbreak: a new challenge coronavirus disease (covid-19) outbreak situation epidemiology, causes, clinical manifestation and diagnosis, prevention and control of coronavirus disease (covid-19) during the early outbreak period: a scoping review advice for public -covid19 jordanian ministry of health. covid-19 in jordan preliminary identification of potential vaccine targets for the covid-19 coronavirus (sars-cov-2) based on sars-cov immunological studies available online at available online at available online at: http:// www.pm.gov.jo/category/7603/??? the origin and prevention of pandemics the signature features of influenza pandemics -implications for policy preparing for the future: critical challenges in crisis management responding to crises and disasters: the role of risk attitudes and risk perceptions available online at understanding the mental health and psychosocial needs, and service utilization of syrian refugees and jordanian nationals how do we leave lockdown? comment beware of the second wave of covid-19 world health organization. strengthening health-system emergency preparedness : toolkit for assessing health-system capacity for crisis management higher health council. the national strategy for health sector in jordan world health organization. country & technical guidance -coronavirus disease (covid-19). (2020) the author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.copyright © 2020 al-tammemi. this is an open-access article distributed under the terms of the creative commons attribution license (cc by). the use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. no use, distribution or reproduction is permitted which does not comply with these terms. key: cord-312136-o5xsmg3z authors: kuznetsova, lidia title: covid-19: the world community expects the world health organization to play a stronger leadership and coordination role in pandemics control date: 2020-09-08 journal: front public health doi: 10.3389/fpubh.2020.00470 sha: doc_id: 312136 cord_uid: o5xsmg3z the coronavirus disease 2019 (covid-19) pandemic has been accompanied by the return of the concept of national state and exhibited signs of crisis of globalism and liberalism. the pandemic affected most aspects of society and human activity, including socioeconomic impact. economic problems, shortages of medical supplies and personnel, xenophobic sentiments, and misinformation led to the use of unethical practices and human rights violations. to navigate through this crisis, many countries resorted to traditional diplomacy in the absence of effective international instruments. thus, the world faced the urgent need in functioning global governance. the pandemic also manifested the increasing importance of international organizations as sources of technical expertise, providing scientific basis for politicians to legitimize their decisions and actions. the article addresses the topic of implications of the pandemic for governance and forecasting a post-pandemic future. the research focus of this paper, therefore, is the assessment of the role of the world health organization (who) in prevention and response to pandemics. the work is aimed at identifying the functions of the who and assessing its activities in prevention and control of pandemics and response to the covid-19 pandemic in particular. furthermore, the objective of this article is to identify gaps in the who pandemic control efforts and formulate recommendations on addressing them. the coronavirus disease 2019 (covid19) pandemic and other recent and ongoing infectious disease outbreaks, emerging, re-emerging, and neglected infectious diseases, as well as bioterrorism, posing a threat to health security, suggest the necessity and significance of pandemics-related research. the control of pandemics is impossible without international cooperation, due to their transboundary nature, and intergovernmental organizations are to play an important role in pandemic preparedness and response. the world health organization (who) is the only source of legally binding international regulations for pandemic response, the importance of which is growing, and a provider of technical assistance and standard guidelines to the states (1) . strong national health systems are the foundation for effective pandemics prevention and control, and their strengthening is crucial, especially in low-income countries. the international system of mechanisms of response to pandemics is currently in the process of formation, and it is a dynamic process. the challenge for such system is to ensure the existence of supranational legal authority and make it function. the authority and the capacity of the who to lead the international response have been questioned during the ebola outbreak and the covid-19 pandemic. the crises also revealed the lack of resources of the who to effectively prevent and respond to pandemics (2) . at the same time, the role of emerging influential and resourceful actors in pandemic control has been growing, including the world bank group, the bill and melinda gates foundation, médecins sans frontières, and other organizations. one of the central issues in international efforts to prevent and control pandemics is the aid to the poorest countries to develop health systems and ensure availability and accessibility to the basic health services by their population (3). the role of international mechanisms advanced significantly from adopting the who international health regulations (ihr) in 1969, focusing on just three diseases (cholera, plague, and yellow fever), to approving the current version of the ihr in 2005 and to creating the who contingency fund for emergencies (cfe) in 2015 (4, 5) . during the sars outbreak in 2003, the problem of coordinating response actions in different countries already became obvious. the existing response mechanisms were rather slow and disorganized. the outbreak revealed the necessity to modify the ihr. the revision of the ihr in 2005 allowed the who to declare public health emergency of international concern (pheic) and required the member states to strengthen national emergency response capacity. the revised version of the ihr was tested by h1n1 influenza outbreak in 2009, when weaknesses in the global response to influenza pandemic were revealed again. the who issued recommendations to the member states to create more extensive reserve global health workforce and establish $100 million contingency fund for future pandemics. however, these recommendations were not implemented until 2014 (6) . the ebola crisis revealed the importance of legal instruments and raised legal and ethical issues, due to, for example, introduction by some governments of trade and travel restrictions. this outbreak questioned the who credibility and the effectiveness of the ihr (7). the who plays a key role among all intergovernmental organizations involved in tackling pandemics, and it is the only source of legal authority. the core functions of the who related to pandemics prevention and control include the following: support member states in developing national capacity to respond to pandemics, support training programs, coordinate member states for pandemic and seasonal influenza preparedness and response, develop guidelines, and strengthen biosafety and biosecurity (8) . the main instruments used by the who for pandemic prevention and control include the ihr, the global outbreak alert and response network (goarn), the public health emergency operations centre network (eoc-net), the contingency fund for emergencies, and the pandemic influenza preparedness (pip) framework. at the strategic level in pandemic control, the who focuses on reinforcing national public health systems, one health approach, and strengthening global partnership. the ihr is a legally binding regime for protection and management of disease threats. it is a framework for collective response to the threats, involving one or more countries, or to public health events of global significance. the current version of the ihr entered into force on 15 june 2007, and they are binding on 196 countries across the globe, including all who member states (1). to date, the progress has been achieved in some areas of the ihr implementation, for example, introduction of national focal points to connect with different government sectors, stakeholders, and the who; increased transparency in reporting; improved use of early warning systems; and enhanced cooperation between organizations dealing with human and animal health. nevertheless, there are still significant gaps related to the ihr. by the original deadline of june 2012, only onefifth of the 192 who member states had met the core capacity requirements, and by 2019, one-third (9) . the problems related to the ihr implementation are lack of resources and difficulties in developing effective public health services. the ihr are not flexible enough to be adapted to local conditions. the criteria and mechanisms for declaring public health emergencies and for complying with the ihr need to be improved. the procedures should be simplified for the countries with scarce resources (3, 10) . in order to provide rapid access to resources and expertise for effective response to public health emergencies, in 2000, the who and partners established goarn. the network provides a global operational framework encompassing a wide range of capacities and expertise, and it is aimed at coordinating support to countries and effectively deploying response teams. goarn links over 200 institutions and networks and includes over 600 partners around the world (11) . since its establishing, the network has been involved in 135 field missions in 90 countries, deploying over 2900 professionals to the field (12) . goarn is considered to be effective, and it has gained trust and respect. the who stresses the importance of training and maintaining a reserve global health emergency personnel (13) . goarn focuses on the technical support roles and improving surveillance. despite its efficiency, during ebola outbreak, it became clear that goarn needs to strengthen its leadership, respond faster, and broaden its capacity (6) . in 2012, the who established eoc-net to identify and disseminate best practices and standards for eocs and support eocs' capacity building in member states. the who works with eoc-net partners to develop evidence-based guidance for establishing, operating, and improving eocs (14) . considering the criticism of the who in terms of lack of resources and slow response to emergency situations, cfe was established by the world health assembly in 2015, with the target funding of us$100 million for the 2018/2019 biennium. this target has been achieved. since the establishment of cfe, the member states have contributed over us$130 million to it (15) . the distinctive feature of this fund is that it can be mobilized within 24 h, while the other financing mechanisms have different funding criteria and slower disbursement cycles. for this fund to be effective, it needs to attract greater levels of multi-year flexible financing (16) . pip framework for the sharing of influenza viruses and access to vaccines and other benefits is an international agreement adopted by the world health assembly in 2011 to improve global pandemic influenza preparedness and response. the framework includes a pip benefit sharing system that foresees an annual partnership contribution to the who from influenza vaccine, diagnostic, and pharmaceutical manufacturers through the who global influenza surveillance and response system (17) . through this mechanism, the who will ensure the immediate availability of necessary products in case of influenza pandemic. furthermore, who partners have contributed us$198 million to improve pandemic influenza preparedness and response. according to gostin et al. (18) , even though pip framework is not a treaty, it has features of international law, such as collective accountabilities, partners collaboration, and compliance procedures. global partnership is one of the main areas of work to guide the ihr implementation. key partners to support the who implementation include the food and agriculture organization, the world organization for animal health, the un children's fund, the international labour organization, the european union (eu), international aid agencies, who collaborating centers, and non-governmental organizations and foundations (19) . according to the provisions of the ihr, on 30 january 2020, the who declared the outbreak a pheic and assessed the risk as very high for china, and high at the global level. on 11 march, the who said that the outbreak can be characterized as a pandemic (20) . the who did not recommend limiting trade and movement, in line with ihrs. many countries, however, have not followed these recommendations (21) . shortly after announcing the pandemic, the who launched the covid-19 solidarity response fund. this initiative allows individuals and organizations around the world to directly support the work of who and partners to help countries with greatest needs prevent, detect, and respond to the covid-19 pandemic. the disbursement mechanism for money raised through the fund is quick and flexible. as of july 2020, the solidarity response fund collected more than 200 million usd from more than 500,000 individuals and organizations (22) . furthermore, the who has also been involved in other fundraising efforts, such as establishing the who foundation and organizing charity concerts. another key initiative to respond to drastic medical supply shortages and potential food crisis in a number of countries, the who in collaboration with the world food program established the un covid-19 supply task force in april 2020, within the framework of covid-19 supply chain system. this mechanism has been created to coordinate the procurement of medical supplies to countries with overwhelmed health systems. this initiative will be run by the who and the world food program, together with a number of un partners. the supply chain hubs will be located in belgium, china, ethiopia, ghana, malaysia, panama, south africa, and the united arab emirates. according to the who, the supply chain may need to cover more than 30% of the world's needs in the acute phase of the pandemic (23, 24) . prior to launching this mechanism, the who has already shipped personal protective equipment and diagnostic tests to over 120 countries. the who has also launched a "solidarity trial" initiative, an international clinical trial, with the participation of 90 countries, aimed at finding effective treatment through rapidly discovering whether any existing drugs can slow the progression of the disease, or improve survival (25) . in collaboration with partners, the who launched a global collaboration to accelerate the development, production, and equitable access to new covid-19 diagnostics, therapeutics, and vaccines (26) . the who has been extensively involved in providing training and technical assistance thought its openwho platform and goarn knowledge hub and in deploying experts via goarn network (27) . the who tackles misinformation through carrying out various online campaigns and being active on all social media channels. it releases daily situation reports and holds press conferences for updating the media about the pandemic. in march 2020, the who has started allocating the funds from cfe by releasing $9 million to the most vulnerable countries (28) . the response initiatives by the who have come under criticism, mainly by the us president donald trump, who accused the who for failure to control the pandemic and for promoting the interests of china. in april 2020, d. trump announced the suspension of the us financing of the who and later on the withdrawal of the us membership in the who. however, other members such as china, france, and germany pledged extra funding to the who to compensate for the lack of resources (29, 30) . thus, the who has been engaged in political confrontation, which has led to changes in balance and redistribution of influence among the member states. covid-19 and previous pandemics have tested the leadership of the who and revealed a number of problems in its activities. the who response to both the 2009 influenza pandemic and the covid-19 pandemic has been extensively criticized. the main points related to the who pandemic prevention and control activities that have come under criticism are as follows: 1. over/underestimation of threat. 2. conflict of interest and political bias. 3. problems related to the ihr implementation. 4. slow response. 5. lack of financial resources. 6. the who is seen as a more political and less technical organization (6). 7. the who pandemic preparedness plans are ill-equipped to foresee and solve unique ethical challenges that may arise during different infectious disease outbreaks (31) . apparently, the allegations of overestimation of threat and accusations of conflict of interest following the 2009 influenza pandemic have led the who to be more cautious in its statements and in declaring pheic and pandemic. the who followed experts' advice to mobilize the wider national, regional, and international community at earlier stages of an outbreak prior to a declaration of a pheic (3). the majority of countries do not meet the core capacity requirements for the implementation of the ihr (9). a number of provisions the ihr have been violated by countries during the covid-19 pandemic, as it had already happened during the ebola pandemic (32) . there is no multilateral strategy or funding to address the problem of pandemic preparedness and developing capacities for implementation of the ihr in lowincome countries (7) . at the same time, progress has been achieved in such areas as surveillance and communication among stakeholders involved in pandemics control and organizations dealing with human and animal health. some experts argue that the ihr do not create international law that is binding on the participant countries, due to the implementation and compliance problems. in practice, the international community applies "soft law" that implies nonbinding duty to collaborate with other countries and with the who with regard to infectious disease surveillance and control of outbreaks. although such "soft law" is neither mandatory nor enforceable, it is powerful politically. the reasons for why this "law" is functioning are that contributing to and enhancing international collaboration in infectious disease response is in a country's self-interest and that the who managed to create a framework for international cooperation on infectious diseases that is able to withstand the increasing global threats posed by pathogens (33) . suthar et al. (34) consider sanctions and embargoes a viable alternative to the functioning ihr. while using such measures can be inevitable in certain situations, as practice shows, these instruments can be based on the principle of double standard and be used for political manipulation purposes. the who has been working on adjusting its policies and activities according to identified gaps, for example, by establishing the cfe. experts point out evident progress in the who response to the ebola outbreak in congo in 2018, compared to its response to the 2014 outbreak (32) . during the covid-19 pandemic, the role of the who as a source of information and knowledge dissemination organization turned out to be critical, due to uncertain rapidly evolving situation and a lack of data and scientific knowledge about the virus and the disease. given the significant impact of misinformation on countries' pandemic control efforts, this function of the who is especially important in the countries with low trust in government. the who pays special attention to developing collaboration with other organizations involved in pandemics preparedness, focusing on one health approach. during the covid-19 pandemic, the who has been collaborating and coordinating response with a wide range of international organizations, including the world bank group, various un agencies, gavi, the global fund, the eu, etc. (35) . the recommendations to improve the who capacity to prevent and control pandemics are as follows: 1. continue the ongoing reform of the who. 2. member states should ensure stable financing for the organization. 3. the who should work on increasing its credibility, paying special attention to ensuring the organization's transparency, political and business neutrality, and adapting evidence-based decisions and policies. 4. the member states should develop political trust, and the organization should be unbiased, distance itself from politics, and focus on its technical functions. 5. focus the international efforts to tackle pandemics on longterm development aid programs and projects. 6. concentrate efforts on developing basic health infrastructure and strengthen health systems in countries most vulnerable to pandemics. 7. further consider the options for the ihr enforcement mechanism and the ihr revision. 8. create a coordinated, adequately funded global health initiative to deliver assistance to the vulnerable countries to build their capacities to implement the ihr. 9. the who should further collaborate with partners to resolve the issues, indirectly related to the who functions, that impede effective prevention and control of pandemics. the most vulnerable countries to pandemics are conflict-affected countries (36) . therefore, a powerful instrument to prevent pandemics is the prevention of conflict escalation. the aid efforts, including the efforts to strengthen health systems, will be ineffective and inefficient as long as the governments are involved in conflicts in the pursuit of taking over natural resources and boosting the profits of military corporations. furthermore, the countries-beneficiaries of development aid can critically perceive the contradiction between the negative effects of economic policies dictated by the donors and development aid initiatives aimed at mitigating various effects of such policies on society and health of the population (37) . such issues, however, do not fall under the direct responsibility of the who, and the who cannot be held accountable for these shortcomings. in response to the covid-19 pandemic, the who has been working in line with its core functions related to pandemic control. it has used some of the existing mechanisms for pandemic prevention and control and created new ones to respond to covid-19. overall, given the situation of uncertainty and lack of knowledge about covid-19, the who has taken timely appropriate steps in the initial response to the pandemic. the measures adopted by the who lie within the scope of the organization and have been limited by its mandate and available resources. lessons learned from covid-19 pandemic response should be further analyzed, and the organization's emergency response mechanisms and capacity should be improved, as discussed above. many experts agree on the necessity to provide the who with more resources and stable financing and extend its mandate (2, 3, 38) . the world community expects the who to play a stronger leadership and coordination role. the original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author/s. world health organization. strengthening health security by implementing the international health regulations independent oversight and advisory committee for the who health emergencies programme. interim report on who's response to covid-19 global preparedness monitoring board. a world at risk: annual report on global 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(2020) goarn partners deploy experts to fight the covid-19 pandemic world health organization. contingency fund for emergencies pledge hundreds of millions of extra funding to world health organization china to give who an extra $30m to fight coronavirus ethics for pandemics beyond influenza: ebola, drug-resistant tuberculosis, and anticipat-ing future ethical challenges in pandemic preparedness and response do not violate the international health regulations during the covid-19 outbreak global health security demands a strong international health regulations treaty and leadership from a highly resourced world health organization lessons learnt from implementation of the international health regulations: a systematic review timeline of who's response to covid-19 identifying future disease hot spots: infectious disease vulnerability index medicina preventiva y salud pública covid-19 reveals urgent need to strengthen the world health organization the author confirms being the sole contributor of this work and has approved it for publication. the author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.copyright © 2020 kuznetsova. this is an open-access article distributed under the terms of the creative commons attribution license (cc by). the use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. no use, distribution or reproduction is permitted which does not comply with these terms. key: cord-327005-7zgolyqf authors: zhang, lan; huang, songming title: clinical features of 33 cases in children infected with sars-cov-2 in anhui province, china–a multi-center retrospective cohort study date: 2020-06-16 journal: front public health doi: 10.3389/fpubh.2020.00255 sha: doc_id: 327005 cord_uid: 7zgolyqf background: as of 23rd february 2020, china had 77,048 patients with confirmed sars-cov-2 infections, and only 2. 1% of patients were under the age of 19 years. morbidity among children was much lower, with milder or absent signs and symptoms; chest ct scans showed milder symptoms, if at all, compared to adults. objective: report the epidemiological, clinical features, laboratory, radiological characteristics, and treatment of sars-cov-2 infections. compare additional signs and symptoms, investigate familial clustering, compare laboratory results, and find out relevance between age and typical chest ct scans in patients. methods: we studied 33 young patients with laboratory-confirmed sars-cov-2 infection in anhui province of china by 16th february 2020. their signs, symptoms, and familial clustering were analyzed. we compared the laboratory test results, age, and gender among three parts based on their chest ct scans. results: familial clustering was seen in 30 (30/33; 90.91%) patients; three families had seven confirmed members infected with the disease. eight (8/33; 24.24%) patients had no symptoms, 12 (12/33; 36.36%) patients had only fever, nine (9/33; 27.27%) patients had fever and additional symptoms, and 12 (12/33; 36.36%) patients had no fever. dry cough was the most common additional symptom. in 25 (25/33; 75.76%) patients, the percent of lymphocytes decreased; 26 (26/33; 78.79%) patients were older than 7 years. more male than female patients and patients older than 8 years showed typical abnormalities in the chest ct scans (p = 0.038). only two 18 years old patients had hepatic injury. conclusion: children's infection is mild and familial clustering was the most common channel. the older patients had more typical ground glass opacity (ggo) or consolidation in chest ct scans. cases without fever strongly suggested that non-symptomatic children should not be assumed to be free of infection when their family members have confirmed infection. most children showed clinical features distinguishable from adults and with increased susceptibility within family members. since december 2019, the epidemic of coronavirus−2019 (sars-cov-2) has spread throughout the world, rapidly resulting in 4,330,982 confirmed cases and 295,671 deaths as of 6th may 2020. anhui province was the third region to be affected by coronavirus-2019 in china, with hubei and guangdong provinces being the first two. among the patients, only 2.1% were under the age of 19 years. not only was their morbidity less than adults, their clinical features were also milder. and a few of them showed no signs and symptoms of the infection. however, every child with a confirmed sars-cov-2 infection is being diagnosed as having novel coronavirus pneumonia ("ncp"), even though some of them had no fever, cough, fatigue, or typical radiological characteristics in a chest ct. here, we report 33 patients under the age of 19 years with confirmed covid-19 infection from anhui province, china, and describe the clinical features, laboratory, and radiological characteristics of a chest ct, treatment, and clinical outcome. we also report the patients' history of contact with infected person/s (direct or indirect), and (familial clustering). these cases highlight the importance of familial clustering clinical features, chest ct characteristics, and age. we aim to share our findings and recommend that pediatricians reconsider the diagnoses of children with confirmed infection. a total of 33 patients were enrolled in this study who were admitted to one of the 10 hospitals in anhui province in china between december 2019 and february 2020. the inclulsion criteris was: being under 19 years of age having respiratory specimens that were analyzed twice by real-time rt-pcr, and being diagnosed according to the world health organization's interim guidance (1) . all the cases were discharged with twice negative real-time rt-pcr up to 6th may 2020. all case data can be provided on request. the medical data were analyzed by the medical team from the pediatric department at the first affiliated hospital of ustc. information recorded included demographic data, medical history, familial clustering, details of the confirmed patients, if any, in the family, whether they were residents of wuhan, or traveled to wuhan, whether they came in contact with confirmed patients, signs, and symptoms, including pharyngodynia, fever, cough, vomiting and diarrhea, fatigue, tightness in the chest, total wbc and lymphocyte percentages, levels of c-reactive protein (crp), il-6, liver function, ckmb, a marker of myocardial injury, chest ct, administration of inf a, lopinavir and ritonavir, ribavirin, or arbidol, and titers of mp-igm, anti-parainfluenza virus igm, anti-influenza virus igm, and anti-adenovirus igm. the laboratory test results and statistical analyses were the first ones carried out since the symptoms were noticed. as lymphocyte population vary according to age a lymphocyte content of <60% in patients below 7 years of age and <30% in patients over 7 years of age is considered as "lymphocyte percentage decrease." we divided the chest ct images into three classes: (1) typical abnormalities, with bilateral multiple lobular and subsegmental areas of consolidation or bilateral ground-glass opacity (ggo) and subsegmental areas of consolidation or ggo; (2) non-typical abnormalities, showing nodal and patchy shadow of bilateral median and extrapulmonary zone; and (3) normal. we divided the 33 cases under study based on various aspects. when the incidence of fever was considered, they were classified into two groups: with fever (2) and without fever, and the baseline characteristics and differences in other signs and symptoms between the two groups were analyzed. from these data, the percentage of confirmed familial cluster among the cases, and the predominance of different signs and symptoms in the cases were estimated. based on the laboratory results, we divided the cases into three phases: total wbc≤5x109/l, 5-10x109/l, and >10x109/l, and counted the cases in different phases. we also divided the cases into two categories: decreased and nondecreased, based on the percentage of lymphocytes, and scored the number of cases in each of these categories. when the radiological characteristics of chest ct were considered, the cases were divided into three parts: typical, non-typical, and normal. we also considered differences based on age and gender, details of the treatment, including the drugs administered in all cases, and identified the most widely used ones among these cases. a retrospective cohort study was used to analyze the epidemiological data, clinical symptoms, and signs, changes in wbc and total lymphocyte counts, chest ct, and the different treatments in children infected with sars-cov-2. a comparison of the baseline characteristics of the data and signs and symptoms revealed that in both the groups fever was a common symptom. the data were analyzed using cases number (n) and percentage (%), except for the age of the patients, which was calculated as the mean. cases were divided into three categories, according to the severity of chest ct (typical, non-typical, and normal), and compared the differences in age and sex between the three categories. variables between these were presented as numbers and percentages, and continuous variables were presented as mean ± standard deviation. chisquare test or fisher's exact test was used to compare categorical variables, and student's t-test was used for continuous variables. a two-sided p < 0.05 was considered statistically significant. data were analyzed using spss statistics version 19.0 (spss inc., chicago, il, usa). the studies involving human participants were reviewed and approved by anhui provincial hospital (the first affiliated hospital of ustc) medical research ethics committee. written informed consent to participate in this study was provided by the participants' legal guardian/next of kin. in particular, written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article. among the 33 cases, the fever group (n = 21) had more patients than the non-fever group (n = 12). baseline characteristics, including demographic data, familial clusters, wuhan residence, travel to wuhan, and contact with confirmed patients were not significantly different between the two groups ( table 1) . among the 33 cases under study, 12 (12/33; 36.36%) had only fever, six (6/33; 18.18%) had a dry cough, two (2/33; 6.06%) had vomiting and diarrhea, and 13 (13/33; 39.39%) were placed in the "others" group, showing symptoms like rhinorrhea, sneezing, sore throat, fatigue, and herpes ( table 2) . thirty cases (30/33; 90.91%) exhibited familial clustering. there were three families, each of whom had seven members with confirmed sars-cov-2. fourteen families (14/33; 42.43%) had two confirmed members (figure 1) . overall, eight (8/33; 24.24%) cases had no symptoms, 12 (12/33; 36.36%) had only fever, nine (9/33; 27.27%) had both fever and additional symptoms, while 12 (12/33; 36.36%) were without fever. dry cough was the most common symptom in addition to fever, and additional symptoms included vomiting, diarrhea, and fatigue (figure 2) . total wbc count was <5 * 109/l in 13 cases, between 5x109/l and 10x109/l in 14 cases, and more than 10x109/l is six cases. twenty-five cases presented with a decreased lymphocyte population, while eight cases did not (figure 3) . among the patients under study, seven were under 6 years, 13 were school-age children, and 13 were older than the school-age children. in the three classes based on chest ct images, typical abnormalities occurred in children older than 8 years (figure 4) . we divided 33 chest ct images into typical abnormalities (n = 6), non-typical abnormalities (n = 8), and normal (n = 19). the mean age of the group showing typical abnormalities was higher (11.83 ± 3.71 years) than that of the other two groups (8.16 ± 5.32 years and 10.68 ± 4.71 years, respectively), but the differences were not statistically significant. the number of female patients in the normal group was higher than in the other groups and the differences were significant (p = 0.038) ( table 3) . most of the typical abnormalities showed ggo with patchy consolidations at subpleural focal changes on ct image ( figure 5a ) and non-typical abnormalities ct image mostly showed increased lung marking or dense hilar shadows ( figure 5b) . among various treatment categories, nine cases were administered with only inf-a, 17 cases had inf-a combined with other antiviral drugs, including lopinavir and ritonavir, ribavirin, and arbido, while four cases used only chinese patent medicine as an antiviral drug. we did not find any difference in the curative effects of these drugs. we present here a descriptive study on the clinical and epidemiological characteristics of the covid-19 infection. we collected data on 33 young patients (<19 years of age) who were as of february 23, 2020, among the 33 patients included in this study, no dyspnea or similar complications were reported, and none of them were critically ill. covid-19 infection is associated with clustering onset (5) . the data in this cohort study showed that only three patients had no familial clustering history, including two patients who were residents of wuhan. a majority of these patients (30, or 30/33; 90.91%) cases showed familial clustering. three families had seven members each, and five families had four patients each with confirmed infection. among all cases, two were twins, two were sisters, and four were cousins. this suggests rapid personto-person transmission of covid-19, similar to what happens in adults. covid-19 is mainly transmitted through respiratory droplets or through contact (6) . in addition, current research shows that it may also be transmitted through the fecal-oral route (7) , inhalation through aerosols produced through coughing by the infected family members, relatives, and healthcare workers, or though other sources in the environment (8) . a recent study also suggested that infection in the womb or during birth could not be denied completely (9) . nevertheless, in children, familial clustering is an important factor in rapid human-tohuman transmission of covid-19 through close family contacts. therefore, vigilant control measures should be taken at an early stage of the infection in a family (4) . as other studies reported, we noticed that sars-cov-2 less commonly affects children (10) , and that they have much fewer symptoms and less severe cases (11) compared with adults, and also much lower case-fatality rates (10) . in our study, none of the cases had difficulty breathing or needed oxygen support; this is different to adult cases. the common symptoms at the onset of illness were fever and dry cough. huang (12) reported fever [40 of 41 patients [98%]], cough (76%), myalgia or fatigue (44%), headache (8%), hemoptysis (5%), and diarrhea (3%). wang et al. (13) reported common symptoms, including fever (98.6%), fatigue (69.6%), dry cough (59.4%), myalgia (34.8%), and diarrhea and nausea (10.1%). however, 12 (12/33; 36.36%) cases in the present study were without fever and a small proportion of patients presented initially with atypical symptoms, like fatigue, sore throat, rhinorrhea, sneezing, vomiting, diarrhea, and herpes. one of them had a sore throat at the onset of symptoms and one had fatigue; the status was the same as that of adults. a 27-year-old man (14) was reported with vomiting and loose stools before admission. michelle et al. (15) reported the first case in the united states which was that of a 35year-old man, with a "subjective fever" of 37.2 • c. this patient presented with a persistent dry cough, nausea, and vomiting. in a report (5) of 99 cases, 20% had no fever or cough at the onset. this suggests that measuring the body temperature cannot be considered as a decisive screening method. furthermore, in our report, there were eight (8/33; 24.24%) cases without any early signs or symptoms. when present, the signs and symptoms were from the respiratory system (upper and lower) to the digestive system. we speculate that this observation probably indicates that the target cells might be located in different tissues, and this may change with age. in most of the cases enrolled in this study, the total wbc count was normal or decreased. the percentage of lymphocytes decreased in 25 (25/33; 75.75%) cases. many reports (12, 13, 15, 16) of adults showed the routine blood test was useful as a diagnostic tool. a decrease in lymphocyte count indicates that sars-cov-2 affects immune cells and inhibits cellular immune function (5) . t lymphocyte damage (17) might be an important factor in exacerbating the condition of patients. the decreasing percentage of lymphocytes could prompt sars-cov-2 infections in the clinic. in addition, huang et al. (12) reported that 40% of the cases they studied showed hepatic injury, five cases had myocardial injury, and injuries were more severe in critical patients. in our study, none of the patients showed myocardial injury, only two 18-year-old patients showed hepatic involvement. this difference may be attributed to better liver regeneration capacity and better ability to recover from myocardial injury. six (6/33; 18.18%) cases had typical ggo or consolidation (18) of the lungs as the primary findings on ct scans. all the patients were more than 8 years old. the infants and preschool-age children had atypical chest ct scans or normal ct. a familial clustering report suggested that the symptoms of covid-19 were non-specific, but the three oldest patients in that family had more critical symptoms (4) . it may be because the trachea, bronchi, and capillaries are relatively thin in childhood, and children's lungs are rich in connective tissue, poorly developed elastic tissue, abundant blood vessels, capable of holding less air, have fewer alveoli, and a less well-developed pulmonary interstitium. more research focused on the function of ace2 as the sars-cov-2 receptor and proved the binding of sars-cov-2 to ace2 lead to driving the systemic manifestations of covid-19, including respiratory clinical feature and cardiovascular complication (19) . most elderly patients routinely take ace2 receptor antagonists to treat high blood pressure, which increases the expression of ace2 and helps covid-19 enter the cells. on the contrary, the level of ace2 expression in children is low and therefore the symptoms are mild. in both healthy and diabetic individuals, ace2/ace is negatively correlated with age (20) . many reports have shown that older males (21) (22) (23) (24) are more likely to be infected by covid-19. the atypical and normal chest ct scans suggest that more attention needs to be paid to young children. we also observed a greater number of males than females with typical ct scans. in adults (5), the proportion of confirmed infection in men is higher than in women. however, wei et al. (25) reported nine infected infants from 1 to 11 months, and seven of them were females. thus, covid-19 is more likely to infect adult and older males (21) (22) (23) (24) . on january 9, 2020, chinese scientists identified the cause of a new illness as a novel coronavirus, and as of january 10, 41 confirmed cases of coronavirus pneumonia had been reported in wuhan city. this is the first time this disease was called "ncp." this new virus was designated as wh-human 1 coronavirus (whcv) (26) and has also been referred to as "2019-ncov." huang et al. (12) reported that all patients had pneumonia. the virus was given the official name of covid-19 by the who on february 11, 2020 (27) , and this name is more scientific and suitable. in this retrospective study, we report 12 cases without fever and eight cases without any signs and symptoms, and all cases were mild. only six cases had typical ggo or consolidation on ct scans. we divided the patients into those with typical signs and symptoms such as fever, dry cough, and atypical sore throat, fatigue, vomiting, and diarrhea. we also divided the chest ct scans into typical, atypical, and normal. we suggest more attention should be paid on the children without syndrome but with family member infected by covid-19. this is a small case report of patients admitted to different hospitals, and the test results and chest ct scan results were not homogenous. it is necessary to follow up the cases enrolled in this study until all of them are discharged from the hospital, and also to test the respiratory specimens 2 weeks after discharge to re-confirm that all of them are cured of sars-cov-2 infection. children's infection is mild and familial clustering was the most common channel of infection. the older patients had more typical ground glass opacity (ggo) or consolidation in chest ct scans. cases without fever strongly suggested that nonsymptomatic children should not be assumed to be free of infection when their family members have confirmed infection. children were highly susceptible to covid-19 and they showed clinical features distinguishbale from adults. all datasets generated for this study are included in the article/supplementary material. the studies involving human participants were reviewed and approved by anhui provincial hospital medical research ethics committee. written informed consent to participate in this study was provided by the participants' legal guardian/next of kin. written informed consent was obtained from the individual(s) for the publication 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2: sars-cov-2 receptor and regulator of the renin-angiotensin system: celebrating the 20th anniversary of the discovery of ace2 aging healthy, or with diabetes, is associated with ace2/ace this imbalance in the hematopoietic stem progenitor cells prevalence of comorbidities in the middle east respiratory syndrome coronavirus (mers-cov): a systematic review and meta-analysis sex-based 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 soft-tissue infections novel coronavirus infection in hospitalized infants under 1 year of age in china a new coronavirus associated with human respiratory disease in china three emerging coronaviruses in two decades the story of sars, mers, and now covid-19 lz and sh contributed to the conception and design of research. lz gathered the medical data, updated the literature search, made independent quality assessments, and extracted data before comparing results and resolving differences. the nicu team of the first hospital affiliated to ustc analyzed the data. lz edited and revised the manuscript. sh and lz approved the final version of manuscript. the authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.copyright © 2020 zhang and huang. this is an open-access article distributed under the terms of the creative commons attribution license (cc by). the use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. no use, distribution or reproduction is permitted which does not comply with these terms. key: cord-253211-klewqw7u authors: zhang, yan; xie, simiao; wang, pu; wang, guixiang; zhang, li; cao, xiaochen; wu, wenzhi; bian, yueran; huang, fei; luo, na; luo, mingyan; xiao, qiang title: factors influencing mental health of medical workers during the covid-19 outbreak date: 2020-09-22 journal: front public health doi: 10.3389/fpubh.2020.00491 sha: doc_id: 253211 cord_uid: klewqw7u background: since the outbreak of covid-19, physical and psychological harm has been spreading across the global population alongside the spread of the virus. currently, the novel coronavirus has spread to most countries in the world, and its impact on the public is also increasing. as a high-risk group in direct contact with the virus, medical workers should be monitored, and their mental health deserves extensive attention. the aim of this study was to explore the mental health of medical workers facing the novel coronavirus and the main factors affecting it. methods: the present cross-sectional study including 2,100 eligible individuals from 1,050 hospitals in china was conducted through the network platform powered by www.wjx.cn, a platform providing functions equivalent to amazon mechanical turk. we used a self-designed questionnaire to collect demographic information and data on mental states, including gender, age (years), educational level, job rank, body and mind reaction, cognition of risk, and the judgment of the epidemic situation. independent samples t-tests and one-way (anova) analysis were carried out to compare the differences in the mental reactions according to the demographic and psychological states of the participants. results: there were 502 males (23.9%) and 1,598 females (76.1%). the participants reported feeling calm (39.1%), tense (63.0%), scared (31.4%), angry (18.8%), sad (49.0%), afraid (34.7%), optimistic (5.1%), impressed (65.0%), and confident (31.1%) during the epidemic. at the same time, the psychological stress responses of medical staff were significantly different according to the levels of exposure in their environments, duration and personal experience. conclusions: prolonged exposure to the virus and intense work are detrimental to the mental health of medical care personnel. it is necessary to adjust work conditions and intensity according to workers' mental state flexibly and systematically. at the end of 2019, a large outbreak of disease that was widespread with a high speed and a large number of infected people broke out in wuhan (1, 2) , hubei province, china. it spread quickly over a short period of time (3, 4) , and it has been a serious threat not only to physical health (5) but also to mental health issues throughout the population (6) . since april, there have been no additional diagnoses for many days outside of hubei, china (7) , and the number of additional infections in hubei has been largely in the double-digits, as if the chinese epidemic were about to end. however, since the outbreak of the global epidemic (8) (9) (10) , the number of imported cases has been increasing continuously, making the slightly calmer mood tense once again. if the control of imported potential patients is not adequately strong to prevent the epidemic from spreading again, previous efforts could be in vain. according to the latest real-time statistics of johns hopkins university, as of 08:33 beijing time on march 16th, the cumulative number of confirmed cases of coronary pneumonia worldwide was more than 160,000, and the cumulative number of confirmed cases outside china exceeded 86,435. studying the novel coronavirus is not only a matter of fighting covid-19 in china but also an international public health crisis that needs to be fought by the whole world. since the outbreak of the epidemic, tension, anxiety and other negative emotions have spread throughout china on a large scale, so much so that people have fallen into a series of psychological crises (6) . medical care personnel, as the backbone of the front line of epidemic prevention and control, have been taking on heavy work tasks with a high risk of infection and great work pressure (11) . health-care workers, especially those in hospitals who take care of confirmed or suspected patients, are more vulnerable than the general population, experience a high risk of infection and negative emotional stress, and further risk spreading the virus to their family, friends or colleagues (6) . moreover, dangerous and susceptible environments as well as traumatic experiences caused by high exposure can all have a certain impact on an individual's emotional state and induce emotional stress responses (12) as well as severe anxiety and depressive disorders and posttraumatic stress disorder (ptsd, posttraumatic stress disorder) (11, 13) . a psychological survey published in the lancet· psychiatry showed that the prevalence of depression, anxiety, insomnia and stress among medical staff involved in the prevention and control of the epidemic were as high as 50.7, 44.7, 36.1, and 73.4%, respectively (14) . until now, despite the rudimentary principal notice issued by the china national health commission in january regarding the emergency psychological crisis intervention measures for covid-19 pneumonia, no one has been able to provide timely and effective psychological intervention measures for medical staff. therefore, it is urgent and important for psychological researchers to focus on the mental health problems of medical workers during the epidemic, explore the main factors affecting their psychological stability and health, and try to prevent longterm irreversible psychological trauma to medical workers. some scholars (15, 16) in environmental psychology have studied the effects of the environment on the individual, especially in the face of danger. according to ecological theory, the individual behavior and environment are part of an interactive ecosystem, and individual behavior has a temporal and spatial background; that is to say, there is an integrated behavioral situation (17) . for the same environmental phenomenon, arousal theory argues that the influence of the same spatial and temporal background on individuals is determined by the degree of arousal experienced by any particular individual (18) . the level of arousal experienced by individuals is closely related to personal experience. inspired by this theory, this study attempted to investigate whether differences in the exposure environment, personal experience, and exposure duration of medical care personnel would lead to differences in their psychological responses, and advice and assistance were provided to personnel to prevent the development of mental health issues. the questionnaire was designed for medical workers from all provinces in china. in the formal test, 2,100 medical workers were selected from 1,050 hospitals in 31 provinces to fill out the questionnaire, including 659 in wuhan and 1,441 outside of wuhan; 502 males and 1,598 females were included. among them, 2.3% were under 25 years of age, 19.5% were aged 25-30, 39.5% were aged 31-40, 29.0% were aged 41-50 and 9.7% were over 50 years of age. the study was designed in accordance with the tenets of the declaration of helsinki. approval from the ethical authority of the school of educational science, huazhong university of science and technology, was granted. confidentiality and the statement confirming informed consent were managed by anonymous coding of the self-report questionnaires. this survey used wechat, online questionnaires and other online surveys to investigate the emotional and psychological stress states of medical staff. we used a selfdesigned questionnaire to collect demographics and mental state data including factors such as gender, age (years), educational level, job rank, body and mind reaction, cognition of risk, and the judgment of the epidemic situation, which was started in the third week after the outbreak, and the specific time is from february 12 to february 21, 2020. our team sent out questionnaires through the internet platform powered by www. wjx.cn, a platform providing functions equivalent to amazon mechanical turk. participants filled in the questionnaire on the web page through mobile phone or computer. first, information was collected through small-scale interviews; next, we compiled a stress response questionnaire and determined the questionnaire topics and factors through exploratory factor analysis (efa). data from 312 subjects were collected as preliminary test through a web questionnaire with 15 items, including 79 in wuhan and 233 outside wuhan, 80 males and 232 females. before the exploratory factor analysis, the results showed that the kmo (kaiser-meyer-olkin) measure of sampling adequacy was 0.765 (chi-square = 801.389, df = 91, p < 0.001), and the bartlett's test of sphericity indicated that the correlation matrices on which the pca was based were suitable for analysis. according to the factor load matrix after the rotation axis, the analysis process of the items was as follows. first, delete three items with insufficient load and which are difficult to name on each factor; next, compare the load of each item on each factor, and delete three items with small load and similar load on different factors; third, analyze each factor, and delete the items with poor division and which are difficult to explain. as per the above principles, all nine items were retained and three factors were confirmed as the result, and the total variance was 55.90%. the factors, which were named in turn, were cognition of danger (cd), reflecting the evaluation of the environmental risk of the subjects; judgment of the situation (js), reflecting the confidence in successfully combating the epidemic and the psychology of the anti-epidemic work; and the stress reaction (sr), reflecting the physical and mental stress response produced by the subjects' current environment. see table 1 . after constructing a stress reaction questionnaire with good reliability and validity, we used confirmatory factors analysis (cfa) to confirm the validity of the questionnaire to provide a questionnaire that reflected the ideal standard. data from 432 subjects were collected as cfa, including 118 in wuhan and 314 outside wuhan, 118 males and 314 females, and the fitting index tables and model diagrams drawn through amos software of cfa are shown in table 2 and figure 1 ; finally, we conducted a wide range of formal tests. the internal consistency reliability (cronbach α coefficient), partial reliability and the correlation between each factor score and the total score of the questionnaire were calculated by spss 23.0, and the results showed that the overall internal consistency and reliability and the overall parity factor for both was 0.67. see table 3 . all data analysis was carried out using spss 23.0 (spss inc, chicago, illinois), and a two-tailed probability value of < 0.05 was considered to be statistically significant. descriptive statistics for the demographic and psychological states of the medical staff were shown as the mean, standard deviation (sd), number (n), and percentage. independent samples t-tests and one-way (anova) analysis were carried out to compare the differences in the mental reactions according to the demographic and psychological states of the participants. among the 2,100 subjects who filled in the questionnaire, the distribution was not uniform, and 85.3% were doctors (1, 792 in this study, the differences in the health care workers' environmental exposure were demonstrated mainly by whether they participated in the covid-19 resistance front and had direct contact with confirmed patients. there were significant table 4 . the results show that those involved in the first-line response believed they were at greater risk of exposure to infection in the workplace(t = 4.872, p < 0.001), and they had more anxiety about infection (t = 2.943, p = 0.003), thought they were more likely to get sick (t = 4.295, p < 0.001), worried more about family infection (t = 1.982, p = 0.048), had lower confidence in obtaining victory over the epidemic (t = 2.339, p = 0.019), had poor sleep quality (t = 2.559, p < 0.001) and had a higher demand for psychological counseling (t = 3.491, p < 0.001). however, there were no significant differences for the cognition of the current epidemic severity and the fear of epidemic prevention. the differences in health care workers' personal experiences were affected mainly by whether they had experienced sars or another epidemic. there were significant differences in the levels of cognition of danger, judgment of their situation and stress reactions to personal experiences. specific statistical results for the medical care personnel and group comparisons are displayed in table 5 , which shows that medical staff involved in sars prevention believed they had a greater risk of exposure to infection in the workplace (t = 2.220, p = 0.027), were more likely to be infected (t = 2.057, p = 0.040), had more confidence in the success in epidemic prevention and control (t = −2.895, p = 0.004), less fear of fighting the epidemic (t = −3.167, p = 0.002), and poor sleep quality (t = 2.848, p = 0.004). however, there were no significant differences for the items regarding being worried about getting infected, the cognition of the current epidemic severity and the need for psychological counseling. since the outbreak of the epidemic, medical workers have been stressed and made to work for long periods of time, with little time for rest. the difference in exposure duration was reflected mainly by the number of continuous working days. this study compared the differences in the duration of the participants' operational time in medical care work and divided the working hours into four levels for horizontal comparison, which found that the longer the working hours were, the more likely the participants believed they would be infected (f = 5.868, p < 0.001), the more worried they were about family members being infected (f = 2.870, p < 0.035), and the poorer their sleep-quality was (f = 18.403, p < 0.001). however, the fear of epidemic prevention was lower (f = 6.052, p < 0.001). furthermore, there were significant fluctuations in two dimensions, cognition of the current epidemic severity (f = 2.676, p = 0.046) and confidence in anti-epidemic measures (f = 11.275, p < 0.001), caused by the increase in working hours, which at first declined a certain degree, then increased significantly. see table 6 . since the emergence of the new coronavirus pneumonia in wuhan at the end of december 2019, numerous medical staff have been working intensively for nearly 3 months and will continue to do so in the future. the results showed that the current mental health status of health care workers was not stable, with a general mean of more than 3.5 in terms of the cognition of danger, and most of the mean values were above 4 (according to richter's five-point score, which gradually declined from 1 to 5). regarding the dimensions of the judgment of the situation and the stress reaction, the medical staff were optimistic, and there was no obvious negative somatization phenomenon. it was found that the exposure environment, personal experience, and exposure duration had significant effects on the psychological stress and emotional responses of medical staff. medical workers involved in the front-line of prevention were affected to different degrees in these three dimensions, and the statistical level was significantly different. this may be due to direct exposure to close contact with the virus and negative tension in their environment as well as the fear of threats to their own lives. additionally, the medical work environment is infested with patients' senses of grief and panic, resulting in a constant psychological burden for front-line medical workers. at the same time, there is no clear and targeted cure for the novel coronavirus infection. doctors and nurses are not in a position to cope with the suffering of infected patients, which is further increasing their psychological burden. the influence of medical workers who have experienced sars and other epidemic diseases was not synchronized in these three dimensions. in the dimension of the cognition of danger, employees with experience of sars and other epidemic prevention situations felt more serious psychological pressure, while for the dimension of the judgment of the situation, they had more confidence about overcoming this epidemic. this may be explained by the success of the prevention and control of infectious diseases like sars, which has enhanced the collective sense of the efficacy of health care groups in the face of similar diseases, thus enhancing their confidence. however, the difficulties of living through that process and the negative emotions experienced are difficult to describe, and the impact has not gradually disappeared over time. the outbreak of the epidemic quickly awakened the former unhappy memory, so the iteration and development of risk cognition were derived from a certain preexisting foundation. this is also a wake-up call for psychological workers to remind us to do a good job of psychological intervention and health care even after illness. as the time of exposure to the virus increases, the mental state of the medical staff deteriorates. regarding the factor of risk cognition, the negative psychological state of the medical staff gradually intensifies with the passage of time, whereas the optimistic hope dimension presents the inverted u curve change. in the physical and mental response dimension, the sleep-quality of the medical staff is generally poor, but the difference in the level of demand for psychological counseling is not significant. this may be because, in the early days of the outbreak, a large number of patients poured into hospital emergency rooms and fever outpatient departments, increasing the already heavy workload and responsibility of all medical staff. meanwhile, the high intensity of work continued without rest, there were inadequate protective supplies and protective isolation measures, the outpatient procedure organization became cluttered, and other phenomena have continually aggravated the psychological burden of medical staff, reducing the confidence of medical workers in prevention and control. as the epidemic situation gradually comes under control, medical work tends to stabilize, so the confidence in prevention and control has been steadily recovered. however, the negative feelings of health care workers have not been effectively vented, such as the grievances, fears, and powerlessness of medical staff in the face of dissatisfaction from patients and their families because of the lack of timely treatment. the inner suffering cannot slowly dissipate over time. by contrast, it is highly likely that the backlog of negative emotions causes some mental health issues, especially ptsd, requiring the attention of psychological workers. ptsd usually occurs within a few weeks of traumatic events but can also appear after a few months or even a few years, and the duration is usually half a year or more (19) (20) (21) , depending on the severity of the event and the individual state of mind (22, 23) . the current trend of the epidemic situation in china has been obviously controlled, and the tension of the medical staff can be relaxed in stages, which is the best time for online psychological guidance. moreover, the outbreak of foreign epidemics is rapid, and many countries lack the experience of prevention and control. china plans to send some supportive medical workers to countries where the epidemic is ongoing. the relief of tension is about to face new challenges, and it is essential to effectively perform psychological intervention and regulation for medical staff. both chinese and international mental health workers must pay attention to this problem and stabilize psychological security (24, 25) . this study found that the psychological state of medical workers was significantly affected by the high-risk environment of direct contact infection, long working hours, and personal experiences. however, the only factors that can be controlled are the working environment and working hours. the authors suggests the establishment of a matching system between the psychological state and the working intensity of medical staff; after all, only upon a foundation of psychological security can the work be completed efficiently. the psychological security work needs to be carried out in a systematic and hierarchical manner from the local level to a more general investigation by utilizing close attention to ensure that every corner of the mental health of medical staff is explored. first, based on the overall comprehensive investigation, a medical staff psychological state tracking system should be established. second, all mental state files should be classified into attention levels, such as core, focus, general attention, etc. meanwhile, each health worker will be assigned a psychologist who is responsible for paying regular attention to their mental health problems. psychological workers need to evaluate whether the medical staff 's work schedule matches their psychological status and periodically review their appropriate work intensity level. finally, specific psychological interventions need to be carried out for all health workers who are marked as working at a certain level of focus and above by recording any incidents in their mental state file. by investigating the emotional and psychological stress responses of medical staff during the prevention and control of the new coronary pneumonia, it was found that the high intensity of medical work had a variety of negative effects on their risk cognition, confidence in overcoming the epidemic situation and physical and mental reactions, all of which are detrimental to the mental health of medical staff. in addition, the exposed environment, personal experiences and differences in the length of their work hours played important roles. to maintain the mental health and stability of medical staff and avoid the influence of mental health issues like ptsd, psychological workers need to take targeted measures to systematically solve the mental health problems of medical workers in the face of major infectious disease crises. the raw data supporting the conclusions of this article will be made available by the authors, without undue reservation. approval from the ethical authority of the school of educational science, huazhong university of science and technology, was granted. confidentiality and the statement confirming informed consent were managed by anonymous coding of the self-report questionnaires. the patients/participants provided their written informed consent to participate in this study. yz, pw, and lz conceived and designed the questionnaire. lz recruitment and payment of participants. sx, gw, xc, yb, fh, nl, ml, and qx analyzed the data. sx wrote and revised the paper. all the authors have approved the manuscript and agreed with submission to your esteemed journal. a novel coronavirus outbreak of global health concern clinical features of patients infected with 2019 novel coronavirus in wuhan travelers give wings to novel coronavirus (2019-ncov) incubation period of 2019 novel coronavirus 2019-ncov infections among travellers from wuhan, china 2019-novel coronavirus outbreak: a new challenge timely mental health care for the 2019 novel coronavirus outbreak is urgently needed will novel virus go pandemic or be contained? journey of a thai taxi driver and novel coronavirus importation and human-to-human transmission of a novel coronavirus in vietnam community pharmacist in public health emergencies: quick to action against the coronavirus 2019-ncov outbreak vicarious traumatization 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time does acute stress disorder predict post-traumatic stress disorder in traffic accident victims? analysis of a self-report inventory mental health and psychosocial support in crisis and conflict: report of the mental health working group crisis exploitation: political and policy impacts of framing contests we thank all participants for their time and interest as well as the editor and reviewers for their valuable feedback. the authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.copyright © 2020 zhang, xie, wang, wang, zhang, cao, wu, bian, huang, luo, luo and xiao. this is an open-access article distributed under the terms of the creative commons attribution license (cc by). the use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. no use, distribution or reproduction is permitted which does not comply with these terms. key: cord-274163-yxl9a9u7 authors: yadav, uday narayan; rayamajhee, binod; mistry, sabuj kanti; parsekar, shradha s.; mishra, shyam kumar title: a syndemic perspective on the management of non-communicable diseases amid the covid-19 pandemic in lowand middle-income countries date: 2020-09-25 journal: front public health doi: 10.3389/fpubh.2020.00508 sha: doc_id: 274163 cord_uid: yxl9a9u7 the global coronavirus disease (covid-19) pandemic has greatly affected the lives of people living with non-communicable diseases (plwncds). the health of plwncds worsens when synergistic epidemics or “syndemics” occur due to the interaction between socioecological and biological factors, resulting in adverse outcomes. these interactions can affect the physical, emotional, and social well-being of plwncds. in this paper, we discuss the effects of the covid-19 syndemic on plwncds, particularly how it has exposed them to ncd risk factors and disrupted essential public health services. we conclude by reflecting on strategies and policies that deal with the covid-19 syndemic among plwncds in lowand middle-income countries. the entire world has been affected by the coronavirus disease (covid-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (sars-cov-2), which has led to thousands of deaths each day. the covid-19 pandemic is one of the greatest public health calamities since world war ii and, despite best efforts, has been challenging to control (1) . recognizing the rapid spread of covid-19 and the threats it poses, the world health organization (who) declared it an international public health emergency on 30 january 2020. this allowed countries to exert maximum effort and allot resources to limit the rapid transmission of sars-cov-2. despite the low fatality rate and government efforts, people are living in uncertainty and fear, as there is no vaccine for covid-19. covid-19 has weakened healthcare systems and economies, emptied open spaces, and filled hospitals (2). the pandemic has separated many people from their family, friends, and workstations and has severely disrupted modern life. to mitigate this unprecedented pandemic, physical, and social distancing along with nationwide lockdowns and restrictions, have been implemented for the past few months in several countries (3) . covid-19 is creating a profound impact on all parts of the community, including the physical and mental health of the public. the growing pandemic is augmenting existing mental health problems (4), including loneliness, anxiety, paranoia, panic, depression, and hoarding, with long-term psychosocial impacts (5) . social distancing, stress, and fear are the main factors behind these psychological problems, leading to a global increase in suicides (6) . self-isolation and quarantine measures disproportionately affect people, especially older adults, migrants, laborers, refugees, people with chronic diseases, and marginalized and vulnerable populations (7) . the covid-19 cataclysm has become the most serious problem worldwide, and its consequences have left no one untouched (6) . the effects of a pandemic intensify due to its diverse nexus of intertwined biological and socioecological factors. this diverse nexus was coined a "syndemic" by medical anthropologist merrill singer in the 1990s to describe the relationship between hiv/aids, substance use, and violence (8) . a "syndemic" is defined as a synergistic interaction between socioecological and biological factors (figure 1) , resulting in adverse health outcomes (9) . the covid-19 pandemic has escalated into a syndemic due to several driving factors, such as overcrowding, loneliness, uncertainty, poor nutrition, and lack of access to health services; consequently, depression, suicide, domestic violence, and psychiatric illnesses have significantly increased (11) . social determinants of health, such as poverty, social inequality, social stigma, and the environment where people live and work, greatly affect the intensity of the syndemic (12) . additionally, xenophobia, ostracism, and racism are reported in many places. generally, people living in countries with higher social and economic inequalities have more coexisting non-communicable diseases (ncds) and are therefore more vulnerable to the syndemic impact of covid-19. we argue that, for people living with ncds (plwncds), covid-19 is considered a syndemic-a synergistic pandemic that interacts with various pre-existing medical conditions and social, ecological, and political factors and exacerbates existing ncds. studies have reported higher proportions of frailty (13, 14) , malnutrition (15) , psychological problems (16) , and coinfections, including antimicrobial resistance pathogens, among plwncds (17) in low-and middle-income countries (lmics). ncds have been recognized as a key risk factor for covid-19 patients (18); however, vulnerability to catching sars-cov-2 increases in the presence of other pre-existing factors. prevailing inequalities in the social determinants of health, including poor social, economic, and environmental conditions (e.g., social behavioral factors, physical environment, social marginalization, and supportive government policies; figure 1) , have an impact on various aspects of life such as health, wellness, and financial status. for example, plwncds with comorbidities and higher social and economic deprivation are less likely to access health services during this pandemic. this results in worse health outcomes, such as poor quality of life, mortality, suicide (6, 19, 20) , and increased hospitalization due to poor self-management (21, 22) . during the covid-19 pandemic, plwncds from disadvantaged groups are less likely to receive healthcare compared to plwncds from socially advantaged groups. the disadvantaged population (particularly individuals from low socioeconomic conditions) have a high chance of falling sick (23) , dying, and experiencing catastrophe. furthermore, socioeconomically deprived individuals who were dependent on daily wages have lost their jobs; this has pushed them further into poverty and poor health (23) . a synergistic association between the severity of covid-19 and ncds was reported in china (24) , which shows the negative effects of this syndemic. this suggests the urgency of a paradigm shift from a single-condition approach to a syndemic approach to tackle the current and future impacts of pandemics among plwncds in lmics. the pandemic is unlikely to end soon, and it is difficult to predict the arrival of the next pandemic, but the syndemic will certainly continue in lmics. in this paper, we discuss covid-19 among plwncds, exposure to ncd risk factors, and the disruption of essential public health services for ncds. it considers literature on this topic, following a search on google and pubmed to identify publications that considered populations with covid-19 and ncds. we conclude by reflecting on strategies and policies that deal with the covid-19 syndemic among plwncds in lmics. the global covid-19 pandemic has resulted in 16,923,006 cases in 213 countries and territories around the world and two international conveyances, with 664,191 fatalities as of july 29, 2020 (25) . covid-19 cases are decreasing in many countries, but the opposite is true in lmics such as india and brazil. many seriously ill covid-19 patients had multiple comorbidities (26) ; for instance, 96.2% of those who died in hospitals in italy had comorbidities. the case fatality rate increases with age, especially in countries with a high percentage of older adults. the comorbidities were mostly ncds, such as hypertension, diabetes, cardiovascular disease, and chronic lung disease, especially chronic obstructive pulmonary disease (27, 28) . the prevalence of comorbidities is higher among covid-19 patients compared to the general population who are not infected with coronavirus; for instance, 86% of the covid-19 patients in india and 72% of the covid-19 patients in china had comorbidities (28) . the prevalence of comorbidities is expected to be similar in other lmics where the prevalence of ncds is high; however, there is a lack of literature on this topic from lmics. the health condition is more severe and mortality is higher among older adults with ncds (29) and people with bacterial infections caused by antibiotic resistant pathogens, such as superinfections (30) . ncds cause around 72% of deaths worldwide and are the primary cause of death in southeast asia among those aged 30 to 70 years (28) . lmics have a large ncd burden; in some lmics, such as india, there is an early onset of ncds, thereby increasing the risk of covid-19 among young individuals (31) . the addition of covid-19 to pre-existing ncds results in increased morbidity and mortality (32). ncds can exhibit several characteristics with infectious manifestations, including parameters like a proinflammatory state and compromised innate immune response (33) . this condition is further worsened because many plwncds have been deprived of treatment for their diseases since the onset of the covid-19 pandemic. preventive methods for this pandemic, such as physical/social distancing, lockdowns, self-isolation, and quarantine, may increase exposure to ncd risk factors, such as the increased use of tobacco products and alcohol as coping strategies (34), increased reliance on unhealthy processed foods and barriers to physical activities (34), which lead to weight gain (31) . these factors increase the incidence of ncds and related mortality (35) . moreover, financial crises and the lack of social contact might enhance the burden of anxiety and depression among plwncds. the economic slowdown predisposes people to malnourishment, which further increases the risk of infectious diseases (31) . since the covid-19 pandemic began, prevention and treatment services around the globe have been severely impaired, and the disruption is worse in lmics. the results from a survey conducted by the who in 155 countries (36) revealed that plwncds were not able to access services for their health conditions, which made their lives even more difficult during this crisis. more than 53% of the surveyed countries reported partially or completely impaired services for ncds and related complications, particularly after the covid-19 trajectory changed from sporadic to community transmission. this is supported by the stories and pictures of plwncds captured in the news and social media of lmics, where people were unable to access basic medicines or care (particularly in areas with protracted lockdowns) for their chronic conditions. this problem is exacerbated by the reassignment of health staff from ncd facilities to covid-19 in all surveyed countries (36) and the disruption of medical supplies and diagnostics as a result of nationwide lockdowns (23) . for example, in india, some outpatient services have been temporarily closed, and hospitals have been converted into designated covid-19 care homes (23) . this arrangement will have a further adverse effect on access to healthcare services and treatment adherence by plwncds. similar painful stories regarding plwncds have been reported in the news and social media platforms of many lmics, such as nepal, bangladesh, brazil, pakistan, ghana, and iran. governments in various countries have made efforts to focus on ncd services while tackling covid-19, but only 42% of low-income countries have done so compared to 72% of highincome countries (hics) (36) . this shows the global impact of covid-19 on the disruption of healthcare services for ncds. the interaction of covid-19 with other biological and social factors appears to increase the risk of complications, worsen health outcomes, and intensify the burden on healthcare professionals and health systems. on the one hand, there is a global rush to respond to covid-19 by increasing intensive care unit beds, installing ventilators, extending lockdowns, and adopting other containment measures. on the other hand, there is a disruption of routine health services, such as screening and diagnosis, supplies of essential medicines, and access to health service providers and support services. the covid-19 syndemic and other conditions have not only posed a challenge to health systems but have also exposed gaps within the healthcare delivery system in many hics (e.g., italy, spain, and the united states) and lmics (e.g., pakistan, india, nepal, bangladesh, mexico, and brazil). due to covid-19, the priorities of health services have shifted; as a result, the progress required to achieve sustainable development goals is threatened (37) . in the subsequent section, we describe strategies that are essential to overcoming and managing the syndemic condition. we divide these strategies into four broad categories (figure 2) . the sudden lockdowns imposed by authorities caused panic in many countries. to avoid such situations, there should be a supply of basic needs, such as groceries and sanitary items. home delivery is an important strategy that can be implemented with the help of volunteers, especially for older adults and people with disabilities. misinformation and fake news on social media platforms are fuelling this panic. people should follow information from trusted sources such as government guidelines. additionally, authorities should disseminate the appropriate information to the general public in a timely manner. plwncds should be encouraged to monitor their symptoms, practice self-care, adhere to medication, seek healthcare services including counseling, practice physical distancing, wash their hands with soap, and wear masks. providing information on self-management behavior changes for ncds and covid-19 through sms and social media platforms is an important step. in this situation, health literacy (having the necessary information and skills to manage health) and activation (motivation and the ability to take action) can play an important role (37, 38) in self-management (39) of conditions among plwncds in lmics. promoting both the health literacy and empowerment of plwncds would enable patients to navigate health services, use technology to contact healthcare providers, develop problemsolving skills, and adhere to healthy lifestyle behaviors (40) . healthy lifestyle activities must be promoted, such as eating nutritious foods and engaging in physical and wellness activities. individuals should have access to open spaces and be allowed to exercise at scheduled times while maintaining all precautionary measures, and plwncds could be given timecards for physical activity. the expansion of existing community health worker (chw) roles can be crucial to the self-management of ncds and covid-19 and to delivering basic services among plwncds during this extreme health workforce shortage, particularly in lmics with weak health systems. recovered covid-19 patients can also spread information on health and self-care management and help debunk the myths and lessen the stigma related to covid-19. although countries (mostly developed ones) are trying to provide care through telemedicine, it is still in the formative stage. while telemedicine is a boon for developed nations when it comes to the diagnosis, treatment, self-management support, and surveillance of conditions, lmics with fragile health systems often struggle to launch telemedicine services. using digital healthcare platforms in the health system (41) would greatly increase access to the services and information required by plwncds. this would, in turn, improve the management of chronic conditions and provide relief from emotional turmoil and stress (42) . in fragmented health systems, chws can promote coordinated care by improving access to care and providing navigation support (43) . chws can also carry out surveillance of risk factors and implement preventive and self-management strategies for plwncds, who are at high risk of covid-19. potential chw roles in covid-19 management include community engagement, community sensitization, promoting isolation and quarantine, and performing contact tracing (44, 45) . despite their huge potential in pandemic management, chws have been underutilized in the covid-19 pandemic, especially in countries where chws are available, such as bangladesh, india, and nepal. however, before involving chws in the covid-19 response, they must be provided with appropriate training and adequate personal protective equipment (46) . while responding to covid-19, the governments of lmics have failed to ensure health services for plwncds because of the blanket lockdown approach. insufficient attention has been paid to the unnoticed drivers of covid-19-related mortality among plwncds. while governments enforce mitigating measures during this pandemic, they also need to develop strategies to map national-level data on ncd patients, as such data do not exist in many lmics. there is also a need to prepare care pathways for severely ill plwncds by engaging private and public healthcare institutions and delivering basic health services (e.g., screening, medical checkups, and pharmacy services) at the community level via mobile primary healthcare vans. in many lmics, out-ofpocket (oop) health expenditures are high and will rise further during the covid-19 pandemic (28) . to reduce the burden of oop due to covid-19, authorities should make provisions for free diagnostic and treatment facilities and focus on equitable, accessible, and affordable healthcare. these measures will prevent the deterioration of health among plwncds amid the covid-19 pandemic. a situational analysis of available resources and resource planning must be carried out. supportive packages should be provided to vulnerable groups, such as older adults, people with disabilities, and the unemployed. involving the private sector, civil society, academia, non-governmental, and governmental organizations through intersectoral coordination and teamwork would address the situation with a syndemic lens. hics can help lmics in setting up 24/7 helpline support to provide essential information and guidance related to the availability of services and contact in case of emergency. authorities should also consider imposing different levels of restrictions by mapping the incidence and active cases of covid-19, such as by designating red, yellow, and green zones. providing an uninterrupted supply of funds is a major challenge for lmics during the covid-19 pandemic. international organizations, philanthropists, and industrialists through their corporate social responsibility should come forward to help countries facing a financial crisis. highquality research and data on effective interventions to prevent the spread of infection and treatment of active cases are also needed. moreover, authorities should impose taxes on items such as sweetened beverages, tobacco, and alcohol to subsidize prices or lower taxes for nutritious food items and ease movement restrictions for food production, processing, and delivery, which will indirectly lessen the use of unhealthy products. ncds increase vulnerability to covid-19, and covid-19 increases ncd-related risk factors. the covid-19 pandemic may not be the last to threaten the global community. therefore, there is a need to understand the drivers of the syndemic and design safety nets. the health system must address not just one or some medical problems but ensure holistic care for those that need it, particularly plwncds. care for plwncds, who are at most risk of covid-19, must be included in national response frameworks and plans so that the government can protect citizens' health and well-being during the current covid-19 pandemic and for similar crises in the future, otherwise, the interaction of covid-19 and ncds will result in disastrous effects that could be difficult to handle given the preexisting stress on healthcare delivery systems and impede progress in achieving the sustainable development goals. the governments of lmics are crippled by a lack of technical and financial resources to address this overwhelming problem. tackling the covid-19 syndemic is a matter of urgency. funding bodies that advocate for and want to be part of a change in lmics need to invest in prevention and health promotion programs that could address issues within a syndemic framework (47). government agencies positioned to develop and implement policies must understand that asking citizens to sacrifice without providing appropriate support packages will not work. rather than gearing up for a vertical approach, governments, concerned stakeholders, development partners, and civil society must build synergy across healthcare platforms to tackle this 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of figure 1 . key: cord-355425-0te4tqck authors: steele, lindsay; orefuwa, emma; bino, silvia; singer, shepherd roee; lutwama, julius; dickmann, petra title: earlier outbreak detection—a generic model and novel methodology to guide earlier detection supported by data from lowand mid-income countries date: 2020-09-11 journal: front public health doi: 10.3389/fpubh.2020.00452 sha: doc_id: 355425 cord_uid: 0te4tqck infectious disease outbreaks can have significant impact on individual health, national economies, and social well-being. through early detection of an infectious disease, the outbreak can be contained at the local level, thereby reducing adverse effects on populations. significant time and funding have been invested to improve disease detection timeliness. however, current evaluation methods do not provide evidence-based suggestions or measurements on how to detect outbreaks earlier. key conditions for earlier detection and their influencing factors remain unclear and unmeasured. without clarity about conditions and influencing factors, attempts to improve disease detection remain ad hoc and unsystematic. methods: we developed a generic five-step disease detection model and a novel methodology to use for data collection, analysis, and interpretation. data was collected in two workshops in southeast europe (n = 33 participants) and southern and east africa (n = 19 participants), representing midand low-income countries. through systematic, qualitative, and quantitative data analyses, we identified key conditions for earlier detection and prioritized factors that influence them. as participants joined a workshop format and not an experimental setting, no ethics approval was required. findings: our analyses suggest that governance is the most important condition for earlier detection in both regions. facilitating factors for earlier detection are risk communication activities such as information sharing, communication, and collaboration activities. impeding factors are lack of communication, coordination, and leadership. interpretation: governance and risk communication are key influencers for earlier detection in both regions. however, inadequate technical capacity, commonly assumed to be a leading factor impeding early outbreak detection, was not found a leading factor. this insight may be used to pinpoint further improvement strategies. this article adds three innovations to the existing body of research: • the authors propose a generic five-step disease detection model that structures the process of disease detection in order to make it generically applicable and thus comparable; • they describe and apply a methodology to systematically collect and analyze data that provides qualitative insights into key conditions and influencing factors for earlier detection of infectious disease outbreaks using the generic disease detection model; and • this article provides qualitative insights into conditions and influencing factors for earlier detection in low-and midincome countries. the outbreak of ebola viral hemorrhagic fever disease in west africa stressed the importance of functional and reliable health systems that enable early disease detection, rapid response, and sustainable recovery. ebola was not confirmed until three months after the first case, during which the virus spread rapidly from guinea to two of its neighboring countries (liberia and sierra leone). one year after the beginning of the epidemic, the death toll reached over 11,000 people in six countries with estimated gdp losses for these three most affected countries totaling us$ 2.2 billion. (1) the ebola outbreak of 2012-2014 was a poignant reminder that the timeliness of outbreak detection has a significant impact on morbidity and mortality, economies, and social and cultural well-being of populations. in the aftermath of the 2003 outbreak of the severe acute respiratory syndrome (sars), the world health organization (who) updated the international health regulations (ihr 2005) and called for all member states to build and strengthen their capacities to prevent, detect, and respond to infectious disease outbreaks, especially for those diseases that have the potential of international spread. the ihr (2005) addressed modern threats by expanding the usual infectious disease notification requirements to include "all events potentially constituting a public health emergency of international concern (pheic) (2) . through this binding agreement, member states are required to establish core capacities and mechanisms for rapid detection of public health risks, as well as the prompt risk assessment, notification, and response to these risks. risk communication as a core capacity under the ihr plays an important role in the identification and assessment of risks, internal, and external communication of risks, the coordination of response, and the implementation of lessons learned (3) . the international spread of disease can cause global repercussions with impacts on social systems, e.g., health (morbidity, mortality), economics (trade, travel, and employment), and social and cultural implications (education, religious practices, and social gatherings). beyond the biomedical spread of diseases, anxiety and social perceptions can amplify the negative impacts of the disease on societies. global fear and anxiety during the 2003 sars pandemic, along with who and centers for disease control and prevention (cdc) travel advisories, tight quarantine policies, port infection control measures and intensive media coverage of the disease, had significant negative impacts on both travel and business around the world, particularly in asia (4) . outbreaks can lead to stigmatization of populations, such as during the h1n1 outbreak when mexicans and other latinos living in the u.s. were ostracized as carriers of disease (5) , and during the recent ebola epidemic where, upon returning to communities, many survivors faced stigma, rejection, violence, and blame and found their jobs lost and properties destroyed (6) . there can also be impacts on local industry, such as with h5n1, which has severe negative impacts for village poultry farmers in many asian countries (7). past outbreaks demonstrate a strong correlation between timely detection and successful containment measures in the sense that early detection is a key determinant of successful disease management, and mitigating impacts on individuals' health, and countries' economies and social systems. to enable early detection, surveillance systems must be in place. surveillance is a core capacity under the ihr (2005) that requires each member state to have an event monitoring system and strengthened surveillance capabilities for rapid detection, prompt risk assessment, notification, and response to public health risks. according to global health observatory data on the implementation status of ihr surveillance core capacity requirements, reporting countries achieved 85% of the ihr surveillance requirements by 2014 (8) . while there are many infectious disease surveillance systems in place that are meeting ihr surveillance core capacity requirements, a key concern is whether these systems detect diseases early and what measures could be undertaken to enable earlier detection. significant time and funding have been invested in improving timeliness of detection (9) . however, efforts to improve surveillance systems have struggled to determine what factors contribute to abilities to detect earlier. currently, monitoring and evaluation follow a quantitative method that retrospectively measures the time (in days), "time-to-detection" (ttd), to discover and recognize an initial event as an outbreak (10, 11) . this quantitative measure serves as a benchmark for monitoring infectious disease surveillance systems; however, it does not provide guidance on how to enable surveillance to detect earlier. key influencing factors that enable or hinder early detection remain unclear and unmeasured. without clarity about the influencing factors and measures to monitor and evaluate these factors, attempts to improve surveillance remain ad hoc and unsystematic. a recent systematic review of drivers of earlier detection revealed that there is little evidence about factors that influence earlier detection (12) . current efforts lay great emphasis on technologies for improving early detection, with inadequate attention to governance and the role of awareness-both in the community and among health professionals-of the potential risk posed by infectious diseases, especially in the endemic settings of low-to mid-income countries. thus, risk communication would be a central tool in addressing these shortfalls. current research in the field of risk communication as a core capacity under ihr (2005) has suggested an evaluation framework for earlier detection, faster response, smoother coordination, and smarter legacy that can serve as a proxy for a better understanding of the drivers of earlier detection (13) . risk communication, in this usage, is a horizontal activity in the process of infectious disease management that supports and informs core capacities such as surveillance and coordination. risk communication is a governance approach with three strategic key activity areas: information (gathering, assessing, and sharing), communication (methods, strategy, and key contents), and coordination (across different administrative levels) (13) . these risk communication activities are closely linked with the notification and reporting requirements introduced by ihr (2005). "this broad notification requirement aims at detecting, early on, all public health events that could have serious and international consequences, and preventing or containing them at source through an adapted response before they spread across borders" (14) . these risk communication categories (information, communication, and coordination) are the main pillars that can inform and facilitate the surveillance process, outbreak response, and outbreak management. to elucidate the outbreak detection process, we developed a generic five-step model of disease detection, starting with a health "event" and ending with outbreak realization at a higher or national level. the central concept behind this model is to delineate the steps in outbreak detection, in order to provide a platform upon which to investigate what the conditions are for each step and the factors that facilitate or block these conditions (see table 1 ). the five steps are: step 1: local recognition-that there is "something" going on that is unusual, strange, worrying, etc. step 2: local reporting. step 3: local assessment. step 4: higher-level reporting. step 5: higher-level assessment and outbreak realization. for each of the five steps in the detection model, there is a set of conditions that needs to be in place. to gather, identify, and assess key conditions, information and insight is needed to provide this input. this data is collected by applying a systematic methodology working with small, facilitated groups using analytical templates and matrices (see description of the "incubator approach" in box 1). each condition has facilitating and blocking factors. working through scenarios in small working groups, this information is disentangled in a group process. in a quantitative analysis, the most influential ("priority") facilitating and blocking factors can be identified assuming that the most important factors are those that are provided the most frequent in the group decision-making process. step 1 recognition step 2 local reporting step 3 local assessment step 4 higher-level reporting step 5 higher-level assessment box 1 | incubator approach. the incubator approach is a novel methodology developed by dickmann risk communication drc| to gather and analyze social or health system-related information. this approach builds on a variety of social science theories [e.g., positive deviance (15) (16) (17) and behavioral economics (e.g., decision making in groups)] and provides a structured, systematic, interactive, and collaborative process to gather and assess qualitative, context-sensitive information. central to this approach is intense, interactive work with a group of stakeholders applying a logical flow in a series of smaller, facilitated working groups and plenary discussions. participants are stakeholders representing a large range of perspectives, sectors, and disciplines. the group work uses analytical templates and matrices to systematically deconstruct and disrupt current understanding and concepts and rebuild and create interventions to improve the situation (e.g., earlier detection). outputs of these incubators are locally informed, structured insights that can be used to design interventions, monitor progress, and measure outcomes and impact. more on https://www.dickmann-drc.com. these priority factors are the targets of interventions that aim to accelerate detection. in a modified theory of change approach, these interventions are designed in a moderated group process (see table 2 ). the workshop methodology (incubator approach, box 1) was employed in two workshops encompassing four regional infectious disease surveillance networks (see box 2): • applying the incubator approach (box 1), we introduced the detection model as a conceptual framework for the workshop and a sorting structure. participants were divided into smaller working groups to focus on different event types such as human health, animal health, or data (e.g., information via a news provider). participants used the detection model to conceptualize and identify the following for earlier disease detection for each of these event types: results of the working groups from each event type (human and animal health and data) were presented and discussed in plenary sessions. at the end of the 2-day workshops, we had empirically identified the most important conditions and factors that influence earlier disease detection within each step of the detection model for each event type, arising out of the interaction (see box 3). the workshop methodology does not address patients directly, yet participants of the workshops came from a broad range of professions (e.g., medical doctors, journalists, and community care workers) representing cultural and social diversity. to compare the most important necessary conditions for earlier detection, we present a matrix of necessary condition domains in each region (see detailed list in table 3 ). the necessary condition domains are based on the following categories that were used during data collection at the incubator workshops: governance, technical capacity, human resource capacity, knowledge, skills, and attitudes/beliefs. governance emerged as the most important necessary condition for earlier detection in both regions overall. legislation and standard operating procedures lay the groundwork for all aspects of disease detection. it is critical that these governing tools are available, practical, and clear for each step in the detection model. attitudes and beliefs emerged as the most subjective and least important condition for earlier detection across the regions. (2) with experience with or responsibility for the management of emerging health threats and the authority to induce change in their countries (senior level, e.g., head of unit or director). secids: www.secids.com mecids: www.mecidsnetwork.org participants (n = 19) at the dar es salaam workshop were senior "shapers" in their countries with experience or responsibility for the management of emerging health threats and the authority to induce change in their countries (senior level, e.g., director) coming from zambia (4), tanzania (12) , uganda (1), and kenya (2). sacids: www.sacids.org eaidsnet: www.eac.int/sectors/health/disease-prevention-and-control/eaidsnet all networks: www.cordsnetwork.org * this designation is without prejudice to positions on status and is in line with unscr 1244 and the icj opinion on the kosovo declaration of independence. frontiers in public health | www.frontiersin.org box 3 | data analysis. two cords researchers independently reviewed and categorized the conditions and influencing factors identified at each workshop. the researchers discussed and agreed on final categorization. in some cases, multiple final category tags were assigned to influencing factors based on joint discussion. conditions and influencing factor categories were then quantitatively ranked in order of importance, based on count within each step of the disease model. the priority influencing factor list includes the three highest-ranking facilitating and blocking factors at each step in the detection model. more than three facilitating and blocking factors were included if there was a tie for the third highest-ranking factor. 3. feedback on prioritized factors by semi-structured interviews with selected participants we did a quality check with five select participants from each workshop on the priority influencing factors. participants provided feedback via semi-structured phone interviews on the final list of priority influencing factors and context-specific indicators of the factors. three cords researchers discussed interview results to determine how to integrate feedback into the framework. in some cases, this resulted in inclusion of more than the top three most important factors within a step in the detection model. we assumed that factors added by interviewees are the least important within the detection model step unless indicated otherwise during the interviews. the remaining four categories had different relative levels of importance across the two regions. in a low-income setting, the most important condition at the early stages of outbreak detection (stages 1-3: recognition, reporting, and assessment) was technical capacity followed and accompanied by governance and policy. in a mid-income setting, the most relevant condition was governance followed by technical and hr capacities. at higher levels and later stages of outbreak detection (stages 4-5), the most important condition in both regions was governance. influencing factors for earlier detection can, in both regions, be categorized along the main activities of risk communication: information (gathering, assessing, and sharing), communication (methods, strategy, and key contents), and coordination (across different administrative levels), embedded in a politically supportive governance approach with a particular emphasis on local level and local and regional activities (for a detailed list see table 3 ). while facilitating factors refer to functional coordination, leadership, communication, and information sharing, blocking factors mainly describe the lack of these (facilitating factors). at the early local stages of outbreak detection (stages 1-3: recognition, reporting, and assessment), the most important facilitating factors in both regions are coordination at local and regional levels, policy and leadership, and access to information and previous experience. blocking factors at this local level are in both regions lack of knowledge and motivation, lack of communication, lack of information and diagnostic infrastructure, lack of policy, and disincentives to report. at higher levels and later stages of outbreak detection (stages [4] [5] , key facilitating factors are again coordination, communication, and a policy framework, followed by training, tools, and access to information. blocking factors in both regions at these stages are lack of policy, disincentives, lack of information and information technologies, and poor communication. in both low-and mid-income countries, governance was identified as the most important condition allowing earlier detection of infectious disease outbreaks. this comes as a surprise, because many initiatives focus on technical or human resource capacity building, but little attention has been paid to intervening in governance to date. governance refers to implicit or explicit political, social, religious, cultural, and scientific norms. governance is an approach and "management" tool; it is the spirit that leads people, who feel that there is something unusual, to do something about it, e.g., to report to a health worker. factors influencing this condition include awareness, decision-making, communication, coordination, and other social or scientific norms. in order to improve surveillance to detect outbreaks earlier, functional risk communication activities such as coordination, communication, and information sharing, along with leadership, play an important role. these factors ensure that the most important condition, governance, is guiding detection efforts. facilitating factors during the early stages of outbreak detection at the local level are coordination at local and regional levels, policy and leadership, and access to information and previous experience. the blocks in the early stages are seen in a lack of those facilitating factors. the technical capacity at a local level plays a role, in particular in low-income countries, but is not the most important factor. in order to improve detection, the focus on technical infrastructure, as often seen in development and capacitybuilding programs, is probably overstated. in fact, policy and governance activities along with risk communication might be more important targets for strengthening earlier detection. by better understanding the influencing conditions and factors that can lead to earlier detection, interventions can be guided more efficiently and effectively. both workshops resulted in a list of interventions for future implementation. this systematic framework could also be used for future monitoring and measurement of changes and improvements. an interesting question to pose would be where should the most effective interventions be directed: following the logic of earlier outbreak detection, it would be at the local level and its early stages of detection (local recognition, reporting, and assessment). however, it could also be that in order to strengthen local recognition, reporting, and assessment, interventions at regional and national levels are more powerful and interventions to strengthen higher-level reporting and assessment at regional and national levels result in earlier detection. further research needs to be undertaken to complement the evidence using the same methodological framework, possibly including high-income countries, and implementation and testing of interventions could provide more insight into these. the empirical data on conditions and influencing factors of earlier detection is based on a small sample that needs testing and validation. it applies a generic framework and novel, systematic data collection methodology that, too, requires further application and reflection. it is, however, a systematic approach to gain more qualitative insights about how to reduce time to detection-and not just record a quantitative measurement. building on this, we will need to test and validate the key drivers of earlier detection. we propose the following next steps: 1) develop a measurement framework with indicators summarized in a scorecard, to allow benchmarking and continuous monitoring following the application of the framework; 2) design and implement intervention studies to test the validity of the indicators, and if targeting the influencing factors identified (by removing blocking factors and/or amplifying facilitating factors) leads to earlier detection. 3) complement the database with data from high-income countries and compare findings. governance was identified as the most important condition allowing earlier detection of infectious disease outbreaks. this came as a surprise, because many initiatives focus on technical or human resource capacity building, but little attention has been paid to intervening in governance to date. key influencing factors are risk communication activities and policy at local, regional, and national levels. interventions targeting the strengthening of risk communication activities at a local level seem a good starting point to test the model and monitor progress. this research introduced a generic disease detection model and a novel methodology to collect and structure social information. it was applied in low-and mid-income countries. these innovations (model and methodology) can be further used to complement existing evidence and include data from highincome countries and to develop a monitoring framework to assess and evaluate progress. all datasets generated for this study are included in the article/supplementary material. the jena university hospital ethics committee waived the requirement for ethical approval for this study in accordance with the national legislation and the institutional requirements. this study is a method development and not an experimental setting. pd designed the research concept and crafted the workshop material. ls, eo, and pd carried out the data collection and analysis. ls and pd prepared the draft manuscript that eo, sb, ss, and jl reviewed thoroughly. all authors approved the final version. the two workshops were held within the capacity building program on risk management and risk communication for cords' six regional infectious disease surveillance networks that was supported by the rockefeller foundation, grant number 2014 spn 301. update on the economic impact of the 2014-2015 ebola epidemic on liberia available online at core capacity monitoring framework: checklist and indicators for monitoring progress in the development of ihr core capacities in state parties overview on sars in asia and the world the h1n1 pandemic: media frames, stigmatization and coping ebola treatment and prevention are not the only battles: understanding ebola-related fear and stigma impact of avian influenza on village poultry production globally who. ihr core capacities implementation status: surveillance. by who region updated guidelines for evaluating public health surveillance systems: recommendations from the guidelines working group global capacity for emerging infectious disease detection global capacity for emerging infectious disease detection drivers of earlier infectious disease outbreak detection: a systematic literature review making sense of communication interventions in public health emergencies -an evaluation framework for risk communication notification and other reporting requirements under the ihr the power of positive deviance research in action: using positive deviance to improve quality of health care what methods are used to apply positive deviance within healthcare organisations? a systematic review the authors thank the participants and express their appreciation to the participants of the workshops that were conducted to enhance preparedness to detect public health risks earlier. pd is the founder and managing director of the company dickmann risk communication drc.the remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.copyright © 2020 steele, orefuwa, bino, singer, lutwama and dickmann. this is an open-access article distributed under the terms of the creative commons attribution license (cc by). the use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. no use, distribution or reproduction is permitted which does not comply with these terms. key: cord-293154-vudycqos authors: sinha, sanjai; kern, lisa m.; gingras, laura f.; reshetnyak, evgeniya; tung, judy; pelzman, fred; mcgrath, thomas a.; sterling, madeline r. title: implementation of video visits during covid-19: lessons learned from a primary care practice in new york city date: 2020-09-17 journal: front public health doi: 10.3389/fpubh.2020.00514 sha: doc_id: 293154 cord_uid: vudycqos background: during the height of the coronavirus (covid-19) pandemic, there was an unprecedented demand for “virtual visits,” or ambulatory visits conducted via video interface, in order to decrease the risk of transmission. objective: to describe the implementation and evaluation of a video visit program at a large, academic primary care practice in new york, ny, the epicenter of the covid-19 pandemic. design and participants: we included consecutive adults (age > 18) scheduled for video visits from march 16, 2020 to april 17, 2020 for covid-19 and non-covid-19 related complaints. intervention: new processes were established to prepare the practice and patients for video visits. video visits were conducted by attendings, residents, and nurse practitioners. main measures: guided by the re-aim framework, we evaluated the reach, effectiveness, adoption, and implementation of video visits. key results: in the 4 weeks prior to the study period, 12 video visits were completed. during the 5-weeks study period, we completed a total of 1,030 video visits for 817 unique patients. of the video visits completed, 42% were for covid-19 related symptoms, and the remainder were for other acute or chronic conditions. video visits were completed more often among younger adults, women, and those with commercial insurance, compared to those who completed in-person visits pre-covid (all p < 0.0001). patients who completed video visits reported high satisfaction (mean 4.6 on a 5-point scale [sd: 0.97]); 13.3% reported technical challenges during video visits. conclusions: video visits are feasible for the delivery of primary care for patients during the covid-19 pandemic. shortly after its first confirmed case on march 1, 2020, new york city became the epicenter of the novel coronavirus, sars-cov-2, pandemic in the united states (1) . as social distancing became a key public health strategy to minimize viral transmission, medical centers, and physician practices were urged to rapidly implement new models of healthcare delivery which met patients' needs, but also limited exposure risk (2) . as a result, there was a demand for virtual care, especially video visits, as an alternative to traditional in-person care (3) . although video visits have been previously used and have been found to be feasible (4) , their adoption and utilization have been limited (5) (6) (7) . as of 2019, only 8% of americans had ever done a video visit with a physician (8) . reasons for low adoption rates had included: lack of reimbursement, inadequate digital infrastructure, and incompatible workflow (6, 9) . for patients, language barriers and inadequate access to technology platforms and the internet (10, 11) were often cited as barriers to video visits (6) . nevertheless, given the need to care for patients remotely during covid-19, the demand for video visits increased, potentially outweighing many of these prior utilization barriers. herein we report the experiences of one large, academic, urban primary care practice with implementing a video visit program during the covid-19 pandemic in new york city. using a modified version of the re-aim framework (12) , we report on the reach, effectiveness, adoption, and implementation of video visits in order to describe our experiences to other primary care practices across the country who may need to adopt a similar care model. this is a retrospective case study of consecutive adults scheduled for video visits during the 5-weeks period from monday, march 16, 2020 to friday, april 17, 2020 at weill cornell internal medicine associates (wcima). wcima is a large, academic, hospital-based primary care practice of weill cornell medicine and newyork-presbyterian hospital (https://weillcornell.org/ wcima). as a high-volume tertiary-care clinic, it averages 53,000 office visits per year and serves a diverse patient population (13) . at wcima, 31 attending physicians, 11 nurse practitioners, and six registered nurses provide care, alongside 129 residents and interns. because we report on the video visit technology itself, as well as the effectiveness of its implementation, this study is a hybrid type 2-effectiveness implementation design (14, 15) . video visits were first introduced at wcima in september 2019. however, only a few providers utilized this technology with their patients. barriers for use pre-covid-19 included: limited understanding and training on the technology among providers and staff and uncertainty about how best to divide clinician time between video and in-person visits. to address these barriers, training sessions demonstrating how to schedule and perform video visits occurred during faculty meetings in the fall of 2019 and providers were asked to complete training modules. despite these efforts, adoption remained low. developing infrastructure for video visits during covid-19 wcima utilized the epic system for video visits [epic systems, verona, wi]. patients connected to video visits through a weill cornell connect app on their smartphone (any brand) or tablet whereas providers conducted video visits through epic haiku (iphone) or epic canto (ipad). the practice purchased ipads for providers without an iphone or ipad to use. during or after visits, providers documented encounters using traditional epic notes via their phone, tablet, or desktop. to minimize covid-19 transmission and the use of personal protective equipment, starting on march 16, 2020, the majority of care at wcima was transitioned to video visits. providers conducted video visits for patients with covid-19like symptoms, as well as for patients with acute and chronic care needs. while providers were encouraged to maximize the use of video visits, they were permitted to conduct in-person visits for urgent complaints where they deemed a physical exam was needed. to guide providers on how to conduct video visits for covid-19 and usual care, a group of physicians developed a video visit handbook (appendix 1). this handbook was updated twice during the study period to reflect rapidly changing clinical recommendations for the ambulatory management of covid-19. weill cornell's physician organization information services (pois) created an electronic health record template for covid-19 assessments (figure 1 ). providers were asked to use this template for all covid-19 related video and in-person visits. as shown in figure 1 , the template contained 10 structured data elements (free-text or drop-down) for the covid-19 video visit. in addition, pois developed smartphrases in epic for patient instructions, based on cdc guidelines for covid-19 including how to socially distance, and perform self-care monitoring. these smartphrases were developed in english and spanish. to prepare for the shift to video visits, starting on march 16, 2020, clinic staff received training on how to schedule patients for video visits, including how to teach patients to download and use the app. each week during the study period, staff and providers reviewed upcoming scheduled visits for that week, and determined who should be seen in person and who could be converted to a video visit. those eligible for a virtual visit but without access to a smart device and internet connection were offered a telephone visit. a hybrid scheduling model was used, in which providers had half-day sessions devoted to seeing their own patients virtually and others for which they were available for video visits with any patient in the practice, to maximize access. similar to in-person visits, video visits were 20 min in duration, but could be longer at the discretion of the provider. video visits took place monday through friday, with occasional saturday visits. providers conducted video visits from wcima offices or remotely. practice administrators worked with hospital compliance to understand billing procedures, and physicians were trained to document and bill for video visits in accordance with the new rules regarding broadened telehealth payment policies during covid-19 from the centers for medicare and medicaid services (cms) (16) . documentation of verbal consent from the patient to engage in a telemedicine visit was required in each note. the same evaluation and management codes and the same rules for determining level of service for in-person care were used for video visits. as outlined in the video visit handbook, a main goal of each video visit for covid-19 was for providers to determine if patients could be managed safely at home with supportive care, if they needed to be evaluated in-person at wcima's newly established cough, cold, or fever clinic, or if they needed to go to the emergency room. another goal was to provide counseling on management of symptoms, warning signs of clinical deterioration, and prevention of transmission. the goal of non-covid-19 video visits was to approximate traditional, in-person care. although physical examinations were limited by the video visit format, providers were able to assess a patient's general appearance, respiratory effort, and affect. when indicated, providers could visually examine patients' skin, sclera/conjunctiva, and the oropharynx. a limited neurological examination could also be performed. heart rate and respiratory rate could be measured by the patient with provider guidance. for patients with home blood pressure monitors or pulse oximeters, additional vital signs could be collected. depending on the visit type, providers chose to document the visit using the covid-19 assessment template or the usual primary care assessment template. we used a modified version of the re-aim framework to describe the implementation of video visits at wcima during the covid-19 pandemic (12) . as such, we evaluated the reach, effectiveness, adoption, and implementation of the video visit initiative. we plan to collect data on maintenance in the future. de-identified, practice-level data were generated from our electronic medical record and billing data. to assess reach, we obtained data on the number of completed video visits over time during the study period, demographics (age, gender, race, ethnicity, insurance type, relationship to practice) of the patients seen via video, the level of service of these video visits, and the most frequent diagnoses for which these video visits were billed. to assess effectiveness, we collected data on the proportion of scheduled visits that were: completed (as above), failed (due to technical difficulties), canceled, or no-shows. during the study period, but separate from our work, the weill cornell physician organization conducted a satisfaction survey via email among patients who completed video visits within the department of medicine. from this survey we obtained aggregate responses from patients for video visits conducted by wcima providers. the survey asked patients to: (1) rate their video visit experience (5-point likert scale; one worst, five best); (2) report if they were satisfied with the care they received, compared with in-person visits (yes/no); (3) report what percent of care they would like to have as video visits in the future, compared to in-person (fill in %); and, (4) report if technical challenges occurred during the video visit (yes/no). to assess adoption, we collected data on the number of staff who assisted with video visit scheduling and the number and types of providers conducting video visits (attending vs. resident vs. nurse practitioners). to assess implementation, we collected data on the frequency with which the covid-19 template was used and the number of ipads our clinic purchased to conduct video visits. because this study used de-identified, practice-level data, it was deemed exempt by the weill cornell medicine institutional review board. as such, written informed consent was not required for participation in this study. we present absolute counts and percent frequency of occurrence. we used the kruskal-wallis test to evaluate differences between median age categories, and the chi-square test to compare proportions. analyses were conducted using the software package r (version 3.4.1, vienna, austria). in the 4 weeks prior to the study period, 12 video visits were completed at wcima, with 6 (50%) occurring 1 day before our study period. during the 5-weeks study period, we completed a total of 1,030 video visits. the number of these visits by week is shown in figure 2 . in week 1, 113 video visits were completed, followed by 261 in week 2, 228 in week 3, 249 in week 4, and 176 in week 5. of the 1,030 completed video visits, 817 unique patients participated. of these, 675 patients (82.6%) had 1 video visit each whereas 142 (17.4%) had >1 video visit (range: 2-9.) the demographics of patients with completed video visits are shown in table 1 . they had a median age of 50 years (interquartile range: 40.6-61.3), 69% were women, nearly 25% were african american, 23% were hispanic, 49% had commercial insurance, 28% had medicaid, and 13% had medicare. compared to patients who completed in-person visits in our practice during july 1, 2019 to february 29, 2020 (our fiscal year-to-date data prior to the study period), those who completed video visits were younger (median age of 41-50 vs. 61-70 years [p < 0.0001]). the video visit group included more women (69 vs. 65%, p = 0.004), more non-hispanics (61 vs. 51%, p < 0.0001), more whites (39 vs. 35%, p = 0.008), more commercially insured patients (49 vs. 36%, p < 0.0001) and fewer medicare patients (13 vs. 32%, p < 0.0001) than our baseline population. approximately one-fourth (28%) of the video visit group were insured by medicaid, similar to our baseline population, of which 31% are insured by medicaid (p = 0.158). during the study period, 1,475 video visits were scheduled, of which 1,030 (69.8%) were completed and 30 (2.0%) failed due to technical problems and were converted to telephone visits. a total of 19.1% of scheduled video visits no-showed and 9.1% were canceled either by the patient or provider. satisfaction data was obtained for 113 (13.8%) of the 817 patients who completed 1 video visit. patients reported high satisfaction with their video visit (mean score of 4.6 on a 5-point scale [sd: 0.97]) and the vast majority (94.5%) of patients were satisfied with the level of care they received during their video visit compared with prior in-person visits ( table 2) . overall, patients preferred that 49% (sd 0.26) of future encounters with their provider be video visits instead of in-person visits. a total of 13.3% reported technical challenges during the video visit. overall, 70 providers (23 attendings, 38 residents, and nine nurse practitioners) conducted these 1,030 video visits and 22 staff members helped orient and schedule patients to video visits ( table 3) . among the video visits completed, the majority (92%) were associated with level 3 and four billing codes, indicating moderate complexity. review of icd-10 codes associated with primary billing diagnoses revealed that 428 encounters (42%) were potentially covid-19 related with diagnoses including: *level of service of visit: these cpt codes for ambulatory visits denote whether the patient is new or established and the complexity of medical decision making. **other includes visits for preventative health, smoking cessation, anticoagulation counseling and psychiatric illness. "failed" video visits (n = 30), which were converted to telephone only, were not counted in denominator. cough, upper respiratory infection, fever, chills, shortness of breath, anosmia, wheezing, pneumonia, asthma, musculoskeletal pain, and covid-19. overall, 22.9% of video visits used the covid-19 template. a total of 17 ipads were purchased during the study period. this study describes the implementation of a video visit program at a large academic hospital-based primary care practice in new york city during the covid-19 pandemic. overall, 70 providers completed a total of 1,030 video visits over a 5-weeks period, compared to 12 video visits completed in the preceding 4 weeks. video visits increased greatly during weeks 1 and 2, plateaued in weeks 3 and 4, and dropped off in week 5, which may reflect the overall trend of health care utilization for covid-19 in new york city during this time (17) . video visits occur more often among younger adults, women, and those with commercial insurance, compared to those with in-person visits pre-covid. although we were only able to obtain satisfaction data on a subset of patients, the majority reported high satisfaction with their video visit experience. another key finding was that despite our quick ramp-up period, issues with the technology itself among those with scheduled visits appeared to be modest. for example, only 2% of initiated video visits were not completed and converted to telephone encounters. additionally, only 13% of patients reported challenges with technology during their video visit encounter. although we could not assess the number of patients who did not engage with video visits, our findings suggest that video visits may be more feasible than previously thought. that is, prior studies have found patients were uncomfortable with the technology and had technical issues during video visits (18, 19) . we hypothesize that during covid-19, patients and providers may have been more willing to engage with and troubleshoot technological challenges in order to be seen. of note, during the study period, our video visit no-show rate was 19%, which is similar to our in-person no-show rate of 20%. all told, these data signal that in the context of social distancing, and with appropriate workflow and administrative processes, implementation of video visit technology is feasible in primary care. to our knowledge, this is one of the first studies to describe the implementation of video visits during covid-19 in the primary care setting. there have been studies describing the implementation of video visits pre-covid-19 across a range of clinical specialties (20) as well as three studies describing the implementation of video visits during covid-19, one among an inpatient urology consultation service (21) , one among an obstetrics practice (22) , and another in urgent care (23) . a recent nejm catalyst article (3) qualitatively described the experiences of four primary care practices who have gone "virtual" since covid-19. like us, they report low utilization of video visits pre-covid and high utilization during covid-19. our study adds to this body of literature by offering a detailed description of video visit implementation, including a video visit handbook, as well as data on reach, effectiveness, and adoption. our findings not only have implications for clinical care and healthcare delivery during covid-19, but also raise questions about the utilization of video visits in primary care moving forward. first, although we lack data on our entire sample, satisfaction scores for video visits were high and patients preferred to have half of their future visits occur via video, compared to in-person. future research will need to determine if this preference persists after social distancing policies are relaxed. additionally, studies are needed to assess providers' perceptions regarding the clinical effectiveness of video visits for covid and non-covid symptoms. second, although video visits minimized transmission risk, they also limited the ability of providers to perform a complete physical examination and measure vital signs. some practices, including ours, have incorporated aspects of remote monitoring into video visit encounters (24) . moving forward, key questions include: how to best deploy this equipment to patients? which patients benefit from monitoring? how can these data be captured electronically? will the cost of such devices will be reimbursable (25, 26) . third, attention to who is not utilizing video visits will be important to avoid exacerbating existing inequities in health and healthcare. we found that older adults and medicare beneficiaries were less likely to engage, which may be due to difficulties with technology, lower levels of internet use, sensory impairments, or lack of confidence with technology (10, 11, 27) . it is also likely those with limited english proficiency and health literacy, as well as structurally disadvantaged populations, may lack the ability and/or resources to access technology (28) . understanding these barriers will be critical for more equitable implementation. fourth, primary care physicians may need to create new processes and pathways with specialty providers to co-manage covid-19 patients who have persistent or multi-organ complications (29, 30) . finally, as cms and other payers broaden their telehealth payment policies during covid-19, the economic impact of expanding video visit use will need to be monitored. patient satisfaction data was only available from some patients who utilized video visits, which may introduce response bias. additionally, we do not yet have outcome data on patients with completed video visits. finally, this study did not include the perspectives of providers and staff on implementing video visits. at the height of the covid-19 pandemic in new york city, we implemented a video visit program at our primary care practice to evaluate and treat patients for their symptoms while maintaining social distance. during a 5-weeks period, 70 providers completed 1,030 video visits, compared to only 12 video visits completed in the preceding 4 weeks. new workflows for staff, providers, and patients were developed to implement this program. overall, patients reported high satisfaction with the care they received during their video visits. our findings suggest that video visits provide a feasible way to care for patients with and without covid-19 symptoms. additional study on the sustained implementation of video visits in primary care, as well as their effect on patient outcomes, is warranted. the raw data supporting the conclusions of this article will be made available by the authors, without undue reservation. ethical review and approval of our study was granted through the weill cornell institutional review board. because our study used de-identified, practice-level data, it was deemed exempt from full board review based on federal regulations. as such, written informed consent was not required for participation in this study. available online at internists emphasize importance of assessing in-office visits and transitioning to virtual visits during covid-19 emergency rapidly converting to "virtual practices": outpatient care in the era of covid-19. innov care delivery association of structured virtual visits for hypertension follow-up in primary care with blood pressure control and use of clinical services trends in telemedicine use in a large commercially insured population state of telehealth can we live-stream primary care? challenges in the adoption of econsults and video visits available online at key factors affecting the adoption of telemedicine by ambulatory clinics: insights from a statewide survey americans internet access: percent of adults available online at evaluating the public health impact of health promotion interventions: the re-aim framework underserved populations with missing race ethnicity data differ significantly from those with structured race/ethnicity documentation clinical directors network, inc. an overview of hybrid effectiveness-implementation designs effectivenessimplementation hybrid designs: combining elements of clinical effectiveness and implementation research to enhance public health impact cms letter to clinicians to summarize actions cms has taken to ensure clinicians have maximum flexibility to reduce unnecessary barriers to providing patient care new york hospitalizations fall for first time in coronavirus pandemic: governor -reuters telemedicine vs office visits in a movement disorders clinic: comparative satisfaction of physicians and patients efficiency, satisfaction, and costs for remote video visits following radical prostatectomy: a randomized controlled trial patient and health system experience with implementation of an enterprise-wide telehealth scheduled video visit program: mixed-methods study telemedicine and econsults for hospitalized patients during covid-19 rapid development and implementation of a covid-19 telehealth clinic for obstetric patients | catalyst non-issue content. nejm catal innov care delivery covid-19 transforms health care through telemedicine: evidence from the field innovation in home care: time for a new payment model enforcement policy for non-invasive remote monitoring devices used to available online at: https://www.fda. gov/regulatory-information/search-fda-guidance-documents/enforcementpolicy-non-invasive-remote-monitoring-devices-used-support-patientmonitoring-during remote patient monitoring in the time of covid-19-3m inside angle older adults' perceptions of home telehealth services addressing equity in telemedicine for chronic disease management during the covid-19 pandemic | catalyst non-issue content. nejm catal innov care delivery key strategies for clinical management and improvement of healthcare services for cardiovascular disease and diabetes patients in the coronavirus (covid-19) settings: recommendations from the reprogram consortium acute neurological care in the covid-19 era: the pandemic health system resilience program (reprogram) consortium pathway ss, lk, lg, and ms were involved in the study design and methods. er, ms, and ss were involved in the data analysis. all authors contributed sufficiently to the writing and editing of this article. ms was supported by the national heart, lung, and blood institute (k23hl150160). the views expressed here do not reflect those of the national heart, lung, and blood institute. we would like to thank eri telegrafi, bba, and evan sholle, ms for their assistance with data collection. we would also like to thank jonathan tobin, ph.d. for lending his expertise in dissemination and implementation science. finally, we would like to thank the leadership, providers, administrators, and staff at wcima for their unwavering efforts to meet patient care needs during covid-19. the supplementary material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fpubh. 2020.00514/full#supplementary-material key: cord-339861-yq1qeo5d authors: fan, jingchun; hambly, brett d.; bao, shisan title: the epidemiology of covid-19 in the gansu and jinlin provinces, china date: 2020-09-11 journal: front public health doi: 10.3389/fpubh.2020.555550 sha: doc_id: 339861 cord_uid: yq1qeo5d the covid-19 outbreak has become a pandemic. the outbreak was able to be controlled in china by mid-april through the implementation of critical measures; however, significant reverse transmission has resulted in hot spots perturbing prevention and control. to date, there have only been a total of 92 indigenous covid-19 cases confirmed in the gansu province, which is considered to be a consequence of the strict screening approach applied during the outbreak. the emergency response level to covid-19 were able to be decreased from high to low, despite some relatively minor reverse transmission cases from other countries in march 2020. the stringent preparative measures undertaken by the gansu authorities, involving high-level, streamlined cooperation between the transportation, quarantine, and medical resource departments, have underpinned this success. there has been an emergence of clusters of freshly infected covid-19 patients in the jilin province in northeast china. the single largest cluster has been in shulan of the jilin province, involving 43 confirmed infections. a strict lockdown was implemented immediately. the source of the current outbreak of covid-19 is suggested to be travelers returning from russia. the current strategy from the chinese authorities is aimed at preventing reverse transmission via international importation to avert a rebound of covid-19 in china. these data highlight the need for an exceptionally high level of vigilance and for a pre-emptive response that is informative for the development of policy to prevent a second and further waves of infections in general. introduction 2019 novel coronavirus disease , caused by infection with sars-cov-2 virus, was originally discovered in wuhan, hubei province of central china in december 2019 (1) . the outbreak of covid-19 was far more severe than anyone expected due to insufficient knowledge of the sars-cov-2 virus transmission during the initial stages of the spread (2) . currently (as at august 12, 2020) , data on the extent of the pandemic are as follows: the pandemic has involved 215 countries and territories with a total of 19,936,210 confirmed cases that have been reported, including a total of 732,499 deaths (3) . wuhan is located in central china with a population of 15 million (4) . due to the impending chinese new year, more than 5 million people traveled from wuhan for either family reunions and/or holidays (5) , contributing to the subsequent outbreak of covid-19 in every province/region in china within a matter of weeks (6) that evolved into a pandemic within a matter of months (7) . in response to the spread of the virus, a strict lockdown was implemented in late january 2020 in china in an attempt to stop person-to-person transmission, including the mandatory use of face masks in public, no public gatherings, and school and factory closures (8) . it has been striking to observe that these measures were able to substantially reduce the number of covid-19 cases to close to zero within a month, i.e., by february 2020 (9) . in addition, mandatory covid-19 testing was instigated for all staff and patients in every in-patient department in all hospitals, including accompanying family members (10) . as expected, subsequently there have been almost no new covid-19 cases reported in china (11) . since late april 2020, almost all schools in china have been allowed to re-open, following initial online teaching only during march and april 2020 (12) . manufacturing industries around the country have gradually reopened following the reopening of schools (13) . this evidence supports the remarkable achievement in controlling the outbreak of covid-19 within china (14) . while most publications by clinicians and researchers have been focusing on the epicenter of covid-19, i.e., wuhan, china, this manuscript aims to cover the epidemiology of the covid-19 infection in the northern region of china, namely the gansu (northwest) and jilin (northeast) provinces. the primary outbreaks in the gansu and jilin provinces were very similar and mild during the first wave that occurred in january and february 2020. however, once the initial outbreak was under control, gansu accepted the task of quarantining chinese nationals returning from abroad and undertook to provide treatment for those returnees who were infected with coronavirus. on the other hand, jilin subsequently experienced a second wave of infection triggered by asymptomatic cases. in this review, we will outline the differences in the epidemiological approaches adopted by the two provinces in northern china to provide the scientific basis for epidemic prevention and control. we hypothesize that the general population continues to face dangerous sars-cov-2 viral transmission from distant locations, including from the epicenter (wuhan, hubei province, china) , if no effective measures are implemented, despite considerable precautions being undertaken by the provincial governmental authorities. one of the current critical challenges in china is to detect and avert possible reverse transmission of sars-cov-2 virus from overseas. the information from our current studies provides some key points that could be used by other regions/countries where covid-19 is still not yet over the peak of the outbreak. recently, we have demonstrated that the primary covid-19 cases seen in northern china were originally transmitted from wuhan, hubei province, china (2) . it is well-documented that covid-19, originally discovered in wuhan in late december 2019, was transmitted to northern china (2) . we have reported that within 10 days, from january 23 to february 3, 2020, there were 54 people infected with the sars-cov-2 virus, where 35 cases had traveled from wuhan, and 19 were infected by close contact with the identified travelers. however, the identification of case zero or the index case in northern china could not be made with absolute certainty because the index case in most countries has been found to be asymptomatic (15) . thus, it is critically important to develop novel diagnostic tool(s) with both high sensitivity and specificity to combat this devastating pandemic. our data suggest that the implementation of adequate interventions has been able to decrease transmission of the covid-19 virus in the gansu province. following the pandemic of covid-19 within months of the original outbreak in china, the countries most affected at the time point of march 2020 were italy (16) and iran (17). despite some precautions being undertaken in italy and iran in late february 2020, e.g., reducing public gathering and implementing social distancing in italy and cancellation of mosque worship in iran and blockage of interstate travel (18) , the morbidity and mortality was still able to increase with enormous speed in early march 2020 (19) . the increased incidence of covid-19 in italy and iran after emergency response measures were implemented may be due to the long incubation period of the sars-cov-2 viral infection, which may be up to 20 days (20) . furthermore, this rapid spread may also be due to relatively low adherence to the restriction orders within these two countries (21) . to provide shelter for the overseas chinese residents in risky countries from the potential risk of covid-19, the chinese government provided chartered planes to repatriate these chinese citizens back to china (22) . the destination for these returnees from italy and iran was the zhejiang and gansu provinces, respectively (23). we have reviewed the epidemiology of covid-19 in jilin and gansu provinces, northern china. jilin province is located in the middle of the northeast of china, covering an area of 187,400 km 2 with a total population of 27,746,000. due to the strategically important location in the northeast of china, the jilin province is an important gateway connecting the eurasian land route via siberia, e.g., the jilin province is only 4 km from vladivostok, russia, and 15 km from the sea of japan (24) . on the other hand, the gansu province is very similar to the jilin province in several aspects. the gansu province is located in the northwest of china, covering an area of 454,000 km 2 with a total population of 26,257,100 (25) . geographically the gansu province is also a key transportation hub connecting to five provinces in northwest china. although the gansu province is located in a rather remote region in northwest china, it is considered to be the beginning of the silk road (figure 1 ). during the primary outbreak, there were 93 and 92 cases, including two deaths, in the jilin and gansu provinces, respectively (26, 27) . the epidemic of covid-19 was brought under control in these two provinces in march 2020 and remained under control for similarly, within the gansu province, the schools have reopened, and the enterprises have been able to recover and re-commence production. during may 2020, however, there has been a reemergence of covid-19 in northeast china, particularly in the jilin province, while fortunately northwest china has remained free of new infections. it has been reported from the reuters news agency that another outbreak of covid-19 has been detected in the jilin province, in northeast china, since the removal of the restrictive lockdown and the increase in public activity since april 8, 2020 (28) . a single new case of covid-19 was discovered on may 7, 2020, in shulan, in the jilin province, without any obvious history of contact with covid-19 patients and also without a history of interstate/international travel. additionally, 11 covid-19 cases were confirmed on may 9, 2020, which broke the record of 73 days of no new cases in this city (26) . an immediate lockdown was then implemented in shulan, jilin, from may 10, 2020, and the risk level was increased from level ii (moderate) to level iii (high) (26) . the prevention and control measures implemented in shulan are as high as those in wuhan at the peak of infection, which was the original epicenter of covid-19. however, despite the strict lockdown in shulan, the number of new covid-19 cases has continued to increase to 43 as of may 20, 2020, which is thought to be a consequence of the close contact of the infected people in this clustering outbreak. it has been reported that the chinese national returnees coming from russia have mainly traveled back via train, suggesting that poor screening and quarantine measures may have occurred, and that most imported cases in the jilin province are from russia (26) . in response to the primary covid-19 outbreak in their provinces, the authorities from both the gansu and jilin provinces found themselves dealing with this form of emergency for the first time (2) . the response included strict prohibition of public gatherings, limitation of social activity to an extremely minimal level, and in-house working via the internet during the outbreak of covid-19 (29, 30) and these measures were rigorously adhered to. these emergency approaches to deal with covid-19 were closely modeled on those developed within the epicenter, wuhan, hubei province of china. however, during the reverse transmission outbreak (or second wave), these provincial authorities had already had previous experience in dealing with this subsequent covid-19 outbreak (22) . infection in the gansu province has been shown to have occurred in two stages. the first stage was the imported case stage of the epidemic, meaning that the cases arrived in travelers from wuhan (2). in the second indigenous case stage, the patients have been mainly shown to have been infected by the cases from the first imported stage (2) . importantly, during the progression of the covid-19 epidemic in the gansu province, the basic reproduction number (r 0 ) has been shown to have decreased from 2.61 in the first stage to 0.66 in the second stage (31), which largely due to the substantially more strict social distancing arrangements implemented during the second stage. new cases of covid-19 almost reached zero in northern china within the period from late march 2020 to the middle of may 2020 because of the implementation of restrictive orders. in addition, the clinical interventions for covid-19 patients were also effective and efficient in reducing morbidity and mortality, in addition to the restrictive quarantine approach (32) . consequently, the mortality rate in northern china was only two in the gansu (26) and jilin provinces (27) . as the epidemic progressively came under control in china, an alarmingly rapid spread of the virus occurred worldwide, and the epidemic became a pandemic. as the preferred place for receiving chinese returnees by the chinese authority, lanzhou city has received a total of 311 evacuated chinese citizens from iran, amongst whom there has been 37 confirmed positive cases of covid-19 infection, which were only discovered shortly after arrival in lanzhou (32) . compared to the handling procedures utilized during the primary outbreak of covid-19 in the gansu province, the local government had gained substantially increased knowledge and experience in controlling the transmission of sars-cov-2 virus that they were able to apply during the secondary reverse transmission of covid-19 (32) . consequently, due to a substantially more organized level of preparation, local gansu authorities were able to implement an effective approach in advance of the evacuation, involving high-level, streamlined cooperation among the departments of transportation, quarantine and hospitals, aiming to isolate, and quarantine for 14 days all potentially infected evacuees within designated hotels to prevent the potential risk of transmission of sars-cov-2 virus within the chinese communities of origin of the evacuees. in addition to these organized returnees from iran, 10 covid-19 patients have been confirmed in the gansu province among independent travelers from abroad who have traveled from locations such as saudi arabia and the united states of america (33) . unfortunately, a proportion of these infected international travelers who returned to china, including to the jilin and gansu provinces, during the early stages of international spread before march 2020 were able to scatter within the community without being quarantined (34) , which caused a significant potential risk of the spread of covid-19. the reason why these covid-19infected travelers were able to scatter within their local provinces was that no testing for covid-19 was undertaken, as covid-19 testing for returnees was not mandatory in early march 2020the beginning of the first wave of the outbreak. subsequently, the local authorities have learnt a heavy lesson from these mistakes and implemented much greater restrictive orders. these data highlight the need for an exceptionally high level of vigilance and the need for a pre-emptive response to prevent a second wave occurring within a community, where the pandemic had been successfully controlled, from returnees from other international locations where the extent of infection at those distant sites had not yet been fully realized. with the recognition of the seriousness of the sars-cov-2 virus in may 2020, the local and central governments called for strengthening of border biosecurity controls, including in the north-eastern provinces, e.g., the jilin province, where a growing cluster of infections near the russian and north korean borders has threatened to develop into a second wave (35) . in addition to the lockdown in the jilin province, in order to further reduce possible inadvertent transmission, all private clinics in the jilin province have been temporarily suspended until further notice. all patients requiring assessment are now required to attend public hospitals for help, especially for any patients with suspected symptoms associated with covid-19 who should go to the specialist fever clinics. thus, chinese authorities have sought to exhibit flexibility with a rapid response time to enhance the control of the covid-19 epidemic in key areas that require increasing regular prevention measures in line with the changing situation of the outbreak (36) . one effective approach that has been applied by the chinese authorities is to launch a health qr (quick response) code system on each individual's smartphone; it is intended to offer a reasonably good indicator within the general population of potential infective status to keep the virus from spreading further. the healthy tracking application has been used previously in monitoring other chronic illnesses for several different purposes (37) . this healthy tracking system provides either a green or red code, i.e., non-infected or infected person, respectively. this rating system permits the green code individuals to restart normal activities with minimal risk of infection to others. however, the health qr code system is not foolproof. for example, there has been one individual in lanzhou with a green code who had traveled from the hubei province. a nasal swab rna test later confirmed that this individual was infected with covid-19 but asymptomatic (38) . it should be cautioned that there is no significant difference in the secondary infection rate of covid-19 within the population, caused by infected individuals who are either symptomatic or asymptomatic (39) . with this in mind, the chinese authorities have also been paying particular attention to the detection of asymptomatic cases to prevent further spreading. interestingly, a comparable project, the australian sentinel practice research network (aspren) surveillance program, is currently being used for covid-19 detection in australia, which was originally intended for monitoring influenza-like illnesses (40) . nevertheless, this approach is in line with an australian proposal of a system of sentinel testing of people in which large numbers of random, but potentially risky, individuals have been presumptively tested irrespective of showing any symptoms. such an approach has enabled the authorities to gauge the extent of asymptomatic carriers and detect infection clusters before any infected individuals develop clinical symptoms (41) . thus, it is essential for the authorities in china to identify these potential covid-19 risk populations, including local residents and/or overseas returnees, using a more sensitive diagnostic approach, e.g., detection of serum antibodies (42) , in addition to nucleic acid testing, which only detects the presence of the virus. such an approach probably offers greater reliability and flexibility in dealing with potentially infected people within an infection cluster. in wuhan, the epicenter of covid-19 infection, a series of policies were implemented. it was confirmed that sars-cov-2 virus was able to be transmitted from person-to-person on january 20, 2020. although covid-19 was classified as a category b infectious disease, the procedures for preventing and controlling category a infectious diseases (e.g., plague and cholera) were adopted (43) . the implementation of these procedures was undertaken by the wuhan local government, including, firstly, the mandatory wearing of facial masks in a list of public places, including hotels and department stores, and, secondly, strict limitations on outdoor and group activities, particularly in relation to banning public and/or private social gatherings (44) . finally, a complete lockdown of wuhan was commenced on january 23, 2020, and it lasted for 76 days until april 8, 2020 (45) , including a complete shutdown of manufacturing facilities and shops except for essential food and groceries. following the concurrent confirmation of the first covid-19 case on january 23, 2020, in the gansu and jilin provinces (1, 46) , the gansu and jilin provincial governments immediately implemented the following policies for preventing and controlling covid-19; emergency response measures were raised to the highest level, effective immediately, which was equivalent to the policies applied in wuhan at the same time. the emergency response levels to any infectious diseases are classified by the national health commission of china (47) . general population screening in china has included mandatory temperature checking for everyone entering any building, using a temperature gun. in addition, for quarantine purposes, monitoring of people's movements was undertaken using a smartphone qr health code system, where an on-screen qr code (for a quick response) was required at the entrance to all buildings to facilitate contact tracing in the event that any positive case was confirmed within the building. any person with a continuous abnormal temperature was required to have a covid-19 rna test for screening confirmation (47) . nevertheless, using this high-level emergency response has proven to be extremely useful, demonstrating that covid-19 has been effectively brought under control. consequently, on february 26 and march 2, 2020, the jilin and gansu governments lowered the emergency response measures from high to medium and high to low, respectively (48, 49) . however, the policy of screening within the general population, i.e., temperature monitoring, and the use of the qr code app are still being used as a major screening approach to the present time (june 2020). in northern china, the sequential procedures that were adopted were as follows: city lockdown, use of road blocks except for essential travel, maintenance of social distancing, restrictions on social gatherings, mandatory wearing of face masks in public, closure of manufacturing facilities and schools, temperature checking at building entrances, reporting of whereabouts and health condition via qr code app, and remote online working and schooling in the gansu and jilin provinces during the first wave of covid-19. in response to the second wave in the jilin province, the emergency response was immediately re-implemented as described above. the series of strategies implemented to control covid-19 spreading in wuhan were essentially the same procedures that were utilized in both the gansu and jilin provinces, the only difference being the commencement and finishing times ( table 1) . in conclusion, covid-19 is almost completely controlled in the general population of the gansu province in northwest china. the first lesson we have learnt from these studies, up to the present time, is that the sars-cov-2 virus is able to be transmitted among people very effectively. thus, it is necessary that strict prohibition of public gatherings, limiting social activity to an extremely minimal level, and remote online working during the outbreak of covid-19 (29, 30) should be rigorously adhered to. however, it is still debatable whether mandatory wearing of face masks should be undertaken (50, 51) . from a public health and safety point of view, it is crucial to continue robust vigilance and implement aggressive control measures to prevent further outbreaks of covid-19 until complete containment of the pandemic is achieved. despite using primary data collected from the local health officials (23), we acknowledge that there are limitations for the current mini review. one limitation is that there has been only one original research paper published concerning the recent and current situation in the jilin province (46) . additionally, our available data are insufficient to calculate the r 0 in the jilin province and the r 0 during the second wave in the gansu province, and there has been no published data concerning the r 0 in these two provinces, which we will determine in our future studies. notably, the most significant outcomes of the second wave of the outbreak in the jilin province are still evolving and hence are not settled yet. this is despite all necessary measures that were used in the control of the first wave of covid-19 having been implemented. jf and sb have concieved the manuscript and wrote it. bh has editted the manuscript. all authors contributed to the article and approved the submitted version. a novel coronavirus from patients with pneumonia in china epidemiology of 2019 novel coronavirus disease-19 in gansu province, china, 2020 coronavirus disease (covid-19) situation report-204 5 million left wuhan before lockdown, 1,000 new coronavirus cases expected in city update on novel coronavirus infection at 24 hours on 29 january covid-19) situation report-100 bibliometric analysis on covid-19: a comparison of research between english 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describing the epidemiology and clinical characteristics of covid-19 infection in jilin province national health commission of the people's republic of china. the guideline for covid-19 prevention and control change of risk of new coronavirus pneumonia in sub-counties of gansu province notification on adjusting the emergency response to covid-19 from top level i to level ii to in jilin province to mask or not to mask: modeling the potential for face mask use by the general public to curtail the covid-19 pandemic to mask or not to mask children to overcome covid-19 the authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.copyright â© 2020 fan, hambly and bao. this is an open-access article distributed under the terms of the creative commons attribution license (cc by). the use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. no use, distribution or reproduction is permitted which does not comply with these terms. key: cord-260420-4s7akmdp authors: mubareka, samira; groulx, nicolas; savory, eric; cutts, todd; theriault, steven; scott, james a.; roy, chad j.; turgeon, nathalie; bryce, elizabeth; astrakianakis, george; kirychuk, shelley; girard, matthieu; kobinger, gary; zhang, chao; duchaine, caroline title: bioaerosols and transmission, a diverse and growing community of practice date: 2019-02-21 journal: front public health doi: 10.3389/fpubh.2019.00023 sha: doc_id: 260420 cord_uid: 4s7akmdp the transmission of infectious microbes via bioaerosols is of significant concern for both human and animal health. however, gaps in our understanding of respiratory pathogen transmission and methodological heterogeneity persist. new developments have enabled progress in this domain, and one of the major turning points has been the recognition that cross-disciplinary collaborations across spheres of human and animal health, microbiology, biophysics, engineering, aerobiology, infection control, public health, occupational health, and industrial hygiene are essential. collaborative initiatives support advances in topics such as bioaerosol behavior, dispersion models, risk assessment, risk/exposure effects, and mitigation strategies in clinical, experimental, agricultural, and other field settings. there is a need to enhance the knowledge translation for researchers, stakeholders, and private partners to support a growing network of individuals and agencies to achieve common goals to mitigate interand intra-species pathogen transmission via bioaerosols. the transmission of infectious microbes via bioaerosols is of significant concern for both human and animal health. however, gaps in our understanding of respiratory pathogen transmission and methodological heterogeneity persist. new developments have enabled progress in this domain, and one of the major turning points has been the recognition that cross-disciplinary collaborations across spheres of human and animal health, microbiology, biophysics, engineering, aerobiology, infection control, public health, occupational health, and industrial hygiene are essential. collaborative initiatives support advances in topics such as bioaerosol behavior, dispersion models, risk assessment, risk/exposure effects, and mitigation strategies in clinical, experimental, agricultural, and other field settings. there is a need to enhance the knowledge translation for researchers, stakeholders, and private partners to support a growing network of individuals and agencies to achieve common goals to mitigate inter-and intra-species pathogen transmission via bioaerosols. keywords: bioaerosols, microbes, virus, infections, viral dissemination, network, caniban, collaborations the importance of infectious bioaerosols in disease transmission has been long-acknowledged, yet poorly understood. paltry data and methodological heterogeneity limit many related studies. effective ventilation and infection prevention and control (ip & c) measures in the form of droplet and airborne isolation in healthcare institutions underscore the contribution of these modes of pathogen dispersion. moreover, recent outbreaks such as the severe acute respiratory syndrome coronavirus (sars-cov) and middle east respiratory syndrome coronavirus (mers-cov) outbreaks highlight major gaps in our ability to assess and determine risk and to mitigate patient and healthcare worker (hcw) exposure alike (1, 2) . the sars outbreak was eventually controlled in the absence of an effective vaccine or antiviral, strictly through public health interventions and ip & c measures aimed at controlling, among other things, bioaerosols emitted by infected patients (3) . a decade on from this experience, mers-cov has caused community and healthcare-associated severe acute respiratory infections in the middle east and south korea, spreading by similar mechanism(s) (4) (5) (6) . from an animal health perspective, pathogens such as porcine reproductive and respiratory syndrome virus may be transmitted through the air for significant distances and have significant economic impact on the agricultural sector (7) . efforts to characterize this and other relevant organisms have been undertaken previously, specifically looking at the burden of inoculum related to transmission (8) and the prevention of spread of aerosols through various adequate ventilation strategies (9) (10) (11) . emission of african swine fever virus into the air by infected pigs raises the possibility for droplet and/or airborne transmission of this virus, which has recently produced significant alarm after documented spread in china (12) (13) (14) . this hemorrhagic virus is associated with high mortality and significant loss for producers through depopulation and trade restrictions (15, 16) . in recent years, new developments have enabled progress in bioaerosol research, thus establishing a community of practice in the field. although many developments have been technical, one of the major catalysts has been the recognition that crossdisciplinary collaborations across the various spheres of human and animal health, microbiology, engineering, aerobiology, infection control, public health, occupational health, and industrial hygiene are essential. a network approach has proven successful in other cross-disciplinary fields, including one health and eco-health whereby wildlife, computational and evolutionary biologists, microbiologists, virologists, epidemiologists, ecologists, environmental scientists, climatologists, and human, animal, and public health practitioners are collaborating to address challenges in zoonotic diseases research and control (17, 18) . this has enhanced surveillance efforts and launched ambitious, large scale projects such as the global virome project, though gaps remain in stakeholder engagement and monitoring activities (19, 20) . translation of bioaerosol research stands to benefit in a similar fashion, provided coordinated and committed efforts. potentially infectious bioaerosols are pertinent to a wide range of pathogens, some of which may be endemic and cause sporadic infections and outbreaks (e.g., mycobacterium tuberculosis and legionella pneumophila, the causative agents of tuberculosis and legionnaires' disease, respectively) and/or have potential to cause epidemics or pandemics (e.g., influenza virus a) (21) (22) (23) (24) . in addition, the importance of potentially infectious bioaerosols across different settings is underscored. these include, but are not limited to, agriculture (both crop and livestock), wastewater treatment plants, environmental reservoirs (soil and water), acute and long-term healthcare institutions, and shared public spaces (transportation hubs, recreational areas, etc.). here, we discuss the state of the science for this nascent field and identify gaps requiring urgent attention. progress in the field has been stimulated by advances in other areas which have been applied to the study of infectious bioaerosols. these include: (a) enhanced detection by molecular methods, principally real-time and quantitative pcr, nextgeneration sequencing, metagenomics, and biosensors (25) (26) (27) (28) (29) (30) , and (b) establishment of both conventional and novel infrastructure, such as small and large-scale wind tunnels, biocontained rotating drums for aging aerosols, and field-ready aerosol samplers (31) (32) (33) . ongoing research has also facilitated the development and dissemination of procedures and protocols for experimental work, including artificial aerosols, as well as animal models of transmission including the ferret model for influenza virus transmission and macaque model for ebola virus transmission (34, 35) . whilst aerosols can be used as a means of delivery of therapeutic agents directly to the respiratory tract, they may also be used for the nefarious dispersion of human or animal pathogens. scientists focused on bioaerosol generation, pathogen survival in air and aerobiological fitness must be acutely cognizant of any potential for dual use and routinely re-assess projects and proposed experiments with this perspective in mind. oversight by institutional biosafety officers and committees may also consider this aspect of bioaerosol research during risk assessments and other internal approval processes. given the role of potentially infectious bioaerosols to transmit infectious agents to human and animal populations, it stands to reason that their detection and characterization will ultimately contribute to mitigating the spread of disease. this is possible through efforts focused on the following themes: unresolved fundamental questions may be answered by studying infectious bioaerosols. areas meriting attention are numerous and a few are briefly discussed here. in the case of agents for which airborne transmission is well-recognized (i.e., m. tuberculosis), associations between particle size and generation, pathogen content and virulence, as well as the deposition within the respiratory tract may be determined. the physical and chemical aspects of aerosols including the effects of relative humidity can affect pathogen viability and understanding these aspects of bioaerosol behavior may be beneficial to understanding conditions for controlling bioaerosol dispersion (36) (37) (38) . moreover, pathogens such as viruses may vary with respect to isoelectric points, possibly imparting different charges to infectious bioaerosols which may affect their behavior (39, 40) . finally, although climate change and pollution have been major issues within our biosphere, little is known about the impact of pollution particulates and gases, such as ozone, on the biology and physical properties of bioaerosols (41) . our understanding of bioaerosol production from expulsion events such as breathing, talking, sneezing, and coughing have generally been extrapolated from models, though more recent empiric evidence has become available, significantly enhancing our understanding of the transmission potential of bioaerosol emissions from naturallyinfected hosts (42, 43) . awareness of factors contributing to particle velocity and penetration into space enables modeling strategies that inform engineering controls in a multitude of settings. for example, in healthcare, understanding the dispersion of potential pathogens in the environment can inform infection prevention and control practices (44) . there is also potential benefit to determining pathogen characteristics. if enhanced infectious bioaerosol survival in air is associated with certain strains, genotypes or mutations, this provides possibilities for follow-on work to (a) determine the mechanism and (b) enhance surveillance. the latter would have implications for public and animal health. studying these factors individually or in combination can optimize air handling and other mechanical, environmental or chemical means of neutralizing bioaerosols prior to host exposure, thus alleviating dependence on personal protective equipment, which is the last means of protection prior to exposure. new understanding of the role of bioaerosols in the propagation of human and animal pathogens could lead to new practices. as it stands, it remains uncertain which bioaerosol particles are predominantly responsible for personto-person transmission. there may also be differences between pathogen populations in the infected host vs. what is emitted into the air. this poses an excellent opportunity to leverage advances in metagenomics with developments in aerobiology to extract more sophisticated data from aerosol samples and, potentially, determine genetic bottlenecks for transmission. this would feed back into more fundamental work on bacterial or viral determinants of transmission, as well as lead to novel means for surveillance and mitigation. similarly, translational studies enhance our understanding of risk and determinants of exposure. for many settings and situations, several components of risk assessments are based on limited evidence. this is of particular concern from an occupational health perspective, in healthcare (e.g., purported aerosol-generating procedures), agricultural, or specific settings such as wastewater treatment plants (45) (46) (47) . developing the capacity to generate empiric data on pathogen content and biology from bioaerosols can lead to tools for outbreak investigation, surveillance, and development of risk assessment strategies and policies. as the technology for biosensors accelerates, the possibilities for rapid point-of-care testing and even remote sampling are highlighted. integration of biosensors with bioaerosol sampling (26) has significant potential for early warning and public safety. as advances are made, capacity is built to optimize and evaluate known and novel means to control the dispersion of infectious bioaerosols. these include the use of germicidal and pulsed ultraviolet light, mechanical air filtration and respiratory protection which have both mechanical and electrostatic filtering systems (48, 49) . in addition, the potential to use ozone to control indoor bioaerosols in urban and rural settings is being examined. ozone is a strong oxidizing agent having high redox potential and a short half-life, dependent on temperature. it has been used extensively in the food industry (specifically water treatment, washing of produce, and food preparation), as well as in domestic restoration to remediate odors and smoke damage. its historical use and proven efficacy demonstrate its potential to remediate contaminated indoor air (50, 51) . this would present a novel application of a known treatment modality. a number of important gaps have been identified (52) and these can be prioritized based on potential benefit: biocontainment of infectious particles is the first consideration when aerosolizing human and/or animal pathogens in an experimental setting. these systems are generally customdesigned and constructed, with few facilities capable of conducting aerosol work with risk group 2 pathogens, and fewer still with the capacity to work with risk group 3 or 4 agents. as challenges in infrastructure are overcome, opportunities to optimize and improve methods and techniques in bioaerosol research must be taken. a limitation of many studies focused on viral bioaerosols is the pervasive use of nucleic acid detection, rather than infectious virus isolation. the latter is a much more accurate indicator of the infectious potential of a bioaerosol but is infrequently performed due to poor sensitivity and other technical issues (53) . the development of sampling devices and techniques optimized to preserve pathogen viability would considerably advance the utility of studying bioaerosols for risk assessment and management. for other applications, a more rapid, field-ready point of care test would be useful and would offer remote sampling possibilities. biosensors have the potential to fill this gap and integration into aerosol sampling devices is under development (26) . finally, the collection of nucleic acid may be leveraged to obtain more sophisticated information than is available by pcr and sanger sequencing. metagenomics on environmental samples has been well-described in other spheres and is currently being explored for air samples (54) (55) (56) (57) . to advance bioaerosol-related data interpretation, an effort must be made to standardize and share protocols and reagents to reduce the degree of data heterogeneity to enable meaningful analyses across studies. this may apply to animal models, artificial aerosolizations, collection strategies in the field and clinical settings, processing of samples, and detection methods. developing or adopting a standardized approach to aerosol sampling is challenging and requires substantial efforts to select the best sampling strategy to minimize sampling biases, optimize sample concentration and organism retrieval whilst preserving integrity (58) . establishing standard approaches also enables training and implementation and eases knowledge translation amongst different groups (figure 1) . multiple investigators have published small studies on the recovery of viral rna emitted by naturally infected humans using different approaches for recruitment, sampling, processing, and detection. unfortunately, the results are difficult to compare and, standing alone, are of limited statistical significance (45, (59) (60) (61) . by standardizing approaches, a more feasible method can be used to compare separate studies allowing for larger multi-center studies that are substantially more conclusive and impactful. additional educational and operational needs, such as training of research personnel, proper use of personal protective equipment and developing decontamination protocols must be addressed. as more highly qualified personnel are properly trained, the greater the capacity for designing and utilizing experimental systems and for completing meaningful clinical and field studies. the need for cross-disciplinary experience is underscored, since robust knowledge of physics, mechanical engineering, and microbiology are required. fostering this expertise requires a collaborative effort as each discipline offers unique insight. currently, there are a limited number of workshops or accredited courses available to cultivate both interest and baseline knowledge. although the profile of bioaerosol research is rising, few trainees are exposed to the field early in their careers. courses such as bioaã©rosols et aã©robiologie (bioaerosols and aerobiology) developed at the universitã© laval in quã©bec may help close this gap further given the opportunity to expand reach. the relevance of bioaerosol data to occupational health and infection prevention and control requires attention. validation of bioaerosol data for risk assessments and risk management is needed. air sampling was conducted during both sars-cov and mers-cov outbreaks, accruing important insight into the environmental distribution and persistence of these coronaviruses (4, 62, 63) . the absence of data for more common, lower consequence pathogens represents missed opportunities to build a contextual and impactful body of knowledge during inter-outbreak and inter-pandemic periods. to develop evidence-based policy and ensure the relevance of this work, early stakeholder engagement is needed. consultation with human and animal public health, infection prevention and control, industrial hygiene, and occupational health stakeholders will ensure that the work is germane to the challenges presented by bioaerosol exposures. this pull also increases the likelihood that there will be data generated for risk assessment, policy development and implementation. part of the chaos that characterized the sars epidemic can be attributed to a lack of knowledge regarding the route(s) of transmission. this remains true for high consequence coronaviruses, as well as for a range of other respiratory pathogens, both novel and established. we propose the following to address the challenges outlined above and to further develop the field of applied bioaerosol research: 1. an open network approach working in isolation, microbiologists, aerobiologists, engineers, and epidemiologists have made only incremental progress. a synergistic and pluralistic approach is required for action-driven research which effects change. as capacity grows, so will opportunities for training and response. a networked approach will lead to context-specific follow-on research to ultimately inform policy for the mitigation of respiratory pathogens spread in healthcare institutions, agricultural settings and public spaces. toward this end, the present authors have established the canadian infectious bioaerosols network (caniban) that brings together members of each of these disciplines with the primary objectives of understanding transmission of pathogens. a network would form a hub around which key resources such as infrastructure, equipment, and operational procedures could be shared, thus also enabling training and underscoring best practices in biosafety and biosecurity. shared resources may encompass wind tunnels, cough chambers and mannequins, animal exposure and other biosafety enclosures, and rotating drums to examine pathogen survival in air, together with instrumentation and analysis tools for fluid flow measurement and biochemical assays. limited awareness and understanding of infectious bioaerosols among potential knowledge users, coupled with equally limited outreach by bioaerosol researchers has restricted knowledge transfer and applications. knowledgeuser engagement in research planning from the outset and ongoing involvement through to dissemination is key for effective projects. potential knowledge users include infection prevention and control practitioners, infectious disease specialists, veterinarians and animal health epidemiologists, industrial hygienists, and public health agencies. increasingly, bioaerosol sampling has been proposed and implemented in outbreak investigations and pathogen surveillance using ad hoc approaches. the development of best practices in these areas is essential to generating valid and actionable data. in summary, a collective path for researchers, stakeholders, and private partners is needed to support a network of individuals and agencies to achieve common goals. as the field of bioaerosol studies grows, applications will diversify, along with novel technologies for remote sampling and point of care testing yielding results in real time. this stands to mitigate the spread of nefarious pathogens and contribute to early warning and response measures, thus ultimately benefiting human and animal health. sm framed the manuscript and contributed content. ng contributed content and generated the figure. es contributed content and supported manuscript organization. tc, st, js, cr, nt, eb, ga, sk, mg, gk, and cz contributed content and expertise and cd helped to frame and contributed content. transmission characteristics of mers and sars in the healthcare setting: a comparative study extensive viable middle east respiratory syndrome (mers) coronavirus contamination in air and surrounding environment in mers isolation wards research gaps in protecting healthcare workers from sars and other respiratory pathogens: an interdisciplinary, multi-stakeholder, evidence-based approach environmental contamination and viral shedding in mers patients during mers-cov outbreak in south korea mers-cov outbreak following a single patient exposure in an emergency room in south 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sequencing approach with a suitable bioinformatics workflow to study fungal diversity in bioaerosols released from two different types of composting plants distribution of airborne influenza virus and respiratory syncytial virus in an urgent care medical clinic influenza virus emitted by naturally-infected hosts in a healthcare setting quantification of influenza virus rna in aerosols in patient rooms detection of airborne severe acute respiratory syndrome (sars) coronavirus and environmental contamination in sars outbreak units airborne severe acute respiratory syndrome coronavirus concentrations in a negative-pressure isolation room we should like to thank the centre de recherche de l'institut universitaire de cardiologie et de pneumologie de quã©bec (criucpq), assek technology, quebec frqs respiratory health network, the groupe de recherche en santã© respiratoire (geser), and tsi for supporting the 2016 symposium on the transmission of respiratory pathogens in quã©bec city, qc, canada, and symposium participants for their contributions during the course of this event. we are also grateful for support from the canadian institutes of health research, the natural sciences and engineering research council of canada and the ontario ministry of labor. key: cord-330255-dvhuwm7c authors: dropkin, greg title: covid-19 uk lockdown forecasts and r(0) date: 2020-05-29 journal: front public health doi: 10.3389/fpubh.2020.00256 sha: doc_id: 330255 cord_uid: dvhuwm7c introduction: the first reported uk case of covid-19 occurred on 30 january 2020. a lockdown from 24 march was partially relaxed on 10 may. one model to forecast disease spread depends on clinical parameters and transmission rates. output includes the basic reproduction number r(0) and the log growth rate r in the exponential phase. methods: office for national statistics data on deaths in england and wales is used to estimate r. a likelihood for the transmission parameters is defined from a gaussian density for r using the mean and standard error of the estimate. parameter samples from the metropolis-hastings algorithm lead to an estimate and credible interval for r(0) and forecasts for cases and deaths. results: the uk initial log growth rate is r = 0.254 with s.e. 0.004. r(0) = 6.94 with 95% ci (6.52, 7.39). in a 12 week lockdown from 24 march with transmission parameters reduced throughout to 5% of their previous values, peaks of around 90,000 severely and 25,000 critically ill patients, and 44,000 cumulative deaths are expected by 16 june. with transmission rising from 5% in mid-april to reach 30%, 50,000 deaths and 475,000 active cases are expected in mid-june. had such a lockdown begun on 17 march, around 30,000 (28,000, 32,000) fewer cumulative deaths would be expected by 9 june. discussion: the r(0) estimate is compatible with some international estimates but over twice the value quoted by the uk government. an earlier lockdown could have saved many thousands of lives. although the first confirmed case of the novel coronavirus disease covid-19 was identified on 30 january 2020, the uk government hesitated for some time whilst lab confirmed cases in england grew to 11,080 before a lockdown began on 24 march (1) . the lockdown remains in place with no declared end date, but transport usage increased during april and moves to relax restrictions were signalled on 10 may. in describing the spread of an infectious disease, one key parameter is the basic reproduction number r 0, the expected number of individuals who will be infected by a single infectious person if the rest of the population is susceptible. if r 0 > 1, the disease spreads, whilst if r 0 < 1 it will die out. recent preprints (2) (3) (4) and published articles (5, 6) have estimated r 0 for covid-19 internationally, but there is no clear consensus, and the true value may depend on social characteristics of the population. as the disease progresses, patients who recover may acquire immunity, lessening the pool of susceptible individuals. however, at the initial stages almost everyone remains susceptible, and case numbers and deaths grow exponentially. a second key descriptive parameter is r, the rate of increase in log(cases) or log(deaths) during this exponential growth phase. the disease spread can be approximated with a deterministic compartmental seir model (7) based on the numbers of patients who are susceptible, infected, infectious (mild), infectious (severe), infectious (critical), recovered, or dead, and the rates of transition between these states. as a set of linked differential equations, the seir model can be integrated by numerical methods to forecast the future course of the disease. some of the transition rates in the model can be regarded as clinical parameters. for example, the rate at which people move from infected to infectious depends on the average length of the pre-infectious period, which is a clinical characteristic and might be similar in all populations. by contrast, the rate at which mildly ill people infect others depends on the pattern of social interaction in the community. these transmission parameters are likely to vary between countries. uk government data underestimates the number of cases, as for some time there was no testing in the community, and the public was told not to inform the nhs if they felt only mildly ill. until very recently, government data on covid-19 deaths excluded deaths outside hospital. the most accurate available data on deaths is produced by the office for national statistics (ons) using death registrations (8) . the ons coronavirus dataset covers england and wales. this paper begins by using the early ons data to estimate r directly. the default clinical parameters in the seir model are then taken as fixed, and posterior samples of the transmission parameters are obtained, making use of the mean and standard error of the estimate for r and the fact that r is also an outcome of the model, conditional on the parameters. using the model, these samples also generate samples for r 0, giving an estimate and credible interval. the samples can be applied to forecast the spread of the disease in the context of a lockdown of specified effectiveness and duration, and to give credible intervals for the difference between forecasts in different lockdown scenarios. a time series of confirmed covid-19 cases in england and deaths in each uk nation is available from the uk government (1). more complete data on deaths in england and wales is available from the office for national statistics, using death registrations (8) . data on log(cases) and log(deaths) through to 31 march was examined for linearity, and a linear model m1 was then fitted to the appropriate portions before lockdown, as shown in figure 1 . further analysis uses only the ons data. an unpublished implementation of the seir model, together with default parameters, clinical evidence, and r code is available online from alison hill (9, 10) . the code includes functions getr_seir and getro_seir to compute r and r 0, respectively, depending on the parameters and population size. the r estimate uses the approximation that in the early period of growth, virtually the entire population is susceptible, and the seir model reduces to a linear differential equation with growth determined by the largest eigenvalue of its matrix. the model compartments all grow exponentially at this same rate during the early period, and their relative sizes are determined by the components of the corresponding eigenvector. the model is fitted by numerical integration using the r package "desolve" (11) . the transmission parameters pertain to patients whose condition is mild, severe, or critical. although the model also permits asymptomatic and pre-symptomatic transmission and seasonal variation, these options were not considered here. the three transmission parameters are estimated by an adaptive metropolis-hastings (m-h) algorithm, fixing all clinical parameters at the values chosen by hill. a trio of scaled transmission parameters (b1 * n, b2 * n, b3 * n) where n = population, then determines r through getr_seir. the likelihood of the trio is taken to be the gaussian likelihood for the resulting r value, with mean and sd given by the estimate and standard error of the growth coefficient in m1 fitted to the ons data. a trio receives a higher or lower likelihood if the model gives a fitted log growth rate nearer or further from the empirical value obtained directly from the data. the prior for the trio is set as the product of independent gamma priors for each component, using the same shape and rate for each. adaptive m-h was run (r package "mhadaptive") (12) to generate a sample of length 50,000 after burn-in and thinning. convergence was checked by standard diagnostic tests (r package "coda") (13) . the output of m-h is a posterior sample of the trio (b1 * n, b2 * n, b3 * n). since r 0 is completely determined by the parameters, the rest of which are fixed, the sample generates a sample for r 0 . highest posterior density intervals (r package "hdinterval") (14) were used as credible intervals. the code file paramest1.txt implements these calculations. all code files and data are available as supplementary material. forecasting cases and deaths uses the model and parameters and the assumed reduction in transmission as a result of the lockdown, but also requires an initial value for the numbers in each model compartment. as the projections are short term, population was fixed at n = 66 million. the run was started from 18 march, the beginning of exponential growth in the ons data. the unknown initial number ini of infected cases on 18 march determines the numbers of infectious (mild, severe, critical), recovered, and dead on that date as their ratios are determined by the eigenvector for the maximum eigenvalue. for a specified lockdown scenario, the model can be run forward from 18 march as a function of ini, giving a predicted value e of new deaths at each date, and a squared pearson residual (e-o) 2 /e where o is the ons new deaths for that date. to estimate ini, the summed squared pearson residuals for a period in which o is known were minimised. the chosen period runs from 18 march through to 24 april, using the ons data for deaths registered by 9 may (8) . once the initial values on 18 march are estimated, the model can be run with the transmission parameters set at their mean values from the sample. scenarios including a decrease in transmission prior to lockdown were chosen using the transport data in the government daily briefings (15) . one scenario, shown in figure 2 , assumed each b i would be reduced to 5% of its sample mean throughout the lockdown. for figure 3 , with a scenario in which transmission is fixed at 5% for 2 weeks and then rises linearly to reach 15% by 11 may, 1,000 samples were drawn for (b1 * n, b2 * n, b3 * n). the model was run using each sample to reset the initial conditions and forecast severe and critical cases and deaths during the lockdown. highest posterior density credible intervals of mass 0.95 for the results at each time point then gave 95% credible envelopes. the sensitivity of results was further tested by varying the choice of prior for the parameter sampling, or the case fatality rate, or the start date of the 12 week lockdown. in considering the impact of bringing forward the lockdown by a week, figure 4 shows a scenario in which transmission is fixed at 5% for 3 weeks and then rises linearly to reach 30% by the end of 12 weeks, for lockdowns beginning on 24 and hypothetically on 21 and 17 march. for a better understanding of the excess, deaths at the end of 12 weeks as sampled for figure 3 were compared with deaths at the end of a 12 week lockdown beginning 17 march, using the identical choices for (b1 * n, b2 * n, b3 * n), the same lockdown scenario, and the initial conditions as already estimated. the excess deaths due to a later lockdown are estimated by the mean and 95% ci for the pairwise difference of these two samples. the process was repeated using the lockdown scenario for figure 4 . in the code file paramest1.txt, which generates the parameter samples and estimate and ci for r 0, neither getr_seir nor getro_seir depend directly on the parameter u governing the death risk for critical patients, but only on u + g3 which is the reciprocal of the average length of stay in icu (9, 10) . thus the estimates for r 0 are independent of the case fatality rate. as this study uses only freely available anonymous data released by the uk government and office for national statistics, ethical approval was not sought. figure 1 shows log linear growth in the period just before the lockdown with all three data sources, and particularly with the ons data in the period 18-24 march. a linear fit has adjusted r 2 = 0.999, and the coefficient of growth r = 0.254 with s.e. = 0.004. adaptive m-h sampling passed the raftery, geweke, and heidelberger tests for convergence. as discussed below, the gamma prior chosen for b * i n has shape = 1 and rate = 5. posterior estimates of the transmission parameters, scaled by population n = 66 million, are b1 * n = 1.095 with 95% highest posterior density credible interval (1.04, 1.15) whilst b2 * n = 0.218 (0, 0.65) and b3 * n = 0.202 (0, 0.6). r 0 is estimated as 6.94 (6.52, 7.39). eight gamma priors with means ranging from 0.1 to 5 and coefficient of variation from 0.45 to 1.41 were specified by varying shape and rate parameters. the resulting estimates of r 0 ranged from 6.8 to 11.06, with lower prior means giving lower r 0 estimates. priors with higher means also lead to higher estimates of deaths and excess deaths. with prior means in the range 0.1 to 0.5, r 0 varied from 6.8 to 7.24. the chosen prior with mean = 0.2 and cv = 1 (shape = 1, rate = 5) was conservative, giving a comparatively low value of r 0. from the transport data (15) it appeared that transmission reduced after 14 march and reached a stable value around 26 march. lockdown scenarios were considered with a 12 day run down to stable values of 10% and 5% of normal transmission. the estimated number of infections on 18 march (see methods re ini) was over 215,000 for the 10% lockdown, and over 245,000 for the 5% lockdown. whilst the estimated ini gave a plausible fit to the ons data with a 10% lockdown, the fit for a 5% lockdown was excellent, and all remaining scenarios assumed the lockdown began with transmission parameters at 5% of their previous values. figure 2 shows the results of a model run for a lockdown reducing each b i to 5% of its estimate throughout a 12 week period 24 march−16 june, with a run down from 14 march. severe cases peak in early april at over 90,000 but then decline slowly, critical cases peak in mid-april at nearly 25,000, and total deaths are nearly 44,000 by 16 june. figure 3 shows the 95% confidence envelopes for the evolution of severe and critical cases and deaths during a lockdown which begins at 5% but rises frontiers in public health | www.frontiersin.org linearly after 7 april to reach 15% on 11 may and then remains constant (scenario t1). the fit to the ons data through to 24 april is still excellent. these results are very sensitive to the starting date of the lockdown, as shown in figure 4 which assumes 5% transmission for 3 weeks and then linear growth to reach 30% at the end of the 12 week lockdown (scenario t2). for t2 beginning on 24 march, severe cases peak in early april at over 90,000, critical cases peak in mid-april at nearly 25,000, and total deaths are nearly 50,000 by 16 june. if the same scenario began 1 week earlier on 17 march, severe cases would peak at nearly 37,000 early in the lockdown, critical cases would peak at under 10,000 a week later, and deaths by the end of the 12 weeks would be under 22,000. these estimates are obtained by applying the mean values of the transmission parameter samples to each lockdown. when the excess deaths due to delaying the start of the t2 lockdown from 17 to 24 march were sampled (see methods), the mean value was 29,839 with 95% ci (28,037, 31,859) . the corresponding result for a lockdown held at 5% throughout the 12 weeks was 26,783 (25,720, 27,781). the r 0 estimate and ci are independent of the case fatality rate (see methods). the results above and figures were generated with cfr = 2%, the value shown by hill (9) . if cfr = 1%, a t2 lockdown beginning 24 march would result in peaks of around 181,000 severe and 49,000 critical cases, but deaths by 16 june would still total around 49,000. the rise in the predicted cases is due to an approximately doubled estimate of initial infections required to fit the observed deaths to 24 april. r 0 depends on the prior, but not excessively, as discussed above. the choice of prior has a stronger influence on the lockdown forecasts, but the estimates of excess deaths are less sensitive to this choice. priors like the one chosen here, with lower mean values, lead to lower forecasts and lower estimates of excess death. the various scenarios beginning at 5% give similar predictions for total deaths at the end of the lockdown period, and similar figures for the excess deaths caused by delaying its start. however, case numbers at the end of lockdown vary widely. with 5% transmission throughout, only 3,426 active cases are predicted on 16 june, whilst 2,162,742 will have recovered and 43,895 died. over the entire period including the initial estimates on 18 march, an estimated total of 2.15 m mild cases occur, of which 434,200 become severe and of those 109,863 then become critical. with scenario t1, 159,338 active cases are predicted on 16 june, whilst 2,665,106 will have recovered and 51,162 died. case totals over the period are an estimated 2.75 m mild cases, of which 538,088 become severe and of those 132,356 then become critical. with scenario t2, 475,806 active cases are predicted on 16 june, whilst 2,699,764 will have recovered and 49,936 died. over half of the active cases at the end of lockdown would be infected but not yet even mildly infectious. case totals over the period are an estimated 2.9 m mild cases, of which 545,946 become severe and of those 131,057 then become critical. this brief analysis uses an established deterministic seir model (9) for the development over time in the expected numbers of susceptible, infected, infectious, recovered cases and deaths, depending on parameters, some of which can be estimated from clinical studies since the outbreak of covid-19. other parameters concern the rate at which persons who have become infectious will infect others, depending on whether their clinical condition is mild, severe, or critical. clinical parameters, such as the delay between "infected" and "infectious, " may not vary greatly between countries. by contrast, the rate at which infection is transmitted in the community depends on level and types of social interaction, which may vary over time in response to public policy, such as a lockdown, or weather and season. for hospitalised patients, transmission also depends on the level of protection for healthworkers and on environmental and infection control measures including cleaning and air quality. if the evolution of all these parameters were known, the model would predict the numbers of people in different stages of the disease, or death, over time. of course the model itself may be inadequate, no matter how the parameters are chosen. the seir model is much simpler than the hierarchical model being developed in the recent report 13 from imperial college (16) . in the context of the seir model, in the early period of an epidemic, numbers of infected or infectious persons or deaths are all growing exponentially at the same rate, and so the slope of their logs is identical. the true numbers of covid-19 cases in this period are unknown due to the lack of testing. the analysis here uses office for national statistics death registration data in england and wales, whose daily numbers in march are close to twice the uk figures in government briefings, and around 40% above the government figures in the remaining period to 24 april. the uk government figures are also shown on the johns hopkins university covid-19 dashboard (17) . i estimated transmission parameters for the uk, on the assumption that clinical parameters are fixed at the values already estimated by hill. a likelihood was assigned to transmission parameters and samples obtained via the metropolis-hastings algorithm. these samples lead to an estimate and credible interval for the basic reproduction number r 0. in reality, the clinical parameters are not fixed and their estimates will develop with new research. therefore, the samples may be biased by the assumed clinical values and may underestimate the variability of the transmission parameters, so the true ci for r 0 in the uk may be wider. the value found here is compatible with a recent analysis of global data by sanche et al. (preprint (4) ), who estimated r 0 in the range 4.7-6.6, significantly higher than the value of 3.11 cited by the uk government (2, 18) . it is also significantly higher than the european average value of 3.87 [3.01-4.66 ] estimated in imperial college report 13, which is based on hierarchical modelling of 11 countries (16) and will reflect "choice of serial interval distribution and the initial growth rate of observed deaths, " with some choices resulting in uk estimates in the range 4-6. r 0 itself is based on an idealised notion of perfect mixing, and the analysis here is pooled over the entire population, without stratification by age or any other characteristics. the model also assumes that length of stay in each compartment is exponentially distributed, but a recent article by verity et al. (19) fitted gamma distributions to length of stay, and estimated the coefficient of variation at 0.35 which implies shape = 8, rather than shape = 1 (exponential). gamma distributions with higher shape parameters are more tightly concentrated on their mean values, which would reduce the probability of patients remaining infectious for long periods. i have not adapted the model to allow for this. the parameter samples also enable forecasts, which are not based on r 0 but directly on the model and parameter estimates. the forecasts here exclude the possibility that asymptomatic or pre-symptomatic patients are infective, or that after recovery, individuals may again become susceptible. whilst the transmission parameter b1 (mild) influences the spread in the wider community, b2 (severe) and b3 (critical) are key to the risk to healthworkers. the estimates for b2 and b3 are sensitive to the prior, because the likelihood is based on r which is less dependent on b2 and b3 than on b1, as 80% of cases are mild. likewise r 0 is much more sensitive to b1 than to b2 or b3, which narrows the ci for r 0. however, even if a prior is chosen to fix b2 and b3 at 0, the unrealistic limiting case, r 0 is estimated at 6.71 (6.43, 7.00). the various lockdown forecasts assume that b1, b2, and b3 each initially reduce to 5% of their pre-lockdown values, a value chosen from the transport data published with the daily briefings from the government. the forecast depends on estimating the number of cases on 18 march, when exponential growth began. this estimate was chosen to optimise the fit to the ons data for deaths registered by 9 may but which occurred by 24 april, as later data is likely to be revised upwards when registrations become available. with 5% initial transmission, the resulting curves do fit the available ons data. the predicted curves for severe and critical cases throughout the lockdown would have overwhelmed the nhs, if all of these cases were admitted to hospital. on the other hand, as the ons data also shows, many people are now dying in care homes or in their own homes, so not all severe or critical cases are admitted to hospital. as the transport data also shows, bus services outside london continued at around 15% of pre-lockdown rates, and the lockdown began to weaken in mid-april. on 10 may, prime minister johnson signalled that restrictions would be relaxed. three scenarios, all beginning with 5% transmission, were chosen to represent possible dynamics. t2 provides for 3 weeks at 5% followed by a steady rise, reaching around 15% on 10 may and continuing to 30% by mid-june. whilst all three scenarios result in similar numbers of predicted deaths by 16 june, they differ widely in the number of active cases at the end of the lockdown period. t2 appears plausible in england, though not elsewhere in the uk, and would result in 475,000 active cases in mid-june. over half of these cases would not yet show clinical symptoms, and would be undetected without comprehensive testing. they represent a threat for the future course of the disease. the forecasts from three scenarios show cumulative deaths between 44,000 and 51,000 by 16 june, more than double the expert prediction given on 25 march as the lockdown began (20) . speaking to the uk select committee on science and technology, and citing the imperial college modelling report of 16 march (21), its principal author prof. neil ferguson stated "fatalities would probably be unlikely to exceed about 20,000, with effectively a lockdown and an intense social distancing strategy, and it could be substantially lower than that." however, as prof. ferguson also stated, "real-time analysis modelling, of the type we are doing now, will be needed to refine those precise estimates." ons data (8) now shows over 35,000 covid-19 deaths in england and wales by 1 may, suggesting that the forecasts in this paper may be conservative. this analysis is based only on death certificates which mention covid-19. it does not include excess deaths from other causes which may have arisen as nhs facilities were focused on the pandemic. the forecasts are based on assumptions concerning transmission rates, which could be overturned by a systematic programme of testing, contact tracing, isolation and quarantine as advocated by the world health organisation (22) . the uk ended contact tracing on 12 march, and is only now preparing to resume. the delay in beginning a hypothetical 12 week lockdown has a strong effect on the outcome. if the t2 scenario began on 17 march rather than 24 march, deaths by the end of 12 weeks would fall by around 30,000 (28,000, 32,000). the other scenarios give similar results. the excess is due to the rapid increase of cases during the pre-lockdown period. it raises an unanswered question: why did the uk lockdown only start on 24 march? publicly available datasets were analysed for the study. these can be found here: uk government (1); office for national statistics (8) . ethical review and approval was not required for the study on human participants in accordance with the local legislation and institutional requirements. written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements. gd conceived of the study and carried out the analysis. coronavirus (covid-19) in the uk novel coronavirus 2019-ncov: early estimation of epidemiological parameters and epidemic predictions. medrxiv early epidemiological assessment of the transmission potential and virulence of coronavirus disease 2019 (covid-19) in wuhan city: china the novel coronavirus, 2019-ncov, is highly contagious and more infectious than initially estimated. medrxiv real-time tentative assessment of the epidemiological characteristics of novel coronavirus infections in wuhan, china, as at 22 preliminary estimation of the basic reproduction number of novel coronavirus (2019-ncov) in china, from 2019 to 2020: a data-driven analysis in the early phase of the outbreak the mathematics of infectious diseases provisional: week ending 1 modeling covid-19 spread vs. healthcare capacity seir model for covid-19 infection, including different clinical trajectories of infection. github (2020) available online at mhadaptive: general markov chain monte carlo for bayesian inference using adaptive metropolis-hastings sampling output analysis and diagnostics for mcmc available online at uk government. slides, datasets and transcripts to accompany coronavirus press conferences estimating the number of infections and the impact of non-pharmaceutical interventions on covid-19 in 11 european countries covid-19 dashboard estimates of the severity of covid-19 disease oral evidence: uk science, research and technology capability and influence in global disease outbreaks, hc 136 report 9 -impact of non-pharmaceutical interventions (npis) to reduce covid-19 mortality and healthcare demand covid-19: government must change course or risk further wave of infections, scientists warn thanks to wendy olsen for helpful comments on early drafts, to alison hill for her website, and to the reviewers for constructive criticisms of the original submission. the supplementary material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fpubh. 2020.00256/full#supplementary-material conflict of interest: the author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.copyright © 2020 dropkin. this is an open-access article distributed under the terms of the creative commons attribution license (cc by). the use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. no use, distribution or reproduction is permitted which does not comply with these terms. key: cord-302384-gljfslhs authors: al-hanawi, mohammed k.; angawi, khadijah; alshareef, noor; qattan, ameerah m. n.; helmy, hoda z.; abudawood, yasmin; alqurashi, mohammed; kattan, waleed m.; kadasah, nasser akeil; chirwa, gowokani chijere; alsharqi, omar title: knowledge, attitude and practice toward covid-19 among the public in the kingdom of saudi arabia: a cross-sectional study date: 2020-05-27 journal: front public health doi: 10.3389/fpubh.2020.00217 sha: doc_id: 302384 cord_uid: gljfslhs background: saudi arabia has taken unprecedented and stringent preventive and precautionary measures against covid-19 to control its spread, safeguard citizens and ensure their well-being. public adherence to preventive measures is influenced by their knowledge and attitude toward covid-19. this study investigated the knowledge, attitudes, and practices of the saudi public, toward covid-19, during the pandemic. methods: this is a cross-sectional study, using data collected via an online self-reported questionnaire, from 3,388 participants. to assess the differences in mean scores, and identify factors associated with knowledge, attitudes, and practices toward covid-19, the data were run through univariate and multivariable regression analyses, respectively. results: the majority of the study participants were knowledgeable about covid-19. the mean covid-19 knowledge score was 17.96 (sd = 2.24, range: 3–22), indicating a high level of knowledge. the mean score for attitude was 28.23 (sd = 2.76, range: 6–30), indicating optimistic attitudes. the mean score for practices was 4.34 (sd = 0.87, range: 0–5), indicating good practices. however, the results showed that men have less knowledge, less optimistic attitudes, and less good practice toward covid-19, than women. we also found that older adults are likely to have better knowledge and practices, than younger people. conclusions: our finding suggests that targeted health education interventions should be directed to this particular vulnerable population, who may be at increased risk of contracting covid-19. for example, covid-19 knowledge may increase significantly if health education programs are specifically targeted at men. coronavirus disease 2019 is defined as an illness caused by a novel coronavirus, now called severe acute respiratory syndrome coronavirus 2 (sars-cov-2; formerly called 2019-ncov). covid-19 is an emerging respiratory infection that was first discovered in december 2019, in wuhan city, hubei province, china (1) . sars-cov-2 belongs to the larger family of ribonucleic acid (rna) viruses, leading to infections, from the common cold, to more serious diseases, such as middle east respiratory syndrome (mers-cov) and severe acute respiratory syndrome (sars-cov) (2) . the main symptoms of covid-19 have been identified as fever, dry cough, fatigue, myalgia, shortness of breath, and dyspnoea (3, 4) . covid-19 is characterized by rapid transmission, and can occur by close contact with an infected person (5) (6) (7) (8) (9) . the details on the disease are evolving. as such, this may not be the only way the transmission is occurring. covid-19 has spread widely and rapidly, from wuhan city, to other parts of the world, threatening the lives of many people (10) . by the end of january 2020, the world health organization (who) announced a public health emergency of international concern and called for the collaborative effort of all countries, to prevent its rapid spread. later, the who declared covid-19 a "global pandemic" (11) . following the who declaration, countries around the globe, including the kingdom of saudi arabia (ksa), have been leaning on response plans to respond to the pandemic and contain the virus. following the confirmation of its first case of covid-19, on monday 2 march 2020, the saudi government has been vigilantly monitoring the situation and developing countryspecific measures that are in line with the who guidelines in dealing with the outbreak (12) . these includes suspending all inbounds and outbounds flights, closing all malls and shops in the country, except pharmacies and grocery stores, and closing down schools and universities. umrah visas have been suspended, as have prayers at mosques, including the two holy mosques in mekkah and almadina. on 24 march 2020, the government imposed a nationwide curfew to restrict people movements for most of the day hours. despite the unprecedented national measures in combating the outbreak, the success or failure of these efforts is largely dependent on public behavior. specifically, public adherence to preventive measures established by the government is of prime importance to prevent the spread of the disease. adherence is likely to be influenced by the public's knowledge and attitudes toward covid-19. evidence shows that public knowledge is important in tackling pandemics (13, 14) . by assessing public awareness and knowledge about the coronavirus, deeper insights into existing public perception and practices can be gained, thereby helping to identify attributes that influence the public in adopting healthy practices and responsive behavior (15) . assessing public knowledge is also important in identifying gaps and strengthening ongoing prevention efforts. thus, this study aims to investigate the knowledge, attitudes and practices (kap) of ksa residents, toward covid-19 during the pandemic spike. to the researchers' knowledge, this is the first study to investigate covid-19 kap, and associated sociodemographic characteristics among the general population of the ksa. the findings of this study are expected to provide useful information to policymakers, about kap among the saudi population, at this critical time. the findings may also inform public health officials on further public health interventions, awareness, and policy improvements pertaining to the covid-19 outbreak. this cross-sectional study was conducted among the general population of saudi arabia, from 20 march 2020, to 24 march 2020. given the social distancing (physical distancing) measures and restricted movement and lockdowns, data were collected online, via a self-reported questionnaire, using surveymonkey. given the high internet usage among people in the ksa, a link to the survey was distributed to respondents, via twitter and whatsapp groups. the link was also posted on the king abdulaziz university website. the larger the target sample size, the higher the external validity and the greater the generalizability of the study (16) . this study aimed to maximize reach and gather data from as many respondents as possible. according to the latest ksa census, saudi arabia has a population of 34,218,169 (17) . the representative target sample size needed, to achieve the study objectives and sufficient statistical power, was calculated with a sample size calculator (18) . the sample size calculator arrived at 1,037 participants, using a margin of error of ±4%, a confidence level of 99%, a 50% response distribution, and 34,218,169 people. the self-reported questionnaire was developed by the authors, according to guidelines for the community of covid-19, by the centers for disease control and prevention (cdc) (19) . the questionnaire was conducted in arabic language. it was initially drafted in english by h.z.h., and y.a., and was translated from english to arabic by m.k.a and m.a. the questionnaire was translated then back to english by n.a and w.k to ensure the meaning of the content. on the first page of the online questionnaire, respondents were clearly informed about the background and objectives of the study. respondents were informed that they were free to withdraw at any time, without giving a reason, and that all information and opinions provided would be anonymous and confidential. respondents living in saudi arabia, aged 18 years or older, understand the content of the questionnaire, and agree to participate in the study were instructed to complete the questionnaire. online informed consent were obtained before proceeding with the questionnaire. the questionnaire consisted of four primary sections. the first section gathered information on respondents' sociodemographic characteristics, including age, gender, marital status, education level, work status, region of residence, and income level. the second section assessed participants' knowledge of covid-19. this section included 22 items on modes of transmission, clinical symptoms, treatment, risk groups, isolation, prevention and control. the third section assessed participants' attitudes toward covid-19, using a five-point likert scale. for each of six statements, respondents were asked to state their level of agreement, from "strongly disagree, " "disagree, " "undecided, " "agree, " or "strongly agree." the final section of the questionnaire assessed the respondents' practices. this section consisted of five questions related to practices and behavior, including (a) going to social events with large numbers of people, (b) going to crowded places, (c) avoiding cultural behaviors, such as shaking hands (d) practicing social distancing, (e) washing hands after sneezing, coughing, nose-blowing, and, recently, being in a public place. for sociodemographic variables, gender was coded as one for men, and zero for women. the age variable was divided into categories: 18-29 (reference category), 30-39, 40-49, 50-59, and ≥60. marital status was captured as binary, and a value of one was used for marriage and zero for otherwise. education was categorized into high school or below (reference category), college/university degree, and postgraduate degree. work status was broken down into government employee (reference category), non-government employee, retiree, selfemployed, and unemployed. monthly income (saudi riyal, sr 1 = usd 0.27) was divided into eight categories: <sr 3,000 (reference category); sr 3,000 to <5,000, sr 5,000 to <7,000, sr 7,000 to <10,000, sr 10,000 to <15,000, sr 15,000 to <20,000, sr 20,000 to <30,000, and sr 30,000 or more. we also controlled for the 13 administrative regions: almadina almonawra, albaha, aljouf/quriat, aseer/bisha, eastern region, haiel, jazan, najran, northern borders, qaseem, riyadh, tabouk, and the western region. respondents were asked to respond to knowledge items as either true or false, with an additional "don't know" option. incorrect or uncertain (don't know) responses were given a score of zero, and correct answers were assigned a score of one. the total score for knowledge ranged from zero to 22, with high scores indicating better knowledge of covid-19. items were evaluated for internal reliability, using cronbach's α. cronbach's alpha coefficient was 0.70, indicating internal reliability (20) . in the section on attitudes, scores were calculated based on the respondents' answers to each attitudinal statement, 1 = strongly disagree, 2 = disagree, 3 = undecided, 4 = agree, and 5 = strongly agree. scores were calculated by averaging respondents' answers to the six statements. total scores ranged from six to 30, with high scores indicating positive attitudes. the likert scales were assessed for internal reliability, using cronbach's α. cronbach's alpha coefficient was 0.81, indicating internal reliability. in the section on practices, respondents were asked to respond "yes" or "no" to the items. a score of one was given to answers that reflected good practice, and a score of zero was given for answers that reflected bad practice. the total score ranged from zero to five, with high scores indicating better practices. this study employed primarily univariate and multivariable regression data analyses. univariate analysis was used to tabulate the frequency of social and demographic statistics. one-way analysis of variance (anova) was used to assess differences in mean values for kap scores. because the scores were continuous, the overall mean differences were estimated using a bartlett test (21, 22) . a multivariable linear regression analysis was performed, to identify factors related to knowledge, attitudes, and practice. all analyses were conducted using stata software (statacorp lp, texas, usa). all procedures performed in this study, involving human participants, complied with the institutional and/or national research committee ethical standards, and the 1964 helsinki declaration and subsequent amendments or equivalent ethical standards. the study was designed and conducted in accordance with the ethical principles established by king abdulaziz university. therefore, ethical approval was obtained from the biomedical ethics research committee, faculty of medicine, king abdulaziz university . a total of 3,427 participants completed the questionnaire. after excluding 39 respondents who reported living outside the ksa, the final sample consisted of 3,388 participants. table 1 shows the social and demographic characteristics of the study participants. as shown in table 1 , the mean covid-19 knowledge score was 17.96 (sd = 2.24, range: 3-22), and the overall accuracy rate for the knowledge test was 81.64% (17.96/22 * 100). the mean attitude score for covid-19 was 28.23 (sd = 2.76, range: 6-30), indicating positive attitudes. the mean score for practices for covid-19 was 4.34 (sd = 0.87, range: 0-5), indicating good practices. of the total sample, 1966 (58.03%) were women, and 1422 (41.97%) were men. the majority of the sample (57.73%) were between the ages of 18 and 39. of the participants, 2,149 were married (63.43%) and 1,239 were unmarried (36.57%). more than half of the sample (56.20%) had a college or university degree. respondents were grouped according to monthly income, with 846 (24.97%) in the < sr 3000 group, and 246 (7.26%) in the ≥ sr 30,000 group. in terms of work status, 1,073 (31.76%) were unemployed, and 314 (9.27%) were retired. tables 2-4 show the responses to items related to kap towards covid-19. we also assessed the level of kap, across the various income groups. figures 1-3 show the results. figure 1 shows that the covid-19 knowledge score increases with income. the lowest score was for respondents in the lowincome category, < sr 3000, and the highest score was for respondents with an income of sr 20,000 to < 30,000. for attitudes, figure 2 shows that there were no discernible patterns across income groups. furthermore, with regard to practices, there was little variation between income groups, as shown in figure 3 . looking at the univariate statistics for each variable of interest, we took another step to assess the difference in the scores for kap. table 5 shows the results. as shown in table 5 , all scores for kap, were statistically different at the 1% significance level, for all age and income groups. although, across genders, there was a statistically significant difference in attitudes and practices scores, there was no difference in knowledge scores. although assessments showed that knowledge scores were not statistically different between regions, attitudes and practices scores were significantly different at the 1% level. apart from the univariate and non-parametric analyses performed in previous sections, we also focused on regression analysis. scores were logged for all variables, and interpreted using ordinary least squares (ols). increased scores imply increased knowledge, practices, and attitudes. the results are shown in table 6 . table 6 shows that, for knowledge of covid-19, age groups 30-39, 40-49, 50-59 and ≥60, are more knowledgeable about covid-19 than the reference group (18) (19) (20) (21) (22) (23) (24) (25) (26) (27) (28) (29) . all variables for age groups 30-39 (β = 0.047; p < 0.001), 40-49 (β = 0.041; p < 0.001), 50-59 (β = 0.057; p < 0.001) and ≥60 (β = 0.051; p < 0.001), are statistically significant at the 1% level. however, attitudes follow a different trend. only the age group 50-59 (β = −0.021; p < 0.001) is significantly different from baseline. in practices for covid-19, age groups 30-39 (β = 0.039; p < 0.001), 40-49 (β = 0.033; p < 0.05), and 50-59 (β = 0.051; p < 0.001), are associated with good practices. regarding gender, the results indicate that, compared to women, men have lower knowledge (β = −0.018; p < 0.001), lower positive attitudes (β = −0.018; p < 0.001), and few good practices for covid-19 (β = −0.064; p < 0.001). no difference in kap toward covid-19 was observed by marital status. however, the relationships between income, region, education, and variables of interest, are heterogeneous, suggesting substantial differences. we also examined the association between kap scores. because all were logs, the interpretation would be akin to the elasticity. therefore, table 6 shows that every increase of 1% in knowledge score is associated an increase in attitude and practices scores, of 0.095 and 0.16, respectively. covid-19 is an emerging infectious disease that poses a significant threat to public health. given the serious threats imposed by covid-19 and the absence of a covid-19 vaccine, preventive measures play an essential role in reducing infection rates and controlling the spread of the disease. this indicates the necessity of public adherence to preventive and control measures, which is affected by their knowledge, attitudes, and practices (23, 24) . in our study, the high rate of correct answers to knowledge-related questions among participants, was not surprising. this may be due to the characteristics of the sample, as 84% had a college or university degree, or above, and 70% were over 30 years old. it may also be due to the distribution of the questionnaire, amid the covid-19 outbreak. in that time, people may have gained awareness and knowledge about the disease and its transmission, via television, news and media platforms, to protect themselves and their families. the positive association found between knowledge, and educational background and age, supports our claim. most of the participants in our study (98%) were aware of the clinical symptoms, and 96% knew that there is no clinically approved treatment for covid-19 as of the date of this manuscript. viral infections have been documented to be highly contagious among people in close proximity (19) . however, approximately half of the respondents were unaware that sars-cov-2 could spread from person-to-person in close proximity. it was also evident that the current general population (44%) had little knowledge of when and whom wearing masks to prevent infection. according to the who and the cdc, faces mask should only be worn by those who are sick or caring for people suspected of having covid-19 (9, 19) . these findings highlight the need to continue to encourage and emphasize maintaining social distancing, as a means of preventing the spread of the virus. it is important to note that there has been a great deal of efforts at all levels by the government, including public awareness campaigns. the saudi arabian ministry of health (moh) has conducted an intensive awareness campaign, communicated via its website, television and various social media. the moh has produced a guide to covid-19, to provide residents with facts and precautionary messages in more than 10 languages. the moh also works with the public and the media, especially via social media platforms. these early actions on engaging the public in prevention and control measures, as well as efforts to combat rumors and misinformation, have been greatly expanded (25). it is worth noting that the ksa is in the unique position of having dealt successfully with two outbreaks of viral origin, of related viruses (26) (27) (28) (29) (30) . this unique experience has helped the government in taking prompt response and precautionary measures against covid-19 to control its spread. significant predictors of participant knowledge in this study were age, gender, educational level, and income level. this finding is supported by other studies that have found that older, female, and more educated respondents are more knowledgeable about emerging communicable diseases (23, 31) . we also found that high income earners are more knowledgeable about covid-19. education, age, and income have been documented to be highly relevant to knowledge (32) . our findings suggest that greater emphasis should be placed on mass media, to target low-income, low-educated, young people, and men to improve public knowledge on the covid pandemic, through awarenessraising interventions. concerning attitudes, participants showed a positive and optimistic attitude toward covid-19. approximately 94% concur that the virus can be successfully controlled, and 97% are convinced that the saudi government will control the pandemic. positive attitudes and high confidence in the control of covid-19 can be explained by the government's unprecedented actions and prompt response in taking stringent control and precautionary measures against covid-19, to safeguard citizens and ensure their well-being. these measures include the lockdown, and the suspension of all domestic and international flights, prayer at mosques, schools and universities, and the national curfew imposed on citizens. this finding is consistent with a recent study conducted in china, where the majority of participants were convinced that the disease is curable and that their country will combat the disease (33) . however, these results contrast with other findings that suggest people tend to express negative emotions, such as anxiety and panic, during a pandemic that could affect their attitude (34) . nevertheless, our results show that the participants' high knowledge of covid-19 translates into good and safe practices, during the covid-19 pandemic, which suggests that the practices of saudi residents are very cautious. almost 95% of respondents refrained from attending social events, 94% avoided crowded places, and 88% avoided shaking hands. respondents adopted good and safe practices, as a result of saudi arabia's health authorities providing education and outreach materials, to increase public understating of the disease, and influence behavioral change. finally, the study findings may be useful to inform policymakers and healthcare professionals, on further public health interventions, awareness-raising, policies, and health education programs. men were significantly less likely to have knowledge, optimistic attitudes, and appropriate or safe practices toward covid-19. these findings are consistent with other studies showing that, in response to sars and mers, men were significantly less likely take preventive and protective measures than women (24, 35, 36) . our finding suggests that targeted health education interventions should be directed to this particular vulnerable population at high risk of contracting covid-19. for example, covid-19 knowledge may increase significantly, if health education programs are specifically targeted at men. health information can be sent to women (wives, sisters, mothers) who live with men, which may influence their practices, as suggested by a study in hong kong (35) . to the researchers' knowledge, this is the first study to investigate kap toward covid-19, in the general population of the ksa. data collection took place 2 weeks after the ksa confirmed its first covid-19 case. therefore, the prompt results may help health authorities to plan preventive strategies for future events. however, in interpreting the results of this study, some limitations should be considered. data used in the analysis of this study were self-reported, which might suffer from reporting bias. future research might employ administrative data to address this issue. furthermore, there may be some endogenous variables: general attitude and expectation from the government, personal hygiene, for example. however, even if we were to undertake causality analysis, we could not be in a position to do proper econometric identification because the data we used could not have a valid instrument to eliminate the endogeneity. additionally, community-based national sampling surveys were not feasible during this particular period. as such, data were collected online, through self-reported questionnaires, depending on the authors' networks. therefore, the majority of the respondents were in the western region, where most of the authors come from. further research should cover the perceptions of all regions of the country. finally, this study did not address causation. therefore, the regression results should be interpreted as relevant, as some variables may be endogenous. that said, the implication is for the objective of future research to assess whether there is a relationship between covid-19 knowledge and mortality, household consumption patterns, and the demand for unprescribed flue medication. this is the first study to investigate kap for the covid-19 outbreak, among the general population of saudi arabia. our findings suggest that saudi residents, especially women, have good knowledge, positive attitudes, and good practices toward covid-19. knowledge of the disease is considered the first stepping stone to any health education activity that is implemented. knowing the causes and transmission sources of a disease, increases the likelihood that people will become more aware of the spread of communicable diseases, and of the preventive measures to slow transmission. the results of this study suggest that more emphasis should be placed on less educated, lower income, and men. the findings may help policymakers identify the target populations, for covid-19 prevention and health education. the datasets generated and/or analyzed during the current study are not publicly available due to privacy and confidentiality agreements as well as other restrictions, but are available from the corresponding author (mohammed k. al-hanawi) on reasonable request. all authors made substantial contributions to conception and design, acquisition of data, or analysis and interpretation of data, took part in drafting the article or revising it critically for important intellectual content, gave final approval of the version to be published, and agreed to be accountable for all aspects of the work. a new coronavirus associated with human respiratory disease in china a pneumonia outbreak associated with a new coronavirus of probable bat origin a familial cluster of pneumonia associated with the 2019 novel coronavirus indicating person-to-person transmission: a study of a family cluster covid-19 infection: origin, transmission, and characteristics of human coronaviruses importation and human-to-human transmission of a novel coronavirus in vietnam china coronavirus: cases surge as official admits human to human transmission early transmission dynamics in wuhan, china, 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residents during the rapid rise period of the covid-19 outbreak: a quick online crosssectional survey the public's response to severe acute respiratory syndrome in toronto and the united states the impact of community psychological responses on outbreak control for severe acute respiratory syndrome in hong kong a meta-analysis of the association between gender and protective behaviors in response to respiratory epidemics and pandemics the authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.copyright © 2020 al-hanawi, angawi, alshareef, qattan, helmy, abudawood, alqurashi, kattan, kadasah, chirwa and alsharqi. this is an open-access article distributed under the terms of the creative commons attribution license (cc by). the use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. no use, distribution or reproduction is permitted which does not comply with these terms. key: cord-264697-b3wd6gww authors: ma, xiaoxu; li, ang; jiao, mengfan; shi, qingmiao; an, xiaocai; feng, yonghai; xing, lihua; liang, hongxia; chen, jiajun; li, huiling; li, juan; ren, zhigang; sun, ranran; cui, guangying; zhou, yongjian; cheng, ming; jiao, pengfei; wang, yu; xing, jiyuan; shen, shen; zhang, qingxian; xu, aiguo; yu, zujiang title: characteristic of 523 covid-19 in henan province and a death prediction model date: 2020-09-08 journal: front public health doi: 10.3389/fpubh.2020.00475 sha: doc_id: 264697 cord_uid: b3wd6gww certain high-risk factors related to the death of covid-19 have been reported, however, there were few studies on a death prediction model. this study was conducted to delineate the clinical characteristics of patients with coronavirus disease 2019 (covid-19) of different degree and establish a death prediction model. in this multi-centered, retrospective, observational study, we enrolled 523 covid-19 cases discharged before february 20, 2020 in henan province, china, compared clinical data, screened for high-risk fatal factors, built a death prediction model and validated the model in 429 mild cases, six fatal cases discharged after february 16, 2020 from henan and 14 cases from wuhan. out of the 523 cases, 429 were mild, 78 severe survivors, 16 non-survivors. the non-survivors with median age 71 were older and had more comorbidities than the mild and severe survivors. non-survivors had a relatively delay in hospitalization, with higher white blood cell count, neutrophil percentage, d-dimer, ldh, bnp, and pct levels and lower proportion of eosinophils, lymphocytes and albumin. discriminative models were constructed by using random forest with 16 non-survivors and 78 severe survivors. age was the leading risk factors for poor prognosis, with auc of 0.907 (95% ci 0.831–0.983). mixed model constructed with combination of age, demographics, symptoms, and laboratory findings at admission had better performance (p = 0.021) with a generalized auc of 0.9852 (95% ci 0.961–1). we chose 0.441 as death prediction threshold (with 0.85 sensitivity and 0.987 specificity) and validated the model in 429 mild cases, six fatal cases discharged after february 16, 2020 from henan and 14 cases from wuhan successfully. mixed model can accurately predict clinical outcomes of covid-19 patients. in late december 2019, wuhan city, hubei province, china found several cases of unexplained pneumonia. on january 7, 2020, a new coronavirus was detected in the laboratory and the whole genome sequence of the virus was obtained. on january 12, 2020, the world health organization temporarily named this new virus 2019 novel coronavirus (2019-ncov). on february 11, 2020 , the world health organization announced that the same time the international virus classification committee named the new coronavirus "sars-cov-2." although the lethal rate of sars-cov-2 is not as high as sars and mers, it is more infectious than other viruses including influenza virus (1-3). the range of basic regeneration number (ro) is estimated to be 2-5 (4, 5) . china has effectively controlled the epidemic by adopting strict prevention and control measures, but in areas outside china, the epidemic of novel coronavirus is still spreading. the number of infections caused by sars-cov-2 is large and no specific therapeutic is available yet, which is the main cause of so many deaths. sars-cov-2 can cause pneumonia and systemic inflammation, leading to multiple organ failure in high-risk patients. more and more studies have focused on the high-risk factors of death. demographic factors, advanced age, combined underlying diseases, and d-dimer exceeding 1 µg/l have been confirmed as risk factors for death in adult patients (6) . in the absence of vaccines and specific antiviral drugs, targeted application of supportive therapy may be beneficial to relieve symptoms and protect organ functions (7) . how to quickly identify high-risk patients in the early stage of the disease and actively adopt supportive treatment to reduce mortality is an urgent problem to be solved in the clinic. cao bin (6) and others reported some characteristics and clinical progress of the early stage of severe and dead patients, which improved our further understanding of the characteristics of dead patients. however, there are no relevant studies on the application of models to predict covid-19 death. using admission characteristics and laboratory test results to establish a predictive model can calculate the probability of over-all mortality due to sars-cov-2, identify high-risk patients as early as possible and give support to reduce mortality as soon as possible. in this study, we collected data of 523 discharged cases of novel coronavirus infection in henan province, china and compared the demographics, clinical characteristics, laboratory test, imaging between the mild, severe survivors and nonsurvivors. we established a death prediction model using the data upon admission of the severe survivors and non-survivors. from january 22, 2020 to february 20, 2020, a total of 717 patients confirmed covid-19 were discharged in 18 cities of henan province, china, of which 19 died. we designed a data collection table, including age, gender, epidemiological history, past history, clinical symptoms, laboratory examination, chest ct and recorded the treatment process and clinical outcome, and data of 556 patients with novel coronavirus pneumonia discharged before february 20, 2020 was collected. all data were checked by two physicians (al and xm) and a third researcher (qz) adjudicated any difference in interpretation between the two primary reviewers. for different interpretations and missing data, we contacted the doctor who filled out the form and the patient or their family members to review and supplement. excluding 18 cases under the age of 18, 10 cases missing key information and five cases transferred to other hospitals with no end point, 523 cases were included for statistical analysis, of which 19 cases died including three fatal cases with data missing. according to the guidance for corona virus disease 2019 (6th edition) released by the national health commission of china, the enrolled cases were categorized as mild or severe (8) . there were no deaths in the mild. according to the clinical outcome, we divided the severe into severe survivors and non-survivors. up to april 1, there were 22 cases died of covid-19 in henan province. we have managed to collect data of another six fatal cases of henan province and 14 cases from the fourth people's hospital of wuhan to validate the predictive power of the model. the flow diagram of included patients is shown in figure 1 . the incubation period was defined as the interval between the potential earliest date of contact of the transmission source (wildlife or person of suspected or confirmed case) and the potential earliest date of symptom onset (i.e., cough, fever, fatigue, or myalgia). we excluded cases with an incubation period of <1 day or cases of continuous exposure, because those patients continued to be infected. fever was defined as an axillary temperature of 37.3 • c or higher. lymphopenia was defined as a lymphocyte count of <1,200 per cubic millimeter. thrombocytopenia was defined as a platelet count of <100,000 per cubic millimeter. chest ct was divided into normal, mild, moderate and severe infections according to the range of lesions. the range of lesions < 15% was mild; the range of lesions 15-40% was moderate; the range of lesions > 40% was severe. statistical analyses on cohort characteristics were performed on r version 3.6.1. participants' demographic, laboratory findings and questionnaire were summarized with a standardized statistical significance test method, categorical variables were shown as counts and percentages [n (%)], and associations were tested using a fisher' exact test. continuous variables were shown as median (interquartile range, iqr), and differences between groups were analyzed with non-parametric test (wilcoxon's ranksum test). a single-sided p < 0.05 was considered statistically significant. discriminative models were constructed by using random forest with leave-one-out cross validation, features were selected by using embedded backward selection. missing data were filled by chose median value in relative cohort (severe death, severe survival, and mild) for model construction and validation. receiver operating characteristic (roc) curve and precision-recall curve were visualized by using r program package "proc" and "precrec, " respectively. clinical characteristics of the study patients according to disease severity and clinical outcome in severe . muscle and joint pain, runny nose, diarrhea, dizziness, and headache were rare. the symptoms of fever, cough, dyspnea, gasp, chest tightness, nasal congestion, and muscle and joint pain had a higher incidence in severe cases, and the difference was significant; the incidence of chest tightness in non-survivors was higher than that in severe survivors. the patients in the non-survivors had more symptoms at the onset. four (0.82%) had a respiratory rate > 24 breaths/min, one of them died; 8 (4.85%) pulse oxygen saturation < 90%, all severe; median body temperature 37.2 • c (iqr 36.7-37.9), 293 (59.07%) body temperature < 37.5 • c, 16 (3.23%) body temperature > 39 • c and 80% non-survivors body temperature < 37.5 • c upon admission. the median duration from onset of symptoms to first visit to doctor was 2 days (iqr 0-5), from onset of symptoms to first hospitalization 4 days (iqr 2-7) while 8 days (iqr 6-10) in nonsurvivors. the median incubation period was 5 days (iqr 1-9), with no significant difference between the cases. table 2 shows the imaging and laboratory examination results. of all the cases, 419 patients had detailed chest ct data on initial admission, with 17 (4.06%) being normal; 224 (53.46%) chest ct lesions < 15%; 154 (36.75%) chest ct lesions between 15 and 40%; 24 (5.73%) chest ct lesions > 40%, of which 15 were severe. in the non-survivors, 100% of patients had a chest ct lesion area of more than 15% for the first time. in the first nucleic acid testing, 323 (65.25%) were confirmed positive for sars-cov-2. the leucocyte count in non-survivors (8.66 × 10 9 /l [iqr 7-12.335]) was significantly higher than that in mild and severe survivors. lymphocytopenia is more common in the severe than in the mild (39.24 vs. 18.16%). 96.65% of patients experienced a decrease in eosinophil count. the level of d-dimer at admission was significantly higher in severe patients the alanine aminotransferase, lactate dehydrogenase and creatine kinase in the severe were significantly higher than those in the mild, and the non-survivors was more obviously, the difference was significant. the incidence of renal impairment was higher in the non-survivors. the incidence of arterial blood gas hypoxia and respiratory alkalosis on admission in the non-survivors was higher than that in the mild and the severe survivors. three hundred and seventy-two people were tested for c-reactive protein (crp) upon admission. two hundred and eleven (56.72%) had crp > 10 mg/l. the increase rate in the severe (85.51%) was significantly higher than that in the mild (50.17%). two hundred and thirty-five patients were tested for procalcitonin (pct) upon admission, and 100% patients in the non-survivors had elevated pct. patients in nonsurvivors had more laboratory abnormalities than those in mild and severe. two hundred and seventeen (41.49%) patients received respiratory support during hospitalization, of which 18 (4.2%) of mild patients received nasal catheter inhalation, as shown in table 3 . the respiratory support rate of the severe was higher than that of the mild, and the non-survivors all received mechanical ventilation treatment, of which six received noninvasive mechanical ventilation treatment and 11 received invasive mechanical ventilation treatment. nine patients in the severe received ecmo treatment, and no one survived. thirty-nine (52.7%) of the severe survivors were treated with crrt, and only 5 (33.33%) of the non-survivors applied this technique. in terms of drug treatment, antiviral treatment was commonly used in each group. the severe had a higher proportion of antibiotics than the mild, and the non-survivors had a higher proportion of carbapenem and glycopeptide antibiotics than the survivors. one hundred and twelve (21.41%) received glucocorticoid therapy, and the non-survivors received a higher proportion of glucocorticoid therapy than the severe survivors (62.5 vs. 41.03%). we constructed classification models to evaluate death risk for severe patients. model performance was assessed by receiver operating characteristic (roc) curve analysis using the area under the curve (auc). in considering age is among leading risk factors for poor prognosis in several studies (3, 6, 7, (9) (10) (11) , we firstly constructed models by using single age, which could achieve and auc of 0.907 (95% ci 0.831-0.983) for death and alive severe covid-19 patients. mixed models constructed with combination of age, demographics, symptoms, and laboratory tests when firstly admitted to hospital had better performance (p = 0.021) and could achieved an auc of 0.984 (95% ci 0.961-1) for death and alive severe covid patients (figures 2a,b) . in considering fetal cases are with a small sample size, we randomly chose 40 samples from severe cases, then calculated the generalized auc by using death probabilities and the median generalized auc was 0.9852 ( figure 2c ). pulse oxygen, age, creatinine, creatine kinase, d-dimer are the most important features ( table 4) . we chose 0.441 as death prediction threshold (with 0.85 sensitivity and 0.987 specificity), then used six additional fatal cases (henan), 429 mild cases and 14 cases (wuhan) as independent validation cohort, and four in six death cases (0.67%) were assigned as death and majority of predicted death probabilities in the mild henan cases and those wuhan cases were below 0.441 ( figure 2d ). summary characteristics of six henan additional fatal cases and 14 wuhan cases and were outlined in table 5 . henan province has a large population of 95.593 million people, bordering hubei province, china. as of april 1, 2020, there were 1,273 people confirmed covid-19 in henan, which was the second most in china outside hubei province. we collected data of 523 confirmed covid-19 cases who had been discharged from 18 cities in henan province before february 20, 2020 and conducted statistical analysis. our data showed that the main epidemiological characteristics of novel coronavirus pneumonia in henan province were import and cluster, which were similar to other provinces and cities outside hubei in china. among the 523 cases, there were 289 males (55.26%) and 234 females (44.74%). other reports also showed a higher percentage of males (9, 12, 13) , suggesting that males were more susceptible. our study suggested that people of all ages were generally susceptible, with people aged 18-64 accounting for 87.96%, which was consistent with the chinese cdc report (3). in our study, there were 16 fatal cases before february 20, 2020, and 87.5% of the deaths were ≥65 years old, with a median age of 71 years, while the median age for the mild and severe survivors was 42 and 50 years, respectively. the most common comorbidities in the non-survivors were hypertension (46.67%), coronary heart disease (33.33%), diabetes (33.33%), and copd (33.33%). the average number of comorbidities in non-survivors was 1.94. several studies about severe novel coronavirus pneumonia in china suggested that advanced age and comorbidities were highrisk factors for covid-19 patients to develop into severe and death (10, 13, 14) . in our study, advanced age was the biggest risk factor for death, which was consistent with that. a study from italy involving 1,043 critically ill covid-19 cases showed similar results, but male patients accounted for a higher proportion (82%) (9) . the median incubation period of the 523 cases in henan province was 5 days, and there was no significant difference between mild and severe. the median time from the onset of symptoms to hospitalization in the non-survivors was 8 days, and it was significantly longer than the severe survivors, suggesting that a delay in hospitalization might be one of the factors leading to death. fever (88.74%), cough (62.3%), fatigue (39.58%), and expectoration (28.75%) were the most common symptoms. in spite of more symptoms, 60.87% of the severe and 80% of non-survivors had a temperature below 37.5 • c at the time of admission. zhong et al.'s study on 1,099 cases of covid-19 also found that 52% of patients did not have fever when they became ill (12) . the lack of fever symptoms made it difficult to identify covid-19 patients and could also be one of the factors that caused a delay in visiting the doctor. another study on refractory covid-19 also found that the refractory pneumonia cases had a significantly lower fever incidence than the common pneumonia cases, suggesting that slow or poor response to sars-cov-2 was more likely to cause severe illness (15) . compared with the mild and severe survivors, the nonsurvivors had higher leucocyte count, neutrophil percentage, d-dimer, ldh, bnp, and pct levels, while the proportion of eosinophils, lymphocytes and albumin were lower, which was consistent with other studies. white blood cell count, neutrophil percentage and elevated pct suggested that the nonsurvivors might be hospitalized with bacterial infection. low albumin indicated that the patient was seriously depleted and the nutritional level was poor. d-dimer elevation had been confirmed in multiple studies as a high-risk factor for severe illness and death (10, 16, 17) , which was consistent with our study. chen et al.'s study found that in the non-survivors 56% had increased leucocyte count and 91% had lymphopenia, while in the severe survivors 4% had increased leucocyte count and 47% had lymphopenia (10). zhang et al.'s study found that most covid-19 cases combined with lymphopenia (75.4%) and eosinophilia (52.9%), and lymphopenia and eosinophilia were associated with disease severity (17) . in our study, eosinophilia generally occurred in all cases, and there was no significant difference between the non-survivors and the severe survivors, but most of the eosinophils in the severe survivors returned to normal when discharged, while that of the non-survivors continued to decrease. liu et al. also found that eosinophilia might be an indicator of disease improvement (18) . in the non-survivors, 100% of the patients had chest ct pneumonia area > 15% at admission, which was more severe in imaging than the mild and severe survivors. in terms of respiratory support, the rate of mechanical ventilation in the nonsurvivors was significantly higher than that in the mild and the severe survivors, which also suggested that the lung function of the non-survivors was more seriously impaired. in the nonsurvivors, the percentage of invasive mechanical ventilation was 68.75%, higher than other reports from wuhan, china, but lower than those reported by the united states (71%) and italy (88%), and henan province's mortality rate was also lower than that of the united states and italy (9, 19) . in addition to the aging factor, the fatal rate difference between italy and henan province could be due to the fact that the number of covid-19 cases in henan province was relatively smaller and the medical resources were relatively more sufficient. nine patients were applied with extracorporeal membrane oxygenation and technology (ecmo), but no one survived. research showed application of ecmo could reduce mortality of patients with h1n1-related ards and mers-related ards (20, 21), but there was no large-scale glucocorticoids had been widely used in sars-cov and mers-cov, but studies showed that the application of glucocorticoids prolonged the clearance time of virus and the probability of mental illness was significantly increased (24) . similarly, there was no evidence that glucocorticoids were beneficial to improve the prognosis of patients with covid-19. whether glucocorticoids can improve the prognosis of covid-19 still requires long-term follow-up and further research. in our study, some independent risk factors for death were found and we firstly developed a forest tree to accurately predict clinical outcomes of patients with covid-19 based on combination of age, demographic features, symptoms and clinical tests at admission. old age was the most important risk factor for poor prognosis of covid-19 patients. the mixed model conducted by forest tree performed well in predicting survival and death, with auc of 0.984 (95% confidence interval 0.961-1) for survival and death, which is helpful for further understanding and improve clinical strategies against covid-19. we also found the predicted value was positively correlated with the severity of covid-19. of the 14 confirmed cases from wuhan, seven were mild, seven were severe, 13 were cured and discharged, and one was referred to other hospital due to critical illness. in the death prediction model based on wuhan data, those with a predicted value >0.3 were all critically ill, and the respiratory support treatment intensity was higher than the other 10 cases. the predictive value of the case transferred to other hospitals due to critical illness was 0.673, unfortunately we failed to follow up on the clinical outcome. the death prediction model we have established has also been validated in mild and six other fatal cases in henan province. the prediction of death for all mild survivors was below 0.3 and 4 in six death cases (66.67%) were assigned as death. mild patients have rare fetal cases thus we excluded mild cases in the death prediction models. several studies have constructed models for early identification of cases at high risk of progression to severe covid-19 (11) or improved prognosis (25) . however, fatal cases were always rapid disease progression and died in hospitals in a short time, though we have plenty of medical support in henan province. to the best of our knowledge, this is the first death prediction model for covid-19 established by random forest. the model can accurately predict the prognosis of patients with covid-19. our study provided a new method for the evaluation of disease severity. early identification of highrisk covid-19 cases and early supportive therapy is critical to the prognosis. there are some limitations of our study. firstly, this is a retrospective study. there was incomplete documentation of the history, symptoms, or laboratory findings in some cases, even after trying to feedback and recollect. secondly, as a retrospective and observational study, although this random forest model was validated in mild cases and additional fatal cases in henan province and 14 cases from wuhan and showed good predictive effects, there were few validators outside henan province. thirdly, imageology lacked objective judgment standards, and the investigators' judgment was subjective, which might lead to some bias. the raw data supporting the conclusions of this article will be made available by the authors, without undue reservation. the datasets generated for this study can be found here: https:// github.com/xiaoshubaba/covid-henan. the studies involving human participants were reviewed and approved by ethics committee from the first affiliated hospital of zhengzhou university. written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements. albumin 32.8 (30.2-37.6) at the same time, it could cause il-6 increase. this could be a reason for the low success rate of ecmo treatment. how to successfully apply ecmo in the treatment of covid-19 still requires further research. 52.7% of patients in the critical severe survivors applied crrt technology, while 33.33% patients in the non-survivors, suggesting that crrt could help improve the prognosis of covid-19. the application rate of glucocorticoids in the nonsurvivors was significantly higher than that in the mild and the severe survivors, which was consistent with other studies. references 1 characteristics of and important lessons from the coronavirus disease 2019 (covid-19) outbreak in china: summary of a report of 72,314 cases from the chinese center for disease control and prevention preliminary estimation of the basic reproduction number of novel coronavirus (2019-ncov) in china, from 2019 to 2020: a data-driven analysis in the early phase of the outbreak pathogenicity and transmissibility of 2019-ncov-a quick overview and comparison with other emerging viruses clinical course and risk factors for mortality of adult inpatients with covid-19 in wuhan, china: a retrospective cohort study clinical course and mortality risk of severe covid-19 new coronavirus pneumonia prevention and control program. 6th ed. national health commission of the pople's republic of china baseline characteristics and outcomes of 1,591 patients infected with sars-cov-2 admitted to icus of the lombardy region clinical characteristics of 113 deceased patients with coronavirus disease 2019: retrospective study a tool to early predict severe corona virus disease 2019 (covid-19): a multicenter study using the risk nomogram in wuhan and guangdong, china clinical characteristics of coronavirus disease 2019 in china clinical course and outcomes of critically ill patients with sars-cov-2 pneumonia in wuhan, china: a single-centered, retrospective, observational study risk factors associated with acute respiratory distress syndrome and death in patients with coronavirus disease 2019 pneumonia in wuhan, china clinical characteristics of refractory covid-19 pneumonia in wuhan, china prominent changes in blood coagulation of patients with sars-cov-2 infection clinical characteristics of 140 patients infected with sars-cov-2 in wuhan patients of covid-19 may benefit from sustained lopinavir-combined regimen and the increase of eosinophil may predict the outcome of covid-19 progression characteristics and outcomes of 21 critically ill patients with covid-19 in washington state referral to an extracorporeal membrane oxygenation center and mortality among patients with severe 2009 influenza a(h1n1) extracorporeal membrane oxygenation (ecmo): does it have a role in the treatment of severe covid-19 successful treatment of covid-19 using extracorporeal membrane oxygenation, a case report myocardial localization of coronavirus in covid-19 cardiogenic shock clinical evidence does not support corticosteroid treatment for 2019-ncov lung injury a predictive nomogram for predicting improved clinical outcome probability in patients with covid-19 in zhejiang province qz, ax, and zy made substantial contributions to conception, designed the study, had full access to all of the data in the study, take responsibility for the integrity of the data, and the accuracy of the data analysis. xm and al drafted the manuscript, critically revised the manuscript for important intellectual content, and gave final approval for the version to be published. xm, al, mj, qs, and xa did the data analysis. xm, al, mj, qs, xa, yf, hlia, jc, hli, jl, zr, rs, gc, yz, mc, lx, pj, and yw collected the data and checked the data. all authors agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. the authors are very grateful to all the investigators who collected the clinical data of this study. the authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.copyright © 2020 ma, li, jiao, shi, an, feng, xing, liang, chen, li, li, ren, sun, cui, zhou, cheng, jiao, wang, xing, shen, zhang, xu and yu. this is an open-access article distributed under the terms of the creative commons attribution license (cc by). the use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. no use, distribution or reproduction is permitted which does not comply with these terms. key: cord-268822-o86zpu92 authors: anser, muhammad khalid; yousaf, zahid; khan, muhammad azhar; sheikh, abdullah zafar; nassani, abdelmohsen a.; abro, muhammad moinuddin qazi; zaman, khalid title: communicable diseases (including covid-19)—induced global depression: caused by inadequate healthcare expenditures, population density, and mass panic date: 2020-08-18 journal: front public health doi: 10.3389/fpubh.2020.00398 sha: doc_id: 268822 cord_uid: o86zpu92 coronavirus (covid-19) is spreading at an enormous rate and has caused deaths beyond expectations due to a variety of reasons. these include: (i) inadequate healthcare spending causing, for instance, a shortage of protective equipment, testing swabs, masks, surgical gloves, gowns, etc.; (ii) a high population density that causes close physical contact among community members who reside in compact places, hence they are more likely to be exposed to communicable diseases, including coronavirus; and (iii) mass panic due to the fear of experiencing the loss of loved ones, lockdown, and shortage of food. in a given scenario, the study focused on the following key variables: communicable diseases, healthcare expenditures, population density, poverty, economic growth, and covid-19 dummy variable in a panel of 76 selected countries from 2010 through 2019. the results show that the impact of communicable diseases on economic growth is positive because the infected countries get a reap of economic benefits from other countries in the form of healthcare technologies, knowledge transfers, cash transfers, international loans, aid, etc., to get rid of the diseases. however, the case is different with covid-19 as it has seized the whole world together in a much shorter period of time and no other countries are able to help others in terms of funding loans, healthcare facilities, or technology transfers. thus, the impact of covid-19 in the given study is negatively impacting countries' economic growth that converts into a global depression. the high incidence of poverty and social closeness increases more vulnerable conditions that spread coronavirus across countries. the momentous increase in healthcare expenditures put a burden on countries' national healthcare bills that stretch the depression phase-out of the boundary. the forecasting relationship suggested the negative impact of the coronavirus pandemic on the global economy would last the next 10 years. unified global healthcare policies, physical distancing, smart lockdowns, and meeting food challenges are largely required to combat the coronavirus pandemic and escape from global depression. is spreading at an enormous rate and has caused deaths beyond expectations due to a variety of reasons. these include: (i) inadequate healthcare spending causing, for instance, a shortage of protective equipment, testing swabs, masks, surgical gloves, gowns, etc.; (ii) a high population density that causes close physical contact among community members who reside in compact places, hence they are more likely to be exposed to communicable diseases, including coronavirus; and (iii) mass panic due to the fear of experiencing the loss of loved ones, lockdown, and shortage of food. in a given scenario, the study focused on the following key variables: communicable diseases, healthcare expenditures, population density, poverty, economic growth, and covid-19 dummy variable in a panel of 76 selected countries from 2010 through 2019. the results show that the impact of communicable diseases on economic growth is positive because the infected countries get a reap of economic benefits from other countries in the form of healthcare technologies, knowledge transfers, cash transfers, international loans, aid, etc., to get rid of the diseases. however, the case is different with covid-19 as it has seized the whole world together in a much shorter period of time and no other countries are able to help others in terms of funding loans, healthcare facilities, or technology transfers. thus, the impact of covid-19 in the given study is negatively impacting countries' economic growth that converts into a global depression. the high incidence of poverty and social closeness increases more vulnerable conditions that spread coronavirus across countries. the momentous increase in healthcare expenditures put a burden on countries' national healthcare bills that stretch the depression phase-out of the boundary. the forecasting relationship suggested the negative impact of the coronavirus pandemic on the global economy would last the next 10 years. communicable diseases are not novel for the world; governments have learned from different infectious diseases in the past, such as human immunodeficiency virus (hiv), tuberculosis (tb), ebola, and spanish influenza a century before. the history of communicable diseases dates back much further, however we have only reported on the past 100 years. the 1918 influenza pandemic is considered to be one of the most deadly epidemics in recent history, which affected about one-third of the world's population, with a death toll of at least 50 million people globally. the list of communicable diseases is long, as more than 80 infectious diseases across the globe have been reported to date. the united states was largely affected by hemagglutinin type 1 and neuraminidase type 1 (h1n1) virus, where the death toll exceeded 670,000 people (1) (2) (3) . four decades later, the world was again hit by another communicable disease in 1957 with a new mutant influenza a, which is caused by an hemagglutinin type 2 and neuraminidase type 2 (h2n2) virus that spread from east asia, also called "asian flu." asian influenza -a is different from hini virus, as it is comprised of two different genes, i.e., hemagglutinin genes (h2), and neuraminidase (n2) genes. the virus was reported in singapore first in february 1957, and hit the us in the summer of the same year; the world death toll from this virus was 1.1 million people, out of which the death toll around 116,000 in the us, making it the worst hit affected country [(4-6), etc.]. the pandemic did not end as its mutation, caused by influenza -a (1968 pandemic), caused by a hemagglutinin type 3 and neuraminidase type 2 (h3n2) virus. this virus was comprised of h3 hemagglutinin and contained the n2 neuraminidase from asian influenza 1957. it was reported in the us in september 1968, and largely affected the older population; the median age was 65 years and above. the worldwide death toll exceeded 1 million and about 10% of the death toll was reported in the us alone. this virus continued to move worldwide as a seasonal flu that led to severe illness [(7-9), etc.]. this virus did not end, as in the spring of 2009, a new mutant influenza -a caused by h1n1 virus was detected in the us and quickly spread around the world. an estimated range of 151,700-575,400 people globally died from this pandemic virus infection in the first year. it is a seasonal virus that causes serious illness and increases hospitalizations and mortalities [(10, 11), etc.]. on may 12, 2009 , a(h1n1)pdm09 pandemic was detected in two imported cases in thailand, which increased up to 12 cases by the end of the month, and by july the virus had been transmitted and detected in all thai provinces, which increased the death toll up to 65. the pandemic waves followed two irregular interval periods, which started from may 2009, maxing out in july and falling in december, while the second wave began in early january 2010, maxing out in february and ending in april. in between the 2 year time period, around 234,050 registered influenza cases were reported in the country, 47,433 of which were confirmed virus patients with a(h1n1)pdm09 infections, and the death toll reached 347 (12) . the ebola outbreak that was experienced in west africa in march 2014, affected a number of affiliated bordering countries. more than 25,000 cases were registered and more than 10,000 deaths were reported with this virus. however, with unified healthcare policies and strengthening response capacities, the affected countries limited the transmission of the deadly disease in a given course of time [(13, 14) , etc.]. unified healthcare policies are desirable to improve countries' economic growth (15, 16) . in late december 2019, wuhan city in china detected a novel coronavirus (covid-19) that threatened human lives; to date (25th april, 2020) covid-19 has affected 2,831,915 people across 210 countries. the death toll exceeds 197,318 people, while the recovered cases are 807,037 across the globe (17) . the who has declared an alert about this global pandemic, which represents a large family of viruses and causes serve respiratory problems like sars, mers, etc. the covid-19 virus is a mutant strain of the coronavirus family, known as sars-cov-2. figure 1 shows the total death tolls reported in the five most affected countries by covid-19 for easy reference. since the emergence of coronavirus, a great amount of scholarly writing has been done on the given issue. for instance, lai et al. (18) collected a cross-sectional data of 1,257 healthcare workers working in 34 different chinese hospitals and analyzed their mental health states after handling coronavirus patients. the results suggested that, as healthcare workers are directly exposed to the coronavirus, there is a high need for physiological support and interventions to take care of frontline workers to reduce the symptoms of distress, insomnia, depression, anxiety, etc. phelan et al. (19) argued that coronavirus was spreading all over the world from china, thus there was a need to handle this outbreak with global healthcare governance and strategies, including surveillance, testing, treatments, cooperation, technology transfers, and healthcare information. wang et al. (20) discussed the early transmission channel of coronavirus in wuhan city in china by considering a single center case study of 138 patients infected with 2019 novel coronavirus (2019-ncov). the statistics show that the rate of patients administered to the intensive care unit (icu) were 26% of the total, while the death toll was 4.3%. the hospital associated human-to-human transmission rate was suspected to be 41%. the study concludes that the risk of transmission of coronavirus could not be analyzed as it was becoming increasingly dangerous as the weeks progressed. livingston and bucher (21) concluded that the coronavirus pandemic spread with an enormous rate despite aggressive control efforts. the study argued that the case-fatality ratio is higher in the elderly population, with a median age of more than and equal to 60 years. italy is highly infected with coronavirus, which is an issue that needs to be taken seriously and controlled with effective interventions and surveillance. torales et al. (22) reviewed the coronavirus associated studies and confirmed the psychological illnesses that were reported in the healthcare workers, suspected patients, and the general public. the results derived that the coronavirus outbreak is leading to additional health problems, including fear of death, anxiety, depression, insomnia, anger, etc. the need for efficient psychotherapy in suspected patients and counseling to the general masses would have a positive impact on reducing the risk of transmission of this disease. table 1 shows the recent pieces of literature on the interlinkages between the coronavirus pandemic and economic activities all across the globe. the study is important in the given circumstances, where coronavirus fear and depression have appeared around the world, creating chaos among community members as they seek remedial actions to get rid of the pandemic (33) . a few policy actions have been derived by the international community to prevent the epidemic, including maintaining physical/social distancing among community members, increasing healthcare expenditures, and reducing poverty and hunger. this study has included all these factors and has examined their impact on the country's economic growth, which considers a proxy for economic suffering leads to a depression. the epidemic proportionally affected developed and developing countries, therefore, the current studies included both developed and developing countries in a panel of 76 selected countries during 2010-2019. the outbreak of coronavirus creates many healthcare issues, including inadequate healthcare equipment, patents' facilitation centers, quarantine issues, fear, depression, and many other sanitation issues that cause the situation to worsen. the global depression phase becomes lengthier if these critical issues are unresolved. this study intended to explore the answers to the following critical questions: do communicable diseases, including covid-19, exert a greater magnitude of stress in terms of negatively affecting countries economic growth which then converts into global depression? the second question is whether high population density and poverty incidence may increase the length of the coronavirus pandemic around the globe? and finally, how may we reduce human suffering and death tolls from the coronavirus plague across countries? knowing the answers to these questions will aid in helping the world with the coronavirus outbreak and stabilize the world from depression. in a given context, the study prepared a set of research objectives to analyze global depression through some policy instruments, including healthcare expenditures, population density, and poverty incidence in a panel of 76 countries. the research objectives are: (i) to examine the impact of communicable diseases, including (covid-19), on a country's economic growth. 17 and 28% in the us and eu, respectively, is likely due to coronavirus. economic growth is expected to further decrease growth by 3. 8 and 6 .3% in the us and the eu, respectively. hasanat et al. malaysia e-business online business is affected by the coronavirus pandemic due to lockdown, low sales and purchase, less buying intensions, supply chain issues, fear, etc. odhiambo et al. kenya agriculture services, and the manufacturing sector due to the coronavirus outbreak, the agriculture sector decreased the share of 5.65% in total gdp, subsequently, tourism, construction, infrastructure development, and manufacturing dropped their share at around 1.35, 1.1, 2.06, and 0.85%, respectively. it is predicted that in the mild scenario, economic growth will drop in the range of between 3 and 6%, depending upon the country's profile, while in the given sample of 30 countries, the median drop in gdp is expected to be −2.8% in 2020. the service sector is also affected due to breakdowns in the supply chain process, which tends to decrease economic growth in the crisis period as expected between 2.5 and 3% per month. huang et al. china smes business due to the coronavirus pandemic, the smes sector has been badly affected and is highly dependent upon government support in terms of tax rebates, reduction in tax duties, provision of subsidies, flexible repayment of loan schedules, low interest rates, liquidity support, etc. wolf (28) worldwide economic growth macroeconomic policies would largely support country's economic growth during the crisis period associated with coronavirus bandyopadhyay (29) global evidences general discussion on economy the closure of educational institutions, travel restrictions, hospitality industry, financial, and related markets has caused economic declines across the globe. rodela et al. developing countries the coronavirus outbreak increases the high out-of-pocket healthcare expenditures that increases poverty incidences across countries. nseobot et al. nigeria trade due to the coronavirus outbreak, a unit decrease in oil price put a stress on the economic growth by 0.005 units. the death toll from coronavirus has not exceeded 3.4% globally, whereas the death rate increase by air pollution was about 7.6% in 2016 worldwide. due to lockdown, many polluting industries were temporarily shut down, which decreased n 2 o emissions and carbon emissions by 30 and 25%, respectively. (ii) to investigate the role of healthcare expenditures in reducing the coronavirus outbreak (iii) to observe the changes in poverty rates and population density due to the coronavirus pandemic on economic growth across countries (iv) to determine the inter-temporal relationship between the coronavirus pandemic and economic growth over a time horizon. these objectives have been set and analyzed by using sophisticated econometric techniques in order to reach some conclusive findings. the study used the following key factors that affect a country's economic growth and which turn into economic losses during the outbreak of communicable diseases, including covid-19. economic growth (denoted by eg) is used as a proxy variable for analyzing economic losses due to an emerging epidemic, which served as a response variable. the data of gdp per capita in constant 2000 us$ is used in the given analysis. the explanatory variables are as follows: poverty incidence (denoted by pi) is used to get an insight into the "mass panic" among the country's residents during the coronavirus pandemic, as poor populations are directly exposed to communicable diseases caused by a lack of knowledge, low/no direct income, persistent unemployment, and inadequate healthcare facilities. this restlessness then creates more panic during the emergence of the epidemic that negatively affects the country's economic growth. the headcount ratio in percentage form is used for this reason. covid-19 (denoted by covid-dum) is used to assess the magnitude and the intensity of coronavirus that largely increases due to high social contact between the population members, as this virus easily spreads through close contact in the community, like, handshaking, sneezing, coughing, touching, etc., hence it is highly possible to get infected with the virus when people per square km of the land area are living in compact places. thus, the covid-dum is formed and assigned values of 1 and 0. the covid-dum value 1 represents the likely occurrence of coronavirus when the population density is in triple digits (i.e., 100 people per square km of land area) and 0 represents otherwise. the covid-dum data is extracted from the data set of population density (denoted by pd), which is further included in the regression estimates to get more insight into social distancing. the data of deaths caused by communicable diseases (denoted by cd) as a percentage of total deaths and per capita healthcare expenditures (denoted by he) as in us$ is added to the study to minimize the probability of omission bias problems in the given model. further, both the variables have important policy implications on the country's economic growth that can be used to assess global depression caused by insufficient healthcare expenditures, which links to the increasing cause of deaths by communicable diseases including . table a in the appendix shows the list of sample countries used in the study, which covered a period of 2010-2019. the data is taken from world bank (34) and povcal net database. the strong viability of regressors and regressand in the given context need an empirical model that would facilitate answering the causes of global depression associated with high communicable diseases including covid-19. the study utilized a traditional solow growth model that considers a starting point for any growth-specific modeling, i.e., where y shows economic output, l shows labor stock, k shows capital investment, t shows technology, i and t show crosssections and time period, and ε shows error term. equation (1) shows the conventional style solow growth model that comprises labor, capital, technology, and their resulting impacts on economic output. further, the moderation effect of technology with labor and capital stock shows the labor-augmented technology and capital-augmented technology that would increase many times to the output through a multiplier effect. equation (1) is modified and extended by the given set of parameters in order to get fresh insight into the real-time issue faced by the world regarding the coronavirus pandemic, i.e., where eg shows economic growth, comd shows communicable diseases, he shows healthcare expenditures, pd shows population density, pi shows poverty incidence, covid-dum shows covid dummy, i and t show 76 countries and time period from 2020 to 2019. equation (2) shows that it is likely that communicable diseases, including covid-19, will increase economic suffering in the form of decreasing a country's economic output that will have a negative impact on the globalized world, which causes global depression. the other factors, including healthcare expenditures, population density, and poverty incidence, would likely place more pressure on economic output because of insufficient healthcare resources, highly-dense populations, and poverty and hunger. these factors are crucial and need a fair assessment in order to devise strong policies to reduce economic suffering caused by the coronavirus and other factors to lessen global depression through economic opportunities. figure 2 shows the research framework of the study. figure 2 shows the different causes of global depression that are interconnected with poverty incidence, communicable diseases, population density, and healthcare resources. the blend of efficient healthcare, economic, social, and environmental policies are largely desirable to escape from this pandemic with the adoption of curative and preventative policies across the globe. the stated objectives need to be checked by sophisticated econometric techniques to get fresh evidence about global depression due to the outbreak of coronavirus. the study employed a differenced panel gmm estimator. this technique is utilized on longitudinal data sets where the cross-section identifiers are greater than the time period that is used in this study, i.e., cross-sections consist of 76 selected countries while data is used from 2010 to 2019. the second reason is that the differenced gmm estimator controls for possible endogeneity issues and serial correlation issues from the model. third, it includes the dynamic nature of the regressand in the list of regressors, where the regressand is included with the regressors to analyze the initial convergence in the growth model. fourth, the list of regressors can be further utilized as instrumental variables added by their first lagged, hence it can control for possible endogenous issues and autocorrelation issues in the model, and finally, the validity of using regressors as an instrumental variable by their first lagged is a real challenge to check whether the given instruments are reliable or not. for this purpose, the j-statistic and instrumental ranks are used to determine its validity. these features give clear distinctions from the rest of the instrumented techniques, for instance, simple ols, two-stage least squares, three-stage least squares, and simple gmm estimates with fixed and random effect. further, the study benefits from using the innovation accounting matrix that consists of two basic inter-temporal techniques, i.e., impulse response function (irf) and variance decomposition analysis (vda). the technique is based upon both the var specifications and determined by the shocks pertaining to the regressand by their set of regressors over a time horizon. thus, it specified the nature and magnitude of the explanatory factors to the outcome variable in forecasting apparatus. the statistics clearly show that the panel consists of all the representatives of the countries across the globe where highincome to low-income countries have been included in the given model to give equal rank to all of them without any special attention. this uniqueness gives reliable estimates and provides evidence for both sides of the coin. the maximum count of deaths caused by communicable diseases is about 71.500% of total deaths, with a mean value of 13.078 %. poverty incidence shows the maximum value of 72.3% with a mean value of 15.395%. the data of covid-19 dummy is extracted from the population density data, as population density shows that the selected panel of countries has a high to low dense population data; the highest value is 2017.274 people per square km of land area while the lowest value is 1.750. thus, on the basis of ranking the population density data, the covid-dum is assigned a value 1 to those countries where the population density is more than and equal to three digits, i.e., 100, while 0 is assigned otherwise. the mean value of covid-dum shows 0.349, which depicts that on average 35% of the countries in the selected panel have a population density that is more than or equal to three digits, while 65% of countries have a population compactness that is limited to two digits. table 3 shows the differenced panel gmm estimates and found that communicable diseases other than coronavirus increase the country's economic growth in the form of receiving aid and other technology transfers from the rest of the world. this aid has controlled or reduced the intensity of some infectious diseases, like ebola, hepatitis, flu, tuberculosis, measles, rabies, zika, etc. however, the novel coronavirus has largely affected the whole world and the world's biggest economies, including the united states and other european countries that [ the results of this study further show that healthcare expenditures enormously increase in a given scenario that after obtaining the parameter estimates of the studied coefficients, there is a greater need for exploring the forecasted (inter-temporal) relationship between the stated variables for the next 10 years. for this purpose, the study used innovation accounting matrix, which is based upon two innovative functions, impulse response function (irf) and variance decomposition analysis (vda). the irf estimates assist to identify the direction of the stated variables that could be seen by various economic and healthcare shocks over a time horizon. on the other side, the vda estimates showed the magnitude of the candidate variables on the response variable over time. thus, both innovation estimates help to determine future preventive strategies to minimize the covid-19 pandemic across countries. table 4 shows the irf estimates for easy reference. the estimates show that communicable diseases and healthcare expenditures will likely increase countries' economic growth over a time horizon, whereas population density and covid-19 will mainly increase economic suffering in the form of decreasing economic output for the next 10 years. the poor income group experience decreased economic growth up to 2023 however, after 2023 it countries' economic growth begins to increase due to increased income inequality across countries. the rest of the effects can be seen in figure 3 for easy reference. table 5 shows the vda estimates and suggests that population density will exert a greater magnitude on countries' economic growth with a standard error shock of 5%, followed by healthcare expenditures, covid-19, and communicable diseases, while poverty incidence will have the least effect on countries' economic growth over a time horizon. the complete description can be visualized in figure 4 . the world has been relentlessly affected by the outbreak of this deadly coronavirus, even though it is still only developing. in this study, a number of important factors have been identified, which might help researchers and policy makers to understand the emerging global depression. this study has selected a panel of 76 developed and developing countries in order to examine the vulnerabilities caused by coronavirus across all the segments of society. the overall results come to the following policy conclusions: (i) communicable diseases, including covid-19, largely increase economic suffering through the increased demand for healthcare infrastructure, exacerbated by poverty incidence and social compactness. thus, the need for healthcare technology transfers from developed to developing countries, fund allocation for poor nations to reduce global inequality which would help them out from poverty, hunger, and diseases, and smart cities planning with them about symptomatic treatment and immunity boosters to get an increased chance of early recovery from this infectious disease. (viii) population mixing is the main transmission route of spreading coronavirus from one person to another, thus there is a high need to raise awareness among community members to avoid massive gatherings. the government should have to take some initiatives for providing homebased jobs and given them enough salary to convince the massive population to stay at their homes. (ix) extreme physical distancing options, including school closures, business closures, and travel restrictions, may result in a few early achievements as they raise awareness in the community about how to avoid this infectious disease, however, if these strategies are delayed, these activities should be substituted by other options, like online teaching, work at home, meetings conducted online, risk management, online training programs, and other social programs that a person can be engaged with and learn new things to resettle his/her self quickly in a new mode. (x) the lower-income strata group will largely suffer from this pandemic due to low awareness, inadequate healthcare resources, unemployment, illiteracy, the absence of social safety net programs, a lack of voice, etc., and all these vulnerabilities will largely victimize poor people more than non-poor. thus, there is a greater need to support poorer countries through cash transfer programs. the provision of basic food material, basic healthcare services, sanitation facilities, and proper counseling and guidance would minimize the risk of spreading infectious disease. it is a reality in a given context that social/physical distancing and smart lockdowns exert a positive health effect, but these measures have potentially caused more economic suffering that will lead to a global depression. the disruption of the supply chain, fear of business losses, supply-demand production gap, and the global healthcare crisis will make this episode more painful. the need for joint global efforts, unified economic and healthcare policies, and subsidized economic sectors may decrease the intensity of the global depression and progress toward the eradication of the coronavirus. the basic limitation of the current study is inadequate data availability for covid-19; hence, the study selected given countries on the basis of the country's economic growth per capita. the impact of covid-19 on case per million and death per million is also important, which can be further explored in future studies. data is freely available at the world development indicators, published by the world bank. https://databank.worldbank.org/ source/world-development-indicators. mka: conceptualization, methodology, and supervision. zy: software and formal analysis. mk: resources. an: formal analysis, writing-reviewing, and editing. mmqa: visualization. kz: data curation and validation. all authors: contributed to the article and approved the submitted version. pandemic influenza: public health preparedness for the next global health emergency britain and the 1918-19 influenza pandemic: a dark epilogue the origin and virulence of the 1918 "spanish" influenza virus an update on swine-origin influenza virus a/h1n1: a review avian influenza a (h5n1) the next influenza pandemic: lessons from hong kong avian-to-human transmission of the pb1 gene of influenza a viruses in the 1957 and 1968 pandemics impact of influenza vaccination on seasonal mortality in the us elderly population h1n1 influenza detection of molecular markers of drug resistance in 2009 pandemic influenza a (h1n1) viruses by pyrosequencing lessons learned from influenza a (h1n1) pdm09 pandemic response in thailand ebola viral disease outbreak-west africa the spread of the ebola virus disease and its implications in the west african sub-region health care expenditure and economic growth in saarc countries (1995-2012): a panel causality analysis modeling determinants of health expenditures in malaysia: evidence from time series analysis covid-19 coronavirus pandemic factors associated with mental health outcomes among health care workers exposed to coronavirus disease 2019 the novel coronavirus originating in wuhan, china: challenges for global health governance clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in wuhan coronavirus disease 2019 (covid-19) in italy the outbreak of covid-19 coronavirus and its impact on global mental health becker friedman institute for economics working paper the impact of coronavirus (covid-19) on e-business in malaysia modeling kenyan economic impact of corona virus in kenya using discrete-time markov chains economic effects of coronavirus outbreak (covid-19) on the world economy saving china from the coronavirus and economic meltdown: experiences and lessons covid-19 coronavirus and macroeconomic policy coronavirus disease 2019 (covid-19): we shall overcome economic impacts of coronavirus disease (covid-19) in developing countries covid-19: a situation analysis of nigeria's economy the dramatic impact of coronavirus outbreak on air quality: has it saved as much as it has killed so far? does communicable diseases (including covid-19) may increase global poverty risk? a cloud on the horizon world development indicator europe: how do the outbreak patterns compare? the new york times us overtakes china as country with most covid-19 cases available online at what happens when it hits the poor ones? 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report. world health organization the economic impact of coronavirus could worsen food security for the world's hungry people disproportionately hurt the poor-and that's bad for everyone as coronavirus deepens inequality, inequality worsens its spread. the new york times researchers supporting project number (rsp-2020/87), king saud university, riyadh, saudi arabia. the authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.copyright © 2020 anser, yousaf, khan, sheikh, nassani, abro and zaman. this is an open-access article distributed under the terms of the creative commons attribution license (cc by). the use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. no use, distribution or reproduction is permitted which does not comply with these terms. key: cord-331558-6rqd3fmj authors: sun, chuan-bin; wang, yue-ye; liu, geng-hao; liu, zhe title: role of the eye in transmitting human coronavirus: what we know and what we do not know date: 2020-04-24 journal: front public health doi: 10.3389/fpubh.2020.00155 sha: doc_id: 331558 cord_uid: 6rqd3fmj the outbreak of the current 2019 novel coronavirus (2019-ncov, now named sars-cov-2) infection has become a worldwide health threat. currently, more information is needed so as to further understand the transmission and clinical characteristics of 2019-ncov infection and the infection control procedures required. recently, the role of the eye in transmitting 2019-ncov has been intensively discussed. previous investigations of other highly infectious human covs, that is, severe acute respiratory syndrome coronavirus (sars-cov) and the middle east respiratory syndrome coronavirus (mers-cov), may provide useful information. in this review, we describe the genomics and morphology of human covs, the epidemiology, systemic and ophthalmic manifestations, and mechanisms of human cov infection, and recommendations for infection control procedures. the role of the eye in the transmission of 2019-ncov is discussed in detail. although the conjunctiva is directly exposed to extraocular pathogens, and the mucosa of the ocular surface and upper respiratory tract are connected by the nasolacrimal duct and share the same entry receptors for some respiratory viruses, the eye is rarely involved in human cov infection, conjunctivitis is quite rare in patients with 2019-ncov infection, and the cov rna positive rate by rt-pcr test in tears and conjunctival secretions from patients with 2019-ncov and sars-cov infection is also extremely low. this suggests that the eye is neither a preferred organ of human cov infection nor a preferred gateway of entry for human covs for infecting the respiratory tract. however, pathogens that the ocular surface is exposed to might be transported to nasal and nasopharyngeal mucosa by constant tear rinsing through the lacrimal duct system and then cause respiratory tract infection. considering that close doctor-patient contact is quite common in ophthalmic practice and is apt to transmit human covs by droplets and fomites, strict hand hygiene and proper personal protection are highly recommended for health care workers to avoid hospital-related viral transmission during ophthalmic practice. coronavirus (cov) is an enveloped single-stranded positive-sense rna virus that typically causes respiratory and enteric infections affecting both human and wild animals (1) (2) (3) . since first being identified in the 1960s, human covs were considered relatively benign and usually caused mild upper respiratory tract infections (the common cold) until the emergence of the severe acute respiratory syndrome coronavirus (sars-cov) in 2002 and, later, the middle east respiratory syndrome coronavirus (mers-cov) in 2012 (4) . the latter two covs can result in severe lower respiratory tract infection, rapidly proceeding to pneumonia, and have caused thousands of cases of infection and hundreds of deaths in about 30 countries, respectively (2, 4) . in december 2019, another outbreak of highly infectious pneumonia caused by a novel coronavirus (2019-ncov, now named as sars-cov-2) emerged in wuhan, china, and soon became a major global health threat (2, 3) . currently, more detailed information about the transmission of 2019-ncov is urgently needed to prevent its pandemic spread. human covs mostly spread through respiratory droplets expelled by infected individuals and direct contact with viruscontaminated fomites (4) . anatomically, the conjunctiva of the eye is easily exposed to infectious droplets and fomites during close contact with infected individuals and contaminated hands. some respiratory viruses such as human adenovirus (species d) and avian influenza virus (h7) frequently cause highly infectious conjunctivitis or keratoconjunctivitis. hence, conjunctiva is postulated to be an important portal of entry for respiratory viruses, while tear and conjunctival secretions may contain virus and spread viral infection (4, 5) . however, the role of the eye in the transmission of human covs is still under discussion, as considerable controversy exists. this review presents the genomics and morphology of human covs, the epidemiology, systemic and ophthalmic manifestations, and mechanisms of human cov infection, and the role of the eye in the transmission of human covs. infection control procedures and personal protective equipment against human cov transmission in ophthalmic practice are also reviewed. covs have an enveloped single positive-strand rna genome with a 5 ′ -terminal cap structure and a poly(a) sequence at the 3 ′ end. cov genome is approximately 30 kb (27∼32 kb) long and is the largest rna genome known so far (1, 4, 6) . covs belong to the family coronaviridae and the order nidovirales and are classified into four genera: α-cov, β-cov, γ-cov, and δ-cov (1, 6, 7) . until now, a total of seven human covs have been identified, namely hcov-229e, hcov-nl63, hcov-oc43, hcov-hku1, sars-cov, mers-cov, and, recently, 2019-ncov (1-3, 6-8). the former two human covs belong to the genus α-cov, and the latter five human covs belong to the genus β-cov. three recently identified human covs, that is, sars-cov, mers-cov, and 2019-ncov, have been recognized as zoonotic viruses, which transmit between animals and human. recent studies revealed that sars-cov was transmitted from civet cats to humans, mers-cov from dromedary camel, and 2019-ncov (probably) from pangolin (1, 2, (6) (7) (8) (9) . recent investigations indicated that bats were most probably the natural reservoir of sars-cov, mers-cov, and 2019-ncov (1, 6, (9) (10) (11) . genome sequence analysis revealed that 2019-ncov was distinct from sars-cov (about 79% identity) and mers-cov (about 50% identity) yet more closely related to sars-like-covs (about 88% identity) in bats (10, 11) . cov particles have a spherical or elliptical shape with a diameter of about 100 nm (50∼200 nm). they carry three major structural proteins in the envelope and contain a helical nucleocapsid formed by the viral genomic rna and the viral nucleoprotein. the viral spike protein has receptor-binding and fusogenic functions and is essential for initiation of cov infection (1, 8, (12) (13) (14) . further three-dimensional structure analyses suggest that the spike protein is composed of two subunits: s1, which mediates sars-cov binding to receptors on host cell membranes, and s2, which triggers the membrane fusion between the virus and host cells (11, 13) . four human covs, that is, hcov-229e, hcov-nl63, hcov-oc43, and hcov-hku1, are usually low in infectiousness and primarily infect the upper respiratory tract, causing mild respiratory symptoms (the common cold), whereas the other three human covs, sars-cov, mers-cov, and 2019-ncov, are zoonotic and highly infectious and predominantly cause severe lower respiratory tract infection which can rapidly proceed to pneumonia (1-3, 8, 15, 16) . the outbreak of sars in 2002 in china resulted in 8,098 cases and 774 deaths (case-fatality rate, 9.6%) in 37 countries, and the outbreak of mers in 2012 in middle east countries led to 2,494 cases and 858 deaths (case-fatality rate, 34%) in 27 countries (2) . as of february 24, 2020, 2019-ncov has caused 77,262 cases and 2,595 deaths in china, and 2,069 cases and 23 deaths in 29 other countries (total case-fatality rate, 3.3%) (15) (16) (17) . hence, although 2019-ncov can cause a severe respiratory disease like sars and mers, it appears to be less pathogenic than sars-cov and much less so than mers-cov. however, the number of 2019-ncov infected patients in the first two months was nearly 10 times that of sars patients in total, which indicated that 2019-ncov is more transmissible than sars-cov and mers-cov (16) . human covs primarily spread by virus-containing droplets or aerosols expelled by infected individuals when patients cough, talk loudly, or sneeze. direct contact with virus-contaminated fomites is also a route of human cov transmission (4, 8, (18) (19) (20) . recently, sars-cov and 2019-ncov have also been detected in stool and urine samples from patients by rt-pcr assay and have been isolated from the mucous membranes of gastrointestinal tract in a few cases (9, 16, 21) . hence, fecal-oral route may also be a route of transmission for sars-cov and 2019-ncov. the clinical features of coronavirus disease 2019 (covid-19) are similar to those of sars and mers. most patients present with fever, dry cough, dyspnoea, and bilateral ground-glass opacities on chest ct scans (2, 3, (22) (23) (24) . however, covid-19 rarely results in notable symptoms of upper respiratory tract infection (e.g., rhinorrhea, sneezing, or sore throat), which are commonly manifested in sars and mers. some covid-19 patients even manifest no apparent respiratory symptoms at onset, which never occurred in sars and mers (24) (25) (26) . mathematical models have revealed that the 2019-ncov virus may replicate very slowly in the first days after infection and that it could be below detection levels during the first four days post infection (26) . recent investigations have also revealed that covid-19 occasionally manifests as enteric infection symptoms such as diarrhea, whereas about 20∼25% of patients with mers or sars had diarrhea (25) . moreover, more than 80% of covid-19 has manifested as mild or moderate pneumonia, and the severe covid-19 has mostly occurred in the patients of over 60 years old, usually accompanied by at least one underlying disorder, for example, cardiovascular disorders, diabetes, chronic obstructive pulmonary disease, and hypertension (24) . the eye is rarely involved in human cov infection. until now, conjunctivitis has been reported in only five cases with 2019-ncov infection, and in four cases with hcov-nl63 infection, whereas no conjunctivitis or other ocular complications have been reported in patients with sars-cov and mers-cov infection (4, (27) (28) (29) (30) (31) . recently, human cov rna in tears and conjunctival scraping samples were tested by reverse transcription-polymerase chain reaction (rt-pcr) assay in patients with sars and covid-19, yet the positive rate of the rt-pcr test was extremely low (4, 30-37). loon and colleagues detected sars-cov in tear samples from 36 consecutive sars suspects (eight patients were laboratoryconfirmed later) by rt-pcr (32). sars-cov was positive only in three of the eight sars cases. three patients whose tears were sars-cov positive were sampled in the early phase of their illness (on days 3, 4, and 9 after onset of fever, respectively), whereas the other five sars cases, whose tears were sars-cov negative, were sampled in the later phase (mean 19.4 days) of their illness (32) . nearly at the same time, chan and colleagues reported their negative results of sars-cov testing in tear and conjunctival scraping samples from 20 probable sars patients (17 patients were laboratory-confirmed later) by rt-pcr and virus culture (33) . among 17 confirmed sars patients, 6, 8, and 3 cases were recruited during the first, second, and third week of their diseases, respectively. sars-cov rna was not detected by rt-pcr and sars-cov was not isolated in virus culture in any of the tear and conjunctival scraping samples (33) . leong and colleagues tested for sars-cov in 126 conjunctival specimens from 64 sars patients in the convalescent phase by rt-pcr but did not detect sars-cov in any of the patients' conjunctival samples (22) . on january 22, 2020, a chinese respiratory specialist who visited wuhan as a member of the national expert panel on pneumonia claimed that he was infected by 2019-ncov despite being fully gowned with a protective suit and n95 respirator (34) . his first clinical manifestation was unilateral conjunctivitis, followed by fever and catarrhal symptoms 2 or 3 h later. he postulated that 2019-ncov probably first infected the conjunctiva, then spread and cause viral pneumonia (34) . soon after his report, health care personnel in china were urged to use eye protection when they were in close contact with covid-19 patients or suspected patients. however, zhou and colleagues, in a preprint posted at medrxiv, reported that conjunctivitis was identified only in one patient out of 63 covid-19 cases and 4 suspected covid-19 cases (27) . conjunctivitis was also the first symptom of 2019-ncov infection in this patient. however, 2019-ncov rna tested by rt-pcr was positive and probably positive in conjunctival swab samples from only one and two covid-19 cases without conjunctivitis, respectively. none of the above three patients had ocular symptoms. 2019-ncov rna was not detected in conjunctival swab samples from the covid-9 patient complicated by conjunctivitis, who was an anesthesiologist. her ocular symptoms occurred soon after performing tracheal intubation for a patient who was confirmed as having covid-19 later, and this was followed by fever and cough. unfortunately, the personal protections used by this anesthesiologist during the tracheal intubation procedures were only a surgical mask, cap, and gloves, without a gown, face shield or goggles. her five colleagues were also infected by the same patient, yet none of them exhibited any ocular complications (27) . more recently, two investigative groups from china simultaneously reported conjunctivitis and 2019-ncov rnapositive tests in conjunctival swab samples from covid-19 patients (28, 31) . zhang and colleagues, in a preprint posted at medrxiv, reported conjunctivitis in two patients out of 72 laboratory-confirmed covid-19 cases; however, 2019-ncov was detected in conjunctival swab samples by rt-pcr in only one patient who was a nurse working in the emergency department (28) . this patient presented with excessive tearing and redness in both eyes, which were typical ocular manifestations of viral conjunctivitis, accompanied by a moderate fever of 38.2 • c that occurred 1 day earlier. 2019-ncov rt-pcr tests for the conjunctival and oropharyngeal swabs sampled 2 days after the onset of fever was positive, but for those sampled 9, 18, and 20 days after the onset of fever were all negative (28) . xia and colleagues reported unilateral conjunctivitis in one patient out of 30 confirmed covid-19 cases; conjunctival swabs sampled from this patient 3 and 5 days after the onset of covid-19 were both positive for 2019-ncov by rt-pcr, whereas 58 conjunctival swab samples from the other 29 covid-19 patients were all negative for 2019-ncov (31) . however, 2019-ncov was not isolated and cultured in the conjunctival swab samples from the covid-19 patient with conjunctivitis. in contrast, 55 of the 60 sputum samples from 30 covid-19 cases showed positive pcr results for 2019-ncov (31) . although tears have been reported by the world health organization in 2003 to be one of the body fluids that might contain sars-cov, the infectivity and clinical importance is not yet understood (35) . recent investigations have revealed that highly infectious human covs (mainly sars-cov and 2019-ncov) are rarely detected by rt-pcr and never isolated by virus culture in tears and conjunctival secretions from sars and covid-19 patients (27) (28) (29) (30) (31) (32) (33) (34) 36) . hence, it is hard to assess the infectivity of tears and conjunctival secretions and their roles in virus transmission. the extremely low positive rate of human cov rna test by rt-pcr in tears and conjunctival secretions from patients with sars and covid-19 may have several interpretations. firstly, the sensitivity of rt-pcr testing still needs to be improved. previous reports on the sensitivity of rt-pcr in excretions reported a range from 50% to 60% (33, 37) . in current clinical practice, some suspected 2019-ncov cases often had 2∼3 repeated tests of nasopharyngeal swabs before the positive results were obtained (28) . the need remains for a highly sensitive and specific pcr test to diagnose human cov infections. secondly, the samples were not collected at the right time. recent evidence indicated that human cov rna-positive cases were all sampled in the early part of the disease course, whereas human cov rna-negative cases sampled in the later or convalescent phase of their illness (33) . de wit and colleagues demonstrated that, based on their rhesus macaque model study, mers-cov rna could be detected in the conjunctiva only within 6 days post infection (38) . hence, it is reasonable to postulate that human cov may present in tears only for a short period during the early phase of the disease. thirdly, the contribution of antimicrobial agents, including lactoferrin and secretory iga, in tears and constant tear rinsing, which continuously eliminates the virus on the ocular surface into the nasal cavity through the nasolacrimal duct (37, 39, 40) , should be considered. lactoferrin can inhibit the binding of sars-cov to its entry receptor, angiotensin-converting enzyme 2 (ace2), by preventing the adhesion of sars-cov to its attachment receptor, heparan sulfate proteoglycans (hspgs) (41) . secretory iga is another important antimicrobial agent in tears that helps to kill both bacteria and viruses. the host immune system can be activated and result in a significant increase in lactoferrin and secretory iga levels in tears and circulating igm level in plasm on the 3rd to 5th day and circulating igg level in plasm on the 10th to 15th day after cov infection or inoculation (39, 41) , which may contribute to why cov rna presents only in the early phase of the disease. fourthly, the collection technique may not appropriate. the world health organization highly recommends the use of only synthetic fiber swabs with plastic shafts rather than calcium alginate swabs or swabs with wooden shafts for specimen sampling, as the latter two types of swabs may contain substances that inactivate some viruses and inhibit pcr testing (40) . topical anesthesia is also not recommended for tear and conjunctival scraping sampling, for a topical anesthetic agent maybe also have a negative influence on the viability of viruses (40) . moreover, the volume of tears collected when sampling may also have some influence on the positivity of the rt-pcr test. anatomically, the mucosa of the ocular surface (i.e., conjunctival and corneal epithelia) and the upper respiratory tract are connected by the nasolacrimal duct (4). when dropped into the eye, liquid is partially absorbed by the cornea and conjunctiva but mostly drained into the nasal cavity through the nasolacrimal duct and then transported toward the lower part of the respiratory tract, including the nasopharynx and trachea, or swallowed into the gastrointestinal tract (37) . this allows pathogens to which the eye is exposed to be transported to respiratory and gastrointestinal tract mucosa. moreover, previous investigations have revealed that the mucosa of the ocular surface and respiratory tract share the same receptors for some respiratory viruses (4, (42) (43) (44) . ace2, the entry receptor of sars-cov, hcov-nl63, and 2019-ncov, is highly expressed on human lung alveolar epithelial cells, enterocytes of the small intestine, and the proximal tubular cells of the kidney (4, 42) . positive expression of ace2 was also detected in human conjunctival and corneal epithelial cells; however, ace2 expression in human ocular surface is much lower than in human lung and kidney tissues (43) . the binding capability of ace2 protein on conjunctival epithelial cells to sars-cov spike protein is much lower than that on vero e6 cells and that in lung tissues (44) . the efficacy of virus entry into host cells depends on three points: the invasiveness of the virus, viral receptors on host cell membrane, and the immune conditions of the host. the virus binding to host cell membrane by its receptors is the first and key step for viral invasion. ace2, a metallopeptidase, also the entry receptor of sars-cov, hcov-nl63, and 2019-ncov, is responsible for binding to spike protein on the sars-cov and hcov-nl63 surface and mediating sars-cov and hcov-nl63 entry into host cells (4, 11, (42) (43) (44) (45) , while mers-cov and most α-covs have been identified to utilize dipeptidyl peptidase 4 and aminopeptidase n as an entry receptor of their host cells, respectively (46) . further investigations have revealed that the invasion of sars-cov and hcov-nl63 into host cells not only relies on the presence of ace2 on host cell membrane as an entry receptor but also is modulated by other factors on host cell membranes such as hspgs, which serve as attachment receptors (40, 45, 47) . at present, the mechanism of human cov invasion into host cells is still not clear. lang and milewska described the possible mechanism of ace2-mediated host cell entry for sars-cov and hcov-nl63 virus (41, 45, 47) . first, the virus docked and bound to host cells by the interaction between the spike protein on viral surface and heparan sulfate chains of hspgs on host cell membrane. this action facilitated further binding of spike protein on viral surface to its entry receptor, ace2, on host cell surface. then, the binding of spike protein of the virus to ace2 protein of host cell membrane triggered the recruitment of clathrin, followed by clathrin-mediated dynamindependent endocytosis of viral particles, which required actin cortex remodeling (39, 45, 47) . considering the 2019-ncov has similar spike protein to sars-cov, and also uses ace2 as its entry receptor to infect host cells, it is reasonable to presume that 2019-ncov has the same invasive strategy for host cell entry as sars-cov and that hspgs may also act as attachment receptors during the entry of 2019-ncov into its host cells. patients infected by 2019-ncov, similar to sars cases, mostly present with non-specific symptoms such as fever, dry cough, and dyspnoea, or, in some cases, no evident symptoms, at the early phase of the disease (9, 16, (23) (24) (25) (26) (27) 48) . hence, it is a challenging task for health care professionals in the northern hemisphere to distinguish early 2019-ncov infection from influenza and other respiratory viral infections in the seasons of winter and spring when respiratory diseases frequently break out (48) . hospitalrelated viral transmission, especially transmissions between patients and health-care workers, is frequently reported just before the outbreak of a highly infectious novel respiratory virus such as sars-cov and 2019-ncov (8) . previous investigations have revealed that patients infected by a novel virus never identified before can easily transmit the pathogen to health personnel without enough personal protection; the latter getting infected will further become a source of spread and soon cause hospital-related viral transmission (8, (49) (50) (51) (52) (53) . in fact, 386 of 1,755 patients (21.9%) and eight deaths were health-care workers during the sars outbreak (49) . as of february 11, 2020, a total of 3019 medical health workers have been infected by 2019-ncov in china, among whom 1,716 cases were laboratoryconfirmed covid-19, and five cases passed away, including an ophthalmologist named wenliang li, the whistleblower of 2019-ncov infection in china (9, 16) . at present, the physicochemical properties of 2019-ncov are not yet clear. based on previous experience in sars-cov and mers-cov infection control, it is postulated that 2019-ncov is sensitive to ultraviolet irradiation and heating. sterilization can be achieved by heating at 56 • c for 30 min and by lipid solvents including 75% ethanol, chlorine-containing disinfectant, peroxyacetic acid, and chloroform but not by chlorhexidine (50) (51) (52) . many ophthalmic instruments, i.e., probes for atype and b-type ultrasound, ocular contact lenses such as the goldmann three-mirrored lens and gonioscope, trial frames, slitlamp microscope, direct ophthalmoscope, automatic perimeter, and fundus camera, are frequently used by direct or close contact with patients and may act as media for virus spread. a non-contact tonometer may create an aerosol when measuring intraocular pressure by punching air onto the cornea of patients; hence, it may also facilitate virus spread by aerosol transmission. therefore, complete sterilization by 75% ethanol or hydrogen peroxide cleaning or immersion should be performed soon after each use of above the ophthalmic instruments (50) (51) (52) . complete sterilization using chlorine-containing disinfectant, peroxyacetic acid, and hydrogen peroxide is mandatory for clinics and operating rooms. hand washing, preferably with the use of chlorhexidine alcoholic hand rub, after each ophthalmic examination or therapeutic procedure is highly recommended for the prevention of cross-infection. routine ophthalmic examinations such as slit-lamp examination and direct ophthalmoscopy are all performed by close contact, which means that the ophthalmologists can easily be exposed to the droplets and tears or ocular secretions from, or to the ophthalmic instruments contaminated by, patients with or suspected of having sars, mers, or covid-19. hence, strict hand hygiene and proper personal protection equipment, including masks, gowns, gloves, and goggles, are highly recommended to avoid hospital-related viral transmission during ophthalmic practice (49) (50) (51) (52) (53) . when an ophthalmologist examines general ophthalmic outpatients, primary personal protection with disposable cap, surgical mask, and gown is recommended. when high-risk procedures are performed on these patients, for example, direct ophthalmoscopy, lacrimal irrigation and probing, intraocular pressure measurement with non-contact tonometry, ophthalmic laser therapy, and ophthalmic surgeries, n95 respirator, gloves, and goggles or face shield, are highly recommended (50) . for patients with confirmed or suspect sars, mers, or covid-19, any ophthalmic consultation should be completed within the quarantine ward to avoid cross-infection. personal protective equipment, including disposable caps, n95 respirator, goggles, face-shields, gloves, top and pants, and protective gowns, should be worn at all times (51, 53) . moreover, hand washing, preferably with the use of a chlorhexidine alcoholic hand rub, and gloves changed after each high-risk procedure are mandatory to prevent crossinfection. ophthalmic personnel are also recommended not to touch their goggles, face shield, surgical/n95 mask, eye, head, and neck region before the handwashing procedure is completed (51, 53) . non-urgent ophthalmic operations and interventions, for example, cataract operations, ophthalmic plastic surgeries, squint extraocular muscle surgeries, intravitreal anti-vegf injection, retinal photocoagulation, and yag: nd laser capsulotomy should be delayed if possible (50) (51) (52) (53) . ophthalmic emergencies such as acute angle-closure glaucoma and severe ocular injury should be operated upon immediately, but the operating theater should be regarded a high-risk area, and the use of proper personal protection equipment (i.e., disposable caps, n95 respirators, face shields, goggles, surgical gowns, and gloves) should be practiced strictly. when ophthalmic emergency surgeries are performed on patients with confirmed or suspected sars, mers, or covid-19, the recommended personal protection equipment are similar to those for ophthalmic consultation of these patients. to avoid aerosol transmission during tracheal intubation, local ophthalmic anesthesia is highly recommended rather than general anesthesia, and patients should wear n95 respirators during ophthalmic surgeries under local anesthesia (51, 53) . the outbreak of the current 2019-ncov infection has become a worldwide health threat. although respiratory droplets and direct contact have been identified as the main routes of transmission for human covs, the role of the eye in transmitting human covs is still under discussion. considering that the conjunctiva of the eye is directly exposed to infectious droplets and fomites during close contact with infected individuals and contaminated hands and that the mucosa of the ocular surface and the upper respiratory tract are connected by the nasolacrimal duct and share the same entry receptors for some respiratory viruses, it is reasonable to postulate three roles that the eye may play in human cov infection. firstly, it may be a target organ for human covs. secondly, the conjunctiva may be a portal of entry for or a transporter of human covs to infect the respiratory tract. thirdly, tears and conjunctival secretions may act as media that spread human covs. however, the eye is rarely involved in sars-cov, mers-cov, and 2019-ncov infection; conjunctivitis has been reported in only five cases with covid-19 but never in sars and mers patients. this suggests that the eye is neither a preferred organ for human cov infection nor a preferred gateway of entry that enables human covs to infect the respiratory tract. although it is quite rare, the possibility cannot be excluded that pathogens exposed to the eye might be transported to nasal and nasopharyngeal mucosa by constant tear rinsing through the lacrimal duct system and then cause respiratory tract infection, since mild to moderate symptomatic sars can be developed in a cynomolgus macaques model by nasal and conjunctival sars-cov inoculation as well as by nasal and bronchial sars-cov inoculation (4, 54) . moreover, the extremely low positive rate of human cov rna tests by rt-pcr in tears and conjunctival secretions from patients with sars and covid-19 may be related to the relatively low sensitivity of the current rt-pcr technique, later timing sample collection, and the activation of the host immune system and significant increases in lactoferrin and secretory iga levels in tears and in circulating igm and igg levels in plasm. hence, current negative rt-pcr results cannot exclude the possibility of the presence of sars-cov and 2019-ncov in tears and conjunctival secretions. considering that close doctor-patient contact is quite common in ophthalmic practice and is apt to transmit human covs via droplets and fomites, strict hand hygiene and proper personal protection are highly recommended for health care workers to avoid hospital-related viral transmission during ophthalmic practice. emerging coronaviruses: genome structure, replication, and pathogenesis preparation for possible sustained transmission of 2019 novel coronavirus: lessons from previous epidemics a new coronavirus associated with human respiratory disease in china ocular tropism of respiratory viruses viral infections in workers in hospital and research laboratory 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of an outbreak of 2019 novel coronavirus diseases (covid-19) in china covid-19) situation report-35 what to do next to control the 2019-ncov epidemic? respiratory virus shedding in exhaled breath and efficacy of face masks infection and rapid transmission of sars-cov-2 in ferrets virus-specific rna and antibody from convalescent-phase sars patients discharged from hospital clinical characteristics of 138 hospitalized patients with epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in wuhan, china: a descriptive study clinical characteristics of coronavirus disease 2019 in china clinical features of patients infected with 2019 novel coronavirus in wuhan inhost modelling of covid-19 kinetics in humans ophthalmologic evidence against the interpersonal transmission of 2019 novel coronavirus through conjunctiva. medrxiv the evidence of sars-cov-2 infection on ocular surface human coronavirus nl63, france identification of a new human coronavirus evaluation of coronavirus in tears and conjunctival secretions of patients with sars-cov-2 infection the severe acute respiratory syndrome coronavirus in tears tears and conjunctival scrapings for coronavirus in patients with sars peking university hospital wang guangfa disclosed treatment status on weibo and suspected infection without wearing goggles. xinjing newpaper update 27 -one month into the global sars outbreak: status of the outbreak and lessons for the immediate future conjunctiva-upper respiratory tract irrigation for early diagnosis of severe acute respiratory syndrome sars and mers: recent insights into emerging coronaviruses immunoglobulin a as an early humoral responder after mucosal avian coronavirus vaccination centers for disease control and prevention. interim guidelines for collecting, handling, and testing clinical specimens from persons under investigation (puis) for coronavirus disease inhibition of sars pseudovirus cell entry by lactoferrin binding to heparan sulfate proteoglycans tissue distribution of ace2 protein, the functional receptor for sars coronavirus. a first step in understanding sars pathogenesis expression of sars coronavirus s proteinfunctional receptor-angiotensin-converting enzyme 2 in human cornea and conjunctiva mechanism of the action between the sars-cov s240 protein and the ace2 receptor in eyes entry of human coronavirus nl63 into the cell dipeptidyl peptidase 4 is a functional receptor for the emerging human coronavirus-emc human coronavirus nl63 utilizes heparan sulfate proteoglycans for attachment to target cells guidelines for the diagnosis and treatment of novel coronavirus (2019-ncov) infection by the national health commission (trial version 7 world health organization. world health organization summary of probable sars cases with onset of illness from 1 suggestions for disinfection of ophthalmic examination equipment and protection of ophthalmologist against 2019 novel coronavirus infection precautions in ophthalmic practice in a hospital with a major acute sars outbreak: an experience from hong kong chinese preventive medicine association, beijing ophthalmological society and youth committee of beijing ophthalmological society. suggestions from ophthalmic experts on eye protection during the novel coronavirus pneumonia epidemic novel coronavirus disease (2019). (covid-19): the importance of recognising possible early ocular manifestation and using protective eyewear cynomolgus macaque as an animal model for severe acute respiratory syndrome this study was supported by the ophthalmology star program (qmx2019-01-001). the funding organization did not have any role in the design or conduct of this study. key: cord-294427-6eiligyy authors: salimi, ali; elhawary, hassan; diab, nermin; smith, lee title: the north american layman's understanding of covid-19: are we doing enough? date: 2020-07-03 journal: front public health doi: 10.3389/fpubh.2020.00358 sha: doc_id: 294427 cord_uid: 6eiligyy background: in the absence of an effective vaccine, public health policies are aimed at awareness, and education of the general public in order to contain the quickly spreading covid-19 pandemic. most of the recommended precautionary measures are dependent on human behaviors and therefore their effectiveness largely depends on peoples' perception and attitudes toward the disease. this study aimed to assess the level of knowledge, risk perception, and precautionary measures taken in response to covid-19 in north america. methods: in this cross-sectional observational study, an online survey targeted to north americans focused on the public's knowledge of covid-19, risk perception, and precautionary behaviors taken in response to this pandemic. descriptive analyses were performed for the whole population and the subgroup analyses contrasted the differences between americans and canadians. results: the cohort comprised 1,264 relatively young participants with an average age of 28.6 ± 9.8 years. the vast majority (>90%) were knowledgeable about covid-19. regarding risk perception, about a quarter assumed to be at less risk to contract the disease, and 42.8% considered themselves to be less contagious than others. while the vast majority avoided performing risky behaviors, only a small proportion (13.2%) wore a face mask—which is in line with the public health recommendations of the two countries at the time of data collection. overall, a larger proportion of canadian participants (55.8%) were satisfied with the performance of their national public health in response to the current pandemic, compared to their american counterparts (12.2%). discussion: data regarding the public's knowledge of covid-19, risk perception, and behaviors in response to this pandemic is limited. the results of this study highlight that this relatively young and educated sample of north americans had a high level of knowledge about covid-19 and a large proportion of them were taking the precautionary measures against this pandemic. however, a significant number of individuals believe to be at less risk of contracting the disease compared to the general population. educating the public that no one is safe from this disease, could play a role in further limiting risky behaviors and ultimately facilitating disease containment. what started as an influenza-like virus in wuhan, china, the sars-cov-2 virus and its associated coronavirus disease has rapidly evolved and been declared a global health emergency by the world health organization (who) (1) . within several months the virus quickly spread to over 195 counties (2, 3), millions were infected and hundreds of thousands of individuals lost their lives among whom were frontline physicians and healthcare professionals battling against this pandemic (4) . emerging evidence shows that around 80% of individuals who test positive for covid-19 present with mild respiratory symptoms while almost 14% of cases develop severe-enough symptoms that warrant hospitalization (5) . more alarmingly, it has been estimated that around 6% of patients who test positive will experience critical illness and require intensive care admission (5) . while the global incidence rate of covid-19 is exponentially increasing, different countries have been affected to varying degrees (6) . in the absence of an effective vaccine, most countries implemented public health policies that aimed at awareness and containment of the disease (7, 8) . however, a recent analysis demonstrated that only half of the countries have strong operational readiness capacities to respond to health emergencies such as covid-19 (8) . furthermore, different official health agencies recommend different measures to prevent the spread of disease. one example of such differences is the use of face masks for healthy asymptomatic individuals; early on after the outbreak, china's national recommendations included wearing face masks for both health-care professionals as well as the general public while the united states'(us) surgeon general advised against using face masks for asymptomatic patients citing the absence of strong evidence against covid-19 infection (9) . over time, these recommendations have been subject to change, as more is discovered about the virus (10) . many of the precautionary and preventative measures taken in different countries are dependent on human behaviors and therefore public health response effectiveness largely depends on peoples' perception of the disease and their attitude toward it (11) . previous studies have shown significant differences between europeans and asians' attitudes and risk perceptions of the 2003 severe acute respiratory syndrome (sars) outbreak (12) . similar differences have been evidenced between countries with relatively similar cultures and close geographic location (13) . to that end, this study aimed to compare and contrast the level of knowledge, risk perception, and precautionary measures taken in response to covid-19, between populations of the united states of america (us) and canada. to date, the us has reported the highest rate of covid-19 positive cases in the world and therefore, by understanding the public's attitude and risk perception toward the current pandemic, we hope to provide valuable information to help develop adequate populationtailored communication protocols that are effective in disease prevention and containment. this cross-sectional observational study reports on unique aspects of knowledge, risk perception, and precautionary behaviors related to covid-19, among a large sample of north americans. voluntary informed consent was presented on the front page of the questionnaire and was electronically signed by all participants before gaining access to the questions. the study was approved by the institutional review board of mcgill university, montreal, canada. the questionnaire was developed on a secure and encrypted cloud-based database and was adapted from similar previous studies on severe acute respiratory syndrome (sars) and the middle east respiratory syndrome (mers) (13) (14) (15) . it entailed a total of 34 questions including demographics, knowledge of covid-19 along with sources from which information was gained and confidence in each, perceived risks of virus contraction and dissemination, as well as changes in individual behaviors following the onset of this pandemic (appendix 1). response to all questions was required for completion and submission of the questionnaire, and incomplete answers were not registered in the database. response rate was the ratio of the completed questionnaires to the total number of individuals who accessed the questionnaire (whether completed or not). to prevent duplicate answers a cookie-based protection system was used. demographic information included age, sex, health status, level of education, self-reported income as a proxy for socioeconomic status (ses), country of residence, and living status. the knowledge questions focused on the self-reported understanding of the disease, etiology, mode of transmission, and phase(s) of contagiousness. risk perception assessed the anticipated likelihood of catching a common cold, getting a heart attack, or contracting covid-19; self-perceived risk of contracting, and disseminating covid-19 compared to the general population; confidence in the ability to avoid contracting the disease; and worry about their health as well as that of their loved ones. behavioral questions assessed abstinence from performing risky behaviors such as traveling, leaving the house, eating outdoors, shaking hands, using public transportation, participating in large gatherings, and touching one's facemore specifically, the eyes, nose, and mouth. additionally, frequent hand washing, and undertaking lifestyle changes including better sleep, a more balanced diet, and exercising, were assessed. data collection occurred in march 2020. the questionnaire was disseminated through social media (facebook, linkedin, research gate, instagram, and twitter) and a variety of webbased platforms and forums such as surverycircle.com and surveyswap.io targeting americans and canadians. the data were only accessible to the lead authors, and to maintain the full anonymity of participants no personally identifiable information was obtained. the shapiro-wilk test verified that the continuous data respected the parameters for normality. descriptive analyses were performed for the whole population and the repeated measures analysis of variance (anovas) assessed differences in reliance and confidence in available information sources concerning the covid-19. data were analyzed for canada and the united states (us) separately and were compared using pearson's chi-square (categorical outcomes) and general linear models (continuous outcomes), accounting for any demographic differences across the two groups. given the online nature of the survey-which typically attracts younger individuals with better technological skills, supplementary analyses including stratification by age and the level of education were performed using student's ttest (for continuous variables) and pearson's chi-square test (for categorical outcomes). participants less than 40 years old were considered as younger adults while those older than 40 years were included in the middle-aged and older adults group (16) . stratification by the level of education consisted of individuals with a high school diploma or less versus those with a minimum of a bachelor's degree. all statistical analyses were performed using spss 25.0 (ibm, new york, usa) with significance set at p<0.05. the survey was accessed by a total of 1,731 individuals, among which 1,264 completed the survey by answering all questionsa response rate of 73.5%. out of the 1,264 participants, 913 (72%) were from the us, and 351 (28%) were from canada. the cohort consisted of 728 females and 536 males, with an average age of 28.6 ± 9.8 years. the majority (64%) cohabited with healthy individuals, 22% resided with vulnerable populations (immunocompromised, elderly, or children), and 14% lived alone. chronic disease was reported among 18%. the majority of the participants had obtained a university diploma (68%) and the remaining 32% had a high school degree or less. two-thirds of the participants were employed, and the remaining one-third were either students, stay-home parents, or retired. ses was reported as low or middle-low among 30%, middle among 40%, and high or middle-high among the remaining 30%. none of the demographic measures were different across the two groups, except the education level where a larger proportion of canadians had a university degree (χ 2 = 13.160; p = 0.003) ( table 1) . self-reported knowledge of covid-19, measured on a 5-point likert scale, was averaged to 3.72 ± 0.77 (out of five). the cause of covid-19 was correctly identified to be a virus by 98.7% and the average mortality rate was reported by the participants to be 3.95 ± 5.69%. respiratory droplets were recognized as the most common mode of transmission by the majority of the participants (90.1%), followed by airborne (9.3%), and feco-oral (0.6%). intergroup analyses highlighted that a significantly larger proportion of canadians (94%) identified droplets as the correct answer compared to americans (88.6%) (χ 2 = 9.365; p = 0.009). the absence of any commercially available vaccine against covid-19 (which was the case at the time of the study) was correctly recognized by 98.2%. in terms of contagiousness of covid-19, 92.1% were aware that the virus can spread during both asymptomatic and symptomatic phases, as opposed to only during the asymptomatic phase (7%) or only during the symptomatic phase (0.9%). participants reported gaining the majority of their covid-19 information from official health agency channels (4.00 ± 1.01, out of five), which was significantly higher (f-value = 370.998; p < 0.001) than the alternative information sources: printed or online version of newspapers and magazines (3.13 ± 1.35), social media (2.70 ± 1.30), friends or relatives (2.31 ± 1.04), and television (1.93 ± 1.14). similarly, confidence in information released by public health authorities was 4.44 ± 0.82 (out of five), significantly higher (f-value = 2350.686; p < 0.001) than printed or online newspaper and magazines (2.90 ± 1.05), friends or relatives (2.15 ± 0.87), television (2.13 ± 0.99), and social media (1.71 ± 0.82). no statistically significant differences were found between the american and canadian participants with regards to their information sources or the confidence in each source ( table 2) . on average, both groups of participants were significantly more concerned for the health of their loved ones (4.18 ± 0.98, out of five) over that of their own (2.97 ± 1.22; 95% ci = 1.145-1.271; p < 0.001). participants rated the likelihood of contracting covid-19 during this pandemic to be 3.24 ± 1.01 (out of five), which was significantly less likely than catching a common cold (4.71 ± 0.71; 95% ci = 0.313-0.449; p < 0.001) but significantly more likely than getting a heart attack in their lifetime (2.86 ± 0.90; 95% ci = 1.405-1.531; p < 0.001). no significant differences were found between the two groups. while over half of the participants (58.2%) believed they have the same risk of contracting covid-19 as the rest of the population, a quarter (25.8%) believed they are at less risk, while 16% believed to be at more risk compared to the general population. interestingly, the perceived degree of contagiousness was rated to be 1.66 ± 0.91 (out of five). moreover, 42.8% of the participants considered themselves to be less contagious than others with only a minority (5.5%) believing to be more contagious than the general population. about half of the population (49.4%) believed that they can avoid contracting covid-19, while the other half (50.6%) were unsure or believed otherwise. the results show that jobs were notably affected by the current pandemic; among those employed, over half (53.5%) had transitioned to working remotely from home, 22.6% had stopped working, while only 23.9% were still physically going to work. this impact was larger on canadians, as a larger proportion (83.1%) had stopped working or transitioned to working online (vs. 72.8 % americans) and a smaller proportion (16.9%) were still physically going to work (vs. 27.2% americans) (χ 2 = 21.988; p < 0.001). abstinence from risky behaviors was reported by a large proportion of the participants, including avoiding traveling (97.0%), leaving the house (95.0%), eating outdoors (97.2%), shaking hands (97.2%), using public transportation (95.9%), participating in large gatherings (98.6%), and touching their face (69.0%). comparisons between the two groups highlighted that a larger proportion of canadian participants abstained from traveling (99.4 vs. 96.1% americans; χ 2 = 9.893; p = 0.008), and avoided touching their face (81.2% vs. 64.3 americans; χ 2 = 33.857; p < 0.001). frequent hand washing was reported by 95.3% of the participants, and regular use of disinfectants to clean surfaces at home was described by 62.7%. on average, wearing a mask outdoors was reported by only 13.2%, which was significantly higher among american participants (14.5%) compared to their canadian counterparts (10.0%; χ 2 = 4.450; p = 0.028). life-style changes in response to this pandemic included healthier sleep habits (62.7%), a more balanced diet (59.3%), and exercising (52.1%). the latter two were more prominent amongst canadian participants, as a larger proportion implemented a healthier diet (67.2 vs. 56.2% americans; χ 2 = 12.818; p < 0.001) and exercising (62.4 vs. 48.1% americans; χ 2 = 20.802; p < 0.001). the participants were asked about their presumed behavior under a hypothetical assumption where they have been suspected of being a covid-19 carrier and are recommended to remain in self-isolation; under this assumption, the majority (96.8%) reported to conform to the recommendation and remain in complete self-isolation, 2.3% stated that would obey the recommendation but would prioritize personal affairs, and 0.9% reported to refuse isolation and leave the house. the comparison between the two groups highlighted that a larger proportion of canadian participants (99.4%) would conform with the isolation recommendations if they were to become suspected of being a covid-19 carrier (compared to 95.8% americans; χ 2 = 10.677; p = 0.001) finally, the overall satisfaction with regards to the national public health response to covid-19 was significantly higher among canadians. over half of the canadian participants (55.8%) believed that the national public health response was sufficient or adequate while only 12.2% of the american participants shared a similar belief about the us public health response (χ 2 = 263.084; p < 0.001). with a cut-off age of 40 years, the younger adults group consisted of 1,118 individuals with an average age of 25.9 ± 5.8 years vs. the middle-aged and the middle-aged and older adults group (referred to older adults group herein, for simplicity) included 146 individuals with an average age of 49.5 ± 8.4 years. differences in demographics, in addition to the age (95% ci = 22.551-24.687; p < 0.001), included more individuals in the older group with a higher level of education (76 vs. 67% in the younger group; χ 2 = 5.026; p = 0.025), living with immune-compromised individuals (36 vs. 20% in the younger group; χ 2 = 27.309; p < 0.001), and having comorbidities (45 vs. 15% in the younger group; χ 2 = 74.711; p < 0.001). self-reported knowledge of covid-19, measured on a 5point likert scale, was significantly higher among the older adults (4.09 ± 0.76) compared to younger adults (3.67 ± 0.76; 95% ci = 0.282-0.544; p < 0.001). older adults, compared to their younger counterparts, relied more on television as a source of information (2.2 ± 1.3 vs. 1.9 ± 1.1; 95% ci = 0.102-0.495; p = 0.008) and less on social media (2.4 ± 1.3 vs. 2.7 ± 1.3; 95%ci = 0.099-0.545; p = 0.005). older adults, when compared to their younger counterparts, were more concerned for their own health (3.64 ± 1.09 vs. 2.88 ± 1.21; 95%ci = 0.548-0.962; p < 0.001); though, both groups were equally concerned for the health of their loved ones (p > 0.05). the perceived risk of disease contraction and the degree of contagiousness was not different between the two groups (p > 0.05). there were no differences between the two groups in terms of taking precautionary actions and abstaining from risky behaviors, except for face-mask-wearing which was reported among a larger proportion of older adults (21% compared to 12% in younger adults; χ 2 = 7.747; p = 0.005). interestingly, a larger proportion of older adults reported to exercise (61 vs. 51% among young adults; χ 2 = 5.241; p = 0.022) and to keep a balanced diet (73 vs. 57%; χ 2 = 13.461; p < 0.001), in response to covid-19. satisfaction with public health response was similar among the two groups (χ 2 = 0.255; p = 0.682). the less educated group (high school diploma or less) consisted of 406 individuals with an average age of 24.6 ± 9.9 years vs. the more educated group (a minimum of bachelor's degree or equivalent) which included 858 individuals with an average age of 30.6 ± 9.1 years. in terms of the demographic differences, in addition to the younger age among the less educated group (95% ci = 4.886-7.097; p < 0.001), a larger proportion of them had lower ses (39 vs. 25% in the more educated group; χ 2 = 27.958; p < 0.001), and a smaller proportion were living alone (7 vs. 17% in the more educated group; χ 2 = 27.344; p < 0.001). in terms of knowledge, a larger proportion of those with lower education wrongly identified bacteria as the cause of covid-19 (2.5 vs. 0.8% in the more educated group; χ 2 = 5.636; p = 0.018) and associated the main mode of transmission to airborne (12 vs . 8% in the more educated group; χ 2 = 9.589; p = 0.008). those with a lower level of education relied more on social media as a source of information (2.9 ± 1.3 vs. 2.6 ± 1.3 in the more educated group; 95%ci = 0.152-0.456; p < 0.001) and less on official public health sources (3.9 ± 1.1 vs. 4.1 ± 1.0 in the more educated group; 95%ci = 0.032-0.270; p = 0.013). in terms of risk perception, a larger proportion of those with lower education thought to be at lower risk of disease contraction (33 vs. 22% in the more educated group; χ 2 = 19.415; p < 0.001) and to be less contagious relative to the general population (49 vs. 40%; χ 2 = 8.040; p = 0.018). with regards to the precautionary actions against covid-19, a larger proportion of those with lower education reported risky behaviors such leaving the house (8 vs. 3% in the higher educated group; χ 2 = 12.483; p < 0.001), shaking hands (4 vs. 2% in the higher educated group; χ 2 = 5.433; p = 0.020), participating in gatherings (3 vs. 1% in the higher educated group; χ 2 = 4.600; p = 0.032), and touching their face outdoors (40 vs. 26% in the higher educated group; χ 2 = 23.330; p < 0.001). frequent handwashing was reported among a smaller proportion of those with lower education (92 vs. 97% in the higher educated group; χ 2 = 9.955; p = 0.002). a larger proportion of those with higher education reported adopting healthier sleeping habits (67 vs. 53% in the lower educated group; χ 2 = 22.076; p < 0.001), exercising (56 vs. 42% in the lower educated group; χ 2 = 20.283; p < 0.001), and keeping a balanced diet (65 vs. 47% in the lower educated group; χ 2 = 36.946; p < 0.001), in response to covid-19. no differences were found between the two groups in terms of facemask-wearing (χ 2 = 1.396, p = 0.237) or satisfaction with public health response (χ 2 = 2.221; p = 0.136). to the best of authors' knowledge, this paper represents the first study to assess perception and attitudes toward the covid-19 pandemic, among a large cohort of individuals in north america. our results show that this sample of relatively young and educated american and canadian participants had a high level of subjective and objective knowledge of the covid-19 disease. however, over a quarter of the sample believed they were less likely to contract the disease compared to others, and more interestingly, almost half of them considered themselves to be less contagious than the general population. that being said, both canadians and americans participants reported avoiding many risky behaviors associated with the covid-19 spread such as, participating in large gatherings, shaking hands, eating outside, and using public transportation, and they mostly engaged in healthy habits such as frequent hand washing. canadians were more likely to avoid touching their face, implement a healthier diet, and exercise, compared to americans. both populations reported to not frequently use face masks-which was in accordance with the public health recommendations of the two countries at the time-with americans using them slightly more than canadians. one of the public health priorities during pandemics is to influence the general public's attitudes and perceptions (17) . this notion of public perception becomes vitally important during pandemics such as covid-19 where a vaccine or effective treatment is not available. there is a prevailing view that the general public was resistant to public health recommendations during pandemics such as h1n1 influenza and sars outbreaks (17) . while the findings of this study cannot be directly related to public health performance, it sheds light on the knowledge and perception of covid-19 among a relatively young and educated sample in north america. our results show that both groups have a very accurate understanding of the sars-cov-2 virus including the methods of transmission and the average mortality rate. this contrasts with findings of some of the sars pandemic studies that found that almost half of the people thought sars was curable early on during the pandemic (compared to only 1.8% of our sample who believed that there is a cure or vaccine for covid-19) (18) . similarly, several previous studies showed that the public perceived their risk of contracting sars to be quite low, a finding that contrasts with our results in the context of the covid-19 pandemic (14, 18) . these differences are likely multifactorial. differences in age, ethnicity, and level of education of the samples could explain some of the differences in the findings. for instance, our sample constituted of relatively young and educated participants that had access to the internet and were willing to participate in our online study in contrast to lau et al. study, where age and education were more evenly distributed (18) . other reasons include the timing and the era in which the study was conducted. living in the era of technology and abundance of information facilitates access to the information; hence, comparing the public knowledge about a pandemic today and contrasting it to that of 17 years prior could be erroneous. further, our study was conducted at least 90 days after the disease outbreak compared to that of lau et al., which was conducted from day 11 to 60 of the sars outbreak, leaving the public with limited time to inform themselves of the reality of their time. lastly, while we cannot make a direct association, the role of prompt public health response in the us and canada based on the lessons learned from previous pandemics cannot be ruled out. a notable proportion believed they are at less risk of contracting covid-19 and are less contagious than the general public (25.8 and 42.8%, respectively). a possible explanation to these findings could be related to the relatively young average age of our study participants (28.6 ± 9.8 years) and the widespread perception that younger individuals are unlikely to be affected by covid-19 compared to older individuals (19) . one can mitigate the risk of contracting the disease, and hence be less contagious, by taking the necessary precautionary measures; however, this idea that adverse outcomes only happen to others stems from the human psyche. previous studies across different domains have shown that people generally tend to be optimistic regarding their health and usually underestimate their own risk of suffering from diseases or health-related negative outcomes (20, 21) . this could be one of the explanations for why almost half of our sample believed they were able to avoid contracting covid-19. while being optimistic and having a sense of internal locus of control are not necessarily undesirable, they can both lead to less caution and riskier behaviors among individuals and ultimately contribute to the spread of the disease. our findings show that both american and canadian participants gain most of their covid-19 health-related knowledge from official health agencies. similarly, they had higher confidence in the knowledge gained from these sources compared to other sources. this could be explained by the fact the majority of both canadian and american participants in our sample was relatively well-educated and therefore were more likely to have confidence in more trusted sources such as official public health agencies. this hypothesis can be supported by our sub-analysis that showed that the participants with a lower level of education (high school diploma or less) relied more social media and less on public health resources to gain their covid-19-related information. finally, it is important to acknowledge that public health information is often linked with political information and while the questionnaire included clear examples of what constitutes a public health source of information, it is often difficult for the public to differentiate them and therefore our results should be interpreted in this context. both the center for disease control and prevention (cdc) and health canada published several precautionary measures to be taken by the general population including frequent hand washing, practicing social isolation, and avoiding gatherings, or unnecessary travel (10, 22) . our data highlights that the majority of our sample were taking many of these precautionary measures. however, while both american and canadian official health agencies recommend against touching one's eyes, nose, or mouth, a significantly larger portion of canadians follow that recommendation compared to their american counterparts. this could be partially explained by the fact that more canadian participants correctly identified that the sara-cov-2 virus is transmitted through respiratory droplets. moreover, more canadian participants implemented a healthier diet and exercised to help prevent contracting covid-19; recommendations suggested by the who (23) . while these findings are quite positive, they must not be overgeneralized. our sample consisted of relatively young and educated participants and therefore the findings might not apply to the general population. our sub-analysis showed that a smaller proportion of those with a lower educational level engaged in such lifestyle changes. the majority of the participants in both groups did not wear face masks which could be attributed to the recommendations set by both official health agencies against mask-wearing among the asymptomatic individuals at the time of the conduction of the study. it is important to note that both canadian and american official healthcare guidelines changed following data collection, in favor of wearing face masks due to the strong evidence supporting its benefits (24) (25) (26) . it would be interesting for future studies to re-assess the population's perceptions and behaviors regarding wearing facial masks after this change in recommendations. the study's main limitation is its selection bias and that the majority of the participants are young and highly educated, in line with the online nature of the data collection. this limits the generalizability of the results and thereby the findings should be interpreted within the context of this limitation. in an attempt to mitigate this limitation to certain extents, a sub-analysis of data stratified by age and level of education was performed; nevertheless, the limitation still exists. moreover, the study only included north americans. as previous studies show, people from different regions and cultures have different attitudes and risk perceptions of pandemics (14, 18) . therefore future works should study the level of knowledge, risk perception, and precautionary behaviors taken by individuals in different regions. our study did not assess the differences in attitudes and perceptions across different states and provinces of each country; given to the large and heterogeneous multi-cultural populations of the us and canada, future studies should assess any differences in these factors. finally, we encourage future studies to study the types of messages that are being received from health sources and to compare this between the two countries. this will help provide useful information for future health care emergencies and pandemics. the covid-19 pandemic represents a global health emergency that has affected virtually all countries. due to the rapidly rising incidence rate in north america coupled with the lack of available vaccination or cure, public health response along with people's attitudes toward this pandemic is of paramount importance in preventing the spread of disease. the present study highlights a high level of knowledge about covid-19 and good precautionary measures taken against this pandemic, among relatively young and educated north american participants. however, with many young individuals believing to be less at risk or able to avoid contracting the covid-19, the authors believe that more resources should be invested in educating the public that no one is safe from this disease and therefore everyone should continue taking maximum precautionary measures until the disease is contained. the raw data supporting the conclusions of this article will be made available by the authors, without undue reservation. this study was approved by the institutional review board of mcgill university (montreal, canada). voluntary informed consent was presented on the front page of the questionnaire and was electronically signed by all participants before gaining access to the questions. as and he substantially contributed to the conception and design, data acquisition, analysis and interpretation of data, and drafting of the manuscript. nd and ls contributed to the design, data interpretation, and revised the manuscript critically. all authors agree to be accountable for all aspects of the work. covid-19, an emerging coronavirus infection: advances and prospects in designing and developing vaccines, immunotherapeutics, and therapeutics estimation of coronavirus disease 2019 (covid-19) burden and potential for international dissemination of infection from iran physician deaths from corona virus (covid-19) disease rapidly increasing cumulative incidence of coronavirus disease (covid-19) in the european union/european economic area and the united kingdom real-time estimation of the risk of death from novel coronavirus (covid-19) infection: inference using exported cases early containment strategies and core measures for prevention and control of novel coronavirus pneumonia in china health security capacities in the context of covid-19 outbreak: an analysis of international health regulations annual report data from 182 countries rational use of face masks in the covid-19 pandemic update: public health response to the coronavirus disease 2019 outbreak-united states risk perceptions and behaviour: towards pandemic control of emerging infectious diseases : international research on risk perception in the control of emerging infectious diseases perceived threat, risk perception, and efficacy beliefs related to sars and other (emerging) infectious diseases: results of an international survey sars knowledge, perceptions, and behaviors: a comparison between finns and the dutch during the sars outbreak in 2003 sars risk perception, knowledge, precautions, and information sources, the netherlands middle east respiratory syndrome risk perception among students at a university in south korea a survey of world wide web use in middle-aged and older adults beyond resistance: social factors in the general public response to pandemic influenza monitoring community responses to the sars epidemic in hong kong: from day 10 to day 62 clinical features of covid-19 in elderly patients: a comparison with young and middle-aged patients smokers' unrealistic optimism about their risk mass media and risk factors for cancer: the under-representation of age public health agency of canada. coronavirus disease (covid-19): prevention and risks. ottawa: public health agency of canada, government of canada world health organization. mental health and psychosocial considerations during the covid-19 outbreak mass masking in the covid-19 epidemic: people need guidance covid-19: face masks and human-to-human transmission. influenza other respir viruses the role of masks and respirator protection against sars-cov-2 the supplementary material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fpubh. 2020.00358/full#supplementary-material conflict of interest: the authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.copyright © 2020 salimi, elhawary, diab and smith. this is an open-access article distributed under the terms of the creative commons attribution license (cc by). the use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. no use, distribution or reproduction is permitted which does not comply with these terms. key: cord-261517-j9kw1a9x authors: boccia, stefania; cascini, fidelia; mckee, martin; ricciardi, walter title: how the italian nhs is fighting against the covid-19 emergency date: 2020-05-08 journal: front public health doi: 10.3389/fpubh.2020.00167 sha: doc_id: 261517 cord_uid: j9kw1a9x nan italy, with more than 183,957 cases as of april 22nd (1) has the second highest burden of coronavirus disease 2019 in europe after spain, and the third highest worldwide. the speed with which the epidemic grew took all concerned by surprise (2) . within a week of the first case being identified in codogno, lombardy, the number had grown to 821, with 21 deaths. this placed the local health services under exceptional pressure and, as in spain (3), created tensions within the decentralized italian health system. italy comprises 20 regions, with differing levels of autonomy. the italian prime minister threatened to take back powers from the regions and autonomous provinces as they were "in charge of implementing healthcare but not prepared to face a national emergency" (4). the national response came in the form of a series of seven decrees from the presidency of the council of ministers (in effect the prime minister's office) progressively extending countermeasures. after the first declaration of emergency of january 31st, a decree (february 23rd) isolated cities with covid-19 clusters within the northern italian regions (lombardy and veneto) ( table 1) . the following deecrees adopted further restrictions, closing schools and universities, prohibiting all public events, such as concerts and major sports competitions, and limiting business hours. the last three decrees imposed restrictions on mobility of the population. early on, several towns had introduced varying forms of quarantine, but further clusters continued to emerge. as a consequence, the new decrees extended restrictions from the region of lombardy to all of northern italy and, by march 11th, to the entire country (figure 1) . detailed surveillance is being conducted by a task force in the department of infectious diseases of the instituto superiore di sanità (5) . according to the latest available reports, threequarters (70.8%) of cases were over 50 years of age and only 1.6% were aged 18 years or younger, with 27.4% between 19 and 50 years old. the majority (52.4%) were men, the same as in early reports from china (6) . healthcare workers represented 10.3% of the reported cases, and among them lethality was 0.3%. as of april 22nd, nearly half of all cases were diagnosed in lombardy (69,092), followed by emilia romagna (23,434 cases) and piemonte (22,739 cases) (supplementary table s1 ). with clinical data available for 52,577 cases, most (35.7%) were classified as having mild pneumonia but 17.4% were severe (dyspnoea, respiratory rate ≥30/min, blood oxygen saturation ≤93%), and 1.9% were critical (respiratory failure, septic shock, and/or multiple organ dysfunction or failure), while 30% had few or no symptoms. obviously, international comparisons of case fatality must be interpreted with caution due to differences in the intensity of testing and, with deaths, the criteria for establishing the underlying cause. at present it appears that all deaths in someone who has tested positive for covid-19 are attributed to the virus and this may, and probably is not the case everywhere. by april, 22nd, where we had 23,085 deaths, giving a case fatality rate of 12.3%. this is higher than has been reported in many other countries but is likely to be explained, at least in part, by the age distribution. the median age of cases in italy is 62 years, compared to 47 in china (6) . however, the median age of those dying in italy is 80 years. again, noting the need for caution because of issues with denominators, there was a clear association between age and outcome. there were no deaths among those aged under 30 years old, but the case fatality rate was 19.1% in those aged 70 to 79, increasing to 27.1% in those 80 years and older. outcomes were also strongly associated underlying conditions: 48.6% of deaths were among people with 3 or more comorbidities, 26.6% had two, 23.5% had one, and only 6 deaths (1.2%) were of people who had apparently been healthy. suspension to the entire productive chain (unless "essential", e.g. food production and distribution) in the country figure 1 | number of new cases, deaths and total cases due to covid-19 in italy, from 21st february to 22nd april 2020. gray arrows represent the legislative decrees with a regional impact. black once the legislative decrees with national impact. the challenge to the national health service has been immense starting from the red zones in the northern italy. for instance, before the current crisis lombardy had approximately 720 intensive care beds (2.9% of all hospital beds in the region) (7) . in the first 18 days of the epidemic, 482 of them were required to treat patients with covid-19 (7) . in these circumstances the national health service has had to innovate. first, separate testing sites were established, and the ministry of health asked general practitioners to refer anyone meeting certain criteria based on their symptoms, to divert them from health facilities facing extreme pressure. second, the ministry of health put in place measures to recruit additional doctors and nurses to increase the capacity of intensive care units (icu). this included an extraordinary plan, launched on march 7th, to employ medical students and retired healthcare professionals. meanwhile, on march 8th, e845 million was allocated for additional medical devices and equipment (8) . unfortunately, these measures have been implemented against a backdrop of the loss of many health care workers who have been quarantined or fallen ill with the infection, some of whom, tragically, have died. the approaches taken by the italian health system to the covid-19 emergency have varied among the most severely affected regions fall into three broad types (9). type 1 is a hospital based model, adopted in lombardy. type 2 is a territorial based model, in veneto. type 3 is a combined hospitalterritorial model, as in emilia-romagna and piedmont. the first type places the main emphasis on the role of hospitals, with a relatively low level of community testing. this has, as might be expected, been associated with substantial pressure on hospitals and, particularly, icu beds. an average of 50% of those diagnosed with covid-19 have been admitted to hospital in lombardy (vs. an average of 45% in other regions). although this seems a small difference, the duration of stay in icus means that, at any one time, he ratio of patients treated in icus to those treated at home is twice as high in lombardy than in veneto, emilia romagna and piedmont. this also means that daily occupancy of icu beds has been exceeding 100%, in contrast to emilia-romagna, the second most severely affected region, where occupancy is 38% (9). the territorial management approach is characterized by a lower hospitalization rate and a higher incidence of testing. an extreme example is the town of vò, in veneto region, where all 3,000 inhabitants were tested (10) . in veneto, only 22% of patients with a positive result are hospitalized (compared to the 45-50% of the other italian regions) and nasopharyngeal swabs, which are also administered to asymptomatic individuals, reached 3.13% of the regional population (vs. an average of 1.25% of the other regions) (9). the combined hospital-territorial management model, adopted in emilia-romagna and piedmont, is characterized by an intermediate level of hospitalization and an intermediate level of testing. in a situation such as the current pandemic, where the optimal course of action is uncertain, italy's decentralized structure has provided an important natural experiment. while there is still much to be learned, the emerging evidence points to the territorial management model being the best response to this emergency. sb, wr, and fc: substantial contributions to the conception and design of the work. mm: critical revision of the manuscript, interpretation of data for the work. available online at what other countries can learn from italy during the covid-19 pandemic the resilience of the spanish health system against the covid-19 pandemic covid-19: preparedness, decentralisation, and the hunt for patient zero integrated surveillance of covid-19 in italy clinical characteristics of coronavirus disease 2019 in china critical care utilization for the covid-19 outbreak in lombardy, italy: early experience and forecast during an emergency response covid-19, in gazzetta ufficiale il decreto per il potenziamento del ssn we showed mass testing could eradicate the coronavirus we thanks leonardo villani for his support in the elaboration of the figure the supplementary material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fpubh. 2020.00167/full#supplementary-material key: cord-347898-appzi43a authors: hu, zeming; chen, bin title: the status of psychological issues among frontline health workers confronting the coronavirus disease 2019 pandemic date: 2020-06-05 journal: front public health doi: 10.3389/fpubh.2020.00265 sha: doc_id: 347898 cord_uid: appzi43a nan in late december 2019, an outbreak of a pneumonia caused by novel coronavirus disease 2019 (covid19) infection was reported in wuhan, hubei province, china, which has since spread domestically and internationally (1) . according to a report by the world health organization (who), as of may 22, 2020, 4,995,996 cases of covid-19 infection have been confirmed globally using specific laboratory rt-pcr (2) . among these cases, 84,520 were from china, 228,006 from italy, 129,341 from iran, and 1,525,186 from the usa. most of the infected patients are admitted to designated hospitals for systemic treatment and isolation. this has resulted in unprecedented psychological distress and other mental health symptoms among frontline health workers worldwide engaged in the fight against the covid-19 pandemic (3). in the lancet, unfortunately, it was reported that 16 healthcare workers were infected at a stage when the transmissibility of covid-19 was not well-defined (4, 5) . as an increasing number of studies about the transmission routes of severe respiratory syndrome coronavirus 2 (sars-cov-2) have been conducted, healthcare workers who come into direct contact with confirmed or suspected patients are at high risk of infection despite the use of personal protective equipment (ppe). according to the national health commission of china, more than 3,300 medical professionals have been infected with covid-19. in italy, as of april 16, 2020, 16,991 healthcare providers who handled confirmed patients had been infected, and 127 physicians died (6) . this implies that medical staff, especially those at the frontline in the fight against the pandemic without sufficient ppe or other essential equipment, are likely to fear for their own safety and that of their close friends, colleagues, and even families. infected health workers confirmed covid-19 patients potentially causing a negative feeling of frustration and helplessness. healthcare workers are therefore under tremendous mental health stress during the ongoing covid-19 crisis (7) . prevailing evidence indicates that elderly patients complicated with chronic diseases or common comorbidities are susceptible to acute respiratory distress syndrome (ards), acute respiratory failure, and multiple organ failure among other conditions (5) . with no specific and effective antiviral drugs or vaccines, patients infected with covid-19 are seemingly staring death in the eye. such patients are primarily given symptomatic treatment to relieve severe clinical manifestations with the help of breathing machines. effective communication with patients and relatives is compromised by the use of ppe, which covers most of the face. this challenging situation makes health professionals feel guilty, helpless, and depressed, which eventually results in common mental disorders such as anxiety, depressive disorders, and post-traumatic stress disorder (ptsd) (8) . as the covid-19 outbreak continues to spread, many suspected infections or close-contact visits to designated hospitals increase the workload and number of working hours for healthcare providers. this leads to emotional strain and physical exhaustion. the critical situation mentioned above is a reminder of previous infectious disease outbreaks. healthcare providers who participated in the fight against the previous 2003 sars outbreak have experienced a broad range of psychological problems, including stress, depression, and anxiety, some of which have persisted for several months after the outbreak (9) . research from the h1n1 influenza epidemic shows that many healthcare workers developed symptoms of ptsd, depression, anxiety, and burnout within a few weeks of the outbreak (10). this is consistent with a recent psychological survey that demonstrated that the odds of developing depression, anxiety, stress, and insomnia symptoms among health professionals working in the designated hospitals are 50.7, 44.7, 73.4, and 36.1%, respectively (11) . another recent survey from china indicated that a considerable proportion of medical staff who participated in the epidemic prevention and control reported symptoms of depression (50.4%), anxiety (44.6%), distress (71.5%), and insomnia (34%) (12) . therefore, effective strategies to subvert mental breakdown among medical providers are needed as part of the public health response to the ongoing covid-19 pandemic. in this opinion piece, we highlight the utility of psychological services and support systems for healthcare workers participating in the control of covid-19 pandemic. strategies and initiatives employed by the chinese health authorities to handle the psychological issues among frontline health workers during the early stage of the covid-19 epidemic as well as the lessons learnt are discussed. the chinese government has set up multidisciplinary mental health teams, including the psychosocial response team, psychological intervention technical support team, psychological intervention medical team, and psychological assistance hotline team, all of which are mandated to implement preparedness strategies to reduce the negative psychological impact of covid-19 on medical providers (8) . the strategies utilized include telephone-, internet-, and application-based counseling and intervention by online platforms. the who and many other institutions have designed guidelines to provide psychological support for medical staff during the current pandemic outbreak. for instance, the who has released a 30-point guideline for mitigating the developing psychological issues among healthcare workers (13) . the guideline highlights the need for medical professionals to protect themselves, their family members, friends, and colleagues accordingly. in addition to the social support systems provided by organizations, building proper self-awareness, peer support, and team support will equip medical workers with the capacity to cope with mental health stress during the current pandemic. a smooth relationship between healthcare workers and covid-19 patients should be established (14) . healthcare workers should work as team to avoid burnout (15) . mechanisms for effective communication should be put in place to allow health care workers update their leaders about their working conditions and schedule for break from work (16) . during treatment, medical professionals should ensure that each treatment procedure is effective, understand the availability of medical resources, and learn to establish self-confidence (17) . medical workers should have enough sleep since inadequate sleep and high workloads may weaken the immune system (17) . thus, hospitals should provide essential services such as a place to rest, food, daily living supplies, avenues for communication with families to alleviate anxiety, and sufficient ppe (18) . this will improve the psychological well-being of medical staff. the importance of peer and team support from colleagues or teams should not be underestimated. peer groups share common experiences through shorthand ways known to all members. members of the peer group communicate freely without the fear of breaking taboos as their social rules have been established. talking to co-workers who may be conversant with the experiences in the working environment is an approach with which we can control emotional stress during this pandemic (19) . furthermore, teams need to encourage each other and find approaches to assist new members feel safe, valued, and welcome as quickly as possible. constant encouragement, cheering, and affirmation of each other will improve the treatment outcomes. team members should not blame each other, and, in case of mistakes, solutions should be developed in a timely manner. observance of these factors will undoubtedly improve the capacity of healthcare workers to cope with the immense psychological pressure during the on-going covid-19 pandemic (20) . the safety and mental health of first-line medical workers must be closely monitored during the fight against a pandemic. frontline health workers need effective support to help them cope with arising mental health problems. first, health authorities worldwide must implement strategies to address problems such as high workloads, hospital supplies, hospital beds, among others. second, social support, including online services and guidelines provided by organizations, should be utilized to timely, effectively, and efficiently mitigate the psychological impacts among health workers. third, proper self-awareness, peer support, and team support are encouraged as part of healthcare system response in the context of public health emergency. healthcare workers should prioritize their own well-being as much as possible, addressing their essential needs for food, rest, and sleep and understanding the treatments they can afford. in addition, the feasibility and effectiveness of communication and encouragement within groups or teams should be suggested to minimize the detrimental consequences during the covid-19 pandemic. the timely address of psychological crisis among medical workers preferably based on the above strategies is important. zh drafted and revised the manuscript. bc reviewed the manuscript for approval. all authors agreed the final version. a novel coronavirus outbreak of global health concern novel coronavirus (sars-cov-2) situation reports managing mental health challenges faced by healthcare workers during covid-19 pandemic clinical features of patients infected with 2019 novel coronavirus in wuhan epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in wuhan, china: a descriptive 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the covid-19 pandemic psychological stress of medical staffs during outbreak of covid-19 and adjustment strategy mental health care for medical staff in china during the covid-19 outbreak looking after doctors' mental wellbeing during the covid-19 pandemic the psychological impact of quarantine and how to reduce it: rapid review of the evidence the authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.copyright © 2020 hu and chen. this is an open-access article distributed under the terms of the creative commons attribution license (cc by). the use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. no use, distribution or reproduction is permitted which does not comply with these terms. key: cord-270467-es6dnx36 authors: frisardi, vincenza title: commentary: coronavirus and obesity: could insulin resistance mediate the severity of covid-19 infection? date: 2020-07-07 journal: front public health doi: 10.3389/fpubh.2020.00351 sha: doc_id: 270467 cord_uid: es6dnx36 nan insulin resistance (ir) might be a potential key factor behind the covid-19 severity found in people with obesity. an article published on frontiers public health supported the evidence of possible mechanisms linking ir and covid-19 severity via the upregulation of ace 2, the protein involved in virus entry (1) . this research area is worthy of being investigated further for its implication in the prevention and treatment of this dramatic pandemic. we need to understand the molecular mechanisms related to the higher risk both of being infected by sars-cov-2 and of developing a more severe disease (covid-19). recent reports of hospitalized covid-19 patients have found obesity to be a risk factor for the worst adverse outcomes (severity and mortality). the intensive care national audit and research centre (icnarc) report on 2,621 patients in intensive care units in england showed that the case fatality rate was higher in obese patients 1 . the international severe acute respiratory & emerging infection consortium (isaric) international report of 1,123 patients with suspected or confirmed covid-19 found that obesity was the fifth most observed comorbidity in hospitalized patientsonly somewhat less common than "high-risk" pulmonary conditions 2 . systematic reviews and meta-analyses confirmed, surprisingly, that metabolic disorders seem to play a more pivotal role for negative outcomes in covid-19 compared with preexistent chronic respiratory disease (2) . starting from this, it would be appropriate to think of obesity in relation to covid-19 outcome in a more complex way, rather than considering only the mechanical effects of abdominal compression on the respiratory dynamic. finucane and davenport argued that the insulin-mediated metabolic and inflammatory processes could be the cause of the negative sars-cov2-related trajectory in obese patients. in the last few decades, insulin was believed to intervene in other degenerative diseases both as a principal leading factor and in a cross-talk with other metabolic disorders (3, 4). because obesity and ir have a bidirectional relationship and the adiposeinsulin axis was postulated (5, 6) , the research needs to be more addressed toward the convoluted route linking lipid and glucose metabolism as a unique molecular platoon. insulin is a critical regulator of many cellular pathways, with many already demonstrated tissue-specific actions. rapid changes in protein phosphorylation and function as well as changes in gene expression mediate the insulin-related metabolic effects (6). finucane and davenport reported the evidence that insulinmediated ace2 expression varies in a tissue-specific manner with significant expression in the lungs. whether the high glucose level rather than elevated insulin levels is responsible for this overexpression is worthy of investigation because it might have clinical relevance. as reported from the authors, in people with obesity and diabetes, it is clear that other mechanisms independent of ace2 expression are likely to contribute to the more severe phenotype of covid-19. the clinical manifestations of covid-19 are heterogeneous, with the lungs the most triggered organ. nevertheless, other clinical expressions of sars-cov2 were reported, suggesting an interesting hypothesis about the host-pathogen interaction via the metabolism 1 . tmprss2, the most accused protein involved in virus activation, has also been detected in other tissues playing a metabolic role, in particular in bile ducts and the pancreas (7). furthermore, adipose tissue is not only a simple fat store tissue, but is also a somewhat active endocrine organ. gender and age differences in peptides and hormones secreted were also reported (5) . likely, this might explain why older people and males are more at risk of developing a negative outcome. lipids are structural elements of viral and cellular membranes. viruses induce the formation of novel cytoplasmic membrane structures and compartments, in which viral genome replication and assembly occurs with, in some cases, shielding from host innate immune response. for instance, several enveloped and non-enveloped viruses are cholesterol-dependent for entry into cells and their replication (8) . moreover, the sterol pathway is involved in other cases of virus infection (9) . viruses require not only membranes on which to replicate but also specific lipids; lipotoxicity in obesity might answer to these requirements. ir is the molecular feature of metabolic syndrome (mes), a cluster of metabolic risk factors for cardiovascular disease as an analogy, the global risk would not depend on the sum of every single factor, but is likely to be affected by the exponential and multiplicative elements (3). therefore, to build an integrated pathogenetic model to be as extensive as possible is advisable. ir was found in patients with hepatitis c virus (hcv) infection and often leads to the development of type ii diabetes (10) . as role of mes in covid-19 is not clear, patients need an accurate metabolic assessment. finucane and davenport concluded with suggestions for clinical implications for studying insulin action in relation to covid-19 severity. unfortunately, in the initial studies of covid-19, no data about insulin determination, bmi, or other systematic metabolic determinations are available. currently, regarding the application in routine clinical practice, concerns arise about the feasibility of measuring ir in acutely ill patients. furthermore, it is arguable how valid the measure could be in people who fell sick and then fasted for several days before admission to the hospital. therefore, a noninvasive way to assess the long-term consequences of insulin and lipid impairment could be done through the screening of nonalcoholic fatty liver disease (nafld, the hepatic manifestation of mes and ir), i.e., through the use of fibroscan (11) . these preliminary observations are highlighting the need to intensively investigate ir and other components of mes in covid-19 pathogenesis. for this purpose, advanced digital solutions (big data, artificial intelligence, machine learning) for the development of sophisticated real-world based algorithms must be promoted. the author confirms being the sole contributor of this work and has approved it for publication. coronavirus and obesity: could insulin resistance mediate the severity of covid-19 infection? front public health prevalence of comorbidities and its effects in coronavirus disease 2019 patients: a systematic review and meta-analysis is insulin resistant brain state a central feature of the metabolic-cognitive syndrome? metabolic-cognitive syndrome: a cross-talk between metabolic syndrome and alzheimer's disease the role of leptin in the control of insulin-glucose axis obesity and insulin resistance membrane-anchored serine proteases in health and disease progress host lipids in positive-strand rna virus genome replication role of srebps in liver diseases: a minireview hepatitis c virus infection and insulin resistance non-alcoholic fatty liver diseases in patients with covid-19: a retrospective study i thank you all my colleagues and in particular dr. mariangela brunetti who got sick by working all day long in covid area and dr. virginia dolcinia who gave me the timely psychological and material support to keep my professional career ongoing despite the terrible moments everyone experienced as well. the author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.copyright © 2020 frisardi. this is an open-access article distributed under the terms of the creative commons attribution license (cc by). the use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. no use, distribution or reproduction is permitted which does not comply with these terms. key: cord-001427-qw1e5cof authors: cantas, leon; suer, kaya title: review: the important bacterial zoonoses in “one health” concept date: 2014-10-14 journal: front public health doi: 10.3389/fpubh.2014.00144 sha: doc_id: 1427 cord_uid: qw1e5cof an infectious disease that is transmitted from animals to humans, sometimes by a vector, is called zoonosis. the focus of this review article is on the most common emerging and re-emerging bacterial zoonotic diseases. the role of “one health” approach, public health education, and some measures that can be taken to prevent zoonotic bacterial infections are discussed. key points: a zoonotic bacterial disease is a disease that can be very commonly transmitted between animals and humans. global climate changes, overuse of antimicrobials in medicine, more intensified farm settings, and closer interactions with animals facilitate emergence or re-emergence of bacterial zoonotic infections. the global “one health” approach, which requires interdisciplinary collaborations and communications in all aspects of health care for humans, animals, and the environment, will support public health in general. new strategies for continuous dissemination of multidisciplinary research findings related to zoonotic bacterial diseases are hence needed. zoonotic diseases are those infections that can be transmitted between animals and humans with or without vectors. there are approximately 1500 pathogens, which are known to infect humans and 61% of these cause zoonotic diseases (1) . the unique dynamic interaction between the humans, animals, and pathogens, sharing the same environment should be considered within the "one health" approach, which dates back to ancient times of hippocrates (2, 3) . bacterial zoonotic diseases can be transferred from animals to humans in many ways (4): (i) the transfer may occur through animal bites and scratches (5) ; (ii) zoonotic bacteria originating from food animals can reach people through direct fecal oral route, contaminated animal food products, improper food handling, and inadequate cooking (6) (7) (8) ; (iii) farmers and animal health workers (i.e., veterinarians) are at increased risk of exposure to certain zoonotic pathogens and they may catch zoonotic bacteria; they could also become carriers of the zoonotic bacteria that can be spread to other humans in the community (9) ; (iv) vectors, frequently arthropods, such as mosquitoes, ticks, fleas, and lice can actively or passively transmit bacterial zoonotic diseases to humans. (10) ; (v) soil and water recourses, which are contaminated with manure contains a great variety of zoonotic bacteria, creating a great risk for zoonotic bugs and immense pool of resistance genes that are available for transfer of bacteria that cause human diseases (11, 12) . bacterial zoonotic infections are one of the zoonotic diseases, which can, in particular, re-emerge after they are considered to be eradicated or under control. the development of antimicrobial resistance due to over-/misuse of antibiotics is also a globally increasing public health problem. these diseases have a negative impact on travel, commerce, and economies worldwide. in most industrialized countries, antibiotic resistant zoonotic bacterial diseases are of particular importance for at-risk groups such as young, old, pregnant, and immune-compromised individuals (13) . almost 100 years ago, prior to application of hygiene rules and discovery of neither vaccines nor antibiotics, some bacterial zoonotic diseases such as bovine tuberculosis, bubonic plague, and glanders caused millions of human deaths. the spread and importance of some bacterial zoonoses are currently globally increasing. that is precisely why most of the developing countries are sparing more resources for a better screening of animal products and bacterial reservoirs or vectors for an optimal preventative public health service (14) . improvements in surveillance and diagnostics have caused increased recognition of emerging zoonotic diseases. herein, changes in our lifestyles and closer contacts with animals have escalated or caused the re-emergence of some bacterial infections. some studies lately have revealed that people have never been exposed to bacterial zoonotic infection risks as high as this before (15) . it is probably due to closer contact with adopted small animals, which are accepted and treated as a family member in houses. on the other hand, more intensified animal farms, which have a crucial role in the food supply, are still one of the greatest sources of food-borne bacterial zoonotic pathogens in today's growing world (4, 8) . people who have closer contact with large numbers of animals such as farmers, abattoir workers, zoo/pet-shop workers, and veterinarians are at a higher risk of contracting a zoonotic disease. members of the wider community are also at risk from those zoonoses that can be transmitted by family pets. the immune-suppressed people are especially at high risk for infection with zoonotic bacterial diseases. people can be either temporarily immuno-suppressed owing to pregnancy, infant age, or long-term immuno-suppressed as a result of cancer treatment or organ transplant, diabetes, alcoholism or an infectious disease (i.e., aids). this manuscript reviews the most common bacterial zoonoses and practical control measures against them. companion animals are increasingly treated as family members, and pets have many bacteria that may infect their owners. the human population of the european union (eu) was approximately 500 million 1 in 2012. the number of pet owning households was estimated at around 70 million in 2010 2 . the most commonly suffered zoonotic bacterial infections in humans are transmitted via animal bites and scratches. various dog breeds have been characterized for their role in killing dog bite attacks, such as pit bull breeds, malamutes, chows, rottweiler, huskies, german shepherds, and wolf hybrids (16) (17) (18) . in usa, pit bull breeds accounted for almost half of the dog bite-related zoonotic infections, three times more than german shepherds (17) . the oral cavity of healthy dogs and cats contains hundreds of different pathogenic bacteria including pasteurella sp. (19) . only 20% of dog bites get infected overall compared with 60% in cats. there are 10 times higher pasteurella multocida infection risks after a cat bite than a dog bite (20, 21) . p. multocida infected bite wounds appear usually within 8 h. it is estimated that approximately 20% of animal bites or scratches get infected in humans (5) . bacterial culturing from pet bite infections in humans is found to be smilar to the oral microbiota of the pets. infections in dog bite wounds are usually dominated by aerobic bugs: p. multocida (50%), alpha-hemolytic streptococcus (46%), staphylococcus (46%), neisseria (32%), and corynebacterium (12%). however, following anaerobic bacteria are also isolated from infected wounds: fusobacterium nucleatum (16%), prevotella heparinolytica (14%), propionibacterium acnes (14%), prevotella intermedia (8%), and peptostreptococcus anaerobius (8%) (22) . normal human skin bacteria or other environmental microorganisms are scarcely isolated from infected wounds in bitten person (22) (23) (24) . usually, infection occurs within 8-24 h after the animal attack, with variable pain on the site of the injury. the cellulitis might be followed by discharge that contains pus, which can sometimes be foul-smelling. immuno-suppressed patients with diabetes or liver dysfunction are frequently predisposed to develop serious infections after animal bites. in those cases, they may develop bacteremia faster and pass away in a shorter period of time (5) . a penetrating bite close to the joints and bones may cause septic arthritis and osteomyelitis. knowing the microbial composition of dental plaque biofilm formation in pets' mouth is a key factor in wound chronicity in humans (5, 25) . cat-scratch disease is a clinical syndrome that has been reported in people for over 100 years. yet, the etiological agent bartonella henselae, which was transmitted by cat scratches and bites, was only identified in 1992 (26) . however, contact with cat saliva on broken skin or sclera can also cause bartonellosis. a person who has had a cat scratch may show papules and pustules at the site of injury (the first initial sign). the disease may progress with a chronic non-healing wound, fever (sometimes), weak regional lymph circulation, and abscession. cat owners and veterinarians are most at risk (27) . systematic medical treatment is usually needed in people with suppressed immune systems. otherwise, encephalopathy, osteomyelitis, and granulomatous conjunctivitis might develop. horses and humans have always shared a close relationship due to recreation, sporting, and occupational reasons, for over thousands of years. in europe, the number of horses per capita remained relatively stable during the past decade. germany and great britain have the largest horse populations in the eu, whereas sweden has the highest number of horses per capita. the frequency of infected horse bite wounds is estimated to be 3-5% in europe (28, 29) . however, it has been roughly estimated that the horse bites account for as high as 20% of overall animal bites in turkey, which comes after dog bites (70%) (30) . more extensive muscle damage may develop in most of the horse attacks, which is different from small animal bites. a mixture of aerobic and anaerobic organisms has been isolated from horse bites in humans, which are frequently dominated by actinobacillus lignieresii (31, 32) . escherichia coli and bacteroides species have also been isolated from foul-smelling infections and pus drainage after horse bites in humans (33) . infectious diarrhea in companion animals is caused by salmonella sp., escherichia coli, shigella sp., and campylobacter sp. can also be transmitted to people through fecal oral route. it is difficult to estimate the distribution of these ubiquitous microorganisms. but it is known that they can be isolated from many healthy animals, which can be shed in their feces for long periods of time. campylobacteriosis were the most frequently reported zoonotic bacterial diseases in 2009 among the eu member countries in humans (34) . like many other enteropathogens, they can cause gastroenteritis (diarrhea, vomiting), headaches, and depression, sometimes even leading to death. it is obvious that raw food diets for pets dramatically increase the risk of human exposure to such zoonotic bacterial enteropathogens, which cause gastrointestinal diseases. although pet birds, also called songbirds (e.g., canaries, finches, sparrows) and psittaciformes (e.g., parrots, parakeets, budgerigars, love birds) are a small fraction of adopted pets, they are widely popular in europe and they are potential carriers of zoonotic diseases (35) . some of them could have an important impact on human health, such as chlamydophilosis (36) , campylobacteriosis (37) , and salmonellosis (38) . parrot fever (chlamydophilosis), which is caused by intracellular bacteria, chlamydia psittaci, lives within the frontiers in public health | infectious diseases respiratory system of birds. inhalation of dust, dander, and nasal secretions of infected birds is the main way of transmission to humans (39, 40) . the mild to severe flu-like illnesses may develop and infected people might be misdiagnosed as influenza. there is unfortunately a lack of quantitative research into the antimicrobial susceptibility of bacterial zoonotic organisms isolated from bite/scratch wounds or companion animal associated gastroenteritis. zambori et al. (5) revealed an increased prevalence of drug resistance in animal bite isolates from people. furthermore, methicillin-resistant staphylococcus aureus (mrsa) or extended-spectrum beta-lactamases (esbl) producing enterobacteriaceae, which are known as nosocomial infections have been frequently isolated in companion animals (41) , including horses (42) . it might be one of the main reasons for the rising prevalence of these potential zoonotic pathogens in human clinical samples. food producing animals in stock has reached a total of more than 200 million (cattle, pigs, sheep, goats, and chicken) living on farms in europe (see text footnote 1). it has been demonstrated that farm animals are reservoirs of many zoonotic pathogens to humans (34, 43) . however, annually, a large amount of drugs are being used worldwide to sufficient quantities of food to feed a rapidly growing world human population (44) (45) (46) (47) . the farm animals consume worldwide approximately eight million kilograms of antibiotics annually (70% of which is used for non-therapeutic purposes such as growth promotion; forbidden in the eu from january 2006, and disease prevention) compared with only approximately one million kilogram per year used in human medicine (7) . antibiotics are routinely fed to livestock as growth promoters to increase profits and to ward off potential bacterial infections in the stressed and crowded livestock factory environment (48) (49) (50) (51) (52) . despite large differences in methodology, most results demonstrate that not so long after the introduction of an antibiotic in veterinary practice, resistance in pathogenic zoonotic bacteria and/or the fecal flora increases. in particular, the wide-spread use of antibiotics in animals has resulted in an increased emergence of bacterial resistance to antibiotics, in zoonotic organisms such as salmonella, campylobacter, shigella, yersinia, listeria, and enterococcus genera, as well as the e. coli species. these zoonotic bacterial organisms are propagated primarily among animals and subsequently infect people (53) (54) (55) (56) . humans can be infected by contact with animals and their dung or droppings or consumption of infected food. severe diarrhea may develop, sometimes with blood in the feces. at all ages, but especially in children under 5 years and adults over 65 years, very serious illnesses often occur. these complications can result in loss of life or permanent kidney damage. according to the latest epidemiological trends, salmonellosis and campylobacteriosis are indicated as the most frequent food-borne bacterial zoonoses in europe. the main food sources were eggs and mixed foods (57) . furthermore, the recent emergence of esbl-producing and carbapenemase positive enterobacteriaceae bacteria in animal production (58) , the emergence of farm associated mrsa st398 (the main pig associated clone) (59) (60) (61) , and of plasmid-mediated quinolone resistance in animal isolates and food products (62, 63) are great threat for public health. unfortunately, these antimicrobial resistant "superbugs" are not only confined to hospital environments where antimicrobial use was high and many pathogens were prevalent. they are already widespread in the european community and animal populations that have a great hazard on public health (64, 65) . the causative agent of bovine tuberculosis, mycobacterium bovis (m. bovis) has been identified worldwide. thanks to decades of disease control measures that the occurrence of the infection has been greatly reduced. but there are still hundreds of new cases of human tuberculosis reported in the usa (66) . experience in europe and the usa, has shown that m. bovis can be controlled when it is restricted in livestock; however, eradication is almost impossible once it has spread into wildlife as follows; the european badger in the united kingdom (67), elk in canada (68) and white tailed deer in the usa (69) . in the last decade, q fever caused by coxiella burnetii was one of the most devastating farm animal originated bacterial zoonotic bacteria in europe. the netherlands, in particular, has experienced several outbreaks from 2007 to 2010 following identification of a q fever outbreak on various dairy farms in 2007. infected humans were mainly located within the intensive dairy goat farms (<5 km) (70) . the infection is spread by ticks, inhalation of the organism from the placental fluids, urine, and consumption of unpasteurized milk -meat products of sheep, goats, and cattle. the clinical signs in humans might be severe flu-like syndrome that may last for months (71) . in the eu, many vector-borne zoonotic diseases are considered as emerging infectious diseases, which either appear in a population for the first time or may have existed previously but spreading rapidly. the ecology of vector-borne zoonotic bacterial diseases is complex where climate and weather may influence the transmission cycles. milder winters, earlier start of spring or long intervals between winters cause extended seasonal tick activity and hence pathogen transmission between hosts in new regions of the world (72, 73) . many vector-borne infections occurred in new regions in the past two decades, while many endemic diseases have increased in incidence (74) . the following bacterial pathogens were most frequently identified as the causes of emerging vector-borne infections in the last decades in the eu: rickettsiae spp., anaplasma phagocytophilum, borrelia burgdorferi, bartonella spp., and francisella tularensis (75, 76) . rickettsia rickettsii causes rocky mountain spotted fever and spreads to humans by ticks. the signs of this disease are fever, headache, muscle pain, and spots with very dark rash. hiking in an area with many infested ticks is a great risk factor. a tick bite of <20 h is usually not enough to transfer these bacteria to a person (77) . ehrlichiosis (anaplasma phagocytophilum) and lyme disease (borrelia burgdorferi) have emerged as an important vector-borne zoonotic disease since 1980s (78, 79) . hard ticks are principal vectors, whereas small rodents are known as their natural vertebrate reservoir. a wide variety of signs including rash, joint pains, fever, enlarged lymph nodes, and some neurological signs may www.frontiersin.org develop. the trend of house buildings in woodlots where humans share the same ecology with reservoirs and vectors was found to be correlated with the increased frequency of such diseases in humans (79) . bartonella spp. is transferred to humans via fleas, lice, and sand flies (80) . however, recent studies have shown the importance of tick exposure in human bartonellosis (81) . as previously mentioned elsewhere in this article, bartonellosis are usually associated with cat-scratch diseases. lately, researchers have revealed that bartonella spp. can be transmitted via cat fleas without any scratches to humans (82) . symptoms include fever, enlarged lymph nodes (after 1-3 weeks), and a papule at the inoculation site. etiological agent of tularemia, f. tularensis, is a rare disease in europe (83) . bacteria are usually transferred by slaughtering (hunters are at a higher risk), eating of infected hares, respiration of dust, or drinking of contaminated water (84) . the prevalence of f. tularensis was found to be 1-5% from dog ticks in north america (85) . clinical symptoms depend on how the organism is acquired: erythematous papule at inoculation side within 48 h, pneumonia (the most serious form), endotoxemia, which gives continuous fever, acute pharyngotonsillitis, mucopurulent conjunctivitis (rarest form) (86) . among many others, brucellosis, which is not an emerging disease, has a significant impact on the endemic southern european countries with sporadic outbreaks. fortunately, the impact on humans has not increased since 2000 (87) . however, the cross border tracing of some brucella strains isolated in germany revealed concordance with sheep isolates originating from eastern anatolian, turkey. it is a characteristic example for the global spread of such diseases, in that case most probably by turkish immigrants living in germany (88) . plague, caused by yersinia pestis, is the most important reemergent bacterial wild rodent borne disease. the current case reports of plague are primarily limited to africa. however, it is a great potential public health hazard for europe due to increased traveler mobility or a potential bioterrorist attack (89) . bacterial zoonoses have a major impact on global public health. both emerging and re-emerging bacterial zoonoses have gained increasing national and international attention in recent years. the closer contact with companion animals and rapid socioeconomic changes in food production system has increased the number of animal-borne bacterial zoonoses. animal bite injuries in daily human-animal contact are not surprising, especially for the school-aged children. most of these wounds are medicated by patients as first aid and not registered in health systems. in more developed countries, most of the victims with moderate to severe bite injuries will seek professional medical treatment. regardless, all bites should be treated as serious, especially if the skin is broken. prompt diagnostic and treatment can prevent wound complications. the possibility to form biofilms by previously mentioned wound microorganisms is quite high, may cause severe tissue damage and protect the bacteria from innate-immune response and antimicrobials. the most of the commercial topical agents and wound dressings are ineffective against the biofilm matrix. surgical repair (for example, co 2 surgical laser techniques, leon cantas, personal research notes 2014), which is usually used to obtain a better cosmetic result might be needed to remove biofilm formed bite infections. this mechanical debridement is essential in the eradication of a wound biofilm. antimicrobials may be more effective in the treatment of the wound after debridement in the prevention of biofilm reformation. despite the use of currently optimal culturing methods, approximately 7% of infected wounds yield no bacterial growth. in such cases, some other fastidious pathogens, i.e., chlamydia spp., mycoplasma spp., and even viruses should be investigated. new advanced molecular diagnostic techniques are needed. prevention strategies for animal bites include close supervision of child-animal interactions, stronger animal control laws, better reporting of animal bites, and public education for better ownership of pets. regular nail trimming, routine oral examinations under annual health checks and comprehensive dental treatments of the companion animals (i.e., routine removal of the teeth tartar and plaques) by veterinarians will reduce the bacterial mass exposure to humans in case of direct contacts or animal bites. it is important to realize that enteropathogenic zoonoses may be contracted from both clinically sick and apparently healthy companion animals. feeding of pets with raw food diets is a potential source of salmonella, campylobacter, and other important bacterial zoonoses; however, some recalls of commercial pet food diets have also occurred as a result of contamination with those microorganisms. pig ear dog treats, in particular, have been implicated as an important source of salmonella infection for dogs, which can also serve as a source of infection to humans. nevertheless, it can be said that easy-to-use personal hygiene rules should be applied by companion animal owners. thorough hand washing with soap after handling of a companion animal and before eating or drinking, avoiding mouth-to-mouth contact, avoiding aerosolization of dusty fecal matter will help to prevent transmission of the zoonotic disease to humans. the animals with diarrhea should be isolated immediately and veterinary advice should be sought. the household should be cleaned with agents and kept as clean as possible. on the other hand, the prevalence of antimicrobial resistance in small animal pathogens is increasing globally due to overuse of broad spectrum antibiotics by veterinarians. there is an immediate need for worldwide smarter use of antimicrobials that have some positive effect on the recovery of animals from life threatening diseases. national veterinary antimicrobial treatment guidelines should be established by the local authorities according to the updated routine surveillance results. chronic diarrhea, dermatitis, ear and eye infections of pets caused by microbes demand longer durations of antimicrobial remedies at home. more frequent use of advanced laboratory tests, such as; feed/insect/mould allergy tests and differential diagnosis of the other relevant auto-immune disorders may help to investigate the main underlying cause of the such reactions which can be managed in various alternative treatment methods (i.e., hypoallergenic diets) rather than antibiotics solely. herein, pet specific auto-immune vaccines against allergens and auto-lactobacillales (auto-lac, leon cantas, personal research notes, 2011-2014) as dietary supplements can also be more frequently administered within the preventative veterinary practice measures. owners should be encouraged to insure their family animals to afford such costly veterinary services contradictory to the cheaper and sometimes life-long medical (i.e., antibiotic) treatment demanding options. veterinarians should also spear more time to educate the pet owners under consultations to handle infected-antimicrobial treated animals with precaution due to irreversible consequences of the antimicrobial resistance development and its spread in households. proper hand washing and use of gloves are strictly recommended while handling antimicrobial in veterinary clinics. veterinarians should prescribe broad spectrum and synthetic antimicrobials preferably after culturing with extreme precautions (i.e., dosage, dosing intervals and length of the treatment). reduced antibiotic use will hinder the development of antibiotic resistance in animal microbiota which might cause zoonotic infections in humans (50, 52) . food-borne zoonoses are an important public health concern worldwide and every year a large number of people affected by diseases due to contaminated animal originated food consumption. food hygiene education of the consumers is an important competent of food-borne diseases prevention. however, main prevention of food-borne zoonoses must begin at the farm level with in the concept of "one health." herein, control of the production stress especially in intensive livestock industry, with the development of better animal health management routines (i.e., routine vaccinations, immune stimulants: pre-, probiotic feed additives) and the increased animal welfare programs, will contribute eventually to an optimal production of animal health. increased antimicrobial resistance among emerging and re-emerging farm-borne bacterial pathogens in crowded settings (i.e., poultry, pig farms) is a growing problem. restrictive antimicrobial choice with better animal welfare managements are needed to control the spread of antibiotic resistance elements. in the eu, the use of avoparcin was banned in 1997 and the use of spiramycin, tylosin, and virginiamycin for growth promotion were banned in 1998. all other growth promoters used in feeding of food producing animals were banned from january 1, 2006 after a few national bans the years ahead 3 . in the u.s., politicians are still discussing to introduce a similar ban (s-742, 109th u.s. congress (preservation of antibiotics for medical treatment act). despite the ban on the use of all antibiotics as growth promoters in the eu and a ban on the use of quinolones as growth promoters in the poultry feed in the us medical, important antibiotics are still routinely fed to livestock prophylactically to increase profits and to ward-off potential bacterial infections in the stressed and crowded livestock and aquaculture environments in some parts of the world (50, 90, 91) . because stress lowers the immune system function in animals, antibiotics are seen as especially useful in intensive animal confinements (92) . the non-therapeutic use of antibiotics involves low-level exposure in feed over long periods -an ideal way to enrich resistant bacterial population (93, 94) . moreover, antibiotic resistance has been detected in different aquatic environments (95) . fish pathogenic bacteria often produce devastating infections in fish farms where dense populations of fish are intensively reared. bacterial infections in fish are regularly treated with antibiotics in medicated feed. so far, most of the fish pathogenic bacteria with a 3 http://europa.eu history in diseased fish farms have developed drug resistance (96) . modern fish farming relies increasingly on vaccination procedures and improved management to avoid infections (97) . for example, the norwegian aquaculture industry has produced over one million tons farmed fish 4 by using improved vaccines, management techniques, and only 649 kg of antimicrobials in 2011 (98) . vector-borne and zoonotic bacterial pathogens are a major source of emerging diseases, and since the time of hippocrates, weather and climate are linked to the incidence of such infectious diseases. complexity of epidemiology and adoptive capacity of microorganisms and the arthropods make the vector-borne disease almost impossible to eradicate. insect repellants, routine tick checks after outdoor activity in risk regions, prompt-proper tick removal, use of long sleeves and trousers (light-colored), and routine insecticide treatment of pets are recommended as general preventative measures (99) . herein, lyme disease, tick-borne illness, is vastly underestimated over past decades and clearly the urgent prevention is needed. besides individual awareness of such vector-borne diseases, better national surveillance and reporting programs will contribute to improved the disease control strategies. clinicians have an important role in the effective management of vector-borne zoonotic diseases, with enhanced differential diagnostic skills based on clinical symptoms and rapid molecular identification techniques (100) (101) (102) (103) . most of the time, the clinicians are on the first line of detection of these epidemics due to large group of patients with novel sets of similar symptoms. increased medical networking via online databases offer a broad overview to followers with regard to changes in temporal patterns of illness in real time, which helps faster detection of new epidemics (104) . identification and control of emergent zoonotic bacterial diseases require a "one health" approach, which demands combined efforts of physicians, veterinarians, epidemiologists, public health workers, and urban planners. collaborative international routine surveillance strategies, prompt -reliable agent identification techniques, and optimization of the treatment regiments will ensure the prevention and management of such infections. leon cantas defined the review theme, manuscript design, established the coordination and the collaborations, designed the manuscript, contributed to the data collection, data analysis, and drafting, writing and editing of the manuscript. kaya suer contributed to drafting and editing of the manuscript. all authors have seen, and approved the manuscript. risk factors for human disease emergence professor emeritus of veterinary epidemiology the components of 'one world -one health' approach animal associated opportunistic infections among persons infected with the human immunodeficiency virus biofilms in oral cavity of dogs and implication in zoonotic infections sensitive populations: who is at the greatest risk? monitoring and identifying antibiotic resistance mechanisms in bacteria emerging foodborne diseases: an evolving public health 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a potential conflict of interest. key: cord-285228-famhbr16 authors: larsen, joseph r.; martin, margaret r.; martin, john d.; kuhn, peter; hicks, james b. title: modeling the onset of symptoms of covid-19 date: 2020-08-13 journal: front public health doi: 10.3389/fpubh.2020.00473 sha: doc_id: 285228 cord_uid: famhbr16 covid-19 is a pandemic viral disease with catastrophic global impact. this disease is more contagious than influenza such that cluster outbreaks occur frequently. if patients with symptoms quickly underwent testing and contact tracing, these outbreaks could be contained. unfortunately, covid-19 patients have symptoms similar to other common illnesses. here, we hypothesize the order of symptom occurrence could help patients and medical professionals more quickly distinguish covid-19 from other respiratory diseases, yet such essential information is largely unavailable. to this end, we apply a markov process to a graded partially ordered set based on clinical observations of covid-19 cases to ascertain the most likely order of discernible symptoms (i.e., fever, cough, nausea/vomiting, and diarrhea) in covid-19 patients. we then compared the progression of these symptoms in covid-19 to other respiratory diseases, such as influenza, sars, and mers, to observe if the diseases present differently. our model predicts that influenza initiates with cough, whereas covid-19 like other coronavirus-related diseases initiates with fever. however, covid-19 differs from sars and mers in the order of gastrointestinal symptoms. our results support the notion that fever should be used to screen for entry into facilities as regions begin to reopen after the outbreak of spring 2020. additionally, our findings suggest that good clinical practice should involve recording the order of symptom occurrence in covid-19 and other diseases. if such a systemic clinical practice had been standard since ancient diseases, perhaps the transition from local outbreak to pandemic could have been avoided. the current pandemic of coronavirus disease 2019 , caused by severe acute respiratory syndrome coronavirus 2 (sars-cov-2), has undergone an observed exponential increase of cases that has overrun hospitals across the world (1). many people have mild forms of the disease and are advised not to go to the hospital or to seek a diagnostic test because they can recover at home. a large number of others are asymptomatic (2) . infected individuals are highly contagious and can transmit the disease even if they are asymptomatic, and this fact furthers the need to isolate and test often (2) . in addition, covid-19 is two to three times more contagious than influenza (3) . due to these characteristics, outbreaks of covid-19 occur in clusters (4) . identifying covid-19 early could reduce the number and size of clusters, but early symptoms are not well-defined. the center for disease control and prevention (cdc) in the usa and the world health organization (who) currently advise the public to call their doctor if they believe they have been exposed to covid-19 or exhibit fever and cough (5) . however, fever and cough are associated with other respiratory diseases such as influenza (6) (7) (8) . influenza, with an estimated number of symptomatic cases in the millions annually in the u.s. alone (9) , also is commonly associated with fever and cough (6) . similarly to covid-19, the middle east respiratory syndrome (mers) and the severe acute respiratory syndrome (sars) are respiratory illnesses contracted from coronaviruses called the mers-related coronavirus (mers-cov) and sars-related coronavirus (sars-cov), respectively (7) . the symptoms of these diseases also overlap with covid-19. the capacity to discern differences in these common symptoms, such as order of occurrence and likely first symptoms, would aid in early recognition. if health care workers recorded and published clinically-observed and/or patient-reported sequences of symptoms, the reported data could be evaluated as an additional tool for early recognition of covid-19 to increase self-surveillance and reduce spread. if such a widespread clinical practice had been instituted in the past, perhaps local outbreaks of influenzas, coronaviruses, and other diseases might have been contained before becoming pandemics. to this end, we assumed that symptoms and their orders are independent variables and created a model that approximates the probability of symptoms occurring in specific orders using available, non-ordered patient data. the use of these assumptions and data was necessary given the lack of ordered data. to do this, we applied a markov process to determine the order of occurrence of common symptoms of respiratory diseases. we have previously used a markov chain to predict cancer metastasis location (10) (11) (12) (13) (14) . a markov process is defined as a stochastic sequence of events in which the likelihood of the next state only depends on the current state rather than past or future states (15) . in this case, we defined each state to be the specific symptoms that a patient has experienced, and each transition is only dependent on these symptoms. as a result, we can determine the likelihood of each symptom stepwise using a markov process. we defined the state probability of a node as the frequency that a patient has a particular combination of symptoms divided by the total number of patients that exhibit the same number of symptoms. the transition probability between two states is defined as the likelihood of acquiring a single specific symptom divided by the likelihood of acquiring all possible next symptoms. we then applied a greedy algorithmic approach using the transition probabilities to calculate the probability of all possible orders toward determining the most and least likely orders of symptoms. in this study, we first defined this specific application of a markov process applied to a graded partially ordered set (poset), which we refer to as the stochastic progression model. in this case, our graded poset represents all possible combinations of symptoms and all possible orders of symptom occurrence. it is graded because the possible combinations of symptoms are ranked by the number of symptoms that they each represent. for example, the symptom combination of fever and cough has the same rank as the combination of cough and diarrhea. we found that the stochastic progression model for adults that are symptomatic indicates that there may be an order of discernible symptoms in covid-19, but the order of symptoms seems to be independent of severity of the case on admission. from there, we compared the most likely order of symptoms in other respiratory diseases to covid-19. to expand on our results, we analyzed a larger set of symptoms that are common to all respiratory diseases studied here and sought to decipher further distinctions. patient data from this study was collected from various reports in literature on the frequencies of symptoms in covid-19, influenza, mers, and sars (supplemental tables 1, 2) . each dataset was used either to approximate order of symptoms, to confirm our results, or to analyze first symptoms in covid-19 or influenza. for all of these applications, we used the reported patient data to simulate patients with various combinations of symptoms experienced and then applied the simulated data to perform the analyses. the main dataset of covid-19 patients of the world health organization, containing 55,924 confirmed cases, was obtained through review of national and local governmental reports and observations made during visits to areas with infected individuals in china that occurred from february 16 to 24, 2020 (8) . a confirmation dataset of covid-19 patients, containing 1,099 confirmed cases, was obtained by the china medical treatment expert group for covid-19 from medical records and other compiled data of hospitalized patients and outpatients that were diagnosed with covid-19. this data was reported to the national health commission of china from december 11, 2019 to january 29, 2020 (16) . for both covid-19 datasets, myalgia was reported as myalgia or arthralgia. we assumed that most patients with myalgia also had arthralgia, and therefore we used the frequency of myalgia or arthralgia as a frequency for myalgia when simulating data. the influenza dataset, containing 2,470 confirmed cases, was collected by researchers at the university of michigan from a retrospective pooled analysis of mostly unvaccinated patients participating in phase 2 and 3 clinical trials that were conducted in north america, europe, and the southern hemisphere from 1994 to 1998 (6) . this group of patients has a mean age of 35 and each exhibited multiple symptoms. vomiting and diarrhea were not reported in this influenza dataset, but they are common among respiratory disease. although adult patients at times may experience vomiting and diarrhea when infected with influenza, these symptoms are rare (17) . therefore, we approximate the frequency of these symptoms as 0.010 in this case. the datasets representing symptom frequency in mers, containing 245 patients, and sars, containing 357 patients, were collected on admission and were reported as clinical data from physicians, dr. yin, at the beijing chao-yang hospital and dr. wunderink, at the northwestern university feinberg school of medicine (7) . the patients included in these datasets varied in age and pre-existing conditions. in the cases of sars, the patients tended to be younger and have fewer pre-existing conditions than in the cases of mers. we used initial frequency data of mers and sars to further ascertain early symptoms of disease. the mers initial symptom frequency dataset, containing 45 confirmed cases, was collected from electronic medical records at the samsung medical center in seoul, south korea that contained onset symptom data about patients in the 2015 korean mers outbreak (supplemental table 3 ) (18) . the sars initial symptom frequency dataset, containing 144 confirmed cases, was collected from hospital records including information of early symptoms in patients dating from march 7 to april 10, 2003 during an outbreak in the greater toronto area (supplemental table 4 ) (19) . lastly, two additional datasets were collected to determine the utility of using first symptoms as early indicators of covid-19 and influenza. the covid-19 dataset used, containing 138 patients, was independent of all prior covid-19 datasets. this data was obtained from electronic medical records of patients admitted to the zhongnan hospital of wuhan university from january 1 to 28, 2020 (20) . the symptom data was collected at onset of disease and all patients experienced pneumonia due to covid-19. in this dataset, nausea and vomiting were reported separately for covid-19. we assumed that most patients who experience vomiting, which is reported with a frequency of 0.036, also experience nausea, which is reported with a frequency of 0.101, and therefore to simulate the data, we defined the frequency for nausea/vomiting as 0.101. the influenza dataset used reported 20 confirmed cases of influenza and 400 confirmed negative cases of influenza and is independent from any other influenza dataset we used (21) . the symptom data was collected through questionnaires and observations by medical professionals during the influenza seasons of 2006 and 2007 of infected patients admitted at the department of internal medicine and infectious diseases and the department of pulmonology at the university medical center utrecht. like the other influenza dataset described above, vomiting and diarrhea were not reported in this dataset. so, we once again assumed the frequency of these symptoms to be 0.010 (17) . because this study was conducted in 2006 and 2007, prior to the covid-19 outbreak, we assumed these patients were negative for covid-19 as well. so, this 400-patient group was used as the dataset that represents individuals negative for both covid-19 and influenza (supplemental table 5 ). the stochastic progression model was built in r under version 3.5.2 and was illustrated by using the hasse function in the hassediagram_0.1.3 library (code available online: https:// github.com/j-larsen/stochastic_progression_of_covid-19_ symptoms) (22, 23) . each respiratory disease report was represented by a corresponding data frame, with columns as symptoms, one row as the frequency of the symptoms observed in the study, and the other row as the frequency multiplied by 1,000. the multiple of the frequency is defined as the frequency count, which represents the probability of a symptom in a theoretical sample size of 1,000 simulated patients. additionally, the state of an individual is displayed through a character array of ones and zeros, where ones represent the presence of a symptom and zeroes represent its absence. this process of simulating a symptom is analogous to a jar of marbles of either two colors. the probability of pulling one color of marble (i.e., a specific symptom) is illustrated by the frequency count because the total number of marbles in the jar is 1,000 and the frequency count for each is the number of the specific color of marbles in the jar. we then simulated data of 500,000 patients, by randomly selecting if a patient has or does not have a symptom using the procedure described above and storing that information in a data frame that represents patients as rows and symptoms as columns. we assumed the occurrence of symptoms are random and independent. considering these assumptions, we built the character arrays by applying the jar of marbles method for each simulated patient. the method repeats for each patient and involves pulling a marble from a series of jars representing each symptom. the information from each randomly pulled marble is stored in the corresponding cell of the character array in the correct column representing the symptom and the row representing the simulated patient. this process is repeated for all 500,000 simulated patients for all symptoms. the stochastic progression model is illustrated as a directed acyclic graph with nodes, representing the power set of boolean vectors. the power sets of boolean vectors each represent a possible state of a patient by noting the absence or presence of specific symptoms. the edges, which illustrate the transition from one state to another, were selected specifically using key definitions and assumptions to create a poset. we defined the states at the nodes as symptoms that a patient has experienced up until this point. we created and directed edges from states with fewer symptoms to more starting at the minimum set of a boolean vector of all zeros, which indicates a person with no symptoms. first, we assume that each symptom occurs one at a time, even if the difference in time is infinitesimal. with this assumption, a node can only be directed to other nodes that denote the same set of symptoms plus one additional symptom. second, we assume that if a patient does not digress and does not die, they will eventually acquire all symptoms reaching the maximum set of a boolean vector, which represents a patient that has exhibited all symptoms. applying these assumptions to form the directed acyclic graph creates a hasse diagram of a graded poset that follows a markov process altogether comprising the stochastic progression model. the nodes in the hasse diagram represent states of a patient by indicating the specific symptoms exhibited, and the edges represent transitions between these states. therefore, we next needed to apply state probabilities to each node and transition probabilities to the directed edges. first, we labeled each simulated patient by summing the respective boolean vector to find the number of symptoms for each patient. then, to get the state probability of each node, we divided the number of simulated patients that are represented by the current boolean vector by the total number of patients who have the same number of symptoms. to approximate the transition probability between two nodes (originating and terminating), we divided the number of simulated patients that are represented by the terminating node by the number of simulated patients that are represented by nodes characterized by the same number of symptoms as the terminating node, including the terminating node. the error of each node is determined by the sum of the products of the transition probabilities leading to that node subtracted from the state probability of the node. then, the error of each implementation of the model was defined as the error of the node with the highest absolute value of error (supplemental figures 2-13) . the transition probabilities signify the likelihoods of transitions from one node to another, and the aggregates of the transition probabilities in a sequence represent the likelihoods of the paths. these paths illustrate the order of symptoms when infected with a respiratory disease by observing the stepwise addition of symptoms when traversing down nodes in the path. the most and least likely paths were determined using a greedy algorithmic approach. this approach consists of selecting local maximum or minimum edges stepwise, which results in a most and least likely path, respectively. if the maximum (or minimum) transition probability from a specific node was within error of other transition probabilities of edges from the same originating node, we grouped the terminating nodes when finding the most (or least) likely path. in these cases, we could not distinguish a difference in likelihood between these specific transitions. the paths create a possible order of symptoms via the poset, each having a specific likelihood of occurrence. the who-china joint report from february 16 to 24, 2020 includes rates of symptom occurrence at presentation from 55,924 confirmed cases of covid-19 (8) . we identified symptoms that were easily discernible or objective (i.e., fever, cough, diarrhea, and nausea/vomiting) in comparison to other reported symptoms, such as inflammations of blood vessel epithelia (24) , neurological effects (25) , and rash-like symptoms (26) . these symptoms are also common in other respiratory diseases. thus, we chose to implement these four symptoms in the stochastic progression model (supplemental table 1 ). to confirm the validity of the model, we first determined the possible sequences of symptom occurrence when the probabilities are uniformly random for each symptom. in addition to all possible orders of occurrence of the four symptoms, the diagram displays the most and least likely paths of the four symptoms, depicted by red lines and blue lines, respectively (figures 1a,b) . the most and least likely paths describe the most and least likely series of symptoms that a random infected person from the population in the dataset may experience. in this case, each possible path is equally likely, with no path having any higher probability than any other. we then created another implementation of the stochastic progression model and utilized the data in the who-china joint report (covid-19 with n = 55,924) (8) . with this implementation, we determined the most and least likely paths ( figure 1c) . in this case, a person infected with covid-19 is most likely to experience symptoms in the order of fever, cough, nausea/vomiting, then diarrhea ( figure 1d) . the least likely path starts at diarrhea and nausea/vomiting and is followed by cough, and finally fever ( figure 1e) . we confirmed these results with a smaller dataset (covid-19 with n = 1,099) (figures 1d,e , and supplemental figure 1 ) (16) . the likelihoods of transitioning to fever, 0.769, and then to cough, 0.958, are high, and these observations indicate that a large portion of infected symptomatic patients may follow this path. finally, this implementation of the model predicts that nausea/vomiting occurs before diarrhea. these two results suggest that in patients with sars-cov-2, the body first develops fever, then upper respiratory symptoms and finally symptoms of the upper then lower gastrointestinal (gi) tract. to further investigate these symptom paths, we implemented the stochastic progression model with the main dataset (covid-19 with n = 55,924) (8), to determine the likely downstream paths when the first one or two symptoms are forced to a certain state (figures 1f-i) . the gray lines represent the "forced" paths. the rest of the paths were determined as before with a greedy algorithmic approach. we found that the most likely orders of the downstream path are consistent with the most likely orders of the unforced paths. even if the first symptom is forced to be an unlikely one (e.g., diarrhea), the downstream paths maintain the most likely order of the other three symptoms that we originally determined ( figure 1f) . similarly, the gi tract effects occur first in the forced least likely paths ( figure 1g) . when forcing the path one step further by predetermining the first two symptoms for both the most and least likely paths, the findings remain the same (figures 1h,i) . the confirmation dataset of covid-19 cases (n = 1,099) separates the reported 1,099 cases between severe and nonsevere patients as designated on admission (16) . to investigate the effects of severity on the order of discernible symptoms, we implemented each set of cases separately using the stochastic progression model. we found that the most and least likely paths are identical in severe and non-severe cases and to our original findings above (figure 2) . to illustrate the similarities, the largest difference in likelihood is observed when transitioning from no symptoms to fever in the most likely path. in severe and non-severe cases, the probability is 0.775 and 0.818, respectively, indicating a difference of 0.043. these results suggest that severity does not affect the order of discernible symptoms, and they are consistent with the hypothesis of fever as the first symptom of covid-19. the four discernible symptoms are objective and relatively easy for patients and clinicians to confirm. so, we developed implementations of the stochastic progression model using these symptoms to determine the most likely and least likely paths for four respiratory diseases: covid-19, influenza, mers, and sars (figures 3a-d) (6) (7) (8) . the most likely order of occurrence of symptoms in covid-19 is fever, cough, nausea/vomiting, and diarrhea ( figure 3a) . this path is identical to influenza except the order of the initial two symptoms is switched (figure 3b) . on the other hand, the predicted most likely paths (i.e., fever, cough, diarrhea, and then nausea/vomiting) are the same for mers and sars (figures 3c,d) . this order has one difference from the most likely path in covid-19 in that the order of the final two symptoms are reversed. the least likely path of mers starts with either nausea/vomiting or diarrhea as the first step. these steps are followed by cough, and finally fever. in contrast, the least likely path of sars is cough, nausea/vomiting, and diarrhea in any order, and then finally fever. however, the least likely path of symptoms in covid-19 is the same as the least likely path in mers, and the least likely path of influenza is unique compared to the other diseases. it is not detectable whether nausea/vomiting or diarrhea are the first symptoms in influenza, but after these two, the least likely path continues from there to fever then cough. this observation further illustrates the strong link of cough to influenza. as for coronavirus-related diseases, the strongest first indicator is fever followed by cough. although active surveillance of the order discernible symptoms (i.e., fever, cough, nausea/vomiting, and diarrhea) could be useful due to the distinctive most and least likely paths that we determined, we expanded our analysis to the seven symptoms commonly observed in all four respiratory diseases studied here. so, we created a second set of symptoms that amends sore throat, myalgia, and headache to the original set of symptoms (supplemental table 2 ). the three additional symptoms are more subjective (6) (7) (8) . the seven-symptom implementation of the stochastic progression model of covid-19 shows that these additional symptoms did not perturb our initial ordering of fever, coughing, nausea/vomiting, and diarrhea, but instead added another level of intricacy in the middle of the likely paths (figure 4) . we still find that the most likely path first transitions to fever, indicating that fever is the most likely first symptom. from there, the most likely next symptom is cough once again. then, we observe an undetectable difference in likelihood of transitioning to either sore throat, headache, or myalgia, indicating that all three are likely to occur next before proceeding. the final two nodes are consistent with the foursymptom order by indicating that nausea/vomiting then diarrhea occur last. although this implementation is more complex because it has seven symptoms, it is consistent with our earlier findings. the most likely path of covid-19 symptoms is fever, then cough, and next either sore throat, myalgia, or headache, followed by nausea/vomiting, and finally diarrhea, and this order is the same as the one indicated by the implementation developed from the confirmation dataset (covid-19 with n = 1,099) (figure 4) (16) . we also implemented the stochastic progression model with the same seven symptoms in influenza, sars, and mers datasets to compare and contrast disease progression with that in covid-19 ( figure 5 ) (6) (7) (8) . the results for influenza indicate that cough or myalgia may occur first (figure 5a ). after these two symptoms occur, the order of symptoms is headache, sore throat and fever. finally, vomiting/nausea and diarrhea have an undetectable difference in probability of occurring last. the mers implementation displays a most likely path in which fever will occur first, followed by cough, headache, and then myalgia ( figure 5b ). these are followed by an undetectable difference in likelihood of headache and diarrhea occurring. finally, sore throat and nausea/vomiting will occur last with an undetectable difference. the implementation for sars shows that fever is most likely to occur first, followed by an undetectable difference in transition probability of cough and myalgia, which is similar to the other coronavirus-related diseases ( figure 5c ). next, headache is most likely. finally, diarrhea, sore throat and nausea/vomiting occur with an undetectable difference in likelihood. to illustrate the uniqueness of the most likely path of covid-19, we found the transition probabilities of the same path in the other respiratory diseases (figure 6) . when comparing and contrasting the probabilities, we found that the implementation representing covid-19 strongly asserts that the first symptom will be fever and cough will soon follow because the transition probabilities are 0.731 and 0.783, respectively (figure 6a) , whereas the influenza implementation indicates that fever is very unlikely to occur first with a probability of only 0.035 ( figure 6b) . additionally, the implementations of mers and sars data also have a high likelihood of transitioning to fever first, with a probability of 0.627 and 0.988, respectively (figures 6c,d) . the second symptom of the most likely path of covid-19 is cough, with a probability of 0.783, but the others do not have a similar high probability. for example, the respiratory disease with the highest probability at that transition is mers at 0.536. however, after fever and cough, covid-19 and the other three respiratory diseases have a similarly high likelihood of the three subjective symptoms (i.e., sore throat, headache, and myalgia). finally, the most likely path of covid-19 ends with nausea/vomiting and then diarrhea. these observations are consistent with the symptoms described by the cdc and support the notion that fever followed by cough seems highly likely to be diagnosed as covid-19 (5) . also, comparing the transition probabilities of paths in the same disease illustrates the significance of the most likely pathways. for example, the lowest transition probability in the most likely path of influenza is 0.578 (figure 5a) , whereas when analyzing influenza as it traverses down the most likely path of covid-19, the transition probabilities observed are 0.5 or less ( figure 6b) . however, in that same path, the transition probability from fever and cough to fever, cough, sore throat, headache, and myalgia is >0.999. this value displays how unlikely nausea/vomiting and diarrhea are to be initial symptoms of influenza. additionally, when observing the most likely path of covid-19, the first two symptoms seem to have a strong probability of occurring in the order of fever and then cough, with a likelihood of 0.731 ( figure 5a) . however, the likelihood of cough occurring first in covid-19 is 0.229, which is a low probability (figure 5a ). this observation further supports the hypothesis of fever occurring first and cough occurring second. the covid-19 and influenza implementations of the stochastic progression model suggest that there is a high likelihood of fever and cough occurring first, respectively. we desired to find metrics quantifying the possible link between first symptom and these two diseases. so, we determined the recall and the selectivity when using the initial symptom as an indicator of covid-19 or influenza, with all other possible diseases excluded in a theoretical patient population. first, we simulated patient datasets using reported data that were independent from all previous work that we integrated in our analyses above (supplemental table 5 ) (20) . two simulated patient datasets were created to analyze covid-19 and influenza separately to portray the specific link of each disease with the corresponding initial symptom that we determined, fever and cough, respectively. the simulated data contained information about the patients' state of disease (covid-19, influenza or not) and their first symptom experienced. based on the information of the first symptom alone, we categorized the simulated patient data as infected with covid-19 or not and influenza or not. the recall was calculated as the number of simulated patients that we correctly identified as having the disease over the number of simulated patients that truly had the disease (27) . selectivity was defined here as the number of simulated patients that we correctly identified as not having the disease over the number of simulated patients that truly did not have the disease (28) . for both diseases, we performed this analysis for five simulated samples of different sizes, each containing 5% infected individuals. we repeated this process 10 times and calculated the average and standard deviation across each sample size for both covid-19 and influenza (tables 1, 2) . the recall ranges from 0.966 to 0.990 with a standard deviation of 0.031 and 0.021, respectively when analyzing the link between covid-19 and fever as a first symptom. the maximum standard deviation of any sample size is 0.063 for the mean of 0.980. on the other hand, the selectivity of fever as a first symptom of covid-19 ranges from 0.661 to 0.668 with a standard deviation of 0.030 and 0.020, respectively, and 0.030 is the maximum standard deviation with corresponding means of 0.661 and 0.665 ( table 1) . as for cough as a first symptom of influenza, the recall ranges from 0.765 to 0.820 with corresponding standard deviations 0.092 and 0.067. the highest standard deviation is 0.110 with a mean of 0.810, and the selectivity ranges from 0.362 to 0.369 with standard deviations of 0.014 and 0.031, respectively, and the maximum standard deviation is 0.031 ( table 2) . the recall in both cases is lower than the selectivity, and this observation indicates that this analysis categorizes patients as infected when they are not, but the high recall indicates that most infected patients did align with the first symptom that we predicted. in the future, we expect to confirm this analysis with data on first symptoms, as opposed to simulated data, but the purpose of this analysis was to display that further study of order of symptoms might lead to earlier recognition. in this study, we found evidence that supports the notion that there is a most common order of discernible symptoms in covid-19 that is also different from other prominent respiratory diseases. the most likely initial symptom is fever in the three diseases studied that are caused by coronaviruses (i.e., covid-19, sars, and mers) and cough in influenza. the most likely order of the four easily discernible symptoms is identical in mers and sars, but the most likely path of covid-19 has one key difference. the first two symptoms of covid-19, sars, and mers are fever and cough. however, the upper gi tract (i.e., nausea/vomiting) seems to be affected before the lower gi tract (i.e., diarrhea) in covid-19, which is the opposite from mers and sars. in all diseases, we found that fever and cough occur before nausea/vomiting and diarrhea. when observing the set of seven symptoms including three subjective ones (i.e., sore throat, headache, and myalgia), we found that the initial symptoms of the most likely path are the same as in the most likely path of the four discernible symptoms. also, in both the four and seven symptoms implementations, the gi tract symptoms are last. a separate mers dataset included the initial symptoms of patients on admission, which listed the symptoms from highest to lowest probability as fever, myalgia, cough, and diarrhea (18) . this order is similar to the most likely path that we determined. a very small percent of patients experienced diarrhea as an initial symptom. this report suggests that diarrhea as an early symptom indicates a more aggressive disease, because each patient in this dataset that initially experienced diarrhea had pneumonia or respiratory failure eventually (supplemental table 3 ). we propose that these patients may be experiencing a more aggressive form of the disease and have accelerated through the most likely path, having already experienced diarrhea. these findings align with another dataset provided for sars, which also contained the percentage of the various symptoms to be reported first (supplemental table 4 ). the highest reported symptom is fever, followed by cough or dyspnea, and then finally, a small percent of patients reported diarrhea (19) . this order confirms the most likely paths that we have determined. the observation that diarrhea was very uncommon as a first symptom and had a nonzero probability of occurrence is consistent with our analysis. this aligns with our hypothesis that early occurrence of diarrhea implies that those patients may have a much more aggressive form of the disease. the simulation data used to approximate the state and transition probabilities in the stochastic progression model relies on the assumption that symptoms included in the model are independent. using the definition of independence, we observed the individual probabilities of fever and cough in a dataset from a case study of influenza, and we found that the product of the individual probabilities of fever and cough is almost equal to the probability of both occurring (21) . considering this outcome, we proceeded under the assumption of independence, which we will reevaluate when more symptom data becomes available. we simulated combinations of symptoms for 500,000 patients, which we chose because it was the lowest attempted number that empirically produced the theoretical expected outcome for random frequency symptoms: that all paths would be equally likely, up to 100ths of a decimal place. we then utilized these simulated patients to approximate the state probabilities and transition probabilities described above. this study supports the idea that symptoms occur in a predictable order, but future work is needed to improve aspects of the stochastic progression model and confirm the results found here. our finding that covid-19 first presents with a fever supports the recommended measures by the cdc which state that the public should take their temperature at home and when entering facilities as an early checking method (29) . this application of the stochastic progression model may be improved if there were objective ways to measure the more subjective symptoms (i.e., sore throat, headache, and myalgia). also, improved error calculations of the transition probabilities would lead to more accurate results. our current error calculation is conservative, because when more symptoms were added, we observed that the error compounded as we progressed further down the paths (supplemental figures 2-13) . the conservative error estimate creates issues in discerning the difference in probabilities of symptoms. specifically, in implementations of seven symptoms, the likelihoods are more difficult to ascertain due to subjective reporting and compounding error calculations. datasets that contain the order of symptoms for each patient would lower the error. additionally, these sorts of datasets would better the approximations of the transition probabilities and increase accuracy. this improvement could be achieved by physicians implementing the practice of recording the order of occurrence of symptoms. with this information, we may approximate the likelihood of a patient acquiring a symptom based on their current symptoms with patient data instead of simulations based on frequency. applying objective criteria for symptoms, improving error calculations, and collecting the order of symptoms would not only allow us to improve our findings here, but also allow the stochastic progression model to predict orders of a larger set of symptoms. the optimal form of the stochastic progression model would be developed by determining state probabilities from observed true frequencies of patients' symptoms and determining transition probabilities from the patients' true order of symptoms. however, until this data is available, improved approximations, simulations and error calculations are needed. furthermore, when analyzing fever as the first symptom of covid-19, a low selectivity indicates a high type i error (i.e., rate of false positive), and a high recall indicates a low type ii error (i.e., rate of false negative). we found a moderate selectivity value and as a result, a moderate type i error in this case. this type i error is acceptable in our use of investigating fever as an initial symptom of covid-19, because it suggests that more people get tested who are not infected, rather than less people get tested who are infected, as with type ii error (30) . we are not proposing initial symptom as a diagnostic test, but instead as a possible sign to get tested. covid-19 outbreaks in clusters, and these unusual clusters of disease are characteristic of a pandemic disease that must be addressed immediately with aggressive testing to curb transmission (31) . the importance of knowing first symptoms is rooted in the need to stop the spread of covid-19, a disease that is two to three times more transmissible than influenza and results in outbreaks of clusters (3, 4) . there is a heightened risk in covid-19 being passed on, so faster testing and social distancing are important, especially when social distancing and quarantine measures are relaxed. our results assert that fever is the most likely symptom to occur first in symptomatic adult patients with covid-19. we hope that the hypotheses generated in this work are tested with prospective clinical data to confirm that a cough occurs first more often in influenza and likewise fever in covid-19. we believe that early detectors that any individual can recognize to seek medical attention earlier is useful. in addition, datasets that contain information of symptom order and strains of covid-19 allow for further studies that may determine whether onset of symptoms vary in specific strains (32) , and whether risk factors, such as obesity (33) , and environmental factors, such as temperature (34) affect symptom order. to slow the spread of covid-19, our results support the practice that fever should be tested before allowing entry to facilities and that those with fever should immediately seek medical attention for diagnosis and contact tracing. such measures as these may help to reduce transmission despite the high contagion of sars-cov-2. publicly available datasets were analyzed for this study. these can be found here: 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virus in feces of hospitalized adults predictive factors for pneumonia development and progression to respiratory failure in mers-cov infected patients clinical features and short-term outcomes of 144 patients with sars in the greater toronto area clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in wuhan symptoms of influenza virus infection in hospitalized patients drawing hasse diagram team rc. r: a language and environment for statistical computing. r foundation for statistical computing endothelial cell infection and endotheliitis in covid-19 nervous system involvement after infection with covid-19 and other coronaviruses petechial skin rash associated with severe acute respiratory syndrome coronavirus 2 infection evaluation: from precision, recall and fmeasure to roc, informedness, markedness and correlation classification of white wine aromas with an electronic nose evaluation of the effectiveness of surveillance and containment measures for the first 100 patients with covid-19 in singapore adaptative significance levels using optimal decision rules: balancing by weighting the error probabilities challenges to global surveillance and response to infectious disease outbreaks of international importance on the origin and continuing evolution of sars-cov-2 obesity in patients younger than 60 years is a risk factor for covid-19 hospital admission temperature decreases spread parameters of the new covid-19 case dynamics jl and jh conceived the model. jl and jm conceived the project. jl created the model. jl, mm, and jm analyzed results. jl and mm wrote the manuscript. pk and jh supervised the project. all authors read, edited, and approved the final manuscript. we wish to thank dr. jorge nieva for discussions and advisement and libere ndacayisaba for critical reading of the manuscript. the supplementary material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fpubh. 2020.00473/full#supplementary-material conflict of interest: mm is employed by the company nexus development pa llc. jm is employed by the company nanocarrier co., ltd.the remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.copyright â© 2020 larsen, martin, martin, kuhn and hicks. this is an open-access article distributed under the terms of the creative commons attribution license (cc by). the use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. no use, distribution or reproduction is permitted which does not comply with these terms. key: cord-340563-hsj53inh authors: baud, david; dimopoulou agri, varvara; gibson, glenn r.; reid, gregor; giannoni, eric title: using probiotics to flatten the curve of coronavirus disease covid-2019 pandemic date: 2020-05-08 journal: front public health doi: 10.3389/fpubh.2020.00186 sha: doc_id: 340563 cord_uid: hsj53inh nan despite strategies based on social distancing, hygiene, and screening, covid-19 is progressing rapidly throughout the world, with healthcare systems at risk of being overwhelmed. while identification of effective drug therapies is ongoing, vaccines will not be available in the near future. therefore, additional preventive strategies are urgently needed. covid-19 presents with a spectrum of disease severity, ranging from mild and non-specific flulike symptoms, to pneumonia, and life-threatening complications such as acute respiratory distress syndrome (ards) and multiple organ failure. while transmission of sars-cov-2 is thought to occur mainly via respiratory droplets, the gut may also contribute toward the pathogenesis of covid-19 (1) . sars-cov-2 rna has been detected in the gastrointestinal tract and stool samples from patients (2-4), and in sewage systems (5) . coronaviruses, including sars-cov-2 can invade enterocytes, thereby acting as a reservoir for the virus (4). indeed, large clinical studies from china indicate that gastrointestinal symptoms are common in covid-19, and are associated with disease severity (3, 4) . probiotics are live microorganisms that when administered in adequate amounts confer a health benefit on the host (6) . clinical evidence shows that certain probiotic strains help to prevent bacterial and viral infections, including gastroenteritis, sepsis, and respiratory tract infections (rtis). the reason for adding probiotic strains to the overall prevention and care strategy is founded in science and clinical studies, albeit hitherto none directly on the etiological agent of this pandemic. probiotics can prevent antibiotic-associated diarrhea, and infections in the gastrointestinal tract, but also infections at other sites, including sepsis, and rtis (7) (8) (9) (10) (11) (12) (13) . meta-analyses are the gold standard for evidence-based medicine. in one analysis of more than 8,000 preterm infants included in randomized control trials (rcts), patients receiving enteral supplementation with probiotics showed a reduction in necrotizing enterocolitis, nosocomial sepsis, and all-cause mortality (14) . a well-conducted rct including >4,000 newborns in india found a reduction in sepsis and lower rtis in infants treated with a strain of lactobacillus plantarum combined with prebiotics (which are growth substrates specific for beneficial microorganisms) (15) . viruses are etiologic agents of over 90% of upper rtis. the positive impact of probiotics on prevention of upper rtis is documented in a number of studies. a meta-analysis of 12 rcts including 3,720 adults and children reported a 2-fold lower risk of developing upper rti in subjects taking probiotics, and a small but significant reduction in disease severity in those infected. a randomized, double-blind, placebo-controlled intervention study of 479 adults showed that lactobacillus gasseri pa 16/8, bifidobacterium longum sp 07/3, and bifidobacterium bifidum mf 20/5 with vitamins and minerals lowered not only the duration of common cold episodes but also days with fever (16) . the impact of probiotics on prevention of upper rtis caused by specific viruses has also been documented. an rct including 94 preterm infants showed that galactooligosaccharide and polydextrose prebiotic mixture (1:1), or probiotic lactobacillus rhamnosus gg given between 3 and 60 days of life lowered the incidence of clinically defined virusassociated rti by 2-to 3-fold compared to placebo (17) . the incidence of rhinovirus-associated episodes, which comprised 80% of all rtis in this study, was also strongly reduced with probiotics or prebiotics. the incidence of influenza rti was reduced following consumption of lactobacillus brevis in an open label study of 1,783 school children (18) . pertinent to the pandemic affecting adults more than children, these positive findings were confirmed in an rct that included 27 elderly subjects receiving bifidobacterium longum or placebo (19) . furthermore, lactic acid bacteria, from which many probiotics are selected, are part of the upper respiratory tract microbiota in healthy people, and some strains are being considered for prevention of recurrent otitis media (20, 21) . this makes their use for contributing to slow down progression of the coronavirus pandemic worthy of consideration. probiotics have also been used to prevent bacterial lower rtis in critically ill adults. meta-analyses of rcts including close to 2,000 patients found that probiotic strains reduce the incidence of ventilator-associated pneumonia (22, 23) . but low quality of evidence and conflicting results among different studies calls for additional well-conducted rcts. it should be noted that not all probiotics, even those with gastrointestinal benefits, necessarily contribute in every way to reducing the risk of respiratory infection. for example, lactobacillus rhamnosus gg and bifidobacterium animalis ssp. lactis may contribute to intestinal benefits, but do not reduce the number of viruses in the nasopharynx (24) . examples of products that could be considered, depending on availability in a given country, are provided in table 1 . mechanisms that might explain clinical success of probiotics include enhancement of the intestinal epithelial barrier, competition with pathogens for nutrients and adhesion to the intestinal epithelium, production of anti-microbial substances and modulation of the host immune system (28) . an rct of 55 infants showed that enteral supplementation with a combination of bifidobacterium bifidum and streptococcus thermophilus reduced the incidence of diarrhea and shedding of rotaviruses (29) , an effect that has been confirmed in subsequent studies (30) . this would indicate interference with viral entry into cells and/or inhibition of viral replication in the intestine. while this mechanism may have a role in reducing dissemination of coronavirus via the gut, the probiotic strains were not administered to the respiratory tract. so, direct inhibition may appear impossible at this site. having said that, lungs have their own microbiota and a gut-lung connection has been described whereby host-microbe, microbe-microbe and immune interactions can influence the course of respiratory diseases (31) . rtis such as influenza are associated with an imbalance in the microbial communities of the respiratory and gastrointestinal tracts (32, 33) . this dysbiosis may alter subsequent immune function and predispose to secondary bacterial infection. as reports from china indicate that covid-19 might be associated with intestinal dysbiosis causing inflammation and poorer response to pathogens (34, 35) , the case exists for probiotic strains that restore gut homeostasis (36) . it is feasible that orally administered probiotic strains could further influence this gut-lung axis, as some can migrate from the gut to distant sites, such as the breast to treat mastitis (37) . the gut microbiome has a critical impact on systemic immune responses, and immune responses at distant mucosal sites, including the lungs (38, 39) . administration of certain bifidobacteria or lactobacilli has beneficial impact on influenza virus clearance from the respiratory tract (39, 40) . probiotic strains improve levels of type i interferons, increase the number and activity of antigen presenting cells, nk cells, t cells, as well as the levels of systemic and mucosal specific antibodies in the lungs (16, 19, 39) . there is also evidence that probiotic strains modify the dynamic balance between proinflammatory and immunoregulatory cytokines that allow viral clearance while minimizing immune response-mediated damage to the lungs. this might be particularly relevant to prevent ards, a major complication of covid-19. an rct with lactobacillus plantarum dr7 showed suppression of plasma pro-inflammatory cytokines (ifn-γ, tnf-α) in middle-aged adults, and enhancement of anti-inflammatory cytokines (il-4, il-10) in young adults, along with reduced plasma peroxidation and oxidative stress levels (25) . given the cytokine storm that appears to occur in many covid-19 patients, this type of modulation may prove to be very important. the manner in which orally administered probiotic strains contributes to this appears to involve the immune response emanating from the intestine, a focal point of the body's defenses. therefore, probiotic strains documented to enhance the integrity of tight junctions, for example through increasing butyrate, a fuel for colonocytes could theoretically reduce sars-cov-2 invasion. evidence for antiviral activity of probiotic strains against common respiratory viruses, including influenza, rhinovirus, and respiratory syncytial virus comes from clinical and experimental studies (17) (18) (19) 41) . while none of these effects or mechanisms have been tested on the new sars-cov-2 virus, this should not negate considering this approach, especially when effects of probiotics against other coronavirus strains have been reported (42) (43) (44) (45) . furthermore, patients are dying from secondary bacterial infections. a recent study in mice has shown that oral administration of lactobacillus acidophilus cmcc878, started 24 h after pulmonary inoculation of pseudomonas aeruginosa and staphylococcus aureus reduced bacterial load in the lungs, and decreased lung damage and systemic inflammation (46) . probiotics are generally safe, even in the most vulnerable populations and in intensive care settings (14, 47) . cases of probiotic-associated bacteremia and fungaemia have occurred on extremely rare occasions, mainly in premature and immunocompromised patients treated with preparations lacking adequate quality control (48, 49) . rather than consider intensive care patients too ill to receive probiotic and prebiotic therapy, rcts of probiotics for the prevention of ventilatorassociated pneumonia provide a reason to consider them (22, 23, 26) . moreover, in an rct of 65 critically ill, mechanically ventilated, multiple trauma patients, the synbiotic pediococcus pentosaceus 5-33:3, leuconostoc mesenteroides 32-77:1, l. paracasei ssp. paracasei 19, l. plantarum 2,362 plus inulin, oat bran, pectin, and resistant starch resulted in reduced rate of infections, systemic inflammatory response syndrome, sepsis, days of stay in the intensive care unit, days under mechanical ventilation, and mortality (27) . in summary, orally administered probiotic strains can reduce the incidence and severity of viral rtis. at a time when doctors are using drugs with little anti-covid-19 data, probiotic strains documented for anti-viral and respiratory activities (not low-quality undocumented imitations) should become part of the armamentarium to reduce the burden and severity of this pandemic. government funding is being used to test numerous drugs but just as important, they should fund probiotic trials. in addition, use of recognized prebiotics (e.g., fructans, galactans) to enhance propagation of probiotic strains and indigenous beneficial microbes should be recommended as part of the overall strategy to flatten the curve (11, 50) . eg, db, and vd contributed conception of the manuscript. eg and vd wrote the first draft. db, gg, and gr wrote sections of the manuscript. all authors contributed to manuscript revision, read, and approved the submitted version. covid-19 and the gastrointestinal tract: more than meets the eye viral load of sars-cov-2 in clinical samples epidemiological, clinical and virological characteristics of 74 cases of coronavirus-infected disease 2019 (covid-19) with gastrointestinal symptoms gastrointestinal symptoms of 95 cases with sars-cov-2 infection sars-cov-2 titers in wastewater are higher than expected from clinically 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pseudomonas aeruginosa and staphylococcus aureus pulmonary infections probiotic use in at-risk populations bifidobacterium longum bacteremia in preterm infants receiving probiotics commercial probiotic products: a call for improved quality control. a position paper by the espghan working group for probiotics and prebiotics preventing respiratory tract infections by synbiotic interventions: a systematic review and meta-analysis of randomized controlled trials conflict of interest: gg and gr provide advice to probiotic and prebiotic companies.the remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.copyright © 2020 baud, dimopoulou agri, gibson, reid and giannoni. this is an open-access article distributed under the terms of the creative commons attribution license (cc by). the use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. no use, distribution or reproduction is permitted which does not comply with these terms. key: cord-347605-6db4gwhk authors: vento, sandro; cainelli, francesca; vallone, alfredo title: violence against healthcare workers: a worldwide phenomenon with serious consequences date: 2020-09-18 journal: front public health doi: 10.3389/fpubh.2020.570459 sha: doc_id: 347605 cord_uid: 6db4gwhk nan verbal and physical violence against healthcare workers (hcws) have reached considerable levels worldwide, and the world medical association has most recently defined violence against health personnel "an international emergency that undermines the very foundations of health systems and impacts critically on patient's health" (1) . two systematic reviews and meta-analyses published at the end of 2019 found a high prevalence of workplace violence by patients and visitors against nurses and physicians (2) , and show that occupational violence against hcws in dental healthcare centers is not uncommon (3) . in the first study (2) , the authors systematically searched pubmed, embase, and web of science from their inception to october 2018, and included 253 eligible studies (with a total of 331,544 participants). 61.9% of the participants reported exposure to any form of workplace violence, 42.5% reported exposure to non-physical violence, and 24.4% experienced physical violence in the past year. verbal abuse (57.6%) was the most common form of non-physical violence, followed by threats (33.2%) and sexual harassment (12.4%). the prevalence of violence against hcws was particularly high in asian and north american countries, in psychiatric and emergency departments, and among nurses and physicians (2) . in the second study (3), a systematic review and analysis of the literature was done using pubmed, sciencedirect, scopus, web of science, cochrane library and proquest. original articles published between january 1992 and august 2019 and written in english were included in the analysis. the violence experienced by dental healthcare workers was both physical and nonphysical (shouting, bullying, and threatening) and also included sexual harassment (3) , and in most cases, male patients, or coworkers were responsible. violent events ranged from 15.0 to 54.0% with a mean prevalence of 32%, and physical abuse ranged from 4.6 to 22% (3). most recently, the world medical association has condemned the increasingly reported cases of health care workers being attacked because of the fear that they will spread sars-cov-2. the situation in india is particularly shocking, with health care workers stigmatized, ostracized, discriminated against, and physically attacked, but incidents have been reported across the world, for instance from france, mexico, philippines, turkey, uk, australia, and usa (4, 5) . the recent systematic reviews and meta-analyses and the world health organization condemnation of the attacks against hcws treating patients with covid-19 have confirmed the seriousness of the situation regarding violence against doctors and nurses worldwide. many countries have reported cases of violence, and some are particularly affected by this problem. a chinese hospital association survey collecting data from 316 hospitals revealed that 96% of the hospitals surveyed experienced workplace violence in 2012 (6) , and a study done by the chinese medical doctor association in 2014 showed that over 70% of physicians ever experienced verbal abuse or physical injuries at work (7) . an examination of all legal cases on violence against health professionals and facilities from the criminal ligation records 2010-2016, released by the supreme court of china, found that beating, pushing, verbal abuse, threatening, blocking hospital gates, and doors, smashing hospital property were frequently reported types of violence (8) . in india, violence against healthcare workers and damage to healthcare facilities has become a debated issue at various levels (9) , and the government has made violence against hcws an offense punishable by up to 7 years imprisonment, after various episodes of violence and harassment of hcws involved in covid-19 care or contact tracing (10) . in germany, severe aggression or violence has been experienced by 23% of primary care physicians (11) . in spain, there has been an increase in the magnitude of the phenomenon in recent years (12) . in the uk, a health service journal and unison research found that 181 nhs trusts in england reported 56,435 physical assaults on staff in 2016-2017 (13) . in the usa, 70-74% of workplace assaults occur in healthcare settings (14) . in italy, in just one year, 50% of nurses were verbally assaulted in the workplace, 11% experienced physical violence, 4% were threatened with a weapon (15); 50% of physicians were verbally, and 4% physically, assaulted (16) . in poland, czech republic, slovakia, turkey many nurses have been physically attacked or verbally abused in the workplace (17) . according to the south african medical association, over 30 hospitals across south africa reported serious security incidents in just 5 months in 2019 (18) , and in cape town violence against ambulance crews is widespread (19) . in iran, the prevalence of physical or verbal workplace violence against emergency medical services personnel is 36 and 73% respectively (20) . the world health organization lists australia, brazil, bulgaria, lebanon, mozambique, portugal, thailand as other countries where studies on violence directed at hcws have been conducted (21) . the consequences of violence against hcws can be very serious: deaths or life-threatening injuries (15) , reduced work interest, job dissatisfaction, decreased retention, more leave days, impaired work functioning (22) , depression, post-traumatic stress disorder (23), decline of ethical values, increased practice of defensive medicine (24) . workplace violence is associated directly with higher incidence of burnout, lower patient safety, and more adverse events (25) . which are the most at-risk services and what are the underlying factors of this growing violence? emergency departments, mental health units, drug and alcohol clinics, ambulance services and remote health posts with insufficient security and a single hcw are at higher risk. working in remote health care areas, understaffing, emotional or mental stress of patients or visitors, insufficient security, and lack of preventative measures have been identified as underlying factors of violence against physicians in a 2019 systematic review and meta-analysis (26) . in public hospital/services, insufficient time devoted to patients and therefore insufficient communication between hcws and patients, long waiting times, and overcrowding in waiting areas (27) , lack of trust in hcws or in the healthcare system, dissatisfaction with treatment or care provided (26), degree of staff professionalism, unacceptable comments of staff members, and unrealistic expectations of patients and families over treatment success (28) are thought to contribute. indeed, in public hospitals worldwide, staff shortages prevent front-line hcws from adequately coping with patients' demands. in private hospitals/services, too extended hospital stays, unexpectedly high bills, prescription of expensive and unnecessary investigations are key factors. finally, the media frequently report extreme cases of possible malpractice and portray them as representative of "normal" practice in hospitals (24) . what can be done to reduce the escalating violence against hcws? hcws worldwide generally advocate for more severe laws, but harsher penalties alone are unlikely to solve the problem. importantly, evidence on the efficacy of interventions to prevent aggression against doctors is lacking, and a systematic review and meta-analysis found that only few studies have provided such evidence (29) . just one randomized controlled trial indicated that a violence prevention program decreased the risks of patient-to-worker violence and of related injury in hospitals (30) , whereas contrasting results in violence rates after implementation of workplace violence prevention programs have been observed from longitudinal studies (29) . there is no evidence on the effectiveness of good place design and work policies aimed to reduce long waiting times or crowding in waiting areas (29) . more studies are clearly needed to provide evidence-based recommendations, and interdisciplinary research with the involvement of anthropologists, sociologists, and psychologists should be encouraged. however, certain measures have to be taken and can be corrected, should they be shown as ineffective in properly conducted studies. security measures have been advocated for years (31) and should be taken to safeguard particularly the most at-risk services. first, staff shortages, so common in public hospitals worldwide, should be acted upon, and increased funding should be allocated to employ more doctors and nurses. hence, the duration of each patient encounter would be augmented, particularly in overburdened public hospitals, allowing the (often young) (32) doctors to develop a meaningful relationship with the patient. second, healthcare organizations and universities should considerably improve the communication skills of current and future hcws to reduce unrealistic expectations or misunderstanding of patients and families. third, hcws who denounce any verbal or physical violence should be fully supported by their healthcare organizations; this would reduce the huge issue of under-reporting of workplace violence (33, 34) . good courses should be organized for hcws to learn how to identify early signs that somebody may become violent, how to manage dangerous situations, and how to protect themselves. prompt communication about delays in service provision should be given to patients and their relatives when waiting times are long because certain conditions are prioritized. alarms and closed-circuit televisions should be placed in the higher-risk departments and in areas where doctors and/or nurses work in isolation. sanctioning of violence by patients, relatives or visitors must be imposed. staff should be increased and security officers should be placed, particularly at night, in remote health posts and emergency departments and at particular times (violence tends to happen in the evenings/nights, when more patients under the influence of drugs and alcohol present); the number of night shifts should be limited (23) . efforts should be made to improve job satisfaction of hcws (25) . finally, media should cease to contribute to the general public's distrust toward hcws and institutions. many patients report their negative experiences of medical care to news or media outlets which are highly interested in these stories and very often do not check the information before publishing it (24) . these biased media reports may exacerbate the tension. all workers have a right to be safe on their job, and healthcare workers are no exception. the idea that violence is inherent to doctors and nurses' work, especially in certain departments, needs to be fought; urgent measures must be implemented to ensure the safety of all hcws in their environment, and the needed resources must be allocated. failure to do so will worsen the care that they are employed to deliver and will ultimately negatively affect the whole healthcare system worldwide. sv had the idea of writing the manuscript and drafted it. fc co-drafted the manuscript. av contributed to the drafting, and reviewed the manuscript. all the authors approved the final version. covid-19 pandemic response prevalence of workplace violence against healthcare workers: a systematic review and meta-analysis prevalence and policy of occupational violence against oral healthcare workers: systematic review and meta-analysis available online at attacks against health-care personnel must stop, especially as the world fights covid-19 stop violence against medical workers in china workplace violence and its aftermath in china's health sector: implications from a crosssectional survey across three tiers of the health system violence against health professionals and facilities in china: evidence from criminal litigation records academic college of emergency experts and academy of family physicians of india position statement on preventing violence against healthcare workers and vandalization of health-care facilities in india covid-19: indian government vows to protect healthcare workers from violence amid rising cases aggression and violence against primary care physicians -a nationwide questionnaire survey agresiones a profesionales del sector sanitario en españa, revisión sistemática. [aggression to health care personnel in spain: a systematic review guidelines for preventing workplace violence for healthcare and social service workers (osha workplace violence in the health sector. world health organization survey questionnaire onu. rapporto italia. rome (2019) un medico su due ha subito aggressioni. i dati preliminari dello studio fnomceo sancho cantus d. violence against nurses working in the health sector in five european countries-pilot study more than 30 sa hospitals report serious security incidents in past 5 months paramedics, poetry, and film: health policy and systems research at the intersection of theory, art, and practice prevalence of workplace violence types against personnel of emergency medical services in iran: a systematic review and meta-analysis world health organization. violence against healthcare workers workplace violence is associated with impaired work functioning in nurses: an italian cross-sectional study workplace violence against healthcare workers in emergency departments. a case-control study medical malpractice, defensive medicine and role of the "media" in italy addressing risks of violence against healthcare staff in emergency departments: the effects of job satisfaction and attachment style prevalence of type ii and type iii workplace violence against physicians: a systematic review and meta-analysis violence towards healthcare workers: a study conducted in abha city, saudi arabia violence against physicians and nurses in a hospital: how does it happen? a mixed-methods study interventions to prevent aggression against doctors: a systematic review preventing patient-to-worker violence in hospitals: outcome of a randomized controlled intervention tackling violence against health-care workers physical violence against doctors: a content analysis from online indian newspapers unreported workplace violence in nursing underreporting of workplace violence: comparison of self-report and actual documentation of hospital incidents the authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.copyright © 2020 vento, cainelli and vallone. this is an open-access article distributed under the terms of the creative commons attribution license (cc by). the use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. no use, distribution or reproduction is permitted which does not comply with these terms. key: cord-325965-kqbeinez authors: boyce, matthew r.; katz, rebecca title: community health workers and pandemic preparedness: current and prospective roles date: 2019-03-26 journal: front public health doi: 10.3389/fpubh.2019.00062 sha: doc_id: 325965 cord_uid: kqbeinez despite the importance of community health workers (chws) to health systems in resource-constrained environments, relatively little has been written about their contributions to pandemic preparedness. in this perspective piece, we draw from the response to the 2014 ebola and 2015 zika epidemics to review examples whereby chws contributed to health security and pandemic preparedness. chws promoted pandemic preparedness prior to the epidemics by increasing the access to health services and products within communities, communicating health concepts in a culturally appropriate fashion, and reducing the burdens felt by formal healthcare systems. during the epidemics, chws promoted pandemic preparedness by acting as community-level educators and mobilizers, contributing to surveillance systems, and filling health service gaps. acknowledging the success chws have had in these roles and in previous interventions, we propose that the cadre may be better engaged in pandemic preparedness in the future. some practical strategies for achieving this include training and using chws to communicate one health information to at-risk communities prior to outbreaks, pooling them into a reserve health corps to be used during public health emergencies, and formalizing agreements and strategies to promote the early engagement of chws in response actions. recognizing that chws already play a role in pandemic preparedness, we feel that expanding the roles and responsibilities of chws represents a practical means of improving pandemic and community-level resilience. disasters are unexpected events that imply serious health, economic, or political threats, and require special considerations beyond routine procedures or resources. large-scale infectious disease outbreaks, therefore, represent one manifestation of such events. importantly, these disease outbreaks appear to be increasing in frequency (1) , and this year alone, there have been outbreaks of cholera, ebola, lassa fever, middle east respiratory syndrome, nipah, rift valley fever, and yellow fever (2) . promoting disaster resilience represents one approach to mitigate the consequences of disasters. the sendai framework for disaster risk reduction describes disaster resilience as the ability of an entity to resist, acclimate to, and recover from the effects of a hazard, including through the preservation and restoration of essential structures and functions. disaster resilience theory further categorizes resilience as being either inherent or adaptive (3) , with inherent resilience referring to the conditions, characteristics, and properties associated with absorptive capacity; and adaptive resilience involving the activation of resources and blending preplanned and reactive actions in response to disaster-related demands. the international health regulations 2005 (ihr) and the corresponding joint external evaluation tool (jee) are the preeminent international frameworks for building and assessing resilient public health systems. these assigned new responsibilities to the world health organization (who) and nations to share resources, information, and expertise to build capacities to help prepare the world for preventing, detecting, and responding to health emergencies. to this end, the jee tool states that countries should have a skilled and competent workforce of physicians, veterinarians, biostatisticians, laboratory scientists, livestock professionals, and field epidemiologists for maintaining sustainable public health surveillance and response mechanisms. still, this guidance prescribes a national-level workforce and assumes that capacity will be dispersed throughout a country. this assumption is rarely a reality, particularly in lowresource or unstable regions where healthcare workforces may be concentrated in wealthier areas of a country. although the recently released jee 2.0 places greater emphasis on building subnational level capacities (4), the impacts of this reality are acutely felt at the community-level during public health crises where health systems assets can be limited or nonexistent. community health workers (chws)-lay persons trained to assist in the communication or provision of health servicesrepresent one method for extending health services at subnational levels, particularly in underserved or remote populations (5) . chws are commonly trained in the context of health interventions to carry out defined functions related to healthcare delivery, but rarely have formal professional or paraprofessional certifications, or degreed tertiary education (6) . chws have traditionally been used to improve community health initiatives, manage the risk of infectious diseases (e.g., malaria, pneumonia, and tuberculosis), and fill gaps in healthcare systems. accordingly, much attention has focused on their importance to primary healthcare systems. however, despite their establishment at the community level, chws are often under-utilized in the response to infectious disease outbreaks (7) and additional roles for chws in promoting pandemic preparedness exist. the who has released training materials for preparing chws to respond to respiratory disease outbreaks (8, 9) but relatively little attention has been given to their potential importance in contributing to the prevention and control of other large-scale infectious disease outbreaks. despite this, chws have been involved in the response to these events. at least 950 chws were involved in liberia's response to the ebola outbreak (10) and over 1,500 chw were involved in côte d'ivoire's precautionary response to the ebola outbreak in neighboring guinea and liberia (11) . acknowledging the importance of chws in extending health services to vulnerable populations filling health system gaps, as well as their involvement in previous outbreaks, herein we discuss several roles chws currently play in promoting inherent and adaptive resilience and discuss future opportunities for chws to better sub-national pandemic preparedness and response. from a public health perspective, inherent resilience could include adequate nutrition, access to clean water, effective sanitation systems, robust health systems, and other means buffering populations against public health emergencies. accordingly, perhaps the most discernible role of chws in pandemic preparedness is inherent to the position-one of increasing the access to health interventions and services within communities (box 1). these efforts can reduce the risk of many morbidities and overall mortality (12) and improve the underlying population health, in theory, reducing the susceptibility of the population to infectious disease threats. another role chws currently fill in promoting inherent resilience is the distribution of culturally appropriate health information and supplies. in the midst of the 2015 zika outbreak, chws known as "brigadistas" were used to communicate important information regarding zika to reduce the risk of infection in at-risk communities prior to the peak of mosquito season (13) . this proactive strategy improved community awareness about the importance of eliminating mosquito breeding sites and promoted condom use to reduce sexual transmission of the virus. brigadistas were also used to distribute zika prevention kits-containing barrel covers, bed nest, condoms, and educational materials-to pregnant mothers. finally, chws can act as a community-level triage systemtreating those with minor illness and referring those with more serious disease. this reduces pressures on often over-burdened health systems and helps to ensure that formal healthcare cadres-those referenced in the ihr and jee tool-are available to provide health services to those most in need. for example, in brazil, chws have been used to triage conditions and provide basic primary care to families to resolve minor ailments (14) . in the event of severe issues, they were trained to refer patients to nurses or physicians who were better equipped to manage illness. ultimately, this strategy reduced the number of hospitalizations and led to significant improvements in clinical outcomes-both with regard to mortality and improving access to healthcare. with regard to pandemic preparedness, the adaptive resilience roles of chws are more complicated. although chws receive box 1 | selected community health worker roles that promote inherent resilience. • increase the access to health services and products within communities to improve population health and reduce the likelihood of an outbreak • communicate important public health concepts in a culturally appropriate fashion • reduce the burden felt by formal healthcare systems and improve the quality of clinical care frontiers in public health | www.frontiersin.org healthcare-related training, expecting or obligating them to medically respond to a large-scale infectious disease outbreak is unethical and impractical. the disproportionate effects of outbreaks on healthcare workers-as seen in the 2003 sars (15) and 2014 ebola outbreaks (16)-are likely to rapidly decimate the healthcare workforce resulting in a reluctance to work and in high rates of absenteeism (17) . chws are not exempt from this trend (18) . still, medical tasks are fundamentally different from other essential response tasks-the former require technical proficiencies, whereas the latter can rely on social competencies, communication skills, and local-level knowledge (19) . it is in these non-medical roles that chws can excel in contributing to the adaptive resilience of health systems (box 2). community health workers often represent a trusted voice in the community and thus also represent valuable assets for social mobilization and the distribution of health information during outbreaks. a key lesson from the 2014 ebola outbreak response was that engaging communities to contain the spread of disease can be challenging unless there was an existing network of healthcare workers embedded within communities (20, 21) . because chws reside in or near the communities they service, they are uniquely positioned to act as communitylevel educators, organizers, and mobilizers in this network. indeed, during the 2014 ebola response, engaging chws in response procedures improved the efficacy of response activities (7) . another adaptive role that chws contribute to is disease surveillance. depending on the locale from which an outbreak occurs, chws could be on the frontlines of responding to a public health emergency and having systems in place for chws to report unusual symptoms or epidemiological patterns while performing their routine activities could enhance syndromic surveillance. this role was validated in côte d'ivoire (11) and sierra leone (7) during the 2014 ebola epidemic where chws conducted community surveillance activities and reported suspected ebola cases to public health authorities. chws can also promote adaptive resilience by resuming their medical roles and filling health service gaps following outbreaks. this role is of great importance should healthcare workforces be depleted by an outbreak response. scholars have noted that sustained political and financial investment in chw programs could create a solid foundation for chws to close sudden or unexpected health system gaps and improve the resilience of health systems (18) . box 2 | selected community health worker roles that promote adaptive resilience. • act as community-level educators, organizers, and mobilizers during infectious disease outbreaks • contribute to syndromic disease surveillance systems while completing routine activities • complete medical tasks unrelated to the infectious disease outbreak to fill health service gaps during or following the outbreak. given these roles in promoting resilience, better involving chws in pandemic preparation efforts appears both logical and practical. there have been direct calls for sustained investment in health worker training, which could include chws, to mitigate the risks posed by disease outbreaks (16, 22) and considering the potential contributions of chws in containing public health emergencies, scaling-up chw strategies could avoid an estimated $750 million in economic losses per year (23) . we now propose several actionable options for improving chw trainings and involvement in health emergency response to better promote pandemic preparedness. first, since chws play a key role in providing health services, and often work on a voluntary basis, their personal satisfaction, and motivation are central to their involvement in health interventions. while much work has investigated chw's motivations for routine activities (24) (25) (26) (27) (28) , less evidence exists regarding chws motivations, satisfaction, and role perception when providing services in environments that warrant special considerations (e.g., during an outbreak). conducting qualitative research with chws regarding their motivations, perceptions, experience, and concerns about working during an infectious disease outbreak could inform larger policy decisions. given that a majority of emerging infectious diseases are zoonotic in origin (29) , and acknowledging chws' competence in communicating important health concepts in a sensitive and culturally appropriate fashion, chws could also be used to develop and promote one health messaging campaigns. doing so could improve inherent resilience by leading to more successful behavioral change campaigns and increased awareness of the risks posed by environmental intrusion, bushmeat consumption, and other factors that promote infectious disease spillover events. third, chws could be used to promote adaptive resilience by serving as a type of reserve heath corps during public health emergencies. as detailed earlier, this role should be not medical which could expose chws to unnecessary risks, but one rooted in social mobilization. engaging chws in national risk communication strategies and plans could act to simultaneously expand the reach of communication networks and enhance the perceived validity of the information dispersed by them. this could help to reduce the risk of misinformation and rumors that can lead to fear, social unrest, and violence during an outbreak response. finally, studies have shown that the late engagement of chws can hinder an outbreak response (30) . thus, formalizing or developing agreements that quickly engage chws during public health emergencies could improve overall response procedures and improve adaptive resilience. at a minimum, the experience, local-level knowledge, and relationships of chws could help to inform and guide higher-level efforts, but clearly defining chw roles and expectations in an outbreak response would bolster response activities. this is especially true in less-permissive environments, where high levels of mistrust are common and chws social standing can provide them with some level of protection. indeed, chw programs in the central african republic demonstrated that they could continue some level of care at all times, reach those most vulnerable populations, and maintain disease surveillance activities even in conflict zones (31) . the guidance outlined in the ihr and jee tool provides a framework to promote global health security and pandemic preparedness where capacities already exist. however, access to these capacities is not always a reality, and chws represent a proven strategy for improving access to healthcare. through their routine work, chws contribute to inherent resilience and pandemic preparedness by increasing access to health products and services, distributing health information, and reducing the burden felt by the formal healthcare system-all of which act to buffer against emergencies. chws can also contribute to adaptive resilience by increasing social mobilization, completing surveillance activities, and by filling health systems gaps left in the wake of infectious disease outbreaks. recognizing that chws already play a role in pandemic preparedness, the roles and responsibilities of chws in pandemic preparedness could be expanded to improve health security and communitylevel resilience. mb contributed to the conception and design of the manuscript and wrote the first draft of the manuscript. rk made substantial contributions to the conception of the manuscript. both of the authors contributed to manuscript revision, and have read and approved the submitted version. global rise in human infectious disease outbreaks available online at the social roots of risk: producing disasters, promoting resilience capacity building under the international health regulations: ramifications of new implementation requirements in second edition joint external evaluation community health workers: what do we know about them? geneva: who lay health workers in primary and community healthcare community health workers during the ebola outbreak in guinea, liberia, and sierra leone 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health worker motivation and experiences with clients in primary health facilities in ghana: a randomized cluster trial motivations for entering and remaining in volunteer service: findings from a mixed-method survey among hiv caregivers in zambia global trends in emerging infectious diseases community matters-why outbreak responses need to integrate health promotion malaria case management by community health workers in the central african republic from 2009-2014: overcoming challenges of access and instability due to conflict the authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.copyright © 2019 boyce and katz. this is an open-access article distributed under the terms of the creative commons attribution license (cc by). the use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. no use, distribution or reproduction is permitted which does not comply with these terms. key: cord-292315-7vwybku8 authors: jung, gyuwon; lee, hyunsoo; kim, auk; lee, uichin title: too much information: assessing privacy risks of contact trace data disclosure on people with covid-19 in south korea date: 2020-06-18 journal: front public health doi: 10.3389/fpubh.2020.00305 sha: doc_id: 292315 cord_uid: 7vwybku8 introduction: with the covid-19 outbreak, south korea has been making contact trace data public to help people self-check if they have been in contact with a person infected with the coronavirus. despite its benefits in suppressing the spread of the virus, publicizing contact trace data raises concerns about individuals' privacy. in view of this tug-of-war between one's privacy and public safety, this work aims to deepen the understanding of privacy risks of contact trace data disclosure practices in south korea. method: in this study, publicly available contact trace data of 970 confirmed patients were collected from seven metropolitan cities in south korea (20th jan–20th apr 2020). then, an ordinal scale of relative privacy risk levels was introduced for evaluation, and the assessment was performed on the personal information included in the contact trace data, such as demographics, significant places, sensitive information, social relationships, and routine behaviors. in addition, variance of privacy risk levels was examined across regions and over time to check for differences in policy implementation. results: it was found that most of the contact trace data showed the gender and age of the patients. in addition, it disclosed significant places (home/work) ranging across different levels of privacy risks in over 70% of the cases. inference on sensitive information (hobby, religion) was made possible, and 48.7% of the cases exposed the patient's social relationships. in terms of regional differences, a considerable discrepancy was found in the privacy risk for each category. despite the recent release of government guidelines on data disclosure, its effects were still limited to a few factors (e.g., workplaces, routine behaviors). discussion: privacy risk assessment showed evidence of superfluous information disclosure in the current practice. this study discusses the role of “identifiability” in contact tracing to provide new directions for minimizing disclosure of privacy infringing information. analysis of real-world data can offer potential stakeholders, such as researchers, service developers, and government officials with practical protocols/guidelines in publicizing information of patients and design implications for future systems (e.g., automatic privacy sensitivity checking) to strike a balance between one's privacy and the public benefits with data disclosure. with covid-19 becoming a worldwide pandemic, each country is attempting various ways to stop or slow down the spread of the virus among people, such as social distancing, preventing events that bring many people together, detecting and isolating the confirmed cases, and so on (1) . in this situation, one of the effective measures is to conduct "contact tracing" (1, 2) . contact tracing is defined as "the identification and follow-up of persons who may have come into contact with an infected person, " and involves identifying, listing, and taking follow-up action with the contacts (3) . it plays an important role in quick isolation of infected persons to prevent potential contact with others. from a stochastic transmission model of the spread of covid-19, contact tracing was shown to be effective in controlling a new outbreak in most cases and reducing the effective reproduction number (2) . however, due to limited human resources for tracing, it could be very difficult to trace the contacts who might be potentially infected, particularly when the number of patients is skyrocketing. therefore, some countries began to proactively open the data of confirmed cases to the public or share it with medical institutions to find close contacts more efficiently. for instance, in singapore, the government discloses the places related to patients, such as residence, workplaces, and other places they had visited (4) . in taiwan, the authorities utilize the airport immigration database combined with the national medical database to quickly determine whether the patient has visited other countries (5) . other governments also are sharing the personal information of the patients with similar components of data, including age and gender, nationality, geographical breakdown of patients, and so on (6) . south korea also disclosed the patients' contact trace data to the public to prevent further spread of the coronavirus. each local government pseudonymizes the patient data, which contains demographics, infection information, and travel logs, and releases it to the public. this information helps the public to self-check whether they were co-located with the confirmed patient. however, there is a potential threat in publicizing the patient's data (7) . efficiently identifying potential contacts may be advantageous in terms of public safety but revealing personal data would infringe upon the patient's privacy. most of the information disclosed could be personal data and combining a set of data reveals additional information. privacy risks, along with online abuses or rumor-mongering based on somewhat uncertain information, may cause blame and social stigma (8, 9) and raise the risk of physical safety (10) . while it is important to find and isolate close contacts quickly for preventing the spread of infectious diseases, it is also critical to minimize breach of patients' privacy. recently, the national human rights commission of korea claimed that the publicized information is unnecessarily specific and may cause privacy violations (11) . in response to this, the korea centers for disease control & prevention (hereinafter "kcdc") announced two guidelines (12, 13) limiting the scope and the period of the data disclosure and recommended the deletion of outdated information (after 14 days from the table 1 | the korean government guidelines for the scope and detail of the information to be disclosed. mar. 14 • personal information: information that identifies a specific person should be excluded • period: information should be from 1 day before the symptoms occur to the date of quarantine • place and transportation: place and transportation should be disclosed where contacts have occurred with the confirmed cases. the detailed address of residence and workplace should not be disclosed. however, the address may be revealed if there is a risk that covid-19 has been spread to random people in the workplace. spatial and temporal information (e.g., building, place names, and transportation) should be specified as possible, except for that of identifying certain individuals. apr. 12 • disclosure period: the data should be only released for 14 days from the date that the patient had the last contact. last contact) on march 14 and april 12, respectively (see table 1 ). although a critical question about the cost-benefit tradeoffs between privacy and public safety still remains, existing studies on location and privacy have not fully reported insights from contact tracing and underlying privacy risks. past studies on location privacy primarily focused on an individual's privacy perceptions and potential risks of leaking current locations to diverse social media (14) (15) (16) . however, these prior works were more of a real-time location sharing of a single spot, rather than sharing one's full mobility data spanning several days to a week or more, as in contact tracing. another key difference to note is that privacy risks regarding contact tracing under special occasions, such as covid-19 are relatively unaddressed in the literature. it is timely to explore this issue as public disclosure of contact tracing data under covid-19 raises questions about data sovereignty and privacy of a patient. thus, the present study assessed privacy risks on the contact trace data disclosed in south korea. specifically, the study first examined what kind of personal information is contained in the data, and how much exposure or inference is made from that data. it then examined how much difference in privacy risk levels exists according to region and time when disclosing the data. while no study to the researchers' knowledge has assessed privacy risks on public disclosure of contact tracing data related to covid-19, the present study first analyzes the real-world data in south korea and provides possible directions for privacy-preserving data disclosure and presents several policy and technical implications that can possibly lower privacy risks. this section describes the data collection and analysis process used to evaluate privacy issues resulting from data disclosure. to assess potential privacy concerns through real-world examples, the contact trace data of 970 confirmed patients was collected. the data listing confirmed cases date-wise from january 20 to april 20 were released by seven major metropolitan cities in south korea. the contact trace data was collected from various publicly accessible online websites, such as the official website and social media sites of the local government, and its press releases and briefing information. since the data was released to the public by the government and any specific individual cannot be identified with it, there is no critical ethical concern for data analyses. as shown in table 2 , the released contact trace data included (1) the patient's demographics (i.e., nationality, gender, age, and residence), (2) infection information (i.e., infection route and confirmation date), and (3) travel log in time series (e.g., transport modes and visited places). the data is processed by the contact trace officer before it is released online (i.e., excluding places which the patient visited but no contact was made), hence the government may possess more information than the public can access. this study covered seven out of eight metropolitan cities in south korea, namely, seoul, incheon, sejong, daejeon, gwangju, ulsan, and busan. the city of daegu was excluded from the data collection process because it did not disclose patient information since the massive contagion outbreak prevented contact tracing. as the guidelines set by the kcdc recommend the deletion of the outdated information (after 14 days from the last contact), all the sample cases of disclosed patient data mentioned in this study were anonymized by the researchers. for instance, the address and name of a place (e.g., building name) were converted into four character long random strings (e.g., g3a5-gu, d12zdong, bqt3 building). similarly, the identification number of the patient was also anonymized (e.g., #w4p). in this study, a codebook was introduced to evaluate the level of privacy risks. the codebook has an ordinal scale of privacy risk levels and the scale quantifies relative risks from five major categories: demographics (nationality, gender, age), significant places (residence, workplace), sensitive information (hobby, religion, accommodation), social relationships, and routine behavior. the details of the codebook generation are as follows: the collected data were manually examined to evaluate the level of privacy risks. the following types of information were identified: demographics, location information (e.g., significant places and behavioral routines), and social relationships. affinity diagramming on contact trace data was performed to iteratively build a coding scheme (18) . as a result, the manual examination generated five categories with eight sub-categories, as described in table 3 . for each data category, an ordinal scale of privacy risk levels was introduced. the scale quantifies the relative privacy risks of the patient's trace data; for example, a high level means that detailed information was released. the following section describes the details of each category and its associated risk levels. this codebook was used to evaluate each patient's contact trace from seven metropolitan cities. the "demographics" category included three sub-categories: nationality, gender, and age. for nationality and gender, two scoring criteria were considered: (1) level 0 for not containing any information for each of the two categories and (2) level 1 for disclosing that information (e.g., patient #5sx is chinese, patient #8nw is a woman). in the case of "age, " three criteria were considered: (1) level 0 for no age information, (2) level 1 for rough description (e.g., the twenties), and (3) level 2 for accurate information (e.g., 30 years old, born in 1990). before describing the methods further, this study explains the administrative divisions in south korea since it could differ from country to country. the administrative divisions can be divided into four levels by their size: province ("do"; the whole country is composed of nine provinces), city ("si"; typically 100-1,000 km 2 ), sub-city ("gu"; typically 10-,100 km 2 ), and district ("dong"; typically 1-10 km 2 ) (19) . people in south korea often use this system when they look for a place or mention a certain location. in the address system of south korea, there are two more detailed steps in describing places: streets (i.e., "ro" or "gil") and the building number. the street is lower level than the "dong, " so a "dong" may contain several "ro"s and "gil"s. the lowest level is the building number and the address provided up to this step would point to the only building throughout the country. a person's home (residence) and workplace are considered significant places. to assess the detailed location information of these places, a two-stage approach was used: (1) direct location identification and (2) indirect location inference by combining the breadcrumbs of visited places and transport modes. the second stage was inferring the locations of personal life using nearby places whose full addresses or names were disclosed. even if the information is limited, reasonable inference based on a travel log is possible by examining the surrounding places and transport modes. for example, there was no explicit description of a patient's home, yet the travel log said "4 min in total to walk from his home to a convenience store, and come back again." and the full address of the store is known (i.e., 441-7, allakdong, dong-gu, ulsan). this log may indicate the approximate location of her house. considering a person's walking speed (e.g., 3 km/h), the area where her home is located could be determined as described in figure 1 . to estimate the time required to travel on foot, the average sizes of the sub-city ("gu"), district ("dong") and street ("ro" or "gil") were used. there were 68 gu, 1,033 dong, and 41,301 street included in the total for the seven cities. given that the total size of these cities was 4,000 km 2 , the average sizes of gu, dong, and street were calculated as 58.8, 3.9, and 0.1 km 2 , respectively. for the convenience of calculation, an assumption was made that the shape of each administrative area was circular. as a result, the radius of each division was 4.3, 1.1, and 0.2 km for gu, dong, and street, respectively. taking the average walking speed of a person this means it is reasonable to infer that a place is under dong level (i.e., privacy level 2) when it takes from 20 to 90 min on foot and street level (i.e., privacy level 3) if it takes 4-20 min. on the basis of these results, the details of a location were labeled where the address was not shown but could be inferred from a known place. for instance, in the case of patient #pr8 of bi1c-gu who went home from the q5eg branch of kjn1 convenience store (i.e., only one store of its kind in that region) on foot in 5 min, this case was scored as level 3 privacy risk. moreover, some places where it took <4 min on foot were labeled as 3.5. in this case, it is more specific than level 3, but it is still not possible to identify the exact place. in some buildings, there is a possibility of revealing sensitive personal information. for instance, if there is information on the travel log that the patient had attended a church service, and its name was disclosed, anyone who reads this could know her religion. this study mainly considered three place categories: (1) hobbies, such as fitness clubs, dance schools, pc cafes (playing games), and karaoke (singing); (2) religion, such as a church, cathedral, and temple; and (3) accommodation, such as hotel and motel. if any of these place categories were described in the travel log, that case was labeled as level 1; otherwise, level 0 was given. privacy issues might arise when information about how one person is related to another is revealed. if the travel log indicates that two people are found to have been together at a certain time or moved together to a place, there is privacy leakage of relationships. therefore, patients' travel logs were examined to check whether they included this relationship information. for not describing such information, level 0 was given. level 1 was rated in case of revealing the relationship only (e.g., patient #t52 in 4xal-gu is the mother-in-law of patient #rb4 in the "gu" of the building is disclosed 2 "dong" of the building is disclosed 20-90 min on foot taken from a known location 3 "ro" or "gil" of the building is disclosed 4-20 min on foot taken from a known location 3.5 <4 min on foot taken from a known location 4 the exact location of the building is disclosed only the relationship is disclosed 2 the location and the relationship are disclosed together routine behavior 0 no place that is visited repeatedly 1 includes places that are visited repeatedly same district). if the relationship was revealed with location (e.g., patient #90x in 8nuw-gu had lunch with her colleague patient #v8l in the same district, at a restaurant near their office), that case was rated as level 2. using information about places that are repeatedly visited in a specific time window (known as behavioral routines) could make it easier to identify a person. if it is revealed that there is a place where a confirmed patient repeatedly visits at a certain time, malicious people may use this information (e.g., robbery). for this reason, it was examined whether the travel log included routine behavior. if there was a place visited more than twice at a specific time, the case was labeled as a level 1 risk, otherwise, a level 0 risk (or no risk at all). this study analyzes 970 cases from seven metropolitan cities in south korea (see table 4 ) and reports (1) the descriptive statistics of privacy risk levels, and (2) their differences across regions and time. the five major categories and eight sub-categories of data types that might potentially reveal personal information (e.g., life cycle, social relationships, etc.) were coded in terms of privacy risk levels. here, a detailed description of the result as well as some noteworthy findings from the analysis of the privacy risk of the contact trace data is provided (see table 5 ). demographics included patients' nationality, gender, and age. in reporting nationality, 91.2% of the data do not contain patients' nationality (n = 885). these cases could be assumed to be koreans. all cases of confirmed foreign expatriates disclosed their nationality, which accounted for 8.8% (n = 85) of the patients. considering that legal foreign expatriates account for only 4% of south korea's total population (20) , and the number of confirmed foreign cases is a small proportion, there is a high chance of identifying an individual: it is easier to pinpoint an individual if cases from his/her nationality are relatively few. for example, there was only one confirmed case from gambia, while ∼260 gambians resided in south korea. this example shows the potential for easier identification of the suspect when the size of a community is small. all cases reported patients' gender, and 839 cases (86.5%) specified the exact age or birth year of a patient (e.g., age 30, born in 1990), whereas 131 cases (13.5%) only reported the age range of a patient (e.g., the twenties). one thing to note is that age and gender are personal details that make up one's social security numbers (3 digits) and collecting such data could be invasion of privacy. significant places refer to the residence and workplace of an individual. in identifying residence, over 70% (n = 759) of the disclosed data ranging from level 2 to level 4 provide highly granular data, such as the district, street, and name of an apartment. with additional data, such as activity type (e.g., walking) and the time taken, it could easily be deduced that an individual lives in that narrowly defined region. only 15 cases were labeled as level 0, which included the following two cases: (1) patients from abroad with no domestic residence, and (2) patients who had come from another city. of the disclosed data, 22.3% (n = 216) ranged from level 3 to 4 in the "workplace" category. one interesting fact to note was that collective infection at a workplace unavoidably revealed a patient's workplace location. for example, a collective infection case which caused about 118 related cases occurred at a call center located in guro-gu, seoul revealed the specific building and floor of the center (e.g., "korea" building, 11th floor). a large fraction of cases had a level 0 on workplace location (n = 703, 72.5%). this low risk of workplace location is possibly due to the confirmed patients being jobless (e.g., older adults, teenagers, patients from abroad). another noteworthy finding is that collective infection at a workplace inevitably exposes the location and the patient's job, which the patient wished to keep private (e.g., patient #u9m from 73tb-gu, seoul, works in the redlight district). other cases classified as "no information" usually had no related information of a workplace. some exceptional cases included the word "office, " but with no location specified (e.g., 9 a.m.-6 p.m., office). the data revealed several cases of patients' regular visits to a certain place, which makes it possible to infer one's personal details-hobby, religion, and accommodation information. in the hobby category, 69 cases (n = 69, 7.1%) were identified from patients' regular visits to the gym, golf club, and other places for amusement or leisure activities (see table 6 ). furthermore, religious orientations were revealed because of the collective infection that occurred through religious activities, such as group prayers (n = 111, 11.4%). after mass contagion, most religious services went online, and only a few infection cases revealed religious places. it was also found that information of a short stay (e.g., a few hours) at a specific accommodation, hotel, or motel, may infringe privacy-although this constituted only a small proportion (n = 15, 1.6%). along with location data, some of the patients' relationship information was also provided. with relationship data alone or combining location and relationship data, it might be possible to guess a patient's social boundaries and even infer more about personal life. thus, the category was divided into "relationship only" and "relationship and location." in "relationship only" (n = 215, 22.2%), family and social relations (e.g., colleagues, friends) of a patient were identified. from the analysis, the disclosure of family relations was shown to contain the following two categories: (1) disclosure of family information involving consecutive infection of family members (e.g., patient #8dj (seoul) mother from daegu visited patient #8dj's house, patient #t5v (seoul) patient #8dj's sister), and (2) disclosure of information on an uninfected family member (e.g., patient #sa3 (seoul) patient #sa3's husband had contact with patient #x6t at work and she was infected while under selfquarantine). in the first category, it was found that information about family relations was usually provided directly as family members' traces overlap and involve consecutive infections. the second category raises questions on the necessity of providing additional information about an uninfected family member. for example, information from the second case unnecessarily reveals that the patient's husband had contact with another patient who was assumed to be his colleague. considering that the patient's husband was not infected, it is difficult to say if his contact with a colleague was an essential piece of information. compared to family relations, social relations of confirmed cases generally provide activities shared together (e.g., carpool, late-night drinks at the bar). in the case of workplace relations, linkage information between patients was revealed largely through collective infection. some cases revealed additional information other than a colleague/friend relationship. for example, contact trace data of patient #9f5 (seoul) revealed his colleague is a member of d0l6 church, a church that was identified as the epicenter of the major outbreak in south korea after the infection of patient #f61, a "super-spreader" from daegu. the local government may have judged that providing this information was necessary considering the severity of the outbreak situation. however, the question still remains as to whether it was an appropriate decision to disclose information about religion along with social relationships. "relationship and location" (n = 257, 26.5%) provides information on visits to certain places that may reveal the presence of another person and lead to speculation and unwanted exposure of one's private relationship. for example, one patient's repeated visits to a motel at regular intervals may lead to speculation that he has an intimate relationship with someone. although excluded from our data analysis, patient #f24 from suwon (one of the cities in south korea) who had his traces overlapped with his sister-inlaw (patient #8if) was highly criticized by the media and social network for having an affair, which turned out to be a rumor (21) . less sensitive cases reported the location of home and workplace of a patient's family, friends, and other acquaintances. from the data, it was able to identify types of frequent activities of a patient (e.g., commuting, exercise), which extends to inference on a patient's routine behavior and lifestyle patterns (n = 234, 24.1%). for example, ∼55% of the contact trace data from seoul reported regular commuting time of the patients. these pieces of information are usually provided along with the type of transportation (e.g., on foot/by car/by bus/carpool with a colleague), which enables a detailed inference on one's time schedule. data of patient #t2n (seoul) showed repetitive commuting to a church and his later mobility patterns centered around the church. the patient also visited a nearby cafe several times at a similar time before the case was confirmed. this consistent pattern leads us to a plausible speculation that he is a christian who works at a church and often visits nearby places. the speculation in this study was confirmed through a news article that revealed his job, a missionary. as the high data granularity provided in this case leads to several assumptions on private information, it was found that inferred details of the patient (workplace, frequent visits, religion) could also belong to other categories, such as "significant places" and "sensitive information." key findings • demographics were observed in most cases (gender: 100%, age: 86.5%) and the data on significant places (residence/workplace) showed different levels of privacy risks in over 70% of the cases. • some places disclosed in the data indicated sensitive information about the patient due to the characteristics of the place (e.g., pc caf 'e -the patient's hobby is playing games, church-the patient is christian). in addition, nearly half of the cases (48.7%) exposed the patient's social relationships by describing information about relationships or by showing them visiting certain places with others. • around a quarter of the cases (24.1%) revealed the routine behavior of the patient from places that had been visited repeatedly and frequently. the patterns that appeared in routine behavior may be an important factor in inferring the patient's lifestyle. first, variation in privacy risk levels across different regions was analyzed by comparing their average privacy levels. the analyses revealed regional differences in privacy risks for the confirmed patients. in the demographics category, four cities, seoul, busan, incheon, and ulsan, often showed the exact age of patients (e.g., 27 years; i.e., level 2), while sejong, daejeon and gwangju showed the age range (e.g., the twenties; i.e., level 1). in terms of nationality, seoul disclosed the nationalities of the confirmed cases of all foreigners. despite its low proportion (∼7%) relative to the number of total cases, seoul reported a higher number of nationalities compared to other cities. it was posited that this was because of capital-specific effects, as the city has ∼400,000 foreigners. gwangju also reported a considerably high number of nationalities. out of the total 30 cases, gwangju revealed nationality information of all the cases (100% disclosure). unlike seoul, one interesting fact to note from gwangju is that the city also reported the nationality of korean patients. currently, no specific guidelines regarding nationality disclosure have been found. as shown earlier, all cities revealed gender information of the patients, and there was no difference in this regard. in addition, a comparison of the privacy level of significant places was conducted. as shown in table 5 , the average privacy level of residence is distributed between 1.21 (ulsan) and 3.00 (sejong). all the cities except sejong released only approximate information on a patient's residence such that more than half of the residential information released by each city was equal to or below level 2 ("dong" level). sejong revealed the most detailed information with level 3 on average (mostly at an apartment complex level), which is partly because of the unique characteristics of sejong, a new multifunctional administrative city with many high-rise apartment buildings. with regard to the workplace, the presence of a mass infection in the same building made the difference. important cases, such as the call center of an insurance company in guro-gu, seoul, influenced the high proportion of level 4 cases in seoul (15.1%) and incheon (27.2%); same was the case with a government building of the ministry of oceans and fisheries in sejong (76.1%). most of the patients in sejong work in government buildings, thereby resulting in a high ratio of level 4. daejeon showed a comparatively high ratio of level 4 (33.3%), despite having no case of mass infection, unlike other cities. in the "sensitive information" category, "hobby" showed a substantial proportion of cases that reported privacy level 0 across all cities. in level 1, sejong reported 17.4%, which is a markedly higher figure compared to other cities. this is interesting to note, as one patient who took a zumba class infected the other students. "religion" showed a moderately high percentage of level 0 in an overall sense, but busan showed 34.1% of cases that were level 1. collective infection occurred at a church that contributed to this relatively high level of disclosure. "accommodation" information appeared only in a small fraction of the dataset, but such visits were often suspected for cheating, as reported in the news articles (10) . from "hobby" and "religion, " it was found that a particular incident that involved collective infection unavoidably led to a disclosure of sensitive information. "routine behavior" showed a higher average level of disclosure than "sensitive information." in this category, sejong and daejeon showed relatively high percentages of 45.7 and 38.5%, respectively. in sejong (n = 46), confirmed cases showed very similar mobility patterns, as collective infection revealed that most of the patients worked at the same government and shared the same leisure activity (i.e., zumba class). it was assumed that the unique characteristics of this newly built administrative city have also contributed to this dense infection within the community, as the population is relatively small and a large proportion of residents are government officials. despite no occurrence of collective infection, daejeon (n = 39), as shown earlier, revealed the workplace of the confirmed patients. disclosed workplaces are usually research institutes or tech companies, as the city is a well-known mecca of science and technology in south korea. from the data, 84.6% of workplace revelations were particularly found in seo-gu and yuseong-gu, districts dense with research institutes. inferring the patients' routine behavior was relatively easier as their workplaces were revealed and they lived in the same area. cases from these two cities demonstrate that characteristics of a city can be reflected in contact trace data and enable an indication of one's routine behavior and daily patterns. in "social relationship, " ulsan showed the highest percentage of data disclosure (level 1 and level 2 combined: 72.4%), followed by gwangju (level 1 and level 2 combined: 63.3%). from ulsan, it was posited that mass influx from abroad and their traces with family members may have contributed to this high percentage of privacy disclosure. the korean government announced a guideline limiting the scope and detail of the information to be disclosed on march 14, 2020. as shown in table 7 , it was analyzed how the release of the government's official guidelines influenced privacy risk levels across different regions, by comparing the average privacy levels before and after the announcement. overall, average privacy risk levels decreased for the workplace, hobby, religion, and routine behavior, whereas other items remained somewhat similar. it is notable that while detailed demographic information (i.e., nationality, gender, and age) is generally considered as sensitive information, the average privacy levels for these remained unchanged even after the announcement. in privacy risk levels in general, every region showed a similar the change in trend. however, notable regional differences were found in accommodation and relationships; as an illustration, for relationships, the average levels decreased for seoul, daejeon, and gwangju, while the levels increased for busan and sejong. these findings indicate that the announcement of government guidelines can lower risk levels. however, the effects of the government guidelines could be limited to several factors, such as workplaces and routine behaviors, and vary across regions (or local governments). key findings • differences in privacy risk levels among the cities were observed. in particular, the data from sejong revealed the most detailed information on significant places (the average privacy risk levels for residence and workplace in sejong were over level 3), whereas ulsan showed a relatively high percentage of data disclosure on social relationships (i.e., 72.4% of the confirmed patients in ulsan). • the government guidelines on data disclosure have been released recently, and the effects were limited to a few factors, such as workplaces and routine behaviors. disclosed contact trace data (e.g., "where, when, and for how long") help people to self-identify potential close contacts with people confirmed to be infected. however, location trace disclosure may pose privacy risks because a person's significant places and routine behaviors can be inferred. privacy risks are largely dependent on a person's mobility patterns, which are affected by several regional and policy factors (e.g., residence type, nearby amenities, and social distancing orders). in addition, the results showed that disclosed contact trace data in south korea often include superfluous information, such as detailed demographic information (e.g., age, gender, nationality), social relationships (e.g., parents' house), and workplace information (e.g., company name). disclosing such personal data of already identified persons may not be useful for contact tracing whose goal is to locate unidentified persons who may be in close contact with confirmed people. in other words, for contact tracing purposes, it would be less useful to disclose the personal profile of the confirmed person and their social relationships, such as family or acquaintances. the detailed location of the workplace could be omitted because, in most cases, it is easy to reach employees through internal communication networks; an exceptional case would be when there is a concern of potential group infection with secondary contagions. likewise, it is not necessary to reveal detailed travel information of overseas entrants (which were not reported in the main results), such as the arrival flight number and purpose/duration of foreign travels. based on the results and discussions, this subsection presents policy and technical implications for contact tracing and data disclosure. detailed guidelines are required: the scope and details of patient data disclosure should be carefully considered in the official guidelines. as shown earlier, some of the information included in the patient data in south korea could be controversial because it is not clear whether it is essential to prevent further spread of covid-19. the current guidelines set by the kcdc, which are shown in table 1 , do not provide detailed recommendations. therefore, the guideline about "information that identifies a specific person" could be interpreted differently by different contact trace officers. at the time of contact tracing, it is difficult for officials to envision how a combination of different pieces of information provides an important clue the patient's identity. to reduce the possibility of subjective interpretation, current guidelines can be augmented with the patterns of problematic disclosure, which could be documented by carefully reviewing existing cases. in this case, the codebook of this study could serve as a starting point for analyzing the patterns of problematic disclosure. for instance, one's residence and workplaces can be generally considered sensitive information. the codebook allows the assessment of privacy risk level on a patient's residence and workplaces when disclosing the patients' visited places and transport modes. in addition, for location privacy protection, privacy protection rules, such as k-anonymity can be applied. the k-anonymity ensures that k people in that region cannot be distinguished (22) . due to public safety, however, its strict application is not feasible, yet a relaxed version of k-anonymity can be used: at least for a given region, when there are multiple confirmed cases with overlapping periods, removing identifiers (or confirmed case numbers) could be considered to further protect their location privacy. proper management of revealed data is required: given that some level of privacy risk is unavoidable due to public safety, it is important to manage the patients' data that have been opened to the public. official guidelines recommend that municipalities erase outdated data from their official websites. while scouring the dataset over several months for this research, it was noticed that contact trace data are replicated on multiple sources, ranging from official channels of municipalities (e.g., homepage, blogs, social media, and debriefing videos on youtube) to online news articles and personal sites. diversifying information access channels would be beneficial for public safety; however, the authorities should set a strict code of conduct or regulations on managing replicated contact trace data (e.g., "register before publish") to promote responsible use (e.g., removing outdated data). it's possible to automatically check privacy issues: contact tracers' subjective interpretation could be a source of privacy risks. one could consider an intelligent system that detects possible privacy issues from the patient data before disclosure. for example, personal data can be detected by utilizing supervised machine learning that analyzes semantic, structural, and lexical properties of the data (23) or by estimating privacy risks with visual analytic tools based on k-anonymity and l-diversity models (22). if a system utilizes a metric for quantifying the privacy threat and evaluation model as proposed in the previous study (24) , the system could not only detect potential issues but also obscure the data automatically until it meets a certain privacy level. however, these automatic approaches should be considered with care because they may hide essential contact trace information that needs to be released for public safety. unified management of contact tracing data could be introduced: decentralized management of contact trace data in each municipality makes it difficult to examine privacy risks and manage data replication. in addition, the quality of user interfaces varies widely across different regions. introducing a unified system that manages and visualizes the contact trace data across all regions would be beneficial. of course, there is a concern of a single point of failure, yet this issue can be overcome by introducing decentralized server systems with cloud computing. to promote responsible replication and management of patient data, one can implement a "register before publish" policy. moreover, an information system can help to manage the people who reprocess the patient data officially provided by the local government and deliver it to the public via news articles. this system should have the ability to (1) authorize data usage, (2) track in which article the data is being used, and (3) delete the data automatically when it is outdated. the system could also provide a built-in sharing feature as in youtube's video embedding. youtube allows users to add a video to their websites, social network sites, and blogs by embedding the video to the sites, while any modification or deletion of the original video on youtube is also reflected in the embedded video (25) . a similar mechanism can also be applied to the system. mobile technologies for contact tracing can be alternatively considered: mobile technologies could be utilized to avoid privacy concerns from public disclosure (26, 27) . short-range wireless communications (bluetooth) can be used to automatically detect close contacts by keeping periodic scanning results of nearby wireless devices [e.g., tracetogether (28) and apple/google's app (29, 30) ]. a confirmed user can now publish its anonymized bluetooth id, which helps other people to check whether they are in close contact with the patient. this approach certainly helps protect user privacy because location information is not explicitly shared. however, there are major concerns about its assumption: a majority of people voluntarily need to install mobile applications. there should be further studies on how to consider multiple contact tracing methods along with traditional methods of public disclosure. with the outbreak of covid-19, as mentioned in the introduction, several countries have been disclosing contact trace data. although this paper presents the privacy risks of contact tracing practices, the results should be carefully interpreted, given the limitations of the study. first, this work is focused on south korea and the results may not be generalizable to other nations due to policy differences. however, our methodologies and insights could still be applied in other nations that make contact trace data public. comparing the differences in disclosure policies and privacy risk levels would be an interesting direction for future work, as slight differences in disclosure exist. for instance, the hong kong government reveals the patient's information in an interactive map dashboard that showed not only the demographics but also the full address of both residential and non-residential places that the patient had visited (31) . the singapore government also released detailed patient information, such as nationality, visited sites, and infection sources (4). aggressive contact tracing and data disclosure were considered effective methods for suppressing the spread of a virus. while there is an ongoing dispute between promoting public safety and protecting personal privacy, there is a growing consensus that a reasonable level of personal privacy needs to be sacrificed for public safety, as shown in a recent survey (32) . for all these cases, our policy and technical implications could help lower privacy risks and yet allow governments to effectively conduct contract tracing. in future studies, researchers could compare the differences between governmental policies of open access to contact trace data and the opinions from the public among these countries to set international guidelines on data disclosure in pandemic situations. next, there are privacy issues that remain to be quantified; for example, revealing foreign travel logs, underlying medical conditions, and even part of a patient's name (i.e., the last name of the patient). place log information may include hospital visits that are not related to covid-19; this could reveal a patient's underlying health or personal conditions (e.g., urology, dermatology, and cosmetic surgery). therefore, this study should be expanded to evaluate diverse privacy-violating elements. it is also necessary to study the media's disclosure patterns of patient information. in some cases, the media provided more specific data than the government through an exclusive report. recently in south korea, new media publicized a patient's sexual orientation by investigating visited places (e.g., specific types of bars) or workplace/social information (e.g., infected healthcare workers). therefore, one could compare the disclosed data from the local government with that from the media to evaluate how much further privacy leakage would occur through the news media. this work mainly focused on analyzing the officially disclosed patient data, nevertheless, it is also important to find out what people (both patients and the public) really think about that data. opinions on sharing my data as opposed to someone else's may differ (33) , and the perception of risk of information disclosure could be influenced by the consequent results of both benefits and risks (34) . thus, researchers could possibly find an optimal level where personal privacy and public benefit are well-balanced. all datasets presented in this study are included in the article/ supplementary material. feasibility of controlling covid-19 outbreaks by isolation of cases and contacts contact tracing during an outbreak of ebola virus disease available online at response to covid-19 in taiwan: big data analytics, new technology, and proactive testing how coronavirus is eroding privacy south korea is reporting intimate details of covid-19 cases: has it helped? fear and stigma: the epidemic within the sars outbreak defect: issues in the anthropology of public health. stigma and global health: developing a research agenda privacy: are south korea's alerts too revealing? (2020) national human rights commission of korea. nhrck chairperson's statement on excessive disclosure of private information available online at division of risk assessment and international cooperation, kcdc. press release-updates on covid-19 in korea (as of 14 march) division of risk assessment and international cooperation, kcdc. press release-the updates on covid-19 in korea as of 21 may sharing location in online social networks location disclosure to social relations: why, when, & what people want to share rethinking location sharing: exploring the implications of social-driven vs. purpose-driven location sharing available online at using thematic analysis in psychology localness of location-based knowledge sharing: a study of naver kin ?here? yonhap news agency. no. of foreign rresidents in s. korea hits record 2.05 mln in 2018 south korea's tracking of covid-19 patients raises privacy concerns using data visualization technique to detect sensitive information re-identification problem of real open dataset private data discovery for privacy compliance in collaborative environments the metric model for personal information disclosure available online at: https:// support.google.com/youtube/answer/6301625?hl=en mobile phone data and covid-19: missing an opportunity? arxiv covid-19 contact tracing and data protection can go together singapore says it will make its contact tracing tech freely available to developers available online at available online at latest situation of coronavirus disease (covid-19) in hong kong americans rank halting covid-19 spread over medical privacy less than half in singapore willing to share covid-19 results with contact tracing tech teenagers' perceptions of online privacy and coping behaviors: a risk-benefit appraisal approach gj and hl collaboratively analyzed the dataset and wrote the main texts (i.e., introduction, results, discussion). ak actively guided the design of the study, helped data analyses/visualizations, and wrote the background and summary sections. ul supervised the overall research, provided detailed feedback for data analyses and paper organization, and reviewed the entire manuscript. all authors contributed to the article and approved the submitted version. the authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.copyright © 2020 jung, lee, kim and lee. this is an open-access article distributed under the terms of the creative commons attribution license (cc by). the use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. no use, distribution or reproduction is permitted which does not comply with these terms. key: cord-284519-cufyqv7h authors: singu, sravani; acharya, arpan; challagundla, kishore; byrareddy, siddappa n. title: impact of social determinants of health on the emerging covid-19 pandemic in the united states date: 2020-07-21 journal: front public health doi: 10.3389/fpubh.2020.00406 sha: doc_id: 284519 cord_uid: cufyqv7h a novel coronavirus (2019-ncov) caused a global pandemic in the months following the first four cases reported in wuhan, china, on december 29, 2019. the elderly, immunocompromised, and those with preexisting conditions—such as asthma, cardiovascular disease (cvd), hypertension, chronic kidney disease (ckd), or obesity—experience higher risk of becoming severely ill if infected with the virus. systemic social inequality and discrepancies in socioeconomic status (ses) contribute to higher incidence of asthma, cvd, hypertension, ckd, and obesity in segments of the general population. such preexisting conditions bring heightened risk of complications for individuals who contract the coronavirus disease (covid-19) from the virus (2019-ncov)—also known as “severe acute respiratory syndrome coronavirus 2” (sars-cov-2). in order to help vulnerable groups during times of a health emergency, focus must be placed at the root of the problem. studying the social determinants of health (sdoh), and how they impact disadvantaged populations during times of crisis, will help governments to better manage health emergencies so that every individual has equal opportunity to staying healthy. this review summarizes the impact of social determinants of health (sdoh) during the covid-19 pandemic. the novel coronavirus (2019-ncov) spread rapidly throughout china during the chinese new year in late january of 2020, a time of increased domestic and international travel for chinese people. the first four cases of the novel coronavirus were reported on december 29, 2019. all four cases were linked to the huanan seafood wholesale market in wuhan, a city with more than 11 million people and the capital of hubei province in central china. the symptoms were described as a pneumonia of unknown etiology (1) . early cases show history of contact with the seafood market. later and more recent cases were found to be transmitted via human-to-human contact (2) . the disease caused by 2019-ncov was named covid-19 by the world health organization (who) on february 11, 2020 (3) . the cdc confirmed that individuals with preexisting diagnoses of asthma, cardiovascular (cvd), hypertension, chronic kidney disease (ckd) and/or are elderly, immunocompromised, or obese have higher risk of severe illness from covid-19 (4) . of the listed at-risk health demographics, asthma, cvd, hypertension, ckd, and obesity can be caused by discrepancies in socioeconomic status (ses). the cdc reports that 94% of patients who have died from covid-19 had at least one preexisting condition (5) . because these conditions specifically put an individual at higher risk of being infected with sars-cov-2, these vulnerable populations must be given the resources needed to endure infectious outbreaks. this review summarizes the impact of social determinants of health (sdoh) during a pandemic of covid19 . it can provide essential information to support the government's decisionmaking body to strategically manage health emergencies at community, national, and even international levels in the future if a similar situation was to arise. calculated measures can be taken to prevent or reduce further transmissions in a vulnerable population that is at risk. the social determinants of health (sdoh) are social and economic conditions that are categorized into five key determinants as summarized in figure 1 . health and health care, social and community context, neighborhood and built environment, education, and economic stability (6) . health and health care include access to health care, access to primary care, health insurance coverage, and health literacy (7) . low health literacy can cause patients difficulty with navigating the complex healthcare system and understanding medical advice or prescriptions. individuals without health insurance are less likely to utilize or even have access to primary care, which makes detecting and managing chronic conditions, such as cvd, asthma, diabetes, and cancer, difficult. social and community context are the circumstances a person lives, learns, and works in. this domain of sdoh includes community involvement and discrimination. lower mortality rates are associated with social and community support and cohesion. neighborhood and built environment include housing, neighborhood, transportation, access to healthy foods, air quality, water quality, and access to green space (7) . air pollution has been shown to be associated with incident asthma. the cdc has confirmed that individuals with asthma are at higher risk for severe illness from covid-19 (8) . safety plays a major role in health. people are more likely to walk or run outside if they feel safe in their neighborhood. without the worry about crime and danger, safe neighborhoods also allow people to maintain good mental health. immune function is influenced by psychological stress. algren et al. state that individuals living in deprived neighborhoods were observed to have more stress when compared to those living in non-deprived neighborhoods. stressors of those living in deprived neighborhoods include, "overcrowding, high crime rates, perceived danger, poor transportation, poor housing, disrepair, limited services, poor infrastructure, and a lack of social support" (9) . education includes high school graduation, enrollment in higher education, and language and literacy. the higher one's level of education, the higher his or her life expectancy is (7) . it is important to disclose information regarding health in a patient-specific manner, taking into account the patient's education level. economic stability includes employment, poverty, food security, and housing stability. the american medical association (ama) states that as the poverty level increases, the percentage of adults who are 25 years and older with an activity-limiting chronic disease increases (7) . unemployment impacts an individual's health in many ways, as it has associations with depression, domestic violence, substance abuse, and physical illness. specific examples of sdoh include income, education, employment, and social support (10). simply put, they are conditions into which one is born, grows, lives, works, and ages (11) . they look at the person as a whole. altogether, these conditions impact health status of individuals and communities. disparities in any of these conditions are translated into a measure of social hierarchy called socioeconomic status (ses). the lower individuals are on the spectrum of ses, the poorer health outcomes they face. due to poor outcomes, life expectancy decreases for those at the lower end of the spectrum (10). socioeconomic inequality piles health complications on top of the financial woes already burdening disadvantaged segments of the population. the five sdoh are interrelated and played major role during covid-19 pandemic. for example, education level of an individual can impact his or her occupation, which determines economic stability and income level, which can impact the type of healthcare the individual is eligible for and what neighborhood the individual lives in, which then impacts the social and community context the individual is surrounded by and those factors played important role in current covid-19 pandemic. therefore, one can conclude that socioeconomic factors play a key role in infection and mortality rates. specific examples include some county's in new york, such as bronx, brooklyn, and queens have suffered higher mortality rate compared to other county's suggested that large of population of individuals with low economic status lived in these areas. another example to consider is from the perspective of a child growing up in a family that does not have much economic stability. the child's parents have low-income jobs, which forces them to live in povertystricken neighborhoods that may not have a great school system. this child will not obtain the same quality of education as a child that lives in an affluent neighborhood that has a richer school district. since, public schools in the u.s. are funded by local, state, and federal governments (12) . funding comes from income and property taxes. affluent neighborhoods and districts collect more taxes; therefore, they have more funding. low-income districts collect less funding and have substandard school facilities and teachers who are the least qualified (12) . therefore, below average quality of education will not lead to high college admission test scores, which will keep the child out of top colleges if he or she chooses to pursue a college education. even with a low-tier college education, the child may not have many high-income job opportunities. this will land the child in the same position as his or her parents, with a low-income job living in a poverty-stricken neighborhood. ham et al. (13) state that children living with their parents in poverty-stricken neighborhoods are more likely to end up in the same situation themselves later in their life. the five determinants can be thought of as a cycle of events that impact one another rather than as individual entities even in current covid-19 pandemic. health literacy is defined by the u.s. department of health and human services (hhs) as "the degree to which individuals have the capacity to obtain, process, and understand basic health information needed to make appropriate health decisions" (14) . this includes the ability to read and understand healthrelated pamphlets, prescriptions, written instructions from a healthcare provider, etc. not being able to read or understand health-related information makes it difficult for individuals to take care of themselves, even if the awareness to do so is present. low health literacy is associated with poorer health outcomes. certain population groups have been noted to have low health literacy compared to other groups (14) . those who are living in poverty, not highly educated, from a certain race/ethnic group, or with disabilities are more likely to have low health literacy (14) . patients who demonstrate low health literacy may have high overall literacy and high verbal fluency, which causes the patient to present as having high health literacy. it is important to recognize people who may have low health literacy especially during times of a pandemic, because health literacy is an important means of preventing communicable diseases, such as covid-19. understanding infectious diseases to a certain degree, including mode of transmission and viability of pathogens, will help people readily accept the circumstances in situations like this rather than question the recommendations. health literacy can allow people to understand their responsibility of adhering to social distancing and other recommended measures during the covid-19 pandemic and the reasoning behind the measures being taken to prevent the spread of the virus. a gallup poll conducted in the months of april and may of 2020 looked at how many americans considered social distancing to be significant by assessing their confidence level in the impact social distancing has on reducing the spread of covid-19. further, determined whether each group that was divided by confidence level followed social distancing. the study found that 54% of americans were "very confident" and 31% were "moderately confident" in their belief that social distancing helps save lives during covid-19 pandemic (15) . however, 14% of americans who participated expressed skepticism about social distancing and its role in saving lives. overall, 88% of americans who participated in the poll reported that they "always" or "very often" practiced social distancing, which included measures such as avoiding crowded places and leaving their homes unnecessarily. of those who were "very confident" or "moderately confident" that social distancing makes a difference, 95 and 87% reported that they "very often" practiced social distancing, respectively. fifty-seven percentage of those who expressed skepticism "very often" practiced social distancing. the percentages were drop when it comes to "always" practicing social distancing. seventy-one percentage of those who were "very confident" that social distancing making a difference "always" practiced it, whereas 47% of those who were "moderately confident" "always" practiced it. only 27% of those who were skeptical "always" practiced social distancing. therefore, health literacy was played a major role in whether an individual understands a health emergency situation, such as covid-19 pandemic, and whether he or she will follow recommendations, such as social distancing. access to health care is described as the "timely use of personal health services to achieve the best possible health outcomes" by the national academies of sciences, engineering, and medicine (14) . many people face barriers to health care, which may hinder their ability to take responsible actions toward their well-being. barriers include limited or no access to transportation for health appointments, lack of health insurance, limited education about health care, limited health care resources, provider hours limited to work hours, etc. lack of health insurance is usually seen in populations with lower incomes and minorities. a study by gallup and west health found that 14% of adults in the u.s. revealed that they would not seek healthcare if they experienced a fever and dry cough (16, 17) . fever and dry cough are the most common symptoms of covid-19. when adults were specifically asked whether they would seek healthcare if they had believed they had been infected with covid-19, 9% still answered that they would not (16) . the individuals that reported that they would not seek healthcare were non-white adults under the age of 30 who had a high school education or less earning less than a $40,000 income per year (16) . reluctance to seek healthcare is associated with socioeconomic status. hispanics and african americans were less likely to have health insurance compared to non-hispanic whites (16) . without health insurance, primary care visits may not be feasible, or people may hesitate to use health care resources. this puts those without health insurance at risk of not being screened for chronic conditions, such as cvd, hypertension, asthma, and diabetes. access to health care also relies on the availability of resources (14) . those who are minorities and/or have low incomes already face difficulty-accessing healthcare. many of them primarily depend on student-run clinics for obtaining healthcare. the university of nebraska medical center college of medicine has a student-run clinic, called the student health alliance reaching indigent needy groups (sharing) clinic, which provides low-cost primary health care and services to the underprivileged populations in the omaha community. this clinic has been closed due to the covid-19 pandemic. therefore, the underserved populations who already face barriers to healthcare now face a barrier to access primary care at these student-run clinics, which are their primary means of maintaining their well-being. food deserts are neighborhoods that are defined as low income areas with little access to healthy foods by the u.s. department of agriculture (usda) (18) . a study found that there was association between food deserts and cardiovascular risk factors in an atlanta metropolitan area. they found that income was more strongly associated with cvd risk than access to healthy food (18) . recognizing that income had a greater part than location of residence, they then studied individual income vs. neighborhood income by observing people with low individual income living in low income neighborhoods and compared them with people with low individual income living in high income neighborhoods. results showed that individual income is associated with higher risk of cvd than neighborhood income or food access. those with high individual incomes who lived in low-income neighborhoods had lower cvd risk than those with lower individual incomes who lived in lowincome neighborhoods (18) . individuals with high income who lived in neighborhoods with poor healthy food access had better cardiovascular profiles compared to individuals with low income living in high-income neighborhoods. this confirms that the perceived association between food deserts and cvd risk is partly due to individual income status rather than access to healthy foods. further, another study suggested that there is a similar relationship between ses and cvd and found that mortality from cvd is higher in individuals with lower education levels and lower occupational class (19) . the correlation between lower income and heightened risk of cvd, with cvd increasing the risk for serious illness related to infection from covid-19, suggests an inverse correlation between income and covid-19 health complications. low income has also been associated with hypertension and ckd. healthier foods, such as fruits and vegetables, tend to be costlier. this makes it hard for low-income families to afford healthy diets. individuals have access to high amounts of processed meats and fats instead of fruits and vegetables in low-income neighborhoods and food deserts. a qualitative study done by suarez et al. has revealed that 80.3% of participants living in food deserts and those with low incomes reported that they "always" or "most of the time" have fruit available at home (20) . this is compared to 87.0% of participants that do not live in food deserts and are in the highest income category. 71.6% of participants living in food deserts and those with low incomes reported that they "always" or "most of the time" have dark green vegetables available at home compared to 82.0% that do not live in food deserts and are in the highest income category (20) . qualitatively, family income demonstrated a stronger association with diet, blood pressure, and ckd than living in a food desert (20) . the same study also found that serum carotenoids were low in individuals living in food deserts and individuals with low incomes (20) . carotenoids are a measure of fruit and vegetable intake. they also found that average protein, potassium, sodium, calcium, and magnesium intake were lower among individuals living in food deserts and individuals with low incomes. measuring levels of these minerals gives insight into the measure of dietary acid load in an individual's body. low levels of these minerals indicate a higher measure of dietary acid load (21) . foods rich in protein (meat, cheese, eggs, etc.) increase acid production in the body. fruits and vegetables lead to base production. diets high in acid induce metabolic acidosis, which can lead to hypertension, ckd, insulin resistance, diabetes, and other complications (20) . a high dietary acid load has also been linked to obesity (22) . food deserts contain more fast food restaurants than grocery stores. individuals living in a food desert tend to have a poor diet, which increases the risk of obesity (23) . obesity is classified as a bmi greater than or equal to 40 by the cdc (8) . individuals living outside of food deserts have better access to grocery stores and are more likely to have diets consisting of more fruits and vegetables. these individuals are less likely to be at risk of obesity (23) . individuals who are obese are at higher risk of being diagnosed with a breathing disorder known as obesity hypoventilation syndrome, also known as pickwickian syndrome. it is not clearly understood why this syndrome affects obese individuals, but it is thought that extra fat on the neck, chest, or abdomen may make breathing deeply difficult. this leads to a buildup of carbon dioxide and decreased amounts of oxygen in the blood. hormones that affect breathing pattern may also be secreted in response to difficulty in breathing (24) . body mass index (bmi) is calculated by dividing a person's weight in kilograms by the square of their height in meters (kg/m 2 ). bmi is a screening tool used to determine whether a person is in a healthy weight range, overweight, or obese. a bmi of <18.5 classifies a person as underweight. bmi between 18.5 and <25 is normal. bmi between 25.0 and <30 puts an individual in the overweight range. bmi 30.0 or higher puts an individual in the obese range (25) . a study with 24 patients who tested positive with covid-19 was conducted in seattle. of the 24 patients, 7 were classified as overweight and 13 as obese. the study showed that 85% of the obese patients required mechanical ventilation (26) . sixty-two percentage of the obese patients died from the virus. sixty-four percentage of non-obese patients required mechanical ventilation, and 34% of them died from the virus (26) . the percentages of requiring mechanical ventilation and deaths are clearly higher in obese individuals compared to nonobese individuals. a bmi >40 was found to be the second strongest independent predictor of hospitalization in patients with covid-19 at an academic hospital in new york city (27) . a study in france that collected data from 124 patients who tested positive for covid-19 reported that the ones who required mechanical ventilation were those who had a bmi greater than or equal to 35. the study mentions that the reason behind why patients usually require mechanical ventilation is because of impaired respiratory mechanics, increased airway resistance, and impaired gas exchange (28) . in obese individuals, respiratory problems include low respiratory muscle strength, possible due to the extra fat on the neck, chest, or abdomen as mentioned earlier, and low lung volumes due to the extra fat making it difficult to take deep breaths (24, 28) . the study also concluded that the disease severity of covid-19 increased with increasing bmi (28) . unfair or unjustified socially structured actions against a certain group or population contribute to discrimination. these actions tend to favor the affluent and powerful population at the detriment of the impoverished population. discrimination occurs at both the individual and structural level in health care (17) . individual discrimination includes negative interactions between a patient and a health care provider due to race, gender, etc. negative interactions may limit health care resources and well-being of the patient. structural discrimination is seen in the form of residential segregation according to race or ethnic groups, unequal job opportunities due to gender, unequal access to quality education, inequalities in incarceration, etc. forms of structural discrimination can trickle down to affect individuals and populations in terms of health care. residential segregation plays a major role in the inequalities observed between african americans and caucasian populations. african americans are more likely to live in high-poverty neighborhoods than other americans. high-poverty neighborhoods consist of low quality and poor schools, limited access to healthcare and jobs, weak social networks, high rates of crime, pollution, and congestion (29) . because of congestion in impoverished neighborhoods, it can be difficult to follow social isolation recommendations. keeping physical distance from others may not be an option for some families. many individuals living in poverty are also in a predicament during times like this when people are asked to work from home, because minorities and african americans are more likely to hold jobs in professions in which it is not feasible to work from home (30) . many latinos and african americans are facing the dilemma of having to pay rent and putting food on the table vs. staying home and keeping their families healthy during this covid-19 outbreak, as they are the ones who work in warehouses, food industry, construction, janitorial services, etc., and these are jobs that cannot be done from home (30) . though race and ethnicity data are available for only 35% of those who have fallen victim to the virus, discrimination is clearly evident in the existing data (31) . new york city, the hardest hit city in the u.s., has had more latinos per capita fall victim to covid-19 than any other ethnic groups (29) . latinos make up 29% of new york city's population. approximately 34% of covid-19 deaths in new york city are of latinos. african americans make up 22% of the city's population and 28% of covid-19 deaths (32). overall, african americans are 2.4 times more likely to die from this virus compared to their counterparts of other races. broken down by state, the statistics are alarming. african americans make up ∼13% of the u.s. population, and their population as a whole has endured 32% of covid-19 deaths. on the other hand, caucasians are disproportionately facing deaths based on which u.s. state they reside in. as a whole, caucasians are less likely to die than expected at 0.8 times their counterparts (32) . social support is an important component of an individual's wellbeing. social cohesion, one of the terms used to describe social relationships, describes how strong relationships are and whether there is a sense of solidarity among members of a community (14) . social capital, an indicator of social cohesion, measures the extent of shared group resources within a community, perceived fairness, perceived helpfulness, group membership, and trust (14) . researchers found these aforementioned measures of social capital to be inversely correlated with mortality (33) . social capital decreases as income inequality increases. it is believed that social capital is the element that relates income inequality and mortality (14) . social cohesion is associated with lower neighborhood violence, better self-rated health, and less stress/anxiety. stress has many impacts on the body, including on the immune, cardiovascular, and neuroendocrine systems. a study has showed that higher amounts of social support were associated with lower levels of atherosclerosis in women predisposed to a higher risk for cvd (34) . another study in california demonstrated that social support among mexican adults served as a barrier against the detriments of the discrimination they faced (35) . it is evident that people and communities have come together during this difficult time. medical students have been suspended from clinical clerkships, which prevents students from all patient care activities. across the nation, medical students have been helping out resident physicians and attending physicians who are on the front-line with childcare, pet care, and running errands. medical students from the university of nebraska medical center have also been utilizing time off from clinical clerkships by volunteering in the community. those who know how to sew have been sewing masks for front-line workers due to a shortage of personal protective equipment (ppe). individuals have been running errands for the elderly who are more vulnerable to falling ill with the virus. during times of a global health crisis in which there is a call for social isolation, such as the one we face currently with the covid-19 pandemic, it is important to find ways to maintain communication and social cohesion to preserve each other's well-being. food is an essential human need. it plays a major role in an individual's health and quality of life. consumption of healthy foods is associated with lower risk of chronic health conditions. a healthy diet consists of a myriad of fruit, vegetables, grains, protein-rich foods (seafood, lean meats, poultry, legumes, soy products, eggs, etc.), and fat-free or low-fat dairy. poor diet and nutrition have been linked to chronic conditions, such as cvd, hypertension, diabetes, and even cancer (36) . the individual components of the neighborhood and built environment domain of sdoh are intertwined and affect one another. there are many barriers to the access of healthy foods. transportation, another component of the neighborhood and built environment domain, plays a major role in the access to healthy foods. a study from 2012 to 2013 found that on average, the nearest grocery store to households in the u.s. was 2.19 miles (36) . this makes it difficult for those without their own vehicles or access to public transportation to make a trip to the grocery store. food deserts are neighborhoods that are defined as low income areas with little access to healthy foods by the u.s. department of agriculture (usda) (23) . these neighborhoods are more likely to contain fast food restaurants and convenience stores than grocery stores. fast food restaurants and convenience stores contain options that are of lower quality and more unhealthy foods (higher saturated and trans-fat and higher calories). individuals living in food deserts are more likely to have poor diets and nutrition as a result. compared to caucasian neighborhoods, african american and latino neighborhoods are more likely to contain a higher amount of fast food restaurants and convenience stores. this explains why minority populations are more likely to have negative health outcomes than their racial counterparts. living in a food desert puts an individual at a higher risk of obesity, which is discussed in another section. income also plays a role in access to healthy foods. studies have shown that low-income families depend on cheap foods that happen to be low in nutrient density. healthy foods, such as fresh fruits and vegetables, are usually more expensive than processed foods. those who cannot afford fresh foods opt to the processed foods option, which is unhealthy (36) . it is important to recognize food deserts and communities that do not have access to healthy foods, especially during a pandemic, when supplies may be in shortage to begin with. if supplies are in shortage, it will be difficult for those who have limited access to healthy foods or food in general to maintain their diet and nutrition altogether. individuals will also have to make more trips to grocery stores to obtain groceries, which can put them at risk of acquiring the virus. minority and low-income populations living in food deserts may face more difficulty accessing healthy foods during the covid-19 pandemic due to customers overbuying and stocking groceries. this could be more of a problem in areas that are food deserts compared to affluent areas. air quality, water quality, pollution, housing, and access to green space can all be discussed under this section. health disparities due to neighborhood and environmental conditions can be understood by studying how certain population ends up in certain geographic locations. there is an association between racial minorities and geographic location of their residences. latinos and african americans are more likely to live in neighborhoods that have higher exposure to pollution from airborne particles such as chlorine, aluminum, and carbon (37). this is due to the fact that high-poverty neighborhoods in which latinos and african americans live are more likely to be located near factories, refineries, and landfills that emit pollutants. for a third of americans, groundwater was found to be the major source of drinking water. groundwater near factories, refineries, and landfills tends to be polluted with hazardous wastes (37) . researchers have suggested that air pollution can make individuals more vulnerable to acquiring covid-19. they reason that pollution particles are acting as vehicles for the virus, which makes it easier for the virus to be transmitted from personto-person. researchers say that air pollution may have worsened the outbreak. this may be due to the fact that air pollution weakens the immune system, which decreases one's ability to fight infections (37) . a study recently found that an increase in the size of pollution particles, referred to as pm 2.5 , can have an effect on the spread of covid-19. the study found that an increase of 1 microgram per cubic meter was associated with an 8% increase in deaths related to covid-19 (38) . safety also plays a major role in health. high-poverty neighborhoods are more likely to contain higher rates of crime, which decreases safety of community members. people are more likely to utilize available green space for walking, running, or exercising. another issue in high-poverty neighborhoods is availability of green space. these neighborhoods are crowded to the point where there is minimal green space available for residents. social distancing has been the key to flattening the curve and decreasing transmission of covid-19. in neighborhoods that are crowded, social distancing may not be feasible. this puts individuals living in crowded neighborhoods at a higher risk of becoming ill with the virus, as well as increases the rate of transmission of the virus. low-income families tend to live in public housing of poor quality (39) . a study found that public housing was found to have several infestations with cockroaches, mice, rats, etc. (40) . mold, lack of air conditioning, and tobacco smoke were also a common find (39) . this study also found that 22% of children who lived in public housing were diagnosed with asthma compared to only 7% of those living in single-family homes (40) . low-income families may be at a higher risk of acquiring covid-19. for most jobs and higher educational degrees, a high school diploma is required (41) . without a high school education and diploma, job opportunities become slim. lack of or less job opportunities can lead to poverty. poverty can lead to negative health outcomes as discussed previously. the home and school environment is the major determinants of whether a student will graduate high school. studies have found that students with parents who are not involved in their education are more likely to drop out of high school. schools with higher crime rates are more likely to higher dropout rates (41) . students from low-income households are more likely to attend low quality schools and have less access to educational resources. during the covid-19 pandemic, schools have had to switch to online education. these children may not have access to computers, or internet. this means that children from high-income families are at an advantage when it comes to learning remotely, while children from low-income families are losing ground. children with parents who are educated and have obtained higher educational degrees may encourage their children to keep pursuing their academic work (41) . non-educated parents may undervalue education compared to educated parents and downplay the importance of maintaining academic standards for their children. this does not make the educated parents better than the noneducated parents. rather, it is a matter of being aware of and having experiences of how to navigate situations keeping in mind that education is important regardless of the hardships. children with non-educated parents may not be getting the support that children with educated parents are getting while having to go to school online during this pandemic. some children are stimulated to do well in a classroom setting and having to participate in distance learning may impact their academic merit. individuals with lower levels of education and minorities are more likely to have limited english-speaking skills and lower literacy. those with language and literacy barriers were noted to have worse health status, chronic health conditions, lack health insurance, and have difficulty following medication directions (42) . the u.s. is home to many who speak a language other than english. a new initiative, called the "covid-19 health literacy project, " started by medical students and physicians at harvard medical school, is intended to bridge the language barrier gap. this initiative has translated important covid-19 information in over 35 languages (43) . languages that information can be translated into include arabic, bengali, chinese, dutch, filipino, german, greek, gujarati, japanese, hindi, and many more. information about the virus, prevention methods to avoid becoming ill with the virus, and treatment options available are included in the fact sheets. this has made it possible to educate the public even with existing language barriers. creating awareness of the virus and educating the public about the situation and what precautions to take is an important step toward controlling the spread of the illness. the level of education one obtains is a major determinant of the type of job one has, the income they earn, and benefits such as health insurance, paid sick leave, and parental leave (44) . racial disparities also exist in the workplace. caucasians are more likely to hold white-collar clerical jobs, while african americans and minorities are more likely to hold blue-collar service jobs (44) . discrimination in the workplace can lead to stress, anxiety, depression, and negative health outcomes. individuals who are unemployed are more likely to have stress-related conditions such as cvd, hypertension, and diabetes, which are all risk factors for covid-19 (44) . the u.s. economic activity has slowed down with stay-athome and quarantine orders. many people have lost income by losing their job, having their salary reduced, or being put on unpaid leave (45). approximately 33.5 million americans have filed for unemployment aid in the last seven weeks (46) . approximately 61% of hispanics and 44% of african americans have reported that they have faced wage or job loss due to the covid-19 pandemic compared to 38% of caucasians (47) . these percentages have increased from 49, 36, and 29%, respectively, since march (47) . unemployment or job loss means individuals do not have or lose their employer-sponsored health insurance. congress has allowed uninsured individuals to be tested for covid-19, however, treatment of the virus is not covered (48) . to address the economic downfall, the president of the united states signed the coronavirus aid, relief, and economic security act (cares) stimulus bill into legislation on march 27, 2020 (45) . the stimulus bill provides a payment of $1,200 for each u.s. citizen or u.s. resident alien with an income of $75,000 or less (49, 50) . $500 is added to the $1,200 for each dependent child (45). though it may seem simple, the criteria that have to be met to receive a stimulus check are numerous and complicated. a schedule for distribution of stimulus checks has not been established. as of now, one stimulus check has been sent out to qualifying individuals (50) . the president and congress have mentioned releasing a second check; however, nothing is set in stone (49) (50) (51) . one check of $1,200 may not be enough for most families. this could certainly be a hindrance for families to eat healthy foods, as they will have to use the money wisely until either another check will be distributed, or the pandemic comes to an end and people can return to work. there is a fine line between trying to decrease the spread of covid-19 and preventing the progression of economic decline. it is evident that social distancing and quarantine methods are helping to flatten the curve, however, at the expense of the country's economic stability. social distancing was recommended early on by each state's governors, and then a lockdown followed. two states, georgia and idaho, demonstrate the rise in incidence of cases in the months of march and april, a decline toward the end of may, and rise again in the months of june and july (51, 52) . georgia's governor issued a lockdown on april 3, 2020, and idaho's governor issued a lockdown on march 25, 2020 (53, 54) . during lockdown, non-essential workers were directed to stay at home and only go out to the grocery store or to a pharmacy if needed. social distancing was to be followed strictly during lockdown. georgia's lockdown was lifted on april 24, 2020 (55) . at the end of april, georgia saw a slight increase in incidence of cases. by mid-june, the incidence is higher in georgia than before lockdown was implemented, and it is only increasing. idaho's governor, on the other hand, issued a lockdown on march 25, 2020 (54) . there was a rise in incidence at the beginning of april and then a decline by mid-april. idaho's lockdown was lifted on april 30, 2020 (56) . the incidence was <40 cases in idaho from mid-april to the beginning of june. since june 1, 2020, the incidence is on the rise, and it is higher in june and july compared to when lockdown was implemented in march. the incidence of covid-19 cases overall in the u.s. is shown in figure 2 (57) . it is evident that incidence is once again on the rise as lockdowns have been lifted across the nation and social distancing is no longer being followed as strictly as during the lockdowns (figure 2) . it is understandable that the nation's economy is an important consideration when implementing a lockdown across the nation. we will have to wait and see what the future holds for our nation's economy while we try to eradicate covid-19. pandemics are more of a social problem than a healthcare problem. the population that lives in poverty and in neighborhoods that are overcrowded with poor maintenance and sanitation is being disproportionately affected by covid-19. it is imperative to provide additional aid for low-income families, such as the stimulus check. this is especially important during times of disease outbreaks, as this is a vulnerable population that is at risk for serious illness. the root cause of being a part of the vulnerable population at risk during outbreaks comes down to income level and racial/ethnic identification. lower income has been associated with poor dietary intake and habits. minority groups, such as latinos, and african americans are at a disadvantage due to individual and structural discrimination, and they are more likely than their caucasian counterpart to be vulnerable to negative health outcomes. therefore, it is evident that the sdoh have been overlooked during this pandemic. dr. richard clarke cabot, an american physician, was the first in the u.s. to consider socioeconomic, family, and psychological factors when practicing medicine (https://www. ncbi.nlm.nih.gov/books/nbk702/). he observed that there was a correlation between lower socioeconomic status of patients and their probability of succumbing to illness. historical reports have shown that poverty, inequalities, and sdoh facilitate the spread of infectious diseases. inequalities in health and healthcare can further add to disparities in morbidity and mortality. quinn et al. suggested that existing studies of influenza pandemics have not recognized the importance of health inequalities nor have they attempted to analyze differences in socioeconomic factors and how they impact health during times of a health emergency figure 2 | the wax and wane in new cases of covid-19 per day in usa, new york, georgia and idaho. the graphs were generated using the online data form cdc and john hopkins web sites. (58) . therefore, it is imperative to respond rapidly and effectively during times of a health emergency. in order to achieve that, it is crucial to be educated about all of the factors that may play a role in health and healthcare before an outbreak of disease even occurs. having insight into factors that play a role in health and healthcare, such as sdoh, can facilitate access to medical and non-medical resources to those who are socioeconomically disadvantaged. public education and creating awareness of the severity of the virus is also important. awareness of the disadvantaged population that is more vulnerable than the average individual and the rapid spread of covid-19 should motivate individuals to reduce exposure to others to stop the spread of the disease. the key to fighting an outbreak is to take into account the various factors that play a role in the well-being of a nation. appropriate and timely education, health care, and social services can be effective measures taken to address outbreaks, such as covid-19. integrating sdoh into efforts to eliminate disparities in health and healthcare can be the solution to reducing disease globally. this can be done through the assembly of an interdisciplinary team that consists of health care professionals, public health professionals, anthropologists, sociologists, researchers, governments, national institute of health (nih), center for diseases control (cdc), world health organization (who), and others, who can all contribute to analyzing and understanding the various factors that play a role in causing health disparities in populations that already face socioeconomic inequalities. it is also crucial to assess what actions and measures were taken correctly and what went wrong during this pandemic, so that, we will be prepared to handle things in a more efficient manner if any future pandemics arise. every person, regardless of where they live, what race they are, and what income they have, should have equal opportunities to stay healthy. by incorporating sdoh into preventing the spread of disease and to approach patient care in a holistic manner, the unfair differences can be minimized socially and economically. ss designed and drafted/wrote the manuscript. aa referencing and edited the manuscript. kc edited the manuscript. sb designed and edited/wrote the manuscript. all authors contributed to the article and approved the submitted version. early transmission dynamics in wuhan, china, of novel coronavirus-infected pneumonia epidemiology, causes, clinical manifestation and diagnosis, prevention and control of coronavirus disease (covid-19) during the early outbreak period: a scoping review the epidemiology and pathogenesis of coronavirus disease (covid-19) outbreak people who need to take extra precautions preliminary estimates of the prevalence of selected underlying health conditions among patients with coronavirus disease 2019 -united states covid-19): people who are at higher risk for severe illness associations between perceived stress, socioeconomic status, and health-risk behaviour in deprived neighbourhoods in denmark: a cross-sectional study the social determinants of health, health equity, and human rights why schools in rich areas get more funding than poor areas intergenerational transmission of neighbourhood poverty: an analysis of neighbourhood histories of individuals healthy people available online at 14% with likely covid-19 to avoid care due to cost. well being (2020) healthy people association between living in food deserts and cardiovascular risk socioeconomic inequalities in cardiovascular disease mortality; an international study food insecurity, ckd, and subsequent esrd in us adults dietary acid load: mechanisms and evidence of its health repercussions higher dietary acid load potentially increases serum triglyceride and obesity prevalence in adults: an updated systematic review and meta-analysis food swamps predict obesity rates better than food deserts in the united states obesity hypoventilation syndrome covid-19 in critically ill patients in the seattle region -case series factors associated with hospitalization and critical illness among 4,103 patients with covid-19 disease in new york city. medrxiv high prevalence of obesity in severe acute respiratory syndrome coronavirus-2 (sars-cov-2) requiring invasive mechanical ventilation for blacks in america, the gap in neighborhood poverty has declined faster than segregation hispanics hit harder by the coronavirus, early u.s. data show how to save black and hispanic lives in a pandemic the color of coronavirus: covid-19 deaths by race and ethnicity in the social capital, income inequality, and mortality hostility, social support, and carotid artery atherosclerosis in the national heart, lung, and blood institute family heart study acculturation stress, social support, and self-rated health among latinos in california access to foods that support healthy eating patterns how air pollution exacerbates covid-19 exposure to air pollution and covid-19 mortality in the united states: a nationwide cross-sectional study. medrxiv quality of housing the role of housing type and housing quality in urban children with asthma high school graduation language and literacy new effort aims to provide covid-19 resources to non-english speakers in u healthy people coronavirus economic stimulus payments: who gets it, how, & impact on other benefits the new york times. stocks rise, with tech index now up for 2020 financial and health impacts of covid-19 vary widely by race and ethnicity intersecting u.s. epidemics: covid-19 and lack of health insurance prevention of mother-to-child transmission services as a gateway to family-based human immunodeficiency virus care and treatment in resource-limited settings: rationale and international experiences what your next stimulus "check" really might look like available online at idaho coronavirus map and case count the atlanta journal-constitution governor little issues stay-at-home order for idaho georgia allowed some businesses to reopen today, but many store and restaurant owners aren't ready to take the risk idaho governor extends stay-home order through april 30 because of coronavirus available online at health inequalities and infectious disease epidemics: a challenge for global health security we thank kabita pandey for help in preparation of figure and douglas meigs for editorial help. the authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.copyright © 2020 singu, acharya, challagundla and byrareddy. this is an open-access article distributed under the terms of the creative commons attribution license (cc by). the use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. no use, distribution or reproduction is permitted which does not comply with these terms. key: cord-291855-wtwz94sy authors: tambone, vittoradolfo; boudreau, donald; ciccozzi, massimo; sanders, karen; campanozzi, laura leondina; wathuta, jane; violante, luciano; cauda, roberto; petrini, carlo; abbate, antonio; alloni, rossana; argemi, josepmaria; argemí renom, josep; de benedictis, anna; galerneau, france; garcía-sánchez, emilio; ghilardi, giampaolo; hafler, janet palmer; linden, magdalena; marcos, alfredo; onetti muda, andrea; pandolfi, marco; pelaccia, thierry; picozzi, mario; revello, ruben oscar; ricci, giovanna; rohrbaugh, robert; rossi, patrizio; sirignano, ascanio; spagnolo, antonio gioacchino; stammers, trevor; velázquez, lourdes; agazzi, evandro; mercurio, mark title: ethical criteria for the admission and management of patients in the icu under conditions of limited medical resources: a shared international proposal in view of the covid-19 pandemic date: 2020-06-16 journal: front public health doi: 10.3389/fpubh.2020.00284 sha: doc_id: 291855 cord_uid: wtwz94sy nan the present pandemic has exposed us to unprecedented challenges that need to be addressed not just for the current state, but also for possible future similar occurrences. it is worth pointing out that discussions on the allocation of medical resources may not necessarily refer to an exception, but, unfortunately, to a regular condition for a large part of humanity (1) . the criteria for admission to an intensive care unit (icu) setting generally take into account multiple factors. there must be a diagnostic and prognostic basis for the decisions made, considering both biological factors and patient values and wishes. furthermore, the decision-making process should, whenever possible, respect the patient's advance directives as well as the relationship with the patient's family or attorney. therapeutic neglect should be avoided. having applied standard clinical evaluation criteria for the appropriate treatment of patients with covid-19, including consideration of prognosis, if a hospital then finds itself unable to provide optimal treatment (e.g., due to a disproportion between the number of patients and the availability of beds, healthcare providers, ventilators, and drugs in the icu), it becomes necessary to evaluate, case by case, how to achieve justice and the best possible good for the greatest number of patients. it is therefore mandatory to explore alternative solutions; these include increasing available beds and healthcare providers, implementing alternative, though suboptimal, approaches (where appropriate), transferring patients to other clinical units, etc. making these decisions properly also involves the recovery of the political role of medicine and science (2) . if the imbalance between needs and resources reaches a critical level, an emergency triage protocol, following the operational and ethical indications of "disaster medicine, " should be activated. these have been deployed in major and serious natural (earthquakes or tsunamis for example) and technological (factory explosions, public transport accidents for example) disasters, as well as following terrorist attacks (3, 4) . the question of the feasibility of developing a clinical evaluation algorithm to support the decision-making of the triage team remains open, though many such protocols have been written. according to the above, we propose the following five ethical criteria for the triage of patients in conditions of limited resources, such as the covid pandemic. they are the result of an interdisciplinary and intercultural dialogue between specialists from different disciplines. several of the authors are working in the main epicenters of the crisis and currently are playing a central role in the bioethical, clinical, social and legal aspects of the management of the covid-19 pandemic. • we take the following three general principles as evaluative references: (a) the good of a single patient should be considered in the framework of the common good. common good means the good of all people and of the whole person. it is rooted in the idea of human dignity, which gives birth to the humanitarian imperative conveyed in the first core principle of "disaster medicine"; the common good also means that, in a global health framework, patients are not just isolated individuals but persons with strong ties to their communities, and therefore both patient and community need to be taken into account (5); (b) no one must be abandoned or discriminated against for any reason (6); (c) before denying a necessary referral of a patient to an icu, due to lack of resources, it is required to consider alternatives both for the immediate case and, based on the experience gained, for similar future cases. • appropriate assistance to any person in need of medical care should be provided whenever possible. in critical situations, the criteria for determining priority are the urgency and severity of the clinical situation. consideration should also be given to the effectiveness and proportionality of the medical intervention, with the goal of obtaining the greatest possible benefit for the greatest number of patients. • triage must be carried out on a case-by-case basis, with reference not only to the patient's clinical condition but also to the availability of resources in the hospital. possible transfer initiatives to other larger and better resourced national or foreign intensive care units must also be considered. triage must not proceed using a standardized approach where the sole decision-making criteria is age (7). • inappropriate treatments are not acceptable. • adequate forms of palliative and spiritual care must be assured, where necessary. timo smieszek t. how to fairly allocate scarce medical resources: ethical argumentation under scrutiny by health professionals and lay people the lancet. health and medicine in 2019: what have we learned? code of conduct for the international red cross and red crescent movement and non-governmental organizations (n-go s) in disaster relief the medical response to multisite terrorist attacks in paris shared responsibility, global solidarity: responding to the socio-economic impacts of covid-19 joint statement. persons with disabilities and covid-19 by the chair of the united nations committee on the rights of persons with disabilities, on behalf of the committee on the rights of persons with disabilities and the special envoy of the united nations secretary-general on disability and accessibility public health and the common good the manuscript is an original work of all authors. all authors made a significant contribution to this paper and have read and approved the final version of the manuscript. the authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.the handling editor declared a shared affiliation, though no other collaboration, with one of the authors ja.copyright © 2020 tambone, boudreau, ciccozzi, sanders, campanozzi, wathuta, violante, cauda, petrini, abbate, alloni, argemi, argemí renom, de benedictis, galerneau, garcía-sánchez, ghilardi, hafler, linden, marcos, onetti muda, pandolfi, pelaccia, picozzi, revello, ricci, rohrbaugh, rossi, sirignano, spagnolo, stammers, velázquez, agazzi and mercurio. this is an open-access article distributed under the terms of the creative commons attribution license (cc by). the use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. no use, distribution or reproduction is permitted which does not comply with these terms. key: cord-313489-i969aqn9 authors: galbadage, thushara; peterson, brent m.; gunasekera, richard s. title: does covid-19 spread through droplets alone? date: 2020-04-24 journal: front public health doi: 10.3389/fpubh.2020.00163 sha: doc_id: 313489 cord_uid: i969aqn9 nan the world is in the middle of a historic public health crisis. as of march 30, 2020, over a third of the population in the united states were under "stay at home" orders given by state governors to protect the vulnerable and the unexposed. unprecedented steps have been taken by governments globally to contain the novel coronavirus disease 2019 (covid-19), a rapidly spreading pandemic. this has resulted in more than 690,000 cases and over 33,000 deaths worldwide (supplementary table 1 ). the index case of the disease, caused by the severe acute respiratory syndrome coronavirus-2 (sars-cov-2) was identified more than 3 months ago. since then, public health authorities worldwide have taken aggressive measures to blunt the exponential spread of this coronavirus. furthermore, several nations, including italy, spain, and france, have imposed nationwide lockdown measures to enforce social distancing to further prevent the spread of covid-19 in their respective countries. while preventative measures have been imposed globally, the observed propagation of covid-19 has noticeable differences among select nations. epidemiologic data show that some countries have exponential increases in disease incidence, while others seem to have "flattened the curve." this raises questions of whether a full scientific understanding of disease transmission modes has yet to be attained, and thus whether there are more effective ways to prevent its spread. this brings us to the fundamental question: does covid-19 spread through droplets alone? to answer this question, we provide epidemiological observational data in conjunction with known molecular characteristics of sars-cov-2. we discuss the ability of this novel coronavirus to remain viable on environmental surfaces from hours to days and describe its increased virulence characteristics compared to the previous sars-cov-1. these biochemical and molecular properties likely allow this novel coronavirus to employ indirect methods of transmission, including fomites and aerosols, in addition to respiratory droplet transmission (figure 1) . public health measures of this aggressive nature have the universal purpose of reducing the exponential rise in incidence rates of disease transmission. observations made in health outcomes following the 1918 influenza pandemic have guided public health policy regarding these preventative measures. importantly, during this pandemic, some u.s. cities chose more effective measures to address the spread of the disease, resulting in observable differences in mortality rates across the nation (1). social distancing is an evidence-based practice to help prevent the transmission of pathogens that are known to spread from person to person within a 3-6 feet distance through respiratory droplets (2, 3) . this practice requires individuals in a community to choose behaviors that increase the physical distance between themselves and others (infected, asymptomatic carriers, or non-infected). social or physical distancing helps reduce the transmission of respiratory droplets containing sars-cov-2 and slows the incidence of the disease by reducing the opportunities for potential viral exposures. furthermore, this is an excellent example of how integral the public health system and policies are to the proper function of medical figure 1 | covid-19 potential modes of transmission. this illustration shows three potential ways sars-cov-2 can spread from an infected host to a susceptible host. first, it is transmitted person to person (direct contact) through respiratory droplets. these droplets can travel for distances 6 feet or less in air. second, sars-cov-2 is likely transmitted through fomites (indirect contact) for the duration it is viable on environmental surfaces. third, it is also likely transmitted through aerosols (indirect contact) for distances longer than 6 feet in the air. to establish an infection, sars-cov-2 needs to first reach an entry point (eyes, nose, or mouth) on a susceptible host. and healthcare systems. acting swiftly and mobilizing precautionary measures can substantially aid in flattening the disease incidence curve, thereby reducing the number of critically ill patients who will need medical treatment all at the same time. this, in turn, reduces the burden on the healthcare system that takes care of patients presenting with the most feared complication of covid-19, i.e., severe bilateral pneumonia (4). this concept, now widely referred to as flattening the curve, gives critically ill patients a fighting chance to survive by obtaining life-saving supportive therapy in hospitals. this, therefore, significantly reduces the mortality rate (1) . if the number of critically ill patients is higher than what can be accommodated in hospitals, many more patients will die due to the lack of life-saving medical attention. the current consensus regarding the transmission of sars-cov-2 is that it spreads person to person through respiratory droplets (5, 6) . precautions to prevent the spread by droplets as recommended by both the centers for disease control and prevention (cdc) and the world health organization (who) are to (1) wash hands with soap, (2) avoid touching viral entry points, such as eyes, nose, and mouth, (3) cover the mouth when coughing or sneezing, (4) wear a facemask if sick and (5) practice social distancing by putting 6 feet of distance between individuals. in addition to these precautions, governmentmandated social distancing measures such as (6) state lockdowns and (7) "stay at home" orders are effective ways to minimize the spread of sars-cov-2 through droplet transmission. despite all these aggressive precautionary measures, sars-cov-2 has succeeded in establishing an exponentially growing pandemic that has spread to almost every nation in the world (supplementary figures 1, 2) . specific epidemiological observations may provide evidence to suspect that the spread of sars-cov-2 may not be limited to respiratory droplets alone. for example, on february 4, 2020, the diamond princess cruise ship carrying 3,711 passengers and crew members reported 10 cases testing positive for covid-19 after their 14-day voyage. as a response to this, the ship was quarantined for 14 days while docked off the coast of japan. following this quarantine period, a total of 634 cases reportedly tested positive for covid-19, despite droplet precautions and social distancing principles practiced on board (7) . in retrospect, public health officials acknowledge this was not the best practice implemented to contain covid-19. additionally, public health officials responded differently to the grand princess cruise ship off the coast of oakland, california, based on suspicions that the dramatically widespread transmission of fomites or covid-19 aerosols may have been exacerbated by interconnected central ventilation between ship cabins (8) . public health officials removed all susceptible and unexposed passengers from this cruise ship, which resulted in a significantly lower number of covid-19 cases (8) . tragically, another story that is unfolding in the covid-19 pandemic is occurring within the country of italy, which currently maintains a mortality rate of 9.3% (supplementary table 1 ). once the number of covid-19 positive cases surpassed 5,000, the government of italy imposed a nationwide lockdown measure on march 9th (supplementary figure 3 , solid black arrow). however, even after these measures were in place for over 2 weeks (dotted black arrow), the number of cases of covid-19 continued to rise exponentially, surpassing 50,000 cases by march 22nd (supplementary table 1, supplementary figures 2, 3) . this may suggest that italy responded far too late to implement preventative measures that could have flattened the curve. or, this example may indicate that even amidst the aggressive precautionary measures taken to reduce droplet spread, other modes of transmission may have also occurred. these observations are not limited to just italy. to date, many of the european nations are experiencing an exponential increase in the incidence rate of covid-19 despite many stringent precautionary measures employed over the past several weeks (supplementary figure 3) . these epidemiological observations in the rapid spread of the disease across nations practicing droplet precautions strongly suggest there may be other modes of disease transmission involved (figure 1) . recent studies have indicated that sars-cov-2 demonstrated 10-20 times greater affinity to angiotensin-converting enzyme 2 (ace2) receptors compared to sars-cov-1, making it a much more virulent virus (9, 10) . this means fewer sars-cov-2 virions are necessary to establish an infection in humans. this, in part, could explain the rapid spread of the disease worldwide compared to the 2002-2003 sars outbreak that infected approximately 8,100 individuals. the primary mode of transmission of sars-cov-1 in the 2002-2003 outbreak was by respiratory droplets up to a distance of about 6 feet (3, 11) . however, sars-cov-1 has also shown to be viable on a variety of common surfaces under environmental conditions up to 96 h post-exposure (12, 13) . sars-cov-2 was recently shown to remain viable on average for about 6.8 h on plastic surfaces and about 5.6 h on stainless steel surfaces, and viable virions were detected up to 72 h post-exposure (14) . these studies have demonstrated that sars-cov-2 can remain viable in the environment much longer than most other viruses transmitted through respiratory droplets. the ability of sars-cov-2 to remain viable longer on surfaces taken together with its higher virulence in establishing an infection makes it very likely that this coronavirus uses other modes of transmission in addition to respiratory droplets (figure 1) . remaining longer in the environment may mean this coronavirus can easily transmit through indirect transmission routes. this can be either a certain level of airborne spread or vehicle-borne (fomites) transmission. pathogens like influenza virus and rhinovirus that usually spread through respiratory droplets have some airborne transmission properties making it plausible that sars-cov-2 may have such characteristics as well (2, 15, 16) . coughing, sneezing, and talking can produce droplets of various sizes. fluid mechanical principles show that exhaled droplets smaller than 10 µm can travel longer distances through air streams (17) . respiratory droplets <50 µm can also remain suspended in the air long enough to contaminate ventilation systems located over 12 feet from the source (18) . with the ability to remain viable longer in the environment, sars-cov-2 likely transmits more than 6 feet in the air. such additional modes of transmission can help further explain the observations made on the diamond princess cruise ship in italy and other european nations. on the cruise ship, contaminated surfaces and utensils (fomites), and aerosolized viral particles traveling beyond 6 feet could have exacerbated the volatile spread of covid-19. in italy, having houses or other domiciles close to one another may have transmitted the disease even with a limited level of aerosolization. this example may also better explain the current exponential spread of sars-cov-2 in many european nations and in the united states that are aggressively practicing social distancing. today, the world is facing a particularly deadly disease to which there is no cure currently nor a vaccine. based on the findings mentioned above, if sars-cov-2 is also transmitted through indirect contact, additional, yet practical methods of precaution may be indicated. there are ways to help prevent such spread. (1) first, it is essential to follow all droplet precautions including washing hands with soap or using an alcohol-based hand sanitizer for 20-40 s, (2) protecting viral entry points, (3) covering one's mouth when coughing or sneezing, and (4) appropriate social/physical distancing. in addition, (5) continually disinfecting contact surfaces can eliminate the risk of fomite-based transmission. (6) furthermore, to prevent the possible spread of aerosolized sars-cov-2 infections, we will need to reevaluate the current recommendations of 6 feet of physical separation between individuals to possibly increasing it further. also (7) , infected hosts can help prevent the propagation of the virus by donning a face mask covering their mouth and nose to disrupt the airflow near the source. (8) cdc's latest recommendation that all individuals wear a cloth face mask addresses asymptomatic carriers, also known as silent spreaders, and will help protect susceptible hosts. finally in areas at increased risk of covid-19 transmission such as hospitals and patient care facilities, (9) appropriately fitted n95 respiratory (facemask), with other personal protective equipment (ppe) and (10) expanded use of special air handling and ventilation systems (e.g., aiirs) need to be in place (19, 20) . this can help contain and safely remove sars-cov-2 likely transmitted through aerosolization. tg compiled the epidemiological data, prepared the figures, and helped with the writing and editing of the manuscript. bp discussed the modes of disease spread and helped with the writing and editing of the manuscript. rg discussed the molecular basis of the study and helped with the writing and editing of the manuscript. the work of rg and tg was supported in part by the discovery institute and the peter & carla roth family. public health interventions and epidemic intensity during the 1918 influenza pandemic aerosol transmission of rhinovirus colds cluster of sars among medical students exposed to single patient, hong kong epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in wuhan, china: a descriptive study cdc. how covid-19 spreads how does covid-19 spread? world health organization (2020) estimating the asymptomatic proportion of coronavirus disease 2019 (covid-19) cases on board the diamond princess cruise ship grand princess updates sars-cov-2 cell entry depends on ace2 and tmprss2 and is blocked by a clinically proven protease inhibitor cryo-em structure of the 2019-ncov spike in the prefusion conformation effectiveness of precautions against droplets and contact in prevention of nosocomial transmission of severe acute respiratory syndrome (sars) stability of sars coronavirus in human specimens and environment and its sensitivity to heating and u.v. irradiation transmission of sars and mers coronaviruses and influenza virus in healthcare settings: the possible role of dry surface contamination aerosol and surface stability of sars-cov-2 as compared with sars-cov-1 human influenza resulting from aerosol inhalation an outbreak of influenza aboard a commercial airliner exhaled droplets due to talking and coughing violent expiratory events: on coughing and sneezing transmission-based precautions review of scientific data regarding transmission of infectious agents in healthcare settings we acknowledge research students, joseph awada and danny ramirez jr. for their discussions on this research topic. the supplementary material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fpubh. 2020.00163/full#supplementary-material key: cord-321098-j3glby40 authors: bodrud-doza, md.; shammi, mashura; bahlman, laura; islam, abu reza md. towfiqul; rahman, md. mostafizur title: psychosocial and socio-economic crisis in bangladesh due to covid-19 pandemic: a perception-based assessment date: 2020-06-26 journal: front public health doi: 10.3389/fpubh.2020.00341 sha: doc_id: 321098 cord_uid: j3glby40 background: the spread of the covid-19 pandemic, the partial lockdown, the disease intensity, weak governance in the healthcare system, insufficient medical facilities, unawareness, and the sharing of misinformation in the mass media has led to people experiencing fear and anxiety. the present study intended to conduct a perception-based analysis to get an idea of people's psychosocial and socio-economic crisis, and the possible environmental crisis, amidst the covid-19 pandemic in bangladesh. methods: a perception-based questionnaire was put online for bangladeshi citizens of 18 years and/or older. the sample size was 1,066 respondents. datasets were analyzed through a set of statistical techniques including principal component and hierarchical cluster analysis. results: there was a positive significant association between fear of the covid-19 outbreak with the struggling healthcare system (p < 0.05) of the country. also, there was a negative association between the fragile health system of bangladesh and the government's ability to deal with the pandemic (p < 0.05), revealing the poor governance in the healthcare system. a positive association of shutdown and social distancing with the fear of losing one's own or a family members' life, influenced by a lack of healthcare treatment (p < 0.05), reveals that, due to the decision of shutting down normal activities, people may be experiencing mental and economic stress. however, a positive association of the socio-economic impact of the shutdown with poor people's suffering, the price hike of basic essentials, the hindering of formal education (p < 0.05), and the possibility of a severe socio-economic and health crisis will be aggravated. moreover, there is a possibility of a climate change-induced disaster and infectious diseases like dengue during/after the covid-19 situation, which will create severe food insecurity (p < 0.01) and a further healthcare crisis. conclusions: the partial lockdown in bangladesh due to the covid-19 pandemic increased community transmission and worsened the healthcare crisis, economic burden, and loss of gdp despite the resuming of industrial operations. in society, it has created psychosocial and socio-economic insecurity among people due to the loss of lives and livelihoods. the government should take proper inclusive steps for risk assessment, communications, and financial stimulus toward the public to alleviate their fear and anxiety, and to take proper action to boost mental health and well-being. the novel coronavirus disease (covid-19) began spreading in november 2019, in wuhan, china. following this, the world health organization (who) announced covid-19 as a global pandemic on march 11th, 2020 (1) . covid-19 has advanced into a pandemic, starting initially as small clusters of transmission that combined into larger clusters in many countries, subsequently resulting in a widespread transmission (2) . social isolation, institutional and home quarantine, social distancing, and community containment measures were applied without delay (3) . through quick administrative action and raising awareness for individuals on social-distancing, stringent steps were taken to manage the spread of the disease by canceling thousands of locations that involved social gathering including offices, classrooms, reception centers, clubs, transport services, and travel restrictions, leaving many countries in complete lockdown (4) . the remarkable actions and ventures in public health to quarantine mass numbers has prevented this virus from spreading exponentially between humans in china, singapore, hong kong, and south korea, despite initial cases (2, 5) . however, a surge of covid-19 outbreaks in all inhabitable continents, with 84,187 deaths alone in the usa, indicates that the infection had passed the tipping point (1, 6) . today, as of the 26th of may 2020, total global covid-19 cases have risen to 5,637,381, with the total number of deaths escalating to 3,49,291 (7) . the accelerating spread of covid-19 and its outcomes around the world has led people to experiencing fear, panic, concern, anxiety, stigma, depression, racism, and xenophobia (8) . bangladesh confirmed their first covid-19 case on the 8th of march 2020 (9), followed by a nationwide lockdown from 26 march which had been extended several times until 30th may 2020 to prevent human transmission. the government deployed armed forces to facilitate social distancing on march 24th. emergency healthcare services and law enforcement were exempt from this announcement. yet more than 11 million people left dhaka to return to their home districts and thus helped spread the diseases nationwide. moreover, from the 25th of april 2020, all ready-made-garment (rmg) factories, industries, private offices, and business centers were allowed to open, leading to a "partial lockdown" in the country. the migration of rmg workers to the industrial districts and less community awareness about the disease has increased the transmission among millions of people. the institute of epidemiology disease control and research (iedcr), under the ministry of health and family welfare (mfhw) and directorate general of health services (dghs), is responsible for researching epidemiological and communicable diseases such as covid-19 in bangladesh, as well as disease control and surveillance. initially, iedcr was the single and centralized laboratory for covid-19 testing in bangladesh (9) . the dghs, on the other hand, is the responsible body for the coordination of testing and sample collections of covid-19 patients (10) . as of the 26th of may 2020, according to iedcr, the total number of covid-19 positive cases stands at 36,751 with 522 deaths (figures 1a,b) . according to iedcr, those aged between 21 and 40 are with the highest number of cases (55%), while those aged above 60 have had fatal cases of the disease (42%). at present, the fatality rate in bangladesh is 1.41% (26th may 2020) which was initially 10.4% (8th april 2020) (9) . although the number of laboratories for covid-19 testing has increased to 48, all these labs are in major urban areas of bangladesh and to get tested requires long waiting hours. more often the tests have been done after the patients had died. very recently, more than 15% of those tested daily have tested as positive (figure 1c) , and the ratio of testing is 1,620/1 million people. in addition, it also takes a long time to get the result of the tests. furthermore, there are only 1,169 intensive care unit (icu) beds in the country, of which 432 beds are in government hospitals and 737 in private hospitals. it is predicted that as the number of patients rise, the required number of icu facilities will not be adequate (9) . in addition, the healthcare staff and doctors were given low quality/no personal protective equipment (ppe) which has caused a high infection rate among them (11) . moreover, as laboratory staff, healthcare staff, and doctors have become increasingly infected, there is also a shortage of specialized trained personal to perform covid-19 tests, meaning patient treatment will be disrupted. amidst the lockdown, due to the fear of contact transmission, private hospitals and clinics are not providing any services (11) . the shortage of healthcare facilities for primary and critical care patients have therefore been depleted. the healthcare workers who have treated patients and become infected have been criticized socially and have faced social stigma from local people. in many locations public protests were observed against the establishment of quarantine facilities, covid-19 care hospitals, and clinics. social humiliation was a common practice of law enforcement authorities and government officials. on many occasions, family members left the infected and the deceased in the hospitals. the deceased were even denied burials in local graveyards, which are basic cultural rights as a muslim (12) . moreover, the lockdown hit hard for those who earn daily wages and low and middle-income people who lost their jobs and their income source. the anxiety and fear of death from hunger or death from infection led to several suicide cases (13) . predictably, any contagious epidemic outbreak has harmful effects on individuals and society (14) . considering the population density, educational status, social structure, cultural norms, healthcare capacity, and often flawed policies taken by the government of bangladesh, it is hard to lock down a country of 165 million people. moreover, bangladesh hosts the largest refugee camps in the world in the cox's bazar district. the rohingya refugees who fled from myanmar reside in the camps of cox's bazar. 21 confirmed cases were found in the camps while the district had reported 435 confirmed cases (9) . this depicts the scenario of public anxiety which should be immediately dealt with by the government, along with the alliance groups, with proper information. amidst the current societal levels of anxiety and fear, the possibility of natural disasters such as tropical cyclones and monsoon floods and the potential for a dengue outbreak, seasonal influenza, or other infections are potentially overlooked. furthermore, the consequences of incorrect disposal of used personal protective equipment (ppe) from covid-19 hospitals without proper treatment in landfill sites has the potential for further disease transmission among the waste management personal and further environmental transmission. considering the given circumstance, this study was designed to analyze the psychosocial, socio-economic, and possible environmental crisis based on public perception in bangladesh due to the covid-19 outbreak. this assessment may inform the government and policymakers of countries with a similar socioeconomic and cultural structure to bangladesh. to understand the possible psychosocial, socio-economic, and environmental impact of the covid-19 outbreak in bangladesh, we considered and identified several relevant and possible items based on the socio-economic situation, political analysis, the existing healthcare system, environmental analysis, possible emerging issues utilized from scenario developments, analysis of local and global reports of the covid-19 pandemic from the print and electronic media, and a literature review. we prepared the questionnaire considering the demographic characteristics of bangladesh, societal mental health conditions (mh), the healthcare system in bangladesh (hsb), governance and political issues (gpi), socio-economic issues (sei), immediate emerging issues (iei) and enduring emerging issues (eei). a total of 46 items were considered in the drafted questionnaires to understand people's perception of the covid-19 outbreak in bangladesh. furthermore, expert consultation was considered to set and validate these 46 items. we prepared the online-based questionnaire through google to operate the survey nationwide. an introductory paragraph describing the objective of the questionnaire was shared with the respondents through email and through social platforms commonly used by bangladeshi groups on facebook, messenger, linkedin, and whatsapp. relevant people were selected for targeted sampling. an online database of target participants was prepared by reviewing relevant websites and online social platforms of different groups in bangladesh. the sample group was targeted considering bangladeshi citizenship, their age, current activities, occupation, social and economic responsibilities, and engagement related to covid-19 response, planning, and policymaking. the questionnaire survey was conducted from 28 march to 30 march 2020 during the lockdown period. the respondents belonged to different social categories, such as university faculty members and scholars, government officials, development workers or practitioners, doctors, engineers and technologists, youth leaders and students, businessmen and industry officials, banking and finance corporates, and independent researchers, among others. the answers to the survey questionnaire were voluntary. data from 1082 respondents were collected through this online survey initially using the simple random sampling method following keeble et al. (15) . following the removal of 16 incomplete questionnaires, 1,066 responses were finally retained for this study. a five-point (1 to 5) likert scale was used for testing the statement descriptions that ranged from strongly disagree to strongly agree with the statements ( table 1) . there was a limitation of the rapid assessment on the publicperception on the psychosocial and socio-economic crisis in bangladesh due to the covid-19 pandemic. as the study was conducted during the lockdown period, it was not possible to reach to general people physically. therefore, we had to keep our samples limited to internet users only. there are more than 95 million mobile internet users in bangladesh and, as a youthdividend country, the majority of the mobile internet users are young educated people. the descriptive statistics [e.g., frequencies, percentages, and ttest (data provided in supplementary tables)] were employed to understand respondents' characteristics. an investigation of psychometric characteristics was included in the classical test theory (ctt) analysis. a set of statistical techniques, including linear regression analysis (lra), principal component analysis (pca), and hierarchical cluster analysis (ca), were applied to explore the association between the items. pca is a data reduction tool that demonstrates each potentiality of parameters and their confidence level in large sample datasets. before conducting the pca, kaiser-maier-olkin (kmo) and bartlett's sphericity tests were applied to confirm the necessity of this analysis. the results of the kmo at >0.5 (the kmo value was 0.931 in this work) and the significance of bartlett's sphericity test at p < 0.01 supported our datasets to be fitted for the pca (16) . the number of factors chosen was based on the kaiser's principle, where the only factors with eigenvalues>1.0 were considered. cronbach's alpha was employed to test the consistency and reliability of the factor loadings in this study. cronbach's alpha values at >0.06 (the cronbach's alpha value was 0.896) are regarded to be suitable in social science research (17) . the ca is a crucial means of detecting associations among many psychosocial and environmental parameters. ca assists to demarcate a population into various groups based on the same feature of a set of the dataset that may reveal causes, effects, and/or the source of any unidentified relationships among the items. furthermore, hierarchical clustering was used to determine the probable number of clusters. statistical package for the social sciences (spss) v. 25.0 was used for the analysis of the datasets. the consent of the respondents was taken before the survey, and their anonymity was guaranteed. all the participants were informed about the specific objective of this study before proceeding to the questionnaire. participants were able to complete the survey only once and could terminate the survey at any time they desired. anonymity and confidentiality of the data were ensured. formal ethical permission of this study was taken from the respective authority. a total of 1,066 (=n) responses were recorded in this study. the proportion of male to female respondents was 3:2 [males (n = 661; 61.5%) and females (n = 405; 38.5%)]. the composition of age groups of the respondents was as follows: 75.2% (18-30 years old), 16.7% (31-40 years old), 6.7% (41-50 years old), 1.1% (51-60 years old), and 0.3% (>60 years old). the average age of the respondents was 27.80 years (sd ± 10.05). on average, the respondents had 12.5 years of formal education (sd ± 8.1). 60% of the youth group were mostly students or at the brink of finishing their studies. the remaining 40% of the respondents were from various professions, including doctors and healthcare workers, civil service officials, non-government officials (ngos), teachers and scholars, policymakers, researchers, and businessmen. the descriptive statistics containing the 46 statements are shown in table 1 . the category of statements were grouped as follows: mental health condition (mh) comprised five statements (mh1-5), the healthcare system of bangladesh (hsb) comprised ten statements (hsb1-10), the governance and political issues (gpi) comprised 7 statements (gpi1-7), the socio-economic issues comprised 11 statements (sei1-11), the immediate emerging issues comprised 7 statements (iei1-7), and for enduring emerging issues 6 statements were considered (eei1-6). in the following section of mental health status, healthcare system, governance and political perspective, socio-economic aspects, and emerging issues, we have discussed the descriptive statistics. in the statement of "i am afraid of the recent outbreak of coronavirus in bangladesh" (mh1) 46.2% of the respondents strongly agreed, followed with a mean of 4.15 ± 1.01. in the second statement (mh2), "i am afraid of getting infected with coronavirus" the difference among strongly agreed (32.7%) and agreed (33.5%) statement with a mean value of 3.89 ± 1.08. for statement three, 46.5% of the respondents strongly agreed to the (mh3) "i am afraid of losing my life or my relatives' life due to this outbreak" with a mean value of 4.08 ± 1.08. in the fourth 62% of the respondents strongly agreed to the statement that the healthcare system of bangladesh is fragile and unable to deal with the recent outbreak of covid-19 (hsb1), with a mean value of 4.36 ± 1.01. for the second statement, 68% of respondents with a mean value of 4.51 ± 0.87 strongly agreed that "a huge population is a pressure to the existing healthcare system to deal with covid-19" (hsb2). 67% of the respondents with a mean value of 4.55 ± 0.776 strongly agreed that "there is a lack of awareness of basic healthcare issues in most of the citizens of bangladesh" (hsb3). moreover, 52% of the respondents with a mean value of 4.22 ± 1.0 strongly agreed that there is "a lack of trained doctors and healthcare professionals to deal with the covid-19" (hsb4). with a mean value of 4.64 ± 0.73, 75.4% of the respondents strongly agreed that "the lack of healthcare facilities will be unable to combat the covid-19 outbreak in bangladesh" (hsb5). again, 73% of respondent with a mean of 4.6 ± 0.77 strongly agreed with "the lack of healthcare infrastructure to deal with covid-19" (hsb6). for statement seven, 68.5% of respondents with a mean value of 4.56 ± 0.734 strongly agreed that "there is a severe lack of bio-medical and hospital waste management facilities in bangladesh" (hsb7). moreover, 82% of respondents with a mean value of 4.72 ± 0.71 strongly agreed that "there is a lack of covid-19 testing facility in bangladesh" (hsb8). 49.2% of respondents (4.05 ± 1.86) strongly agreed that "the budget is inadequate or there is a lack of financial support to respond to this outbreak" (hsb9). finally, 75.8% of respondents with a mean value of 4.64 ± 0.74 strongly agreed that "most of the poor people will not have access to the existing healthcare facilities if they are infected with covid-19" (hsb10). regarding the statement of "the bangladesh government can deal with this outbreak" (gpi1), the public opinion did not vary significantly with a mean value of 2.50 ± 1.28. similar responses were also found in response to "the government is taking this outbreak seriously" (gpi2) with a mean value of 2.76 ± 1.26 and "the government is taking proper decisions at the right time" (gpi3) with a mean value of 2.27 ± 1.19. 68.6% of respondents strongly agreed that "the government needs support from the general public to reduce the impact of covid-19" (gpi5) with a mean value of 4.56 ± 0.77 and that "the government needs to formulate a policy and action plan and implement it immediately" (gpi6) with a mean value of 4.67 ± 0.69. about 31.6% of respondents agreed that "developed nations are going to support bangladesh in response to covid-19" (gpi7) with a mean value of 3.45 ± 1.0. nearly 61-65% of respondents strongly agreed that "the shut down or lockdown of regular activities was a good decision to reduce the chance of infection of covid-19" (sei1) (mean 4.53 ± 0.77), "this will have an economic and social impact in the future" (sei2) (mean 4.51 ± 0.77), and that "both formal and informal businesses will be hampered" (sei3) (mean 4.5 ± 0.71). for the fourth statement, 85.6% of respondents strongly agreed that "poor people living off daily wages will be severely affected" (sei4) with a mean of 4.78 ± 0.60, while 60.5% strongly agreed that "most of the poor people living in urban areas have to leave the city due to not having any options for income" (sei5) (mean 4.42 ± 0.87). 54.8% (mean 4.36 ± 0.85) of the respondents agreed that "many people will lose their livelihood/ jobs at this time" (sei6). a further 42.9% (mean 4.13 ± 0.97) strongly agreed that "there will be a reduced supply of basic goods/ products for daily use" (sei7) and 50.8% (mean 4.28 ± 0.89) strongly agreed that "there was or will be increased prices for basic products" (sei8). consequently, "poor people will suffer food and nutritional deficiency" (sei9) was strongly agreed with by 69.4% respondents (mean value of 4.6 ± 0.712). "the shutdown of education institutes will hamper those currently receiving formal education" (sei10), to which 57% respondents strongly agreed (mean value of 4.38 ± 0.88). for "if there is a chance of social conflict due to this outbreak" (sei11), the mean response was 3.9 ± 1.06. 56.4% (mean 4.39 ± 0.82) of respondents strongly considered that "there is a chance of community transmission of covid-19 in bangladesh" (iei1) and that "a huge number of people will be infected" (iei2) with a mean value of 4.208 ± 0.93. moreover, 69% of the respondents strongly agreed (mean value 4.56 ± 0.74) that "there is a chance that many infected patients will not be detected due to a lack of testing facilities and this will not show the actual number of infected cases" (iei3). approximately 61-67% of the respondents strongly agreed that "there is a chance of an increasing numbers of deaths from infection due to a lack of proper health facilities" (iei4) with a mean value of 4.56 ± 0.74. "a lack of bio-medical waste management facilities in the hospitals will create further transmission" (iei5) received a mean value of 4.50 ± 0.73. for the sixth statement, 46.4% of respondents (mean value of 4.28 ± 0.88) strongly agreed that "there will be many people psychosocially shocked due to this outbreak" (iei6) and that "the general public will lose trust in the government" (iei7) was strongly agreed with by 36.4% respondents with a mean value of 3.83 ± 1.12. we have considered emerging enduring issues (eei), such as potential natural calamities and infectious disease outbreaks, as the monsoon season is approaching. six statements were considered for enduring emerging issues (eei1-6). regarding the statement that "there is a chance of a disaster such as a flood, cyclone, or drought in 2020 considering the vulnerability of bangladesh to climate change" (eei1), there was a mean response of 3.7 ± 1.0. but the statement "if any disaster (flood, cyclone, landslide) occurs after/during covid-19, the situation will create a double burden to the country" (eei2) was strongly agreed with by 74% of respondents with a mean of 4.65 ± 0.68. 50.4% of respondents agreed with a mean of 4.3 ± 0.84 that "there is a chance of severe food scarcity in the country due to these events (covid-19 + disasters)" (eei3). a strong agreement from participants (varied from 50 to 66%) was observed for the statements: "there is a high possibility of huge economical loss" (eei4) with a mean value of 4.59 ± 0.66, "there is a high possibility of increasing poverty level" (eei5) with a mean value of 4.43 ± 0.78, and "there is a high possibility of severe socio-economic and health crisis" (eei6) with a mean value of 4.48 ± 0.72. the association of affected psychosocial wellbeing and the fragile healthcare system during covid-19 outbreak from the regression analysis, among the 45 variables, only five variables showed statistically significant associations with the fragile healthcare system of bangladesh (hsb1) to deal with the recent outbreak of covid-19 in the country ( table 2) . hsb2, hsb5, and iei1 statistically pose a significant positive effect on the fragile healthcare system of bangladesh (p < 0.01). this relationship implies that a huge population and a lack of healthcare facilities are contributing to the community transmission of covid-19 in bangladesh. the presence of community transmission in bangladesh within a short time is present as predicted by the iedcr, who announced a mildlevel community transmission possibility in bangladesh on 1st april 2020 in their press release (9). this assumption is further validated by the number of deaths from covid-19 reported in the news, after the announcement of the partial lockdown, and the opening of rmg factories from 25 april 2020. the number of covid-19 patients increased significantly in industrial zones. there was also a positive significant association between the fear of the covid-19 outbreak (mh1) with the struggling healthcare system (p < 0.05). also, the negative association between hsb1 and government political decision gpi1 (p < 0.05) reveals that the government is unable to make proper decisions at the right time due to the poor governance in the existing healthcare system. the results of linear regression showed that among the 45 variables, only 10 variables showed statistically significant associations with fear of the covid-19 outbreak ( table 2) . for instance, mental health variables mh2, mh3, and mh4 statistically pose a significant positive effect on fear of the covid-19 outbreak (p < 0.01). on the other hand, there is a statistically positive association between fear of the covid-19 outbreak (p < 0.05)and the healthcare system in bangladesh (hsb1 and hsb8), due to the lack of testing facilities and a fragile healthcare system contributing to the fear that has been experienced due to the covid-19 pandemic in bangladesh. the socioeconomic issues (sei 10) and immediate emerging issues (iei2) have a statistically significant positive impact (p < 0.01), e.g., obstruction to the formal education system, and the potentiality of a huge number of people becoming infected may contribute to the fear development of the covid-19 outbreak in this country. there was also a positive significant association between the chance of community transmission of covid-19 for immediate emerging issues (iei1) with fear of the covid-19 outbreak (p < 0.05). results from the regression analysis further showed eight variables have a significant statistical association with the governance and political capacity to deal with the covid-19 outbreak in bangladesh (gpi1). a significant positive association was found among the governance and political issues (gpi1 with gpi2 and gpi3) and socioeconomic issues (sei2) (p < 0.01), implying that the government's decision to lockdown activities was at the proper time and has enhanced the people's perception of the capacity of government to deal with the covid-19 outbreak ( table 2 ). however, the negative association between governance and political issues (gpi1) and the healthcare system of bangladesh (hsb9) (p < 0.01) shows that a perceived lack of budget created a gap in the response to covid-19 ( table 2) . moreover, a negative association of governance and political issues (gpi1) with the healthcare system of bangladesh (hsb4) and socioeconomic issues (sei3) (p < 0.05) shows a perceived lack of trained doctors and healthcare professionals, and that a hampering of formal and informal business activities are reducing the government's capacity to deal with the covid-19 outbreak. nevertheless, a positive association of governance and political issues gpi1 with socioeconomic issues sei11 (p < 0.05) and governance and political issues gpi7 (p < 0.01) shows that there is a perceived possibility of social conflict due to this outbreak if not managed properly, and that the bangladesh government will need support from developed nations and allied forces to deal with this outbreak. it should be mentioned here that containment, risk mitigation, and suppression plans must be as inclusive as possible or risk undermining response efforts. the regression analysis showed that, among the 45 variables, nine showed a significant statistical association with the future impacts of implementing lockdown and social-distancing activities (sei2). a significant positive association of socioeconomic issues (sei2) with governance and political issues (gpi1) and socioeconomic issues (sei3) (p < 0.01) shows that the government took the right decision by shutting down regular activities and implementing the social distancing approach ( table 2) . but due to this initiative, the formal and informal business sectors and the economy will be hampered. again, a positive association of socioeconomic issues (sei2) with mental health (mh3) and healthcare services (hsb5) (p < 0.05) reveals that this decision of shutting down normal activities was imposed due to the fear of losing lives due to covid-19 and having a lack of healthcare facilities. however, a positive association of socioeconomic issues sei2 with sei4, sei8, sei10, and enduring emerging issues eei6 (p < 0.05) shows that due to this shut down poor people will be severely affected, the price of the basic products will increase, the formal education system will be hampered, and the possibility of severe socio-economic and health crises will increase. in the regression analysis, eight variables are statistically associated with the possibility of community transmission of covid-19 (iei1). a significant positive association between mental health variables (mh1, mh3), healthcare system variables (hsb1, hsb7), socioeconomic variables (sei6, sei11), and immediate emerging issues (iei2, iei3) (p < 0.01) reveals that community transmission will increase the number of infected people which will create further fear and mental pressure of others of losing their lives due to covid-19 infection ( table 2) . the fragile healthcare system of bangladesh will be unable to detect most of the infected patients due to a lack of health facilities, which leads to undermining the actual infected cases. as of the last day of the survey for this study on 30 march 2020, the testing rate of covid-19 was at its lowest in bangladesh compared to the other similar countries (10 people/ 1 million). however, as the laboratories increased, the number of testing has increased along with this, with 878 people/1 million. this is still inadequate compared to the population density. also, the inadequate disposal method of covid-19 hospital bio-medical waste management and associated facilities could increase community transmission. subsequently, due to the community transmission of covid-19, many people will lose their lives and livelihoods, which might lead to creating social conflict, as a worst-case scenario. the regression analysis further identified nine variables that are significantly associated with the possibility of climate-induced extreme natural events (flood, cyclone, landslides, etc.) occurring during/after the covid-19 pandemic. the pandemic along with natural disasters may create a double burden to the country due to enduring emerging issues (eei2). the positive association between eei2, sei9, iei5, eei1, eei3, and eei4 (p < 0.01) shows that there is a perceived possibility of a climate-change-induced disaster after the covid-19 situation which would create severe food insecurity ( table 2) . poor people will suffer most from food and nutritional deficiency and the country will face enormous economic loss. also, after the covid-19 situation, a lack of bio-medical and solid waste management will add more problems. moreover, a positive association between eei2, hsb2, and eei6 reveals that, after the covid-19 emergency, existing poverty will create further socio-economic and health crises. overall relationship assessment among the variables from ctt, pca, and ca ctt and pca revealed a confidence level of controlling factors in bangladesh during the covid-19 outbreak and how these components are correlated to the psychosocial, socio-economic, and environmental crisis components (tables 1, 3) . cluster analysis (ca) further detected the total status of regional variations, and how socio-economic and environmental crises influences psychosocial development (figure 3) . from the ctt analysis, according to the corrected interitem correlation analysis, among 46 variables, four variables have low corrected item-total correlations (i.e., the ability of the government to deal the outbreak, −0.054; seriousness of the government, −0.011; government is taking a proper decision, −0.078; and other sectoral involvement to covid-19, −0.04). the remaining 42 variables in the scale had an acceptable corrected item-total correlation (0.257 to 0.602) and the cronbach's alpha (0.896) was acceptable. from pca, nine principal components (pcs) were originally based on standard eigenvalues (surpassed 1) that extracted 55.28% of the total variance as displayed in table 3 . the scree plot was adopted to detect the number of pcs to be retained to provide insight into the underlying variable internal structure (figure 2) . the loading scores were demarcated into three groups of weak (0.50-0.30), moderate (0.75-0.50), and strong (>0.75) (18) (19) (20) . the pc1 (first) showed 8.967% of variance as it encompassed a confidence level of weak positive loading of the healthcare system in bangladesh (hsb1-3: 0.334-0.459); with results being moderate positively loaded for the healthcare system in bangladesh (hsb4-10: 0.50-0.746). the pc2 (second) indicated 8.587% of the variance and was loaded with moderate positive loading for socio-economic issues (sei5-9: 0.606-0.702 and sei11: 0.548) and weak positively loaded for socio-economic issues (sei2-4: 0.336-0.493 and sei10: 0.418). the pc3 (third) showed 7.196% of the variance and was moderate positively loaded for immediate emerging issues iei1-5 (0.546-0.665). the pc4 (four) indicated 6.792% of the variance, and was loaded with a significant level of strong positive loadings for immediate emerging issues iei4 (0.751); results were moderate positively loaded for immediate emerging issues iei2-3 (0.541-0.683) and immediate emerging issues iei5-6: 0.659-0.686), and were weak positively loaded for immediate emerging issues iei1 (0.345). the pc5 (five) and pc6 (six) indicated 6.023 and 5.603% of the total variances, and loaded a significant level of strong positive loading for mental health issues mhi2-3 (0.764-0.832) and government and political issues gpi2-3(0.783-0.787); results were moderate positively loaded for mental health issues mhi1 (0.746), mhi4 (0.613), government and political issues gpi1 (0.571), and gpi4 (0.698). results were weak positively loaded for mental health issues mhi5 (0.41) and government and political issues gpi7 (0.574). the pc7 (seven), pc8 (eight), and pc9 (nine) showed 5.304, 3.743, and 3.064% of the total variances and were moderate positively loaded for government and political issues gpi5-6 (0.627-0.651), socioeconomic issues sei1 (0.574), sei2-3 (0.636-0.637), and immediate emerging issues (iei1:0.519); results were weak positively loaded for socio-economic issues sei4 (0.397), sei9-10 (0.317-0.322), healthcare sector of bangladesh hsb1-2 in the ca all the parameters were classified into four major groups: cluster-1(c1), cluster-2 (c2), cluster-3(c3), and cluster-4(c4) (figure 3) . c1 was composed of two sub-clusters of c1-a and c1-b; c1-a was composed of issues surrounding an increase in the number of deaths due to not having proper health facilities, a lack of bio-medical waste management facilities in bangladesh that will create more problems, many people experiencing psychosocial issues due to this outbreak, with a large number of people becoming infected, and there being a chance of not detecting most of the infected patients due to the lack of health facilities leading to undervaluing the actual infected cases (iei4-6, iei2-3). c1-b was composed of socioeconomic issues that may lead to poor people suffering from a lack of food, thereby leading to nutritional deficiency (sei2-6 and sei9). c2 consists of socio-economic issues (sei7-11). c3 consisted of three sub-clusters of c3-a, c3-b, and c3-c. c3-a covered governance and political issues gpi5-6, and socioeconomic issues (sei1). c3-b consisted of immediate emerging issues iei1-7, while c3-c was composed of issues related to the healthcare system in bangladesh (hsb1-10). cluster-4 consisted of three sub-clusters of the c4-a health system in bangladesh and immediate emerging issues (hbs9, iei1), c4-b covered mental health issues (mhi1-5), and c4-c contained governance and political issues (gpi1-4 and gpi7). this perception-based study tried to visualize the psychosocial as well as socioeconomic stresses due to the covid-19 pandemic in bangladesh. any major epidemic outbreak has negative effects on individuals and society (14) , and people's fear due to covid-19 is rational in the sense that the fatality rate of the virus is around 1% and it can kill healthy adults along with the elderly or those with existing health problems (21) . it is crucial to assess the covid-19 pandemic independently based on its attributes and not on past epidemics like sars or mers (22) . more than 929 covid-19 symptom-like deaths were reported from leading newspapers and electronic media from 8th of march 2020 to 30th of april 2020. the reported case numbers certainly underestimate the actual number of infected persons given the limited number of urban testing centers, the shortage of test kits, and the long waiting times for tests and test results (9) . the covid-19 outbreak caused other critical care and infectious disease patients to be deprived of basic healthcare facilities. patient-management decisions, early diagnosis, rapid testing, and detection are urgently needed (23, 24) . the decentralization of testing and treatment facilities is required for the healthcare system to combat the pandemic. the government needs to aid in implementing testing facilities in both public and private clinical laboratories all over bangladesh. for a developing country, resources need to be assembled appropriately and promptly. with limited screening and testing of covid-19 in bangladesh, and the presence of only 48 laboratories mostly located in urban areas, it is difficult to predict when transmission of the disease will peak and when the curve will flatten (25) . predictably, community transmission in the country is happening and people are being infected and infecting their community, in some cases even without showing symptoms. it is further predicted that covid-19 and dengue together is a deadly combination. as the monsoon season approaches, the risk of dengue infection is on the rise. it is a timely step taken by the dghs to conduct dengue tests on suspected covid-19 patients, as both diseases share common symptoms (reported on 9 may 2020, by dghs in a daily press briefing on covid-19). successful governance is only possible with a competent early warning system, efficient analysis of the situation, and the interpretation, sharing, and use of relevant knowledge and information (26) . public health instructions should be established based on scientific evidence to reduce the anxiety and distress caused by misinformation and rumors. epidemiological outcomes need to be informed on in time so that they can be accurately evaluated and explained (27) . societies where underserved communities exist strongly fear government information and politics. public risk communications are therefore needed to prevent misinformation from social media and electronic media. the psychosocial risk (mental health impacts) for children in this situation are apparent, as they are out of touch with schools, classmates, and playmates, and deprived of physical activities and social activities; these issues need to be addressed. moreover, the isolation and quarantine of parent/s can mentally traumatize them and result in negligence, mistreatment, and abuse in the absence of parents/caregivers frontiers in public health | www.frontiersin.org (28) . in addition, due to lockdown and the required maintenance of family hygiene, the burden of these activities is increased for women, considering the patriarchal nature of the country (where predominantly all household activities are performed by women). moreover, increased levels of violence against women and girls are experienced, as in the lockdown it is almost impossible for victims to escape those family members who are the perpetrators (29) . furthermore, in the rohingya refugee camps, it will have catastrophic outcomes (3) . these kinds of risks, awareness, and prevention methods should be effectively communicated to the public. as the pandemic continues, each new day brings in new conversations on social media and alarming developments of misinformation and propaganda, resulting in unnecessary psychological trauma and anxiety (30) . moreover, religious tension, personal tension, job insecurity, financial loss, and social insecurity could leave some people feeling particularly vulnerable and mentally unstable (22) . honest, transparent communication is vital for risk communication about the pandemic, while confusing or contradictory health messaging engenders mistrust and leads people to seek information from unreliable alternative sources and thus proliferates rumors (31) . the fear of becoming infected or fear for vulnerable family members has amplified along with the administrative procedures of testing and reluctance of other private clinics and hospitals to admit patients. at the bbginning of this pandemic, bangladesh had only 29 icu beds in five dedicated hospitals in dhaka for the treatment of covid-19 patients. there were no icu beds in hospitals outside dhaka (32) . this is a sign of weak governance in the healthcare system of bangladesh. in this scenario, other critical care patients are denied admittance, experience negligence, and are often left to die without treatment. moreover, the administrative procedure for the covid-19 deceased, whether that be burial or cremation, has created more confusion and religious fear in the minds of the common people. often, family members of the deceased have denied claiming the body due to fear of infection. in those cases, government authorities have intervened. moreover, there is a rumor that the victims of covid-19 are buried without the muslim funeral procedures of bathing, which has created further religious tensions among people. it is, therefore, imperative that the government manages people's fear and anxiety. proper information should be circulated to reduce confusion. the bangladeshi electronic and print media is not acting responsibly to disseminate truthful information and are instead reporting misguided stories on social media. since the 26th of march, the government of bangladesh formed a division to monitor media to eradicate rumors or incorrect information being disseminated on social media platforms and in the mainstream media to protect the mental health of the people. the bangladesh meteorological department (bmd) had forecasted heavy rainfall events and intermittent nor'westers and cyclones at many places across the country during april and may 2020 (33) . heavy rainfall and nor'westers related to high windspeed causes tremendous disasters by destroying standing crops and properties and cause death to people and livestock. fair and equitable sharing of health resources could mitigate further risks to public health by meeting community health needs and generating all-important trust and resilience (31) during further climatic disasters. the development of resilience is significant to combat any disasters, even a pandemic. subsequently, to develop resilience in the healthcare systems and to tackle any pandemic, good governance is crucial, along with good coordination. in addition, it also requires financing, service delivery, medicines and equipment for health workers, and information (34) . moreover, governments, institutions, healthcare facilities, and the general public all hold a social and ethical responsibility to assess and mitigate risks for the most vulnerable communities, including homeless people, people without adequate insurance or employment, indigenous communities, immigrant communities, people with disabilities, and certain frontline healthcare workers and emergency responders. prisons, nursing homes, orphanages, old care homes, homeless shelters, and refugee camps can become focuses for disease outbreaks as these settings often have inadequate access to basic healthcare facilities that increases the disease burden (31) . the government should prepare policies and decisions on early recovery plans which should be inclusive to all ethnic groups, religious groups, minorities, and the wide range of vulnerable populations. april and may are the months of natural disasters like tropical cyclones, tornados, and early flooding in bangladesh, which may be evident within the coming days. therefore, utilization of the health-emergency disaster risk management (health-edrm) framework is important to implement. health-edrm refers to the "systematic analysis and management of health risks, posed by emergencies and disasters, through a combination of (1) hazard and vulnerability reduction to prevent and mitigate risks, (2) preparedness, (3) response and (4) recovery measures" (35) . health-edrm is an umbrella term which the who uses to refer to the broad intersection of health and disaster risk management (drm). as the patients of other seasonal diseases such as dengue are rising, and the possibility of a natural disaster remains, the healthcare system should be coping with the changing scenario of the covid-19 outbreak in bangladesh, where resilience is very important. the hotspot areas of the disasters have already been identified in the bangladesh delta plan 2100 (36) . vulnerable areas should be given special emphasis in the coming months for the protection of crops, risk reduction, relief preparation, and rehabilitation. biomedical waste should be disposed of following national and international guidelines on the disposal of infectious biological hazardous materials (37) . when an exponentially rapid spread of a disease or infection breaks out, the generation of biomedical waste and other related healthcare hazards may be considerably increased within a noticeably short period. if improperly treated, this waste may accelerate the spread of disease and pose a significant risk to medical staff, patients, and waste management unit personnel. a complex short-term decision-making problem is required by the authorities to deal with the fast accumulation and transportation mode of the medical waste. healthcare centers can either directly transport the waste to the treatment centers or they can transfer and consolidate via a temporary transit center (38) . the use of ppe should be distinguished by different risk factors to adopt different epidemic prevention measures and reduce the waste of personal protective equipment, as these resources are already in short supply (34) . moreover, repeated use of disposable masks and not washing cloth masks could create further risk of infection that needs to be dealt with through proper information to the public (39) . as the country does not have proper incineration facilities, the government should think of setting up mobile incinerator plants rapidly to responsibly manage bio-medical waste. as we have analyzed the scenario over the past months of partial, a loss of 33 billion bdt a day to gdp is incurring. more than 10 million people are becoming further marginalized due to the loss of wages and jobs (40) . the dilemma of life vs. livelihoods has put people at high risk of community transmission in the industrial districts after the ready-made-garment (rmg) manufacturers trade organization bgmea decided to open the factories even before the end of lockdown. it was predicted that the government would not get support from the allied forces. weak governance and policy put emergency responders, such as medical doctors and healthcare staff, police, security forces, and army personnel, at risk of infection. already, thousands of doctors and members of the police force have been infected and died during this time. the socio-economic fall-out from this pandemic is already high, particularly for the disadvantaged poor communities, day laborers, wage earners, rmg-sector workers, and small and medium business start-ups. already the country's rmg sector has lost many global orders due to the pandemic, and the remittance flow is at its lowest. job insecurity and financial insecurity is foreseeable, and concerns of a global depression will affect the local market as well as investors. the prime minister of bangladesh already declared a stimulus package of 72,750 crore bdt, of which 30,000 crore bdt has been announced for the rmg sector, other large industries, and the service sector in an attempt to defeat the economic losses due to the coronavirus situation (41) . however, on prioritybasis the financial incentives should be given to the povertystricken disadvantaged communities first, as well as insurance for healthcare professionals at the frontline, emergency responders, and caregivers responsible for emergency handling. purchasing intensive care unit (icu) beds, protective equipment, diagnostic test kits, mechanical ventilators, and additional supports is required for these mentally and physically affected persons who have survived covid-19. it is also imperative to continue taking precautions, including screening, isolation of suspected cases, and social distancing, even after the pandemic is over. finally, combating the global pandemic is not easy. the 46 statements that we have included in this analysis aid in identifying the associations among the psychosocial, socioeconomic, and possible environmental crisis based on public perception in bangladesh. risk mitigation measures concerning the psychosocial, socio-economic, and environmental components of the public are necessary to combat a global pandemic. therefore, with great advancements in the speed and power of science, international collaborations are required to provide knowledge about the virus and disease recovery. moreover, it is highly recommended by who and other stakeholders from the national level to raise the testing speed and facilities in bangladesh. multi-sectoral involvement and proper relief facilities for unprivileged populations must be ensured. without ensuring fundamental needs would be met, the lockdown due to covid-19 has imposed mental stress on the public. the weak governance in the healthcare systems and limited healthcare facilities exacerbated the general public's fear and anxiety. the centralized covid-19 testing facility and limitations of dedicated hospital units for covid-19 patients hampered other critical patients from receiving healthcare services. as a country vulnerable to climate change, there might be some additional risk factors of occurring natural disasters, such as a tropical cyclone, which may add further pressure on the country. the closure of all educational institutions may increase the number of mentally depressed young people. as the business centres (except for groceries, pharmacies, and other daily necessities) are closed, it has put further stress on the country's economy. an infectious outbreak of dengue might be on the way that may have a cumulative/synergistic negative impact with covid-19 on public health in bangladesh. however, numerous factors that can be considered in the context of the current covid-19 outbreak in bangladesh are as follows: risk of community transmission, healthcare capacity, governance coordination, relief for the low-income population, biomedical waste management, and preparation for possible natural disasters. the recommendations collected in the perception study can be summarized as a need to increase covid-testing rates and increase medical facilities. the decentralization of the covid-19 medical facilities is particularly important due to the forced migration of more than 11 million people from dhaka city to 64 districts of bangladesh after the announcement of partial lockdown. in addition, proper risk assessment and dependable risk communication, a multisectoral management taskforce development, care of biomedical waste, ensuring basic support to vulnerable people, and good governance was suggested to reduce the psychosocial and socioeconomic impact of the covid-19 outbreak in bangladesh. finally, this assessment process could help the 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laboratories, public health agencies, and industry is essential to control the outbreak to withdraw or not to withdraw? tbs news (2020) crippled community governance and suppressed scientific/professional communities: a critical assessment of failed early warning for the covid-19 outbreak in china taking the right measures to control covid-19 covid-19: children at heightened risk of abuse, neglect, exploitation and violence amidst intensifying containment measures covid-19 and violence against women: what the health sector/system can do the covid-19 pandemic: making sense of rumor and fear covid-19: control measures must be equitable and inclusive bangladesh has only 29 icu beds to fight coronavirus! the business standard nor'wester likely this week. the daily star (2020) the resilience of the spanish health system against the covid-19 pandemic building resilience against biological hazards and pandemics: covid-19 and its implications for the sendai framework general economics division (ged) planning and provision of ecmo services for severe ards during the covid-19 pandemic and other outbreaks of emerging infectious diseases reverse logistics network design for effective management of medical waste in epidemic outbreaks: insights from the coronavirus disease 2019 (covid-19) outbreak in wuhan (china) rational use of face masks in the covid-19 pandemic to open or not to open: lockdown exit strategies can help how will the covid-19 stimulus package be implemented? the daily star (2020) available online at all datasets presented in this study are included in the article/supplementary material. the studies involving human participants were reviewed and approved by department of public health and informatics, jahangirnagar university, bangladesh. the patients/participants provided their written informed consent to participate in this study. mb-d, ms, and mr planned the studies and developed the questionnaire. informatics and data analysis and interpretation were maintained by mb-d, ai, ms, and mr. mb and lb revised and improved the manuscript as suggested by the reviewers. all authors reviewed and read the manuscript before final submission. the authors would like to acknowledge all the frontline doctors fighting this pandemic and all the researchers cited in the references. the supplementary material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fpubh. 2020.00341/full#supplementary-material the authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.copyright © 2020 bodrud-doza, shammi, bahlman, islam and rahman. this is an open-access article distributed under the terms of the creative commons attribution license (cc by). the use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. no use, distribution or reproduction is permitted which does not comply with these terms. key: cord-335578-u8b66oos authors: simões e silva, ana cristina; oliveira, eduardo a.; martelli, hercílio title: coronavirus disease pandemic is a real challenge for brazil date: 2020-06-05 journal: front public health doi: 10.3389/fpubh.2020.00268 sha: doc_id: 335578 cord_uid: u8b66oos nan in december 2019, a cluster of pneumonia cases of unknown etiology was reported in wuhan, china (1). on january 7, a novel coronavirus was identified from the throat swab sample of a patient (2) , and by january 2020, the virus had been isolated and sequenced (3) . the new virus was subsequently named sars-cov-2/human/wuhan/x1/2019 (sars-cov-2) (4). on march 11, 2020 , the who announced that the disease caused by sars-cov-2, designated covid-19, should be considered a global pandemic (5). by may 03, 2020, there were already 3,349,786 confirmed cases of contamination and 238,628 deaths throughout almost the whole world (6) . this first pandemic of the twenty-first century places unprecedented pressure on societies and healthcare systems around the world. as pointed out by jones in a recent commentary, "a history of epidemics offers considerable advice, but only if people know the history and respond with wisdom" (7) . approximately 56 days after the first case reported in china, on february 26, brazil officially registered its first patient with covid-19: a 61-year-old man living in são paulo who had recently returned from a trip to italy. twenty days after the first reported case (march 17, 2020), brazil registered the first death by covid-19 in a 62-year-old man with diabetes and heart disease (8). on march 30, 2020, brazil recorded 4,470 confirmed cases and 159 deaths. by may 25, 2020, brazil had already experienced 363,211 confirmed cases and 22,666 deaths by covid-19 (https://covid. saude.gov.br/). however, it should be noted that these numbers underestimate the real depth of the pandemic in brazil. this is because, to date, capacity for a massive surge in laboratory testing has not been enabled in our country (9) . in this respect, to decentralize the diagnosis of coronavirus, institutes linked to the ministry of health have become responsible for training 27 central public health laboratories on testing, starting in february 2020. since march 18, central public health laboratories from 26 states and the federal district have been considered able to perform tests for coronavirus. nevertheless, in this regard, to date, the country is far below the optimal number of tests for covid-19, as there are not enough tests to achieve a reliable panorama of the real number of cases. currently the rate in brazil is only 14.5 tests/million as compared with the rates of >70 in italy and the uk, for example. the distribution of the resident population according to age group shows a downward trend in the proportion of people <30 years old along with an increase in the proportion of older people. in 2012, people below 30 years old represented 47.6% of the population. this proportion decreased to 42.9% in 2018, while the proportion over 30 years old increased to 57.1% (10) . moreover, chronic diseases, especially systemic arterial hypertension and diabetes mellitus, and their related morbidity and mortality are currently a prevalent public health issue. data from the ministry of health show that the prevalence of hypertension and diabetes among brazilian adults aged 35 and older was 24.3 and 11.7%, respectively. the rates are higher in people aged over 65, in whom the prevalence rises to 54.9 % for hypertension and 19.3% for diabetes. with the rapid spread of covid-19, by the end of march, the main brazilian states had adopted a series of social distancing measures. these included recommending that older adults and individuals with chronic medical conditions stay at home as much as possible, canceling mass events, closing schools, universities, and workplaces, and maintaining only essential services (8) . furthermore, the ministry of health is hiring 5,811 emergency physicians, particularly in poorer cities and indigenous villages, to work to control disease spread. the collapse of healthcare systems is the major concern for most countries hit by the pandemic, especially low-and middle-income countries, such as brazil. for instance, among the confirmed cases in china, 18.5% were considered severe, and 25.3% of those required intensive care. among 4,103 covid-19 patients in new york, 1,999 (48.7%) were hospitalized, and 445 patients (10.8%) required mechanical ventilation (11) . therefore, a critical aspect of the covid-19 pandemic is healthcare system capacity. since 1989, brazil has established a universal public health system (sus, sistema único de saúde) that, in this current pandemic scenario, allowed a coordinated response among the diverse federation units (12) . however, our capacity to deal with critical cases is limited and very heterogeneous across the 26 states. in brazil, the number of intensive care units (icus) through february 2020 amounted to 36,939 beds, according to the cadastro nacional de estabelecimentos de saúde (cnes), with a historical occupancy of not <85%, which yields an ∼5500 free icu beds. the global european number of icus per 100,000 inhabitants is ∼10, with the us leading the world with a ratio of 34.7:100,000; both, however, are far below what is expected to be needed as the number of infections approaches its peak (13) . in the absence of any efficient treatment and/or vaccine to impede the fast spread of the disease, many public policies and governmental strategies, termed nonpharmaceutical interventions (npis), have been used amid the epidemic/pandemic situation. currently, many such public health measures involve reducing social contact in the population and, consequently, the transmission rate of the virus, alleviating the pressure on the health system and providing time for auxiliary measures to be put in place (expansion of the system, creation of military hospitals, and so on). in this regard, another critical aspect is the difference in population adherence to social isolation measures in the different cities and states of the country (14) . it is worth mentioning that all of these measures have critical socioeconomic and ethical implications because they severely interfere with the outflow of industrial products and commodities, reduce spontaneous social aggregations, and so on. therefore, to lift these drastic measures after the control of the initial wave, which is expected to demonstrate exponential growth in the number of confirmed cases, the who has recommended that isolating, testing, and treating every suspected case and tracing every contact must form the backbone for every country's response. this is the best hope for preventing widespread community transmission. most countries with sporadic cases or clusters of cases are still in a position to do this. many countries are following the who recommendations and finding solutions to increase their ability to implement the full package of measures. in summary, the brazilian challenge is not only to stop the spread of covid-19 but also to find agreement between political leaders, scientific societies, and the general population. the brazilian scientific community and healthcare workers are working hard to provide support for political health measures to address covid-19 (15, 16) . hopefully, this pandemic may be an opportunity for political leaders and the general population to clearly comprehend the pivotal importance of science and the public health system in their daily lives. in this regard, a recent editorial highlighted the difficulty of imagining a world that has not been permanently changed by covid-19 (17) . thorp , the editor of science magazine, considered that the success of the world's scientists, along with strong political and social leadership, will determine which scenarios unfold, so it is time to focus on what we can all do to help (17, 18) . thus, the only way to deal with pandemics is with solidarity and cooperative measures from political leaders, scientists, healthcare providers, and the general population. as, eo, and hm collected data, wrote the paper, and aprroved the final version. all authors contributed to the article and approved the submitted version. outbreak of pneumonia of unknown etiology in wuhan, china: the mystery and the miracle epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in wuhan, china: a descriptive study a pneumonia outbreak associated with a new coronavirus of probable bat origin the species severe acute respiratory syndromerelated coronavirus: classifying 2019-ncov and naming it sars-cov-2 who. coronavirus disease 2019 (covid-19) situation report -104 history in a crisis -lessons for covid-19 the impact of early social distancing at covid-19 outbreak in the largest metropolitan area of brazil a model to predict sars-cov-2 infection based on the first three-month surveillance data in brazil. medrxiv available online at factors associated with hospitalization and critical illness among 4,103 patients with covid-19 disease in new york city. medrxiv covid-19 in brazil: advantages of a socialized unified health system and preparation to contain cases datadriven study of the covid-19 pandemic via age-structured modelling and prediction of the health system failure in brazil amid diverse intervention-strategies. medrxiv covid-19 mathematical model reopening scenarios for são paulo -brazil. medrxiv underreporting of death by covid-19 in brazil's second most populous state. medrxiv socio-demographic caracteristics and prevalence of risk factors in a hypertensive and diabetics population: a cross-sectional study in primary health care in brazil thorp hh. stick to science the authors of this opinion article are funded by the minas gerais state research foundation-fapemig, minas gerais, brazil, the national council for scientific and technological development -cnpq, brazil, and the coordination for the improvement of higher education personnel, capes, brazil. the authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.copyright © 2020 simões e silva, oliveira and martelli. this is an open-access article distributed under the terms of the creative commons attribution license (cc by). the use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. no use, distribution or reproduction is permitted which does not comply with these terms. key: cord-291279-8rfx9qde authors: li, zhuman; han, chuangchuang; huang, huihong; guo, zhijun; xu, feng title: novel coronavirus pneumonia treatment with traditional chinese medicine: response philosophy in another culture date: 2020-07-10 journal: front public health doi: 10.3389/fpubh.2020.00385 sha: doc_id: 291279 cord_uid: 8rfx9qde nan in late 2019, novel coronavirus (sars-cov-2) caused pneumonia in wuhan was spread to the whole country and was identified by world health organization (who) as "public health emergencies of international concern" (1-4). on the morning of march 12, 2020 beijing time, who officially identified it as a pandemic 1 . up to june 15, 2020, the novel coronavirus disease (covid-19) has swept over 200 countries and territories, resulting in more than 7.6 million confirmed cases and over 0.42 million confirmed deaths 2 . the novel coronavirus-caused pneumonia has a powerful infectious force for some population groups, and up to now no specific drugs could cure it (5, 6) . since the novel pneumonia outbreak, china national health committee issued seven editions of diagnosis and medical treatment plan 3 . more than 40,000 medical staffs including traditional chinese medicine (tcm) doctors from all over the country were called up to wuhan, and other cities in hubei provinces to treat patients 4 . the epidemic situation displays a good trend after severe prevention and control in china 5 . in the 7th edition of diagnosis and medical treatment plan issued by national health commission (nhc) of china, many tcm remedies are recommended for covid-19 patients in medical observation period. huo xiang zheng qi capsule is recommended for patients when there is clinical manifestation of "fatigue accompanied by gastrointestinal discomfort"; and jin hua qing gan granule, lian hua qing wen capsule, and shu feng jie du capsule are recommended for patients when fatigue with fever occur. according to a news release from the national administration of tcm, the integration of traditional chinese and western medical treatment can achieve satisfactory results for resolution of symptoms of covid-19 6 . in the medicine field of china, there is always a dispute between the modern medicine and the traditional medicine for a long time. the pros and cons of debate have its own perspective and opinion. we are pleased to see that in the face of severe epidemic situation, there are mixed teams of modern medicine doctors and tcm doctors. the majority of covid-19 patients in china have been treated with integrated chinese and modern medicine. hundreds of herbal remedies have been used throughout the country (7). the chinese government and academic experts in herbal medicine have recommended incorporating tcm into conventional treatment methods so as to generate synergistic effect by the combinational therapy of chinese and western medicine (7) . unfortunately, the experience of tcm in the treatment of epidemic situation has not been widely recognized and used for reference in the western occident developed countries. the lack of high-quality scientific evidence may be one of important reason that would lead to reject. another fundamental reason is that the whole theory system of tcm is not acknowledged by western-trained audience. it might be due to different culture, more specifically, different treatment philosophy. tcm has its strong material base from single monomeric compounds to chinese herb extracts in covid-19 treatment. psychosocial pharmacological effect probably plays an important role in the traditional medicine (8) . so what is the exactly treatment philosophy in tcm culture to the novel coronavirus disease? chinese public in general are always long taught that tcm is a national quintessence with an ancient historical origin. in addition to tcm, peking opera, martial arts, and calligraphy are well-known as the "four quintessence of china" both at home and abroad. national quintessence itself is more related with culture and social custom than with natural science. tcm has been played an indispensable role in the prevention and treatment of epidemic diseases in history. during the sars epidemic in 2003, the intervention of tcm has also achieved therapeutic effect (9, 10) . in the broad and profound tcm theory system, the present covid-19 is just one of common epidemics. even covid-19 is brand new emerging severe infectious disease caused by a brand new coronavirus and no specific drug is used to cure in modern medicine, tcm still has confidence to fight the epidemic. in tcm culture perspective, covid-19 is an epidemic disease caused by an epidemic evil with dampness and heat, which is called li-qi in chinese (11) . after li-qi invades the human body, it enters the lung first to make the lung-qi (vital essence of lung, which is in charge of breath function) stagnate, then lead abnormal breath movement, phlegm-heat accumulation and block, and finally bring out the dead yin and the dead yang (12) . according to tcm treatment philosophy, dampness should be eliminated first, and then heat be cleared away. after heat and phlegm are cleared away, the body is restored to normal function at last (13) . there seems to be something in common between virus and li-qi. both think that there is an external cause of disease. modern medicine refer it virus, they usually hope to find specific drug to cure the disease. however, tcm does not know microbiology and could not capture the virus entity, they could only focus on li-qi-induced symptom with herbal remedies. the aim of tcm treatment is simple, so long as tcm remedies provide effective way to regulate functional disorders of the human body. therefore, tcm remedies are used to detoxify poisonous dampness and heat, to strengthen body to resist pathogenic factor, to adjust the harmony of the internal relationship of the human body. that is to say, when tcm doctors treat this kind of disease, they do not have to make the cause clear to start. it is of importance to solve the symptoms for most patients. a small, non-randomized, single center retrospective observational study reported a shorter average duration of viral shedding and faster resolution of radiological pneumonia in hospitalized covid-19 patients prescribed jin hua qing gan granules for more than 2 days as compared with those receiving conventional care (14) . the potential efficacy of this herbal medicine for covid-19 treatment should be further investigated in adequately powered randomized controlled trials. the understanding and description of tcm is based on the ancient macro understanding of nature and the use of speculative philosophy such as yin-yang. in the course of history, since tcm started and developed without synchronizing with modern chemistry, biology and physics, it had to takes the road of philosophical thinking. however, by the aid of advanced science, modern medicine embarks another road of development. it can be said that tcm and modern medicine are two trees growing up in the soil of two different cultures. although high-quality clinical trial evidence is lacking at present, the efficacy of tcm remedy on symptom improvement cannot be ignored. to treat covid-19, tcm and modern medicine should complement each other and cooperate with each other since tcm can contribute as an alternative measure. zl, ch, hh, zg, and fx were responsible for the design of this work and interpretation of finding and drafting the work. fx approved the final version to be published and is accountable for all aspects of the work to ensure its accuracy and integrity. all authors contributed to the article and approved the submitted version. a novel coronavirus outbreak of global health concern clinical features of patients infected with 2019 novel coronavirus in wuhan a novel coronavirus from patients with pneumonia in china a familiar cluster of pneumonia associated with the 2019 novel coronavirus indicating person-to-person transmission: a study of a family cluster discovering drugs to treat coronavirus disease 2019 (covid-19) clinical medication response under new major infectious disease: off-label use and compassionate use traditional chinese medicine contributes to the treatment of covid-19 patients psychological, social, and behavioral factors that influence drug efficacy: a noteworthy research subject in clinical pharmacology is traditional chinese medicine useful in the treatment of sars? effect of glucocorticoid with traditional chinese medicine in severe acute respiratory syndrome (sars) consideration of traditional chinese medicine in treatment of highly pathogenic human coronaviruses sars-cov-2 and sars-cov. chin trad herb drugs analysis and thinking on traditional chinese medicine in preventing and treating severe cases of novel coronavirus pneumonia traditional chinese medicine theory and clinical study on novel coronavirus pneumonia (ncp) infection effect of jinhua qinggan granules on novel coronavirus pneumonia in patients the authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.copyright © 2020 li, han, huang, guo and xu. this is an open-access article distributed under the terms of the creative commons attribution license (cc by). the use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. no use, distribution or reproduction is permitted which does not comply with these terms. key: cord-355537-pckjq1n2 authors: hatef, elham; chang, hsien-yen; kitchen, christopher; weiner, jonathan p.; kharrazi, hadi title: assessing the impact of neighborhood socioeconomic characteristics on covid-19 prevalence across seven states in the united states date: 2020-09-22 journal: front public health doi: 10.3389/fpubh.2020.571808 sha: doc_id: 355537 cord_uid: pckjq1n2 introduction: the spread of coronavirus disease 2019 (covid-19) across the united states has highlighted the long-standing nationwide health inequalities with socioeconomically challenged communities experiencing a higher burden of the disease. we assessed the impact of neighborhood socioeconomic characteristics on the covid-19 prevalence across seven selected states (i.e., arizona, florida, illinois, maryland, north carolina, south carolina, and virginia). methods: we obtained cumulative covid-19 cases reported at the neighborhood aggregation level by departments of health in selected states on two dates (may 3rd, 2020, and may 30th, 2020) and assessed the correlation between the covid-19 prevalence and neighborhood characteristics. we developed area deprivation index (adi), a composite measure to rank neighborhoods by their socioeconomic characteristics, using the 2018 us census american community survey. the higher adi rank represented more disadvantaged neighborhoods. results: after controlling for age, gender, and the square mileage of each community we identified zip-codes with higher adi (more disadvantaged neighborhoods) in illinois and maryland had higher covid-19 prevalence comparing to zip-codes across the country and in the same state with lower adi (less disadvantaged neighborhoods) using data on may 3rd. we detected the same pattern across all states except for florida and virginia using data on may 30th, 2020. conclusion: our study provides evidence that not all americans are at equal risk for covid-19. socioeconomic characteristics of communities appear to be associated with their covid-19 susceptibility, at least among those study states with high rates of disease. the spread of coronavirus disease 2019 (covid-19) across the united states has highlighted the long-standing health inequalities (1, 2) . there are substantial variations in the covid-19 hospitalization and death rates; neighborhoods with the highest proportion of racial/ethnic minorities and the most persons living in poverty are experiencing higher rates of hospitalization and death. such trends are present both nationally (3, 4) and in many small geographic areas hardest hit by the pandemic (5, 6) . to examine the disproportionate burden of covid-19 across communities in the country it is necessary to assess the susceptibility of those communities to covid-19 and the impact of their socioeconomic characteristics on the spread and severity of the disease. such assessment will help to mount an adequate response strategy to better support community attempts to mitigate the ongoing spread of covid-19 and the possible resurgence of the disease (1, 5) . we assessed the impact of neighborhood socioeconomic characteristics on covid-19 prevalence in selected states; arizona (az), florida (fl), illinois (il), maryland (md), north carolina (nc), south carolina (sc), and virginia (va). these states provided a daily count of confirmed covid-19 cases at a zip-code level enabling the assessment of the neighborhood socioeconomic characteristics at a more granular level, compared to county or state level reporting in other states. we used area deprivation index (adi) (7), a composite measure to rank neighborhoods by their socioeconomic characteristics in a jurisdiction of interest, because the social determinants of health are interconnected and impact outcomes in aggregate (8) . using the adi composite measure helped to assess the combination of social conditions and how they would impact the covid-19 risk across different communities. we used data on the number of cumulative confirmed covid-19 cases at the zip-code level and percentage of the population tested for covid-19 in the seven states on two selected dates, may 3rd, 2020 (when covid-19 prevalence had an upward trend across the country) and may 30th, 2020 (when covid-19 prevalence presented a downward trend in selected areas) (9) (10) (11) (12) (13) (14) (15) . zip-code level data was not available on may 3rd in north carolina and virginia. we used the 2018 american community survey (acs), an annual nationwide profile conducted by the us census bureau (16) , to construct adi raw scores for all zip codes in the country. we then sorted and ranked the scores for each community (7) . we developed adi state ranks as deciles and national ranks as percentiles comparing each zip-code to others in the same state and across the country. the higher adi rank represented more disadvantaged neighborhoods. we used u.s. census data to identify estimates for population size, age, gender, and race distribution in the study states (17) . we identified variations in reporting confirmed cases across the states. for instance, some states provided categorical values wherever cases in a neighborhood fell below a certain threshold. to harmonize these variations, we assigned a mean value in each category to the present number of covid-19 cases (see supplementary table for more details) . we calculated covid-19 prevalence using the zip-code resident population as the denominator. we performed descriptive analyses and assessed correlations between covid-19 prevalence with adi (national and state ranks to control for state-specific characteristics) and race. we provided unadjusted correlation coefficients and adjusted ones controlling for age, gender, and the square mileage of each zip-code community to address the impact of population density on covid-19 spread. additionally, we evaluated the correlation between a 40-day (april 20th to may 30th, 2020) change in covid-19 prevalence and adi. moreover, when data were available we assessed the correlation between the percentage of the population tested for covid-19 in a zip-code and adi national and state ranks. we did not obtain institutional review board approval due to the use of publicly available, de-identified data, per usual institutional policy. table 1 presents an overview of population characteristics in selected states. il and md reported the highest covid-19 prevalence on may 3rd (503.79 and 436.81 per 100,000 population, respectively) and may 30th (949.03 and 872.99 per 100,000 population, respectively). both states had the highest number of the state population tested on may 3rd (2.63% and 2.26%, respectively) and may 30th (7.09% and 4.99%, respectively). on may 3rd when the number of tested individuals and covid-19 prevalence was relatively low across the selected states we detected positive and statistically significant correlations between covid-19 prevalence and both national and state-ranked adi in il, md, and sc without adjustment and il and md when adjustments for underlying demographics were made. therefore, zip-codes with higher adi (more disadvantaged neighborhoods) in those states had higher covid-19 prevalence compared to zip-codes across the country and in the same state with lower adi (less disadvantaged neighborhoods). on may 30th when the number of tested individuals and covid-19 prevalence increased across the selected states we detected positive correlations between covid-19 prevalence and both national and state-ranked adi in all states except for va without adjustment and when adjustments for underlying demographics were made. therefore, more disadvantaged neighborhoods in those states had higher covid-19 prevalence compared to less disadvantaged neighborhoods ( table 2) . figure 1 presents the percentage of zip-codes with any covid-19 cases (blue dotted line), covid-19 prevalence (red dotted line), and the correlation between covid-19 prevalence and adi (black solid line) from april 20th to may 30th. the figure reveals the increasing correlation between covid-19 prevalence and adi in az, fl, and sc over time as covid-19 spread across communities. in terms of race, on may 3rd covid-19 prevalence was negatively correlated with the proportion of the community being white in all states, except for il without adjustment and when adjustments for underlying demographics were made. on may 30th covid-19 prevalence was negatively correlated with the proportion of the community being white in all states without and with adjustments for underlying demographics ( table 2) . assessing the correlation between the percentage of the population tested for covid-19 in a zip-code and adi national and state ranks revealed positive correlations in il without adjustment and when adjustments for underlying demographics were made. therefore, zip-codes with higher adi (more disadvantaged neighborhoods) in il had a higher percentage of their population tested for covid-19 compared to zip-codes across the country and in il with lower adi (less disadvantaged neighborhoods). the correlation coefficients were negative in va without adjustment and when adjustments for underlying demographics were made. thus, more disadvantaged neighborhoods had a lower percentage of their population being tested for covid-19 compared to less disadvantaged neighborhoods across the country and in va ( table 3) . the positive and statistically significant correlation between covid-19 prevalence and adi in il and md before and after adjustment on may 3rd, 2020 confirms the higher burden of the disease in disadvantaged communities. both states had higher proportions of their population being tested and more confirmed cases by may 3rd, 2020. in other states with the fewer number of tested individuals and lower covid-19 prevalence we detected negligible correlation, the correlation was not statistically significant (e.g., az and fl before adjustment and sc after adjustment), and/ or reversed after taking into account age, gender, and the square mileage of each zip-code (az after adjustment). using may 30th data when the number of tested individuals and covid-19 prevalence increased across the selected states the correlation between covid-19 prevalence and adi was positive in all states except for va. the negative correlation in va could be attributed to the lower number of tested individuals in disadvantaged neighborhoods ( table 3) . therefore, the magnitude of the disease was not properly detected in va disadvantaged communities. these findings confirm the hypothesis that low levels of covid-19 testing, especially among communities with socioeconomic challenges, might mask the higher burden of the disease in those communities. with an increase in the number and proportion of tested individuals, a higher burden of the disease among disadvantaged communities might gradually be revealed. the longitudinal assessment of the correlation also supported this hypothesis; the relative increase in covid-19 prevalence in az, fl, and sc in the 40-day interval resulted in a stronger correlation with adi. the same trend was detected in il and md with a relative increase in covid-19 prevalence at an earlier time interval (not shown in figure 1) . our results were comparable with wadhera et al. (5) findings. they identified higher covid-19 burden (hospitalization and death) among residents of the bronx, who also had lower income and a higher number of tested individuals comparing to other boroughs of new york city. communities comprised mainly of racial minorities and those economically challenged may be more susceptible to severe forms of covid-19 due to a higher prevalence of underlying conditions such as diabetes, hypertension, and cardiovascular disease (18) . such conditions have been associated with covid-19 poor outcomes (19) . data on race and ethnicity are incomplete across the us and only available through the efforts by local governments (20) . using the available data on may 3rd, 2020 we detected a higher correlation between covid-19 prevalence and racial minorities in all states except for il. in il, covid-19 prevalence was higher in whites comparing to racial minorities. the statistically significant difference in mean adi ranks between the white majority and racial minority neighborhoods was lowest in il compared to az, fl, and sc ( table 1) . in other words, in il the socioeconomic status of predominantly white neighborhoods was similar to communities comprised mainly of racial minorities. this finding might support the hypothesis that the higher covid-19 prevalence among racial minorities is mostly due to their socioeconomic disadvantage rather than any race-linked clinical factors. using may 30th data when the number of tested individuals and covid-19 prevalence increased across selected states we detected a higher correlation between covid-19 prevalence and racial minorities in all states. this study has limitations, including a limited data set on a population level, a lack of data on socio-economic characteristics of covid-19 patients, and variability in methods of reporting covid-19 cases and data quality across selected states. we acknowledge that covid-19 testing and prevalence are inter-connected and higher testing in specific communities might result in higher disease. lack of adequate testing might lead to spurious results in the assessment of the correlation between covid-19 prevalence and adi. despite limitations, our study confirms that not all americans are equally at risk for covid-19. socioeconomic characteristics of communities are likely to determine susceptibility to covid-19 (1) . communities comprised mainly of racial minorities and economically challenged households are more likely to be exposed to covid-19 due to their overrepresentation in the low-wage, essential work at the front lines such as in the healthcare system (20) (21) (22) . for instance, low-wage healthcare workers often have multiple jobs at clinics, hospitals, and nursing homes which results in a dramatic increase in their covid-19 risk (20) . moreover, social distancing is more challenging in socioeconomically disadvantaged neighborhoods with high housing density and overcrowding (20) . our findings highlight the vital role of world-class data and analytics to support disease surveillance and public health decision-making. the current outbreak of covid-19 reminds us of the urgency of the modernization of the public health data enterprise to protect and promote the public's health (23) . policymakers need to recognize the variation in risks across different communities to mount an adequate response strategy. strategies to protect the most vulnerable neighborhoods will require urgent measures to better assess and take into account their socio-economic challenges. this data can be found here: 1. arizona department of health. highlighted infectious diseases for arizona florida's covid-19 data and surveillance dashboard south carolina department of health and environmental control. sc testing data and projections (covid-19 s. county-level characteristics to inform equitable covid-19 response. medrxiv failing another national stress test on health disparities cases of coronavirus disease (covid-19) in the provisional death counts for coronavirus disease (covid-19): weekly state-specific data updates by select demographic and geographic characteristics variation in covid-19 hospitalizations and death across new york city boroughs the african american petri dish area deprivation and widening inequalities in us mortality addressing social determinants of health: time for a polysocial risk score highlighted infectious diseases for arizona division of disease control and health protection. florida's covid-19 data and surveillance dashboard available online at covid-19) outbreak north carolina department of health. ncdhhs' covid-19 response sc testing data & projections (covid-19). (2020) covid-19 in virginia the united states census bureau. american community survey kaiser family foundation united states spotlight. racial and ethnic disparities in health disease presenting characteristics, comorbidities, and outcomes among 5700 patients hospitalized with covid-19 in the new york city area this time must be different: disparities during the covid-19 pandemic available online at: www.bls.gov/cps/cpsaat11.htm (accessed we're not all in this together: on covid-19, intersectionality, and structural inequality straining the system: novel coronavirus (covid-19) and preparedness for concomitant disasters ethical review and approval was not required for the study on human participants in accordance with the local legislation and institutional requirements. written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements. all authors contributed significantly to the project and writing of the manuscript. all authors reviewed the final paper and provided comments as deemed necessary. eh supervised the development of the analysis plan, reviewed and interpreted the results, and led writing this paper. h-yc and ck performed the data analysis. jw contributed to setting the overall scope and goal of the project as well as finalizing the manuscript. hk designed the overall scope and goals of the study and supervised the day-to-day operations of the project. the supplementary material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fpubh. 2020.571808/full#supplementary-material the authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.copyright â© 2020 hatef, chang, kitchen, weiner and kharrazi. this is an openaccess article distributed under the terms of the creative commons attribution license (cc by). the use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. no use, distribution or reproduction is permitted which does not comply with these terms. key: cord-292026-cj43pn0f authors: moirano, giovenale; richiardi, lorenzo; novara, carlo; maule, milena title: approaches to daily monitoring of the sars-cov-2 outbreak in northern italy date: 2020-05-22 journal: front public health doi: 10.3389/fpubh.2020.00222 sha: doc_id: 292026 cord_uid: cj43pn0f italy was the first european country affected by the sars-cov-2 pandemic, with the first autochthonous case identified on feb 21st. specific control measures restricting social contacts were introduced by the italian government starting from the beginning of march. in the current study we analyzed public data from the four most affected italian regions. we (i) estimated the time-varying reproduction number (r(t)), the average number of secondary cases that each infected individual would infect at time t, to monitor the positive impact of restriction measures; (ii) applied the generalized logistic and the modified richards models to describe the epidemic pattern and obtain short-term forecasts. we observed a monotonic decrease of r(t) over time in all regions, and the peak of incident cases ~2 weeks after the implementation of the first strict containment measures. our results show that phenomenological approaches may be useful to monitor the epidemic growth in its initial phases and suggest that costly and disruptive public health controls might have had a positive impact in limiting the sars-cov-2 spread in northern italy. with an increasing number of cases throughout the world, on the 11th of march who declared covid-19 a pandemic and called for governments to take urgent and aggressive actions (1) . italy was the first european country affected by local transmission of sars-cov-2. the first confirmed autochthonous covid-19 case in italy was identified on feb. 21st (2) , followed by the detection of clusters of cases in 11 relatively small municipalities (10 in lombardy and 1 in veneto). on february 22nd, the italian government introduced quarantine on more than 50,000 people from the 11 municipalities. despite this prompt reaction, 1 week later, the number of cases had reached 650 (3) . on march 8th, italy became the second most affected country in the world, after china (4) . in order to contain the sars-cov-2 burden on the national health system, specific measures restricting social contact were first introduced in the northern regions, where most cases had occurred, then extended to the whole country on march 9th. these measures were further tightened on march 21st: all italian businesses were closed, with the exception of those essential to the country's supply chains. in the early phases of an outbreak, epidemiological data is limited and the parameters necessary to inform and calibrate mechanistic transmission models may be difficult to estimate. it is, however, crucial to monitor the pattern of epidemic growth, whilst incorporating uncertainty, in order to understand the current evolution of the outbreak and provide an early assessment of the potential impact restrictive measures. with the current study, we have analyzed public data from the four most affected italian regions (lombardy, veneto, emilia romagna, piedmont) using approaches suitable to the initial phases of an epidemic, which could help the day-by-day monitoring and the decision-making process. we estimated the time-varying reproduction number and used the generalized logistic growth model and the generalized modified richards model to characterize the early behavior of the epidemic. these approaches have been used and validated in previous epidemics and applied to the recent sars-cov-2 epidemic in china and national data from other countries (5) (6) (7) 18) . daily counts of new infections and deaths, to april 30th, were computed from data available from the website of the italian ministry of health/civil protection (3). the time-varying reproductive number, r t , is the average number of secondary cases that each infected individual would infect if the conditions remained as they were at time t (8) . typically, r t decreases over time starting from r 0 , the basic reproductive number, as a consequence of both the depletion of susceptible individuals and effective control efforts (9) . a monotonic decrease of r t over time may indicate the positive impact of measures introduced to control the epidemic; whereas an unstable behavior or a sudden growth of r t may suggest that corrective or additional measures are necessary. we estimated r t using the epi-estim package in the r software environment (10), according to the following equation: where i t is the number of new infections at time t, and interval (namely the time between successive cases in a chain of transmission). we sampled the serial interval from a family of gamma distributions with mean 4.6 days (95% credible intervals (cri): 3.7, 6.0) and standard deviation 2.9 days (95% cri: 1.9, 4.9), as recently observed in china (11) . r t estimates were then smoothed using a 7-day time window. we analyzed the daily count of new infections using two phenomenological models: (i) the generalized logistic growth model (glm), which extends the simple logistic growth model to accommodate subexponential growth dynamics with a scaling of the growth parameter, p (6): where c ′ (t) is incidence growth phase over time t, c (t) is the cumulative number of cases at time t, r is the intrinsic growth rate in the absence of any control, p is a scaling of growth parameter, ranging from 0 (constant incidence) to 1 (exponential growth), and k is the final size of the epidemic; (ii) the generalized modified richards model (grm), which allows departures from the s-shaped dynamics of the classical logistic growth model, and incorporates the possibility of growth deceleration (12, 13) : where a is the deviation from the s-shaped dynamics of the logistic growth model. both models were fitted to data in order to characterize the pattern of the epidemic in its early phases, produce 5 days forecast of the number of new infections, and estimate the peak time and the final size of the epidemic curve. both models allow for estimation of uncertainly, based on bootstrap resampling. to april 30th), and piedmont (observed data: feb. 28th to april 30th). empty circles represent new observed cases, the vertical dashed line indicates where the real observations stop, the red continuous line the best prediction of the epidemic in the following 5 days, the red dashed lines the 95% confidence bands, and the blue lines the bundle of models estimated by the prediction algorithm. bootstrap size was set to 100. r t has decreased over time in all regions, reaching estimates below 1.0 (figure 1) , the threshold under which the epidemic dies out, at the beginning april in lombardy, emilia-romagna, and veneto and at the end of april in piedmont. in all regions, r t started from values ranging between 2.0 and 3.0, consistent with estimates obtained in other contexts (14) . in veneto, the steep increase on march 12th likely reflects changes (increases) in the testing practices (between march 10th and march 11th the daily number of tests increased by 28%; previously, the daily average increase was 7%). the level of uncertainty decreases over time, with the increasing number of events. the four regions experienced an increasing number of observed new cases until march 25-26 in lombardy, until a couple of days later in emilia romagna and veneto, and until 12-14 days later in piedmont, well-captured by the models. forecasts from the glm (figure 2 ) and grm models ( figure s1 in supplementary material) are very similar, supporting their reliability. results are also consistent with the decrease of r t . the estimates of the final epidemic size predicted on april 30th range from 84,000 (grm) to 85,000 cases (glm) in lombardy, 35,000 (glm) to 37,000 (grm) in piedmont, 27,000 (both glm and grm) in emilia romagna, 20,000 (both glm and grm) in veneto. all parameter estimates with their 95% confidence intervals are shown in table s1 . the daily variation may be large, especially in the earlier phases of the epidemic, and strongly affected by variations over time in testing practices and, possibly, reporting. the uncertainty is larger, as expected, when using the more flexible grm model. large daily variations in forecasts are observable in figure s2 , showing consecutive 5-days forecasts of new cases in lombardy, from march 22nd to march 29th, in the week when the epidemic curves reached the peak. figure 3 shows the evolution of the epidemic forecasts in lombardy with an increasing number of observed data, starting from the day of the lockdown (march 21st, day 25 of the epidemic). the first graph shows that on march 21st, the glm predicts a sub-exponential growth but 5 days later it identifies the peak and predicts an over-optimistic decline. glm predictions start appearing reasonable after mid-april, when the model captures a decline that appears much slower than the initial rise. epidemic evolution in emilia romagna, veneto and piedmont are shown in figures s3-s5 , respectively. estimated time trends and 5-day forecasts for daily covid-19 deaths should theoretically follow, by ∼1-15 days, the trends of new cases, and are thus less informative for decision making, but are possibly less affected by testing and reporting variations (figure 4 , results from the glm model only). due to the smaller numbers, the uncertainty in the models for both the observed shape of the epidemic and the 5-day forecast is larger for the number of deaths than for the number of new cases. in this study, we applied empirical models to daily covid-19 incident cases, in the four italian regions most affected by the outbreak, as april 30th. we observed an almost monotonic decrease of the estimates of r t in all four regions and a decrease of incident cases starting approximately from march 25th in lombardy, a few days later in emilia romagna and veneto, and a dozen of days later in piedmont. these findings may reflect the effects of the lockdown, that start being appreciable after ∼2 weeks. these results are consistent with what observed in wuhan province, china (who, 2020 1 ). the monitoring of r t provides a useful tool to describe the real-time epidemic strength and to capture potential impact of the implemented control measures. our results suggest that costly and disruptive public health controls have been effective in limiting the sars-cov-2 spread in northern italy, as suggested by other studies (15, 16, 19) and may support to the implementation of similar policies in other countries. we suggest that reporting of daily updated r t estimates and applying glm and/or grm to observed data may complement more common approaches used to monitor sars-cov-2 epidemics in its early phases. the same approach may be used also in areas less affected by the epidemic but potentially at risk, such as several regions in the centre and south of italy (17) . these phenomenological models are relatively easy to implement and offer opportunities to monitor the positive impact of measures introduced to control the epidemic, characterize the pattern of the epidemic both in its early and late phases, produce short-term forecasts and estimate the peak time and the final size of the epidemic curve. whereas, short-term (e.g., 5 days) predictions can be interpreted and used to make timely decisions as the outbreak proceeds, long-term predictions of the epidemic are interpretable only after the peak of the epidemic has been reached, as observed when phenomenological models were fitted at different time-steps (figure 4) . being empirical, these approaches are affected by testing and reporting changes over time. however, this limitation is potentially common to the majority of models, both mechanistic and empirical, given that they rely on reported data for the estimation or calibration phase. this limitation should be considered when interpreting the results and forecasts. for instance, r t estimates are influenced by the variation over time of testing policies and thus the probability of identifying new cases. this, for example, can be appreciated in the temporary overestimation of r t observed in veneto around the 12th of march (figure 1) , when the number of tests abruptly increased short-term forecasts provided by glm and/or grm may change every day, as the number of reported cases fluctuate, influencing prediction, especially in the early phases of an outbreak. the more flexible (and quick to capture variations) the model is, the stronger the variation. it is therefore essential to consider the full range of uncertainty, as well as to revise the predictions on a daily basis. taking this into account, forecast models yield a good visual fit to the epidemic curves, and the estimated parameters (supplementary material) can be interpreted in terms of describing the epidemic dynamics. like r t , also glm and grm forecasts rely on reported data and are affected by under-reporting. however, taking this limitation into account, their application can help describing and interpreting the epidemic evolution. for instance, lombardy experienced a slower decrease of daily infection than those predicted by glm (figure 3) . this could be explained as an intrinsic pattern of the epidemic curve or as results of a higher testing capacity in the late phase of the epidemic. in conclusion, our study suggests that timely indications for public health authorities and governments are essential to slow down the epidemic and release the pressure on overburdened health systems. models applied in this study may help in underlining early signs of the success of costly and disruptive public health controls and reinforce the idea that collective efforts are working, are vital to "hold the line" and should not be abandoned prematurely. publicly available datasets were analyzed in this study. this data can be found here: https://github.com/pcm-dpc/covid-19/tree/master/dati-regioni. the study was based on publicly available aggregate data. no ethics committee approval was necessary. covid-19: towards controlling of a pandemic covid-19: preparedness, decentralisation, and the hunt for patient zero lessons from the italian outbreak desktop available online at an interactive web-based dashboard to track covid-19 in real time using phenomenological models to characterize transmissibility and forecast patterns and final burden of zika epidemics real-time forecasts of the covid-19 epidemic in china from transmission potential and severity of covid-19 in south korea improved inference of time-varying reproduction numbers during infectious disease outbreaks the effective reproduction number as a prelude to statistical estimation of time-dependent epidemic trends epiestim" title estimate time varying reproduction numbers from epidemic curves serial interval of novel coronavirus (2019-ncov) infections a generalized-growth model to characterize the early ascending phase of infectious disease outbreaks fitting dynamic models to epidemic outbreaks with quantified uncertainty: a primer for parameter uncertainty, identifiability, and forecasts the reproductive number of covid-19 is higher compared to sars coronavirus spread and dynamics of the covid-19 epidemic in italy: effects of emergency containment measures short-term effects of mitigation measures for the containment of the covid-19 outbreak: an experience from northern italy approaches to daily monitoring of the sars-cov-2 outbreak in northern italy: an update (04/04/20) for all italian regions time-varying transmission dynamics of novel coronavirus pneumonia in china. biorxive the effects of containment measures in the italian outbreak of covid-19 all authors conceived the study, carried out the statistical analysis and drafted the final version of the manuscript. the supplementary material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fpubh. 2020.00222/full#supplementary-material conflict of interest: the authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.copyright © 2020 moirano, richiardi, novara and maule. this is an open-access article distributed under the terms of the creative commons attribution license (cc by). the use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. no use, distribution or reproduction is permitted which does not comply with these terms. key: cord-346329-xwbtftju authors: mallow, peter j.; jones, michael title: when second best might be the best: using hospitalization data to monitor the novel coronavirus pandemic date: 2020-07-10 journal: front public health doi: 10.3389/fpubh.2020.00348 sha: doc_id: 346329 cord_uid: xwbtftju the novel coronavirus' high rate of asymptomatic transmission combined with a lack of testing kits call for a different approach to monitor its spread and severity. we proposed the use of hospitalizations and hospital utilization data to monitor the spread and severity. a proposed threshold of a declining 7-day moving average over a 14-day period, “7&14” was set to communicate when a wave of the novel coronavirus may have passed. the state of ohio was chosen to illustrate this threshold. while not the ideal solution for monitoring the spread of the epidemic, the proposed approach is an easy to implement framework accounting for limitations of the data inherent in the current epidemic. hospital administrators and policy makers may benefit from incorporating this approach into their decision making. before government officials relax stay-at-home orders and hospitals resume elective procedures, decision-makers must accurately estimate the trend, severity, and prevalence of the novel coronavirus in a geographic region. ideally, public health agencies would conduct active surveillance of infections in the general population (1) (2) (3) . the results from this first-best solution represent a coincident indicator of covid-19's prevalence in a population. however, the fact that the novel coronavirus has a high rate of asymptomatic transmission hinders the usefulness of this approach (4, 5) . further hindering the disease surveillance is the limited number of novel coronavirus test kits as of april, 2020. many states like ohio prioritize the individuals who are eligible for testing (6) . ohio and many other states recommend that all individuals who exhibit symptoms should be tested. however, hospitalized individuals and healthcare workers are given first priority. individuals in long-term care and first responders are given a lower priority, and individuals in the general population have the lowest priority. while this prioritization redirects resources to their most effective use, the number of positive cases represents a biased sample of the general population. this tradeoff suggests that the number of positive test cases in a population does not necessarily reflect the actual prevalence of covid-19 nor the infection rate trend. as a lagging indicator, covid-19 hospitalizations would normally be considered a second-best solution to measuring a trend in the infection rate. however, given the sample bias reflected in prioritized testing and asymptomatic transmission, we propose that covid-19 hospitalizations combined with a capacity measure offer the best approach to measuring trends in covid-19 infections. covid-19 deaths present an even longer lag time than hospitalizations, and so they are not viewed as suitable of a measure. we chose the state of ohio to illustrate our approach. the state of ohio is one of several states that releases daily hospitalization data (5) . however, they do not release length of stay (los) data. a literature search was performed in pubmed and the cdc coronavirus website to identify studies published in march and april 2020 for los (7) . a patient weighted pooled analysis was conducted to estimate the median los. the historical occupancy rate was obtained from the centers for disease control and prevention (cdc) national center for health statistics for 2016 (8) . hospital capacity was defined as the number of staffed hospital beds (9). the number of hospitalizations on a daily basis were multiplied by the median los to approximate the total number of bed days. discharges based on los were subtracted to estimate a daily number of hospitalized covid-19 patients. the number of occupied beds was calculated by multiplying the number of staffed beds by the pre-coronavirus occupancy rate. a 7day moving average was calculated by adding the number of hospitalized covid-19 patients over each seven-day window and dividing by the time period. the threshold for assessing the passing of a novel coronavirus wave was set at a declining 7-day moving average over a 14-day period. the moving average period of 7-days was chosen to mitigate daily and weekend reporting effects and to be consistent with prior epidemiologic models (10) (11) (12) . the length of time was chosen based on the current knowledge of the high end of the novel coronavirus incubation period (13) . a further check included in the framework is stipulation that the 7-day moving average plus the historical occupancy level did not exceed the number of staffed beds during this window. the research was conducted with de-identified publicly available data and is exempt from institutional review board review. all analysis was conducted in microsoft excel (microsoft, inc. redmond, wa). the application of this approach to the state of ohio found the first wave of the novel coronavirus passed on april 30, 2020 (figure 1) . during the period of january 7 to june 8, 2020, there were 6,620 covid-19 hospitalizations of which 624 did not have an associated admission date (figure 2) . based on the median los of 4.9 days, these hospitalizations accounted for 24,265 hospital bed days ( table 1) . the peak bed utilization based on the 7-day moving average occurred on april 9 with 4,642. at the peak, covid-19 patients occupied 10% of the total staffed beds in ohio. combined with the occupancy rate, ∼73% (24,264) of staffed beds would have been in use on the peak day, remaining under capacity. the results were based on an imputed los and occupancy level for ohio and were intended to illustrate this approach rather than inform decision making. a critical component of monitoring the novel coronavirus pandemic is the availability of reliable and valid data, including data on the capacity and availability of hospital-based resources. preferably, we would have widespread testing data to inform our epidemiological models and provide a leading indicator of future demands of our healthcare system. ohio, and other states, were forced to prioritize testing due to lack of availability. the prioritization of limited covid-19 tests based on cdc guidance emphasized healthcare workers first and those suspectible to the disease second, potentially increasing the spread of the novel coronavirus among those most at risk (18) . the combination of widespread community transmission and lack of testing kits prevented us from having a clear understanding of the novel coronavirus spread, including those most at risk for requiring intensive care. in the absence of wide spread testing prior to or at the initial onset of the epidemic, hospitalizations and hospital utilization become the second-best indicator to monitor the severity and progression of the novel coronavirus. hospital utilization must be monitored to ensure that the hospitalization raw numbers do not become truncated. once hospitals approach maximum capacity, the hospital's decision to triage and an individual's decision to seek care elsewhere or stay at home will introduce bias into the data measure. this necessity to avoid a biased indicator was the motivating reason to track hospitalizations in the first place. in geographic regions that are approaching capacity or where hospitals are already at maximum utilization, hospitalizations may be less indicative of covid-19's prevalence. if this stage is reached however, any discussion about opening up hospitals for elective procedures is moot. using a novel data set from ohio, this proposed framework provided a means to illustrate the monitoring and severity of the novel coronavirus while adjusting for daily fluctuations in the data. our threshold of a declining 7-day moving average over a 14-day period, "7&14, " provided a conservative threshold for informing public policy decisions, such as access to healthcare services, regarding the novel coronavirus pandemic. our approach is broadly consistent with the work of the university of minnesota (um), carlson school of management (19) . the um initiated a covid-19 hospitalization tracking project, and our work expands upon the efforts of um by incorporating hospital capacity and providing a means to assess the ongoing epidemic. baker et al. (20) proposed an approach for tracking influenza intensive care unit bed utilization to monitor severity of the influenza season (20) . however, many states are not reporting hospitalizations reliably or at all, let alone intensive care beds to provide usual information that can be aggregated. the proposed "7&14" framework has two key advantages. first, it can be implemented at the individual hospital level and aggregated by geographic regions, including other countries. it requires three data inputs, hospitalizations, los, and occupancy. second, one of the inherent benefits of using a moving average is to smooth out random short-term fluctuations in daily hospitalizations. these two attributes combined creates an easy to understand dashboard at the chosen level of analysis to assess the severity and spread of the novel coronavirus epidemic. if or when additional healthcare system supply data becomes available (i.e., intensive care bed utilization), this approach can easily be expanded. the approach outlined presumes that a symptomatic patient presenting at the hospital will be admitted and diagnosed as probable or confirmed covid-19 postive. second, patients will remain hospitalized until they no longer require acute care services. if patients were to be discharged while still contagious, it may increase the rate of community spread requiring further hospital capacity. similarly, if patients remain hospitalized until they are no longer contagious, there will be increased occupancy. in either case, the "7&14" approach outlined combining hospitalizations and utilizations can aid policy makers. the proposed "7&14" approach, leveraging hospitalizations and hospital utilization, may not be the ideal method of monitoring the novel coronavirus epidemic. the ideal method would include a robust testing and contact tracing strategy at the onset or prior to community transmission similar to south korea or singapore. however, widespread community transmission and lack of testing kits, elevates this approach to the best available. with improved reporting of covid-19 hospitalizations, los, and hospital occupancy across the country this approach may improve decision making for hospital administrators and policy makers. the underlying data used in this analysis will be made available upon reasonable request. early epidemiological analysis of the coronavirus disease 2019 outbreak based on crowdsourced data: a populationlevel observational study public health surveillance: a tool for targeting and monitoring interventions detection of epidemics in their early stage through infectious disease surveillance aysmptomatic transmission, the achilles' heel of current strategies to control covid-19 covid-19: in the footsteps of ernest shackleton covid-19 presser final available online at: www.cdc.gov/coronavirus national center for health statistics. occupancy rates in community hospitals available online at: www.definitivehc.com/resources/covid-19-capacity-predictor correcting for day of the week and public holiday effects: improving a national daily syndromic surveillance service for detecting public health threats evaluation of the effectiveness of surveillance and containment measures for the first 100 patients with covid-19 in singapore the incubation period of coronavirus disease 2019 (covid-19) from publicly reported confirmed cases: estimation and application severity of coronavirus respiratory tract infections in adults admitted to acute care in toronto, ontario risk factors associated with acute respiratory distress syndrome and death in patients with coronavirus disease 2019 pneumonia in wuhan, china clinical course and risk factors for mortality of adult inpatients with covid-19 in wuhan, china: a retrospective cohort study presenting characteristics, comorbidities, and outcomes among 5700 patients hospitalized with covid-19 in the new york city area covid-19, post-acute care preparedness and nursing homes: flawed policy in the fog of war calling all states to report standardized information on covid-19 hospitalizations real-time surveillance of inluenza morbidty: tracking intensive care unit resource utilization all authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication. the authors would like to thank michael topmiller, ph.d., edmond a. hooker, md, drph, dee ellingwood, ms, and jennifer mallow, mba for their thoughtful comments and suggestions. any errors or omissions are those of the authors alone. the authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.copyright © 2020 mallow and jones. this is an open-access article distributed under the terms of the creative commons attribution license (cc by). the use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. no use, distribution or reproduction is permitted which does not comply with these terms. key: cord-268179-bmtfanax authors: fan, jingchun; gao, ya; zhao, na; dai, runjing; zhang, hailiang; feng, xiaoyan; shi, guoxiu; tian, jinhui; chen, che; hambly, brett d.; bao, shisan title: bibliometric analysis on covid-19: a comparison of research between english and chinese studies date: 2020-08-14 journal: front public health doi: 10.3389/fpubh.2020.00477 sha: doc_id: 268179 cord_uid: bmtfanax background: as an emerging infectious disease, covid-19 has garnered great research interest. we aimed to explore the differences between english language and chinese language medical/scientific journals publications, particularly aiming to explore the efficacy/contents of the literature published in english and chinese in relation to the outcomes of management and characterization of covid-19 during the early stage of covid-19 pandemic. methods: publications on covid-19 research were retrieved from both english and chinese databases. bibliometric analyses were performed using vosviewer 1.6.14, and citespace v software. network maps were generated to evaluate the collaborations between different authors, countries/provinces, and institutions. results: a total of 143 english and 721 chinese original research articles and reviews on covid-19 were included in our study. most of the authors and institutions of the papers were from china before march 1st, 2020, however, the distribution of authors and institutions were mainly in developed countries or more wealthy areas of china. the range of the keywords in english publications was more extensive than those in chinese. traditional chinese medicine was seen more frequently in chinese papers than in english. of the 143 articles published in english, 54 articles were published by chinese authors only and 21 articles were published jointly by chinese and other overseas authors. conclusions: the publications in english have enabled medical practitioners and scientists to share/exchange information, while on the other hand, the publications in the chinese language have provided complementary educational approaches for the local medical practitioners to understand the essential and key information to manage covid-19 in the relatively remote regions of china, for the general population with a general level of education. the seriousness of the rapid spread of the sars-cov-2 virus has caused people to panic around the world since december 2019 (1) . the tremendous danger of sars-cov-2, with a basic reproduction number (r 0 ) ranging from 2.30 to 3.58 (2) , resulting in a pandemic with the number of infections reaching 9,653,048 to date (3) . consequently, considerable attention has been focused on covid-19 from medical practitioners/scientists around the world to inhibit/stop the continuous transmission of sars-cov-2 and to develop guidelines for the effective treatment of severe cases. to fight sars-cov-2, authorities in many countries have enforced social isolation restrictions to control the epidemic of covid-19 throughout their countries, strategies utilized in china include wearing of facemasks in public areas, and minimizing outdoor, particularly mandating no public and/or private social gatherings (4, 5) . the internet classes has allowed schools to continue to educate without classroom (6) . consequently, newly identified local covid-19 cases have been reduced to near 0 in all of the provinces in china (7), mainly due to the active approaches outlined above, and strict limits to interstate/international travel. however, outside china, many countries now face escalating epidemics and are feeling overwhelmed due to the highly contagious nature of covid-19. as an emerging infectious disease, covid-19 has garnered great research interest. medical practitioners/scientists are studying the disease from various scientific and clinical areas, including specialists in infectious diseases, virology, microbiology. many uncertainties remain as to certain epidemiological, seroepidemiological, clinical and virological characteristics of the virus and associated clinical features. the key task is to explore how to enhance host defenses and/or destroy viral resistance (8) . many researchers have published their data within top international, peer-reviewed, highly reputable journals, including nejm, lancet, nature and science (9) . there are many studies that have been published in reputable chinese journals (10, 11) . bibliometrics used in the current study is to analysis quantitatively of citation scientific publications, based on constructing the citation graph, a network representing the citations of different documents. in addition, bibliometrics is also used for exploring comprehensively the impact of their field, a set of researchers, a particular paper within a specific field of research. furthermore, vosviewer software was used for constructing and visualizing bibliometric networks, whereas, citespace v software was utilized for visualizing cocitation networks. there are a few published papers, using bibliometric analysis of covid-19, to explore the activity (12) and trends (13, 14) of covid-19 research. we aimed to explore the differences between english language and chinese language medical/scientific journals publications, particularly aiming to explore the efficacy/contents of the literature published in english and chinese in relation to the outcomes of management and characterization of covid-19 during the early stage of covid-19 pandemic. we have undertaken a bibliometric comparison of research on covid-19 between english and chinese language journals. a comprehensive search was performed online using the english language databases embase (15) and scopus (16) in the present study, only original articles and reviews, published in the chinese or english languages were included. studies including the following were excluded: (1) articles or reviews published on preprint sites such as bioriov and medriox; (2) translated versions of articles or reviews; (3) comments, editorials, and letters; (4) eliminating duplicate literature. two reviewers independently performed study selection and data extraction. differences of opinion were settled by consensus or referral to a third review author. since some authors have the same short name, we added the affiliation behind the author names, if the same name's affiliation was different, it was considered as two different authors. for authors with more than one affiliation, we used the first one. for keywords with different expressions, we have processed them, leaving only one standardized keyword. we also reclassified publications from hong kong, macau and taiwan to china, and publications from england, scotland, northern ireland, and wales to the uk. publication characteristics were tabulated, including titles, authors, co-cited authors, journal sources, keywords, affiliations of authors and, for english journals, the continents, countries or regions to which the authors belong; whereas for chinese language journals, the provinces. co-cited authors means that the authors have been cited together. vosviewer (version 1.6.14) software was utilized to analyze the relationships among the most highly productive countries, research institutions, and frequently used keywords. we performed cluster analysis and generated social network maps (consist of nodes and links) for countries, institutions and keywords by vosviewer (16, 17) . cluster was also obtained by vosviewer via analyzing the frequency of the same keywords appearing within the different papers. we set either twice or four times as the minimum frequency of keywords occurrence in english or chinese publications, respectively, reflecting the number of included studies (143 or 721, respectively) and the consequent analysis results. thus, the main reason for the different settings between english and chinese is because there are more than double the number of keywords from the chinese vs. the english language papers. consequently, there would be too many clusters if the frequency of keywords were set as twice for the chinese publications. different nodes in a map represent elements including a country, institution, or keywords. the size of the nodes reflects the number of publications or frequency, the larger the node, the greater the number of publications or frequency (18) . the links between nodes represent relationships of collaboration, co-occurrence, or co-citations. the color of nodes and lines represents different clusters (19) . the parameters of vosviewer were as follows: counting method (fractional counting) and "ignore documents with a large number of authors" (maximum number of authors per document is 25). citespace is scientific software that reveals the trends and dynamics in scientific literature as well as identifies key points in a given research field (18, 20) . citespace was therefore used to design the social network. in the current study, citespace was used to identify co-occurrence maps of authors, keywords, institutions, countries or provinces and capture keywords. a total of 864 original research articles and reviews were included, of which, 143 were retrieved from embase and scope in english and 721 from sinomed, cnki, vip and wanfang in chinese. a total of 1,062 authors have been identified in the 143 articles published in 62 english journals. the top 10 authors and journals are listed ( table 1 ). the top 10 authors have contributed 46 (32.1%) of the papers. author li y has the highest number of published papers (7, 4.9%), followed by benvenuto d, eurosurveillance editorial team and leung gm (5, 3.5%), and angeletti s, gao gf, ran j, wei y, wu jt, and yang g (4, 2.8%). the top 10 english journals are responsible for the publication of 72 (50.3%) papers, of which, j med virol is the highest (18, 12.6%), followed by euro surveillance (16, 11 .2%) and lancet (13, 9. 1%) ( table 1) . meanwhile, 3,243 authors have been identified in the 721 articles published in 193 chinese journals. the top 10 authors have contributed 45 (6.2%) of the papers. authors wang yg and yang fw have published the highest number of papers (6, 0.8%), followed by wang yj (5, 6.9%). the top 10 chinese journals have published 193 (26.8%) of the papers, the highest is chinese general practice nursing (41, 5.7%), followed by j traditional chin med (23, 3.2%) and chin herb med (18, 2.5%) ( table 1) . for the analysis of the social relationships of authors (affiliated institutions) with more than three articles (figure 1) , it was found that of 38 authors who published english papers, seven clusters corresponding to seven categories were identified (a), and of 29 authors who published chinese papers, clustering identified eight categories (b). these categories demonstrate that the cooperation between the various authors is close. of a total of 143 english papers that were published, there were a total of 1,062 authors from 32 countries or areas, including china (75/143, 52%), usa (34/143, 24%), uk (11/143, 8%), canada (11/143, 8%), and italy (10/143, 7%). there are 252 institutions from 32 countries published covid-19 related english papers. the first five are from china, including wuhan university (15/252, 6%), university of hong kong (12/252, 5%), chinese academy of sciences (9/252, 4%), huazhong university of science and technology (8/252, 3%), and chinese cdc (6/252, 2%). for the analysis of the social relationships of countries with more than three articles (figure 2a) table 2) . for the analysis of the social relationships of provinces/areas with more than three articles, as can be seen from figure 2c , amongst 32 provinces/areas, 28 provinces/areas are clustered into seven categories; amongst 677 institutions, 56 are clustered into nine categories, and the cooperation between them is close with more than three articles ( figure 2d ). for the papers published in english, 471 english keywords are extracted from the 143 articles. a density map is generated for keywords with a co-occurrence greater than twice, including 54 keywords in the map ( figure 3a) . sars-cov-2 was the most frequently used keyword ( figure 3a) , with 93 (19.7%) co-occurrences, followed by covid-19 (44, 9 .3%), china (36, 7.6%), sars (22, 4.8%), and epidemic (17, 3.6%) ( table 3) . among the top 20 keywords, some are related to epidemiological characteristics, such as epidemic, adult, male, female, travel, others are related to a comparison with similar diseases, e.g., mers, sars. some are correlated to the structure of the virus, e.g., endogenous compound, amino acid, cladistics, and phylogeny. cluster analysis is performed on co-occurrence of english keywords with a frequency >2. there are 54 keywords clustered into five categories (supplementary figure 1b) . cluster 1 includes 22 a total of 1,234 chinese keywords are extracted from the 721 chinese-language articles. a density map is generated for keywords with a co-occurrence >4 times, resulting in the generation of five categories ( table 3) . as stated above, there are substantial more chinese keywords identified within the chinese journals. if thence-occurrence of three times or less is adopted for the analysis, the clusters would be too many to offer an objective outcome. covid-19 is the most frequently used keyword, with 543 (44.0%) co-occurrence (figure 3b) , followed by sars-cov-2 (381, 30.9%), tcm (153, 12.4%), prevention and control (141, 11.4%), epidemic (56, 4.5%), management (51, 4.1%), therapeutics (48, 3.9%), and computed tomography (ct) (35, 2.8%). among the selected top 30 keywords with frequency more than 10, there were five clusters generated with such information (figure 3b) . for more detailed clusters, these were as follows: the keywords from the cluster one included clinical symptoms, critical case, ct, diagnosis, nucleic acids, therapeutics, x-ray; the keywords from the cluster two included cancer patients, emergency, infection, management, medical care personnel, mental health, prevention and control; the keywords for the (figure 2a) . for the 21 english language articles jointly authored between chinese and international authors, the institutions involved in cooperation between china and other countries were found to be centered in hong kong, hubei province, beijing and shanghai within china, while the most frequent overseas institution involved in cooperation was the new york blood center from the usa (figure 2c) . this cooperation covered a range of scientific topics, mainly focusing on diagnosis, such as pcr testing in the laboratory, prevention and control, and the viral genome ( figure 3a ). the battle against covid-19 has been highly effective in china up to date, however, the pandemic of covid-19 is highly alarming in around the world with substantial morbidity and mortality (3). the most urgent task for medical doctors/scientists is to control covid-19, including the incorporation of aspects of the chinese approaches. many diverse studies addressing covid-19 have sprung up due to the urgent necessity of prevention and control. we have focused on english and chinese publications only for the comparison. most of the studies captured in this paper on covid-19 in english journals have been conducted by chinese scholars and institutions, which is highly likely to be due to the timing of the literature search for this study, march 1st 2020, at which point the predominantly affected locations were wuhan, and to a lesser extent the remainder of china. of the international publications, particularly from western countries, e.g., italy (21) and south korea (22) , these publications occurred during the latter part of the survey period, from 27 february 2020, which is likely to be attributed to the spread of the sars-cov-2 commencing within these other countries, both raising the index of concern within those other regions and directly making available to those regions affected local populations and biological materials on which studies could be conducted. more authors from hong kong published more english papers than papers in chinese, which may be due to the higher levels of advanced english literacy, reflecting the english-based educational system (23) . furthermore, the majority of the hong kong researchers have more opportunity to study/work and establish links overseas (24), in addition to their preference for english journals. although the impact of covid-19 in iran has been very severe (25) , there has been no studies published on the pandemic at all prior to march 1st, 2020. we speculate that the iranian government has experienced difficulties scaling up its response to combating the epidemic, due to the economic loss and supply issues associated with economic sanctions imposed (26) . similarly, the scholars who published studies on covid-19 in chinese journals are mainly from beijing, hubei, shanghai, guangdong and sichuan. a likely explanation is that most of the first-class medical universities are within these areas, corresponding to the top research institutional distribution in china. apart from wuhan, hubei province, sichuan university has published more papers than other areas, except for beijing, shanghai and guangdong, which are the three provinces with the highest gdp in china (27) . especially relevantly, as the capital of china, beijing is the nation's political, economic, cultural and educational center, and has the largest number of universities in the country. these data support the idea that advanced academic development needs financial support. certainly, less publications are from xinjiang uygur, qinghai, ningxia, and inner mongolia, all of which has fewer covid-19 cases, but also have lower gdp within remote northwest china (gdp rankings out of 31 regions 19, 23, 15, 9, respectively) (28). in the cluster of authors, we found that the cooperation between the various authors is close but there is not a hotspot amongst them, which is in line with the reality that the information sharing was lacking at the early stage. the studies in english related to covid-19 are published in international, highly reputable journals, including nature, science, cell, nejm, jama, and lancet. these publications enable medical practitioners/scientists to share/exchange information efficiently, providing essential background for some key policy decisions (29, 30) , e.g., mandatory wearing of face masks, minimizing social gathering [has been widely accepted, including australia (31), uk (32)], and the lockdown of interstate travel in many countries of the eu (33) . importantly, the ultra-rapid development of an effective vaccine, has been accelerated by the rapid sharing of scientific data, particularly the published sequences of the sars-cov-2 virus. thus, publications in english journals, particularly in well-recognized, top ranking international journals, results in rapid dissemination of key information for use of the data for practical applications. english is the well-accepted communication language of science around the world. our data demonstrated that substantial collaborative research has been undertaken from the very early period of the covid-19 outbreak (34, 35) , and that this research has become more frequent and deep following the declaration of a pandemic. such collaborations are certainly enhancing our understanding of the nature of the sars-cov-2 virus (36, 37) , have supported development of effective vaccines (38, 39) , and has provided vital data to assist clinical diagnosis at the international level (40) . these developments further support our conclusion that publications in english have enabled doctors/scientists to effectively share/exchange information at the international level. the cluster analysis of institutions at the international level demonstrated strong regional representation even at the international level, both within china and within international countries. interestingly, the cluster of cooperation for studies in china was thickest with the usa, suggesting the cooperation was mainly between china and usa, which is consistent with the publications retrieved from the database. the most likely explanation has been mentioned above, namely that the economic resources of each country is the likely most significant factor to impact both the disease and research into it. in contrast, there is a language barrier to the utilization of the information from the papers published in english journals for use by the general population in china. the publications in the chinese language are able to meet a complementary dissemination purpose for china-based medical practitioners to understand the essential key information concerning covid-19, especially for those in the remote areas of china, without proper access of english journals or sufficient language skills (41) . indeed, publications in chinese provide a more acceptable approach for chinese doctors to learn how to deal with covid-19 in the relatively remote regions of china, an outcome that is consistent with the large number of studies that have been published in chinese. the top 10 chinese journals that included covid-19-related papers are mostly from the chinese science citation database, representing the most authoritative and representative core of journals in all disciplines in china (42) . importantly, in this study there are a total of 721 papers that cover covid-19 from various scientific areas within the identified journals, often with a large number of authors, reflecting the chinese authority's intention to accelerate the control of covid-19 and the rapid dissemination of knowledge. there are a total 471 or 1,234 keywords in english or in chinese publications, respectively, used in the studies on covid-19 that we identified till march 1st, 2020. however, more than 78% of the keywords appeared once, only 3.9% of the english keywords have a frequency of >4, indicating the importance of a few keywords. in bibliometrics, a network graph of keyword co-occurrences reflects hot topics (18) . cluster analysis of co-occurrence keywords demonstrates that there are five clusters in this field. cluster 1 consists of 22 keywords, mainly relates to the epidemiological characteristics and clinical features, because these are the basis for understanding key aspects of the disease, such as treatment and control. at the present time, many scholars are focusing on the large proportion of covid-19 patients who exhibit mild symptoms or are asymptomatic carriers, reflecting the seriousness of the nature of viral transmission (43) . cluster 2 contains 11 keywords, mainly focuses on the virus detection and genome. some data demonstrate that bat cov and human sars-cov-2 might share the same ancestor (40) , and similar residues of the key receptor are observed in many species (44) . because of the importance of the original source of sars-cov-2, the evolution and genomics is a hot topic in this field. nine keywords are included in cluster 3, focusing on drug treatment and comparison with sars and mers, making comparisons to these fatal respiratory tract infections by coronaviridae, to explore any clues between the similarity and differentiation. for the papers published in chinese language journals, there are five clusters of keywords, including 2-6 keywords in each field. cluster 1 consists of six keywords, mainly relating to treatment and diagnosis, because these activities are the basis for understanding key aspects of the disease, such as treatment and control. at the present time, many scholars are focusing on the large proportion of covid-19 patients who exhibit mild symptoms or are asymptomatic carriers, reflecting the seriousness of the nature of viral transmission (43) . cluster 2, contains 6 keywords, mainly focusing on emergency, infection, management, medical carers, prevention and control, which are supported by the others, demonstrating the critically importance of covid-19 in such outbreak (45) , transmission (46) and disease control and management (47) . cluster 3 is focusing on tcm or chinese and western treatment for covid-19, mainly to explore the benefit of the combination of tcm and classical western management approaches, especially aiming to provide the guidelines for relatively remote/rural regions of china. the advantage of this particular cluster is its usefulness in the outskirts of metropolitan or rural areas, where there is a relative lack of advanced or first line anti-viral medications (48) . cluster 4 is an extension of the current existing treatment to the cardiovascular system (49) , as well as, using the previous experience in mers (50) , and also places emphasis on antiviral drugs and herbs (51) . interestingly, cluster 5 includes pregnancy and nursing, which is a very venerable population at high risk, either due to compromised immunity during pregnancy (52) or the lack of sufficient data to adequately understand the severity of the potential risk of covid-19 in pregnancy and the need to guard against covid-19 infection in pregnancy (53) . part of the reason for the chinese scholars focus on tcm when publishing in chinese medical journals is the difficulty chinese scholars have to disseminate their findings using modern scientific terminology/theory, compared to rather ancient theory of tcm, e.g., balance of ying and yang. actually, we believe that balance of ying and yang is equivalent to the modern theory of anti-vs. pro-inflammatory responses in the micro-environment, i.e., imbalance of anti-vs. pro-inflammatory responses contributes to autoimmune diseases (54) . thus, from the point of view of the management of covid-19, the efforts should be focused on the suppression of the sars-cov-2 virus, disregarding the backgrounds, theories, and approaches of modern vs. traditional scientific ideology. consequently, analysis of the dissemination of the critical information from english and chinese languages could facilitate such a purpose appropriately. these covid-19 related english language papers, especially at the top end, e.g., nejm (55), lancet (7, 26) , science (8), nature (36) , provide the most critical information in the development of effective vaccinations (31) . on the other hand, for many primary health carers at the front line in the relatively remote regions in china, obtaining the most up dated information of covid-19 particularly, regarding prevention and/or controlling has been from the chinese language. in addition, the local government at the county levels are also heavily dependent on such key information in chinese, in detail, e.g., keep social distance, no public gathering, and lockdown of manufacture and so on (56) . there are some limitations in the current study. first, our study is focusing only on english and chinese journals, which inevitably could miss some important information from other languages. we will further analyze such points by collaborating with researchers from the different regions/countries. second, our study has been undertaken at the vortex of the epidemic before march, 2020, which may miss the most updated information. third, the total number of included studies is relatively small, and the study duration of just more than 2 months from when the first covid-19 patient is identified till march 1st, 2020, is a short cutoff time for data retrieval. the publications related to covid-19 research has been rapidly growing since the disease emerged. more studies have been published in chinese journals than in english, due to the epicenter being located in wuhan, china before march 1st 2020. the publications in english have enabled doctors/scientists to share/exchange information at the international level; the publications in the chinese language provides complementary educational approaches for the local doctors to understand the essential and key information to manage covid-19 in the relatively remote regions of china for the general population. the raw data supporting the conclusions of this article will be made available by the authors, without undue reservation. jf and sb conceived of the presented idea. jf and yg developed the theory and performed the computations. yg and jt verified the analytical methods. nz, rd, hz, xf, and gs collected and synthesized the data. cc and bh encouraged jf and yg to investigate and supervised the findings of this work. all authors discussed the results and contributed to the final manuscript. the supplementary material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fpubh. 2020.00477/full#supplementary-material world health organization. who 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chattu, vijay kumar; adisesh, anil; nurtazina, alma; kyrykbayeva, saltanat; sakhamuri, sateesh; moguilner, sebastian; pandya, shawna; schroeder, starr; banach, maciej; ray, daniel title: telemedicine as the new outpatient clinic gone digital: position paper from the pandemic health system resilience program (reprogram) international consortium (part 2) date: 2020-09-07 journal: front public health doi: 10.3389/fpubh.2020.00410 sha: doc_id: 343205 cord_uid: zjw4fbfd technology has acted as a great enabler of patient continuity through remote consultation, ongoing monitoring, and patient education using telephone and videoconferencing in the coronavirus disease 2019 (covid-19) era. the devastating impact of covid-19 is bound to prevail beyond its current reign. the vulnerable sections of our community, including the elderly, those from lower socioeconomic backgrounds, those with multiple comorbidities, and immunocompromised patients, endure a relatively higher burden of a pandemic such as covid-19. the rapid adoption of different technologies across countries, driven by the need to provide continued medical care in the era of social distancing, has catalyzed the penetration of telemedicine. limiting the exposure of patients, healthcare workers, and systems is critical in controlling the viral spread. telemedicine offers an opportunity to improve health systems delivery, access, and efficiency. this article critically examines the current telemedicine landscape and challenges in its adoption, toward remote/tele-delivery of care, across various medical specialties. the current consortium provides a roadmap and/or framework, along with recommendations, for telemedicine uptake and implementation in clinical practice during and beyond covid-19. coronavirus disease 2019 has challenged the status quo of how we approach, deliver, and receive modern medicine (1) (2) (3) (4) . according to the american telemedicine association, telemedicine is defined as "the remote delivery of healthcare services and clinical information using telecommunications technology" (5) . it allows for patient care while minimizing the need for physical interaction, thus reducing infection transmission and healthcare facility burden. it can be utilized for ongoing management of chronic conditions, medication compliance, physician-topatient consultation, and other remote services (3, 4) . this can be leveraged to benefit broader populations through telehealth platforms and assisted technologies such as the internet of things (iot). telemedicine and digital technologies demonstrate exceptional potential in improving access and delivery in remote settings. there is also an opportunity to exploit the power of artificial intelligence (ai) algorithms to design a better pandemic preparedness and response plan (6) . health systems have had to adapt to address emerging needs quickly, and many medical subspecialties have transitioned from in-person outpatient care to remote tele-or e-health. broadly, telehealth technologies can be deployed for targeted purposes relevant to a pandemic (7) . remote assessment of patients could be undertaken, circumventing visits to outpatient clinics or primary care providers. patient continuity for those with chronic diseases is essential during a pandemic (3, 4) . such patients are also at high risk of infection and poor outcomes, including mortality, among covid-19-positive patients (3) . notably, telemedicine also limits infection exposure to healthcare staff, can provide rapid access to subspecialists who are not immediately available in person, and allows for multidisciplinary team discussions. this is crucial in pandemic settings, as the safety of healthcare professionals is essential to ensure the sustainability of health systems to cater to emergent cases and maintain ongoing care. patients with flu-like symptoms can be triaged, and telemonitoring using video surveillance could be considered for patients who are homebound such as the elderly or frail. telemedicine can increase access for certain populations who are challenged during limited healthcare facility visitation, stay-home orders, and quarantine, such as single parents, immunocompromised patients, and patients who rely on the assistance of others for transportation. monitoring of patients along with remote delivery of home-based exercise, physiotherapy, psychological counseling, social work consultations, and speech and language interventions could be undertaken through telemedicine. our previous work analyzed the status and deployment of telemedicine during covid-19 across the geographical divide (bhaskar et al., under review) . in this article, we analyze the uptake of telemedicine across various medical subspecialties and organizational settings with a focus on the current covid-19 pandemic and propose an operational roadmap for further integration of telemedicine or tele-technologies across health organizations. as hospital systems become strained by the surge of covid-19 patients, methods to improve the efficiency of emergency departments (eds) are required, while maintaining standards of patient care. telemedicine supplies a potential avenue for triage of critical cases. remote and ambulatory monitoring of patients can allow for remote triage and assessment of emergencies such as acute myocardial infarction (mi), allowing patients to bypass the ed (8) . automated forward triage systems that use algorithms to categorize patients into risk groups could also be utilized, as ed physicians experience considerable time pressure. current examples include the multi sources healthcare architecture (mhsa) algorithm and the electronic modified early warning scorecard (9) . telemedicine has also been used to triage, expedite, and streamline the local covid-19 screening process, thereby reducing the strain on healthcare facilities and practitioner exposure. the new york presbyterian hospital, a world leader in digital health innovation, has demonstrated an effective method to reduce the burden of milder presentations (10) . they established an ed-based telehealth express care service, in which after presentation and triage at the ed, patients with milder cases are taken into a private room for a teleconsultation with a physician. prescriptions and patient instructions are then printed to the room, and the patient is discharged. this dramatically reduces ed waiting times and allows the hospital to deal with everincreasing ed presentation numbers (10) . as patients become anxious about ed infection risk, systems such as these are required, and patients need to be able to effortlessly contact eds to query whether their symptoms require a presentation. cardiology is one of the first specialties in which comprehensive telemedicine systems have been implemented. monitoring of heart rhythm in patients with implanted or real-time wearable devices has allowed ecg with holter monitoring, echocardiography records, and virtual auscultation. an emerging body of evidence suggesting cardiac involvement in covid-19 patients has concerned cardiologists (3, 11) . this includes cardiovascular complications such as cardiac injury, heart failure, myocarditis, pericarditis, vasculitis, and arrhythmias (12) (13) (14) . patients with pre-existing cardiovascular conditions who contract covid-19 also experience inordinately poor outcomes, including a 5-to 10-fold rise in mortality (15) . due to the covid-19 pandemic, the american college of cardiology urgently updated its guidance on "telehealth: rapid implementation for your cardiology clinic, " in which it encouraged remote monitoring and virtual visits of patients with cardiac problems (16) . the development of prognostic models based on the recently launched new european register capacity-covid will help to understand the role of underlying cardiovascular disease (cvd) in patients with covid-19 (17) . virtual options can significantly increase efficiency compared to in-person doctor appointments (18) . notably, non-invasive telemonitoring in patients with heart failure reduces allcause mortality and number of hospitalizations, as well as improves the quality of life (19) . in february 2020, the italian society of cardiology published data on the implementation of telemedicine in cvd patients and reported crucial involvement of telemedicine in the prehospital triage for st-elevated myocardial infarction (stemi) cases and remote monitoring by primary care physicians (20) . an american heart association (aha) statement emphasized the role of telemedicine in pediatric cardiology through advanced video technologies like tele-echocardiography, fetal echocardiography in prenatal diagnosis, screening for congenital heart diseases, and confirmatory echo tests, external rhythm monitoring, catheterization laboratory, and personal tele-electrophysiology (21) . due to their comorbidity risk, efforts to prevent covid-19 infection in cvd patients should be undertaken seriously by reducing hospital admission and outpatient visits (3) . treatment adherence is one of the significant issues in the long-term management of cvds (22) . the utilization of mobile phones through mobile health (mhealth) can be one of the reliable potential solutions in this area through measures such as electronic pillboxes and text reminders (22) . the unique advantage of portable devices and smartphones is the ability to reach most patients and caregivers. the widespread use of mobile technologies makes medical support more effective, faster, safer, and less expensive in both outpatient and inpatient settings (23) . mhealth can play an increasingly important role in cardiac care, extensively applied in triage, interventions, management, patient education, and rehabilitation. telehealth solutions are critical now, as we aim to minimize patients at high and very high cardiovascular risk being hospitalized and provide ongoing support to cvd patients during the covid-19 pandemic. in poland, some other systems have been tested in heart failure patients (24, 25) , including e-oximeter, allowing for monitoring of heart rhythm and blood saturation, which might help to decide whether those quarantined should be hospitalized during covid-19. telemedicine allows for prompt assessment of potential emergent neurological cases and can aid those with hospital access issues and those requiring fast acute assessment (2, 4) . acute stroke outcomes are vastly impacted by the speed at which treatment is given, whether it be through tissue plasminogen activator (tpa), endovascular clot retrieval (evt), or antihypertensives. during times of physician shortages, as doctors become re-purposed for covid-19 purposes, rapid approaches to acute stroke management are needed (2) . reperfusion treatment viability through computed tomography (ct) can be assessed remotely, allowing reperfusion treatment using tpa and/or evt to be efficiently undertaken. furthermore, telemedicine can be utilized to determine which patients require an urgent transfer from non-evt-capable hospitals to evtcapable hospitals (26) . a program developed in germany known as transit-stroke, in which rural hospitals established a telemedicine network, saw an improvement in patient outcomes as neurological assessment was made faster, treatments were issued within the required timeframe, and 24 h neurologist access was enabled (27) . similarly, successful programs have been undertaken worldwide, such as telestroke programs in hawaii and south california (28) . there is also evidence to suggest that patients who receive acute stroke assessment through telemedicine do not perceive decreased physician empathy compared to those who receive physical consultation (29) . this somewhat relieves concerns about impaired patientphysician connection through telemedicine. while telemedicine decreases the time it takes to analyze head cts, more work is needed to ensure that this benefit applies equally across different telestroke programs (30). mobile stroke units (msus) go beyond this to provide ct scanners and stroke personnel within an ambulance vehicle. such programs exist in locations such as melbourne (australia), various states in the us, and hamburg and berlin (germany), among others (31). msus improve acute ischemic stroke outcomes by reducing the time to reperfusion; however, further development is needed in the treatment of hemorrhagic stroke. telemedicine could also allow ct assessment of mild traumatic brain injuries (such as concussions). this can help to determine if the patient requires transfer to a major hospital or can be treated locally and will also allow for post-concussion checkups (32) . vulnerable patients who require respiratory management and/or critical care are at increased covid-19 risk due to their impaired state and require effective management with the aid of technology (33) . in 2019, the society of critical care medicine (sccm) tele-icu committee in the united states published an update on developments in telehealth critical care (tcc) (34) . they described three emerging trends in tcc: hub-andspoke structure in which a central hub provides remote technical support, administrative support, and integration to a network of hospitals; decentralized structures in which consultations and patient reviews will be made on a case-by-case and request basis between two sites; and a hybrid structure in which a centralized structure exists but direct contact between spokes can be made for, e.g., specialist consultations. barriers to tcc included cost and reimbursement issues, lack of responsibility for individual hospitals, and legislative issues (34) . a 2012 systematic review and meta-analysis of telemedicine in the us intensive care unit (icu) setting demonstrated decreased mortality and length of hospital stay with telemedicine incorporation (35) . however, a statistical difference between an active model or high-intensity passive model, in which continuous patient telemonitoring is conducted, and a lowintensity passive model, in which only teleconsultation with an intensivist is conducted, was not ascertained and is an area for further research (35) . patients with respiratory issues are at higher risk of covid-19 severe infections due to issues such as ventilator reliance and decreased cough function (33) . this includes patients with chronic respiratory conditions such as chronic obstructive pulmonary disease (copd), bronchial asthma, interstitial lung diseases, as well as chronic neurological conditions such as neuromuscular diseases (33, 36) . telemedicine aids respiratory patients through data collection, such as monitoring of vitals and ventilator status, and by transmitting these data for constant monitoring. in the case of under-resourced or under-developed critical care units in low and middle-income countries (lmics) (bhaskar et al., under review) , frequent international tele-education can serve to upskill doctors and spread critical care knowledge, such as ventilator management (37) . patients with non-acute diseases require ongoing support and cannot be neglected during covid-19 times (1, 3, 4, 33) . studies have shown that telemedicine can lead to similar outcomes as face-to-face delivery of care in the management of patients with heart failure, hypertension, and diabetes (38, 39) . ongoing monitoring of these patients is required to prevent acute manifestations, hospitalization, or disease progression (3, 4) . the differences within medical subspecialties and individual patients need to be considered, rather than broadly implementing uniform telemedicine approaches across all departments. for example, infectious disease cases can be complicated and require careful consideration of patient history and investigation findings. in these cases, asynchronous consultations, in which the physician reviews data before supplying patient recommendations, will be helpful (40) . in other fields such as neurology, cardiology, and endocrinology, realtime, interactive consultations might be more applicable (3, 4) . patients with neuromuscular issues are particularly at risk due to covid-19 (4). patients with motor neuron disease (mnd)/amyotrophic lateral sclerosis (als) are among those who experience considerable disability and will require multidisciplinary telehealth (4). types of telehealth include teleadvice, teleconsultation, tele-prescription, videoconferencing, home-based self-monitoring, and remote non-invasiveventilation (niv) monitoring. videoconferencing involves consultation with a health professional, home-based selfmonitoring involves taking one's own measurements and submitting them to a physician, and remote niv monitoring involves remote monitoring of the patient's niv data (41) . the use of telehealth with als patients has been shown to be associated with positive benefits such as reasonable adoption rates, personalized data, and efficient consultations (42) . other movement disorders such as parkinson's disease (pd) also require ongoing multidisciplinary care (43) . established programs such as the ontario telemedicine network, the parkinsonnet infrastructure in the netherlands, and that of kaiser permanente in the us all display the ability to integrate telehealth into pd patient care (44) . areas for growth include the reimbursement of nursing homes that utilize telemedicine, acceptance by patients and physicians, and reimbursement of at-home telemedicine programs (44) . furthermore, global partnerships can increase international telehealth integration. for example, the international parkinson and movement disorders society africa section, established in the usa, launched a 5-year program to deliver specialist care to disadvantaged areas in africa using whatsapp tm . diagnosis of pd could also be aided by telehealth, with the unified parkinson's disease rating scale (updrs) and montreal cognitive assessment (moca) for pd both being able to be performed remotely (45) . such tele-tools have also been recently proposed in the times of covid-19 for familial hypercholesterolemia patients, who require continuous monitoring of their health due to lifelong high levels of cholesterol and increased cvd risk (46) . in migraine and headache patients, telemedicine could be used to assess new headache profiles for possible covid-19 symptomology or standard outpatient consultations (4, 47) . cancer patients are another group at risk of covid-19 infection due to their immunosuppressed states, which could have fatal outcomes subsequent to infection (48) (49) (50) (51) (52) . oncologists would use telemedicine for ongoing monitoring and compliance with cancer patients (49, 51). this could be useful in monitoring adverse reactions to ongoing chemo-or radiotherapy, as well as to identify patients who might be at high risk of emergent medical attention, such as those at risk of venous thromboembolism. cancer patients could also be offered multidisciplinary care, including psychological interventions, physiotherapy, and specialized interventions such as mindfulness training, to improve the overall quality of life (49). overall, telemedicine offers opportunities for cancer patients to access specialist care in the comfort of their homes. approaches to the use of telemedicine and mobile technologies in increasing access to novel drugs or interventions through clinical trials should be expeditiously pursued. telemedicine could also be used in palliative care and end-of-life planning involving patients' carers, family, and multidisciplinary care team (53) . teledermatology is another promising perspective in the diagnosis and monitoring of skin lesions, including cancer (54) . non-acute ophthalmological telemedicine has been implemented for retinal scans relating to diabetic retinopathy, retinopathy of prematurity, and other non-acute retinal monitoring (55) . fundus scanning and optical coherence tomography imaging are being sent to remote trained healthcare practitioners (hcps) for evaluation and additionally are being evaluated by ai analysis using deep learning. these non-acute services are also being utilized locally by emergency and urgent care services to a certain extent (55) . chronic patients must adhere to medications during this time and should not stop treatment regimens without consulting their physician (3, 4) . patients taking immunosuppressants, steroids, or pain medications may be concerned about their covid-19 risk, and contact with their physicians needs to be ensured. adherence to medications can be monitored through mhealth and telehealth means (56) . such examples include digital adherence technologies (dats) or electronic directly observed therapy (edot) for patients with tuberculosis (56) . measures include ingestible sensors, video observation, digital pillboxes, and smartphone applications and have been trialed in china, india, belarus, and the us (56, 57). the european respiratory society (ers) task force has described the implementation of remote home mechanical ventilation and physical therapy for patients with chronic respiratory disorders (58) . the emphasis is on promoting common standards of clinical criteria as well as analyzing the cost/benefit ratio and evaluating reimbursing rules to implement in different countries (58) . tele diagnosis uses patient data to aid remote diagnosis and can be utilized to identify those with bulbar and respiratory weakness. telemedicine strategies such as electronic inhalers, chipped nebulizers, self-monitoring through apps, and text reminders increase medicine compliance in patients with asthma, copd, and cystic fibrosis (cf) (59) . furthermore, the diagnosis of copd through telemedicine means such as spirometry tracing and teleconsultation provides an opportunity to utilize technology to increase patient care. further studies are needed to stratify which patients, in terms of severity, will be best suited to a telemedicine management approach. another area of potential growth is in using ai algorithms to determine developing copd exacerbations (60) . telemedicine for asthmatics tends to be more focused on treatment compliance and self-monitoring and can be useful in helping patients learn more about their disease, such as recognizing patterns of asthma triggers (61) . other barriers to care include the risk that patient data may be manipulated, networks potentially becoming compromised, and inconclusive data on the benefit of telehealth on specific diseases such as copd (62) . obstructive sleep apnea (osa) is one such disease in which remote monitoring can be utilized to prevent patients from having to spend time in a sleep clinic or respiratory clinic (63) . home polysomnography devices can be used to track patients' breathing and oxygen levels; however, further work is needed to lower the rate of false negatives to the level of in-person sleep clinics (63) . a 2018 prospective study of 780 patients used a portable spirometer, with bluetooth capabilities and connected to a mobile phone application, to trace results and connect the patient to a physician for analysis (64) . this allowed the patient's breathing difficulties to be assessed and categorized as asthma, copd, or normal breathing function (64) . this study shows promising results for remote diagnosis of chronic breathing conditions; however, it does not preclude the need for future testing in some more complicated cases. other smartphone applications have utilized microphones and questionnaires to analyze and detect breathing difficulties associated with other pulmonary conditions such as coughs and lung cancer (65) . covid-19 could impose severe stress on sleep clinics and may limit in-laboratory polysomnography sleep studies for osa assessments and diagnosis. home-based telepolysomnography for osa assessment could be explored so that the delayed diagnosis and the associated impact on patients could be minimized. patients with osa often require continuous positive airway pressure (cpap) while sleeping to improve symptoms and achieve proper rest (66) . in order to see sustained results, patients need to use cpap for at least 4 h at night, combined with lifestyle changes such as weight reduction and smoking cessation (66) . low adherence to cpap remains a continuous problem for osa patients due to lack of motivation, discomfort, loud noise, and claustrophobia (67) . telehealth provides an opportunity to increase cpap adherence by monitoring device output data and patient self-tracking of lifestyle factors. when usage falls, the patient can be contacted to discuss their reasons for low adherence and to motivate them to continue use (68) . telemedicine could be used to monitor bulbar function in patients with a compromised bulbar function such as als (4, 69) . the rapid decline in bulbar function could be captured using technologies that are useful in delivering specialist multidisciplinary care (69) . other diseases in which bulbar function may be impaired include myasthenia gravis, spinalbulbar muscular dystrophy, and riboflavin transporter deficiency (4, (70) (71) (72) . telemedicine can aid with rehabilitation following acute incidents such as stroke and traumatic brain injury (tbi) (2, 4), as well as chronic conditions that require ongoing rehabilitation efforts such as copd, cvd, diabetes, and obesity (3). stroke telerehabilitation programs involving consultations, exercises, games, and therapy aspects have shown positive outcomes such as improving patients' functional abilities and mental health (4) . other benefits include increasing patient motivation and ease due to being in a home setting (73) . it is important that patients receive enough support in areas such as technical setup and troubleshooting. the telerehabilitation in heart failure patients (telereh-hf) trial in poland demonstrated that a 9-week hybrid comprehensive telerehabilitation (hctr) program consisting of remote monitoring of training at patients' homes was well-tolerated (24, 25) . however, the positive effects of the intervention didn't translate into improvement in clinical outcomes over a follow-up period of 12-24 months in comparison to standard care (24) . a 2018 systematic review similarly found that telerehabilitation allowed for equal or more significant patient outcomes than center-based rehabilitation programs in stroke (74) . furthermore, wearable devices can be used in the rehabilitation of various neurological diseases such as stroke, pd, multiple sclerosis, and tbi. inactivity is associated with various comorbidities and is often a result of chronic neurological disease or acute accident recovery. remote monitoring through wearable devices can track activity, gait, and any falls throughout rehabilitation (75) . tbi can result in cognitive issues such as sleep disturbance, photophobia, memory, and behavioral changes (76) . it is crucial that patients are not discharged without a follow-up plan. a neuropsychological test battery in the few years following moderate-to-severe brain injury and inpatient rehabilitation is vital to assess any cognitive decline and plateau. during covid-19 times, it is necessary to move outpatient testing of this sort to remote delivery, wherever feasible and while maintaining efficacy. the brief test of adult cognition (btact) has been shown to be effective over the telephone in patients with tbi to assess cognitive state (77) . remote monitoring of physical activity by physiotherapists and patient consultation with neurologists can also be achieved through telemedicine. however, clear guidelines for rehabilitation management and evidence of efficacy through different delivery systems are lacking (78) . pulmonary rehabilitation is essential for patients with chronic respiratory issues such as copd and can be achieved through telehealth measures such as monitoring, consultation, and education (79) . this is important in copd, as potential exacerbations need to be monitored, and lower levels of rehabilitation access are associated with increased rates of hospitalization (79) . additionally, personal movement tracking devices involving accelerometers are helpful in tracking patient exercise, which is an essential area of pulmonary rehabilitation (80) . telehealth rehabilitation still faces major hurdles, however, such as cost-effectiveness, patient training, and the lack of regulatory frameworks surrounding personal health devices (80) . according to the who, about 40 million people annually need palliative care, and only 14% of them receive it (81) . the importance of primary healthcare in palliative care was highlighted by the first who global resolution on palliative care in 2014. the project echo (extension for community healthcare outcomes), as one of the examples, shows the potential of telemedicine in the training of patients, their family members, and medical workers in palliative care (82, 83) . the training of palliative care via telemedicine/telehealth for outpatients in primary care will increase the coverage and quality of both care and life for these patients. telehealth, including mobile applications, plays a role in making patients more adherent to both pharmacological and non-pharmacological therapies; in remote monitoring of clinical parameters such as cardiovascular and respiratory system function; as well as in monitoring of diet and physical activity. given the overload of respiratory diseases and the flu-like presentations in routine practice, telemedicine offers an alternative that is particularly relevant in the covid-19 era. mental health support to frontline health workers, patients, and carers will be crucial, as long isolation, lack of social interaction, as well as anxiety over one's own and others' health will take a toll on well-being (2) (3) (4) 84) . psychotherapy, psychiatry, and counseling are easily converted to a teleconference format through platforms (such as-but not limited to-zoom tm and skype tm ) and should be utilized by frontline health workers, patients, and carers where necessary (85) . anecdotal evidence also suggests that patients experiencing paranoid, anxiety, or post-traumatic stress disorders, who may be particularly affected by the covid-19 climate (84), may feel more comfortable undergoing telepsychiatry over in-person psychiatry. online delivery will further help to resolve issues such as lack of access to practitioners in rural settings and cultural and linguistic barriers (86) . furthermore, psychoeducation and mental well-being advice can be leveraged through smartphone apps and digital outreach programs (87) . these services will become increasingly crucial in the pandemic setting, as physical isolation and frontline work pose both access issues and mental health stressors. the ethics of such teleservices needs to be ensured, with patient confidentiality, referral and billing practices, and physician eligibility being upheld (88) . psychiatrists, psychotherapists, and psychologists need to ensure that they are maintaining their own mental health during this time, with programs such as professional supervision being of help (4). in 2018, nearly one-fifth of the european population was aged over 65 years old (89) . an aging population has put significant pressure on public spending; therefore, telemedicine can improve the scale and efficiency of delivery and ongoing management of elderly patients. elderly patients with mild cognitive impairment or dementia who might be at high risk of an acute condition should be identified using mobile technologies and telemedicine, and telemedicine solutions for the elderly should be easy to use and possibly automatic (4). this would avoid unnecessary burdens to public health facilities. telemedicine can also be used to act as an interface of the local nursing care staff, carers, and patients with medical specialists. elderly patients will benefit from remote allied health delivery. patients who have had a recent surgery could be monitored at home or in nursing care facilities, preventing extended hospital stays. elderly patients with diagnosed mental health conditions could also benefit from telemedicine. however, self-efficacy and digital literacy presumably have a significant impact on the uptake of telehealth among the elderly (90) . recent data from the us confirm that the most vulnerable age group for covid-19 is people over 65 years old, and the highest mortality is observed in those aged 85 and older (91) . in ontario, canada (as well as in italy and the us), 54% of deaths related to covid-19 occurred in retirement homes and long-term care (92, 93) . strict zero-visitation policies have had debilitating effects for some elderly patients, particularly those with dementia (4). telemedicine has been utilized to connect family members with these patients to prevent further decline in mental status and provide comfort. this is useful, as family members have voiced concerns that physically distanced visits such as through windows may further confuse their loved ones. telehealth allows continual monitoring of vitals, physical examination, ongoing clinical management, and communication with patients. in elderly patients with limited accessibility, telemedicine could provide an alternative, easy-to-access service. elderly patients often suffer from social isolation, and telehealth can bring a sense of community. furthermore, by using ai, falls can be detected among elderly patients (94) . ai can provide personalized medicine solutions to help identify patients at risk of harm. primary healthcare physicians and nursing homes should watch for signs of depression in the elderly, particularly as it has been shown that telemedicine is competent in managing depressive symptoms in the elderly (95) . telemedicine can be useful in delivering interventions in congregate settings (96, 97) . challenges in congregate settings include high population density, limited mobility, built environment issues, and limited access to health. this can make the prevention and management of covid-19 onerous while preserving human rights and ethical issues. some of the potential target populations include refugees and migrants (96) , those living in incarceration, orphanages, old-age homes, or childcare centers; and schools. these populations are especially vulnerable to infection such as covid-19, where an outbreak can have facility-wide implications and adverse health consequences and fatality. a simulation study on the possible impact of covid-19 outbreak in a bangladeshi refugee camp found a dire need for dramatic increases in healthcare capacity and infrastructure (97) . existing approaches to control an outbreak, should it occur, would not be practically feasible, necessitating innovative solutions as well as novel and untested strategies in humanitarian settings (97) . telepsychiatry to monitor and deliver interventions in congregate settings, especially among refugee populations living in resource-constrained areas (98, 99) , could be an alternative when traditional therapy is not possible. telepsychiatry programs for congregate settings should be developed, and further studies are needed to evaluate their long-term impact on patient monitoring and care (99, 100) . telemedicine systems are not novel concepts and have been used to good effect for programs such as forward triage in eds, critical care monitoring, and physician communication. existing systems will need to be reallocated, and innovations will be pushed through in order to provide care across all medical fields and to reduce hospital burden. this needs to be achieved within the constraints of funding, legislation, and supply-chain barriers. temporary government funding will be necessary to roll out telemedicine to both rural and urban settings, as well as relaxations to legislation that allow practitioner reimbursement of telemedicine services (101) . a study by sayani et al., addressing the cost and time barriers in chronic disease management through telemedicine in lmics, found telemedicine to be economically beneficial not only by reducing the socioeconomic barriers to cost and access but also by increasing the uptake of services (102) . another systematic review of studies conducted on costs of home-based telemedicine programs from 2000 to 2017 found that home telemedicine programs reduced care costs, although detailed cost data were either incomplete or not presented in detail (103) . the data on the cost-effectiveness of telemedicine solutions in different medical areas remains inconsistent and confounded by many variables, including the type of disease and "digital maturity" of healthcare systems. however, in critical situations such as the covid-19 pandemic, telemedicine is proven necessary, and costing, billing, and reimbursement solutions are needed. there are variations in reimbursement policies across regions and healthcare systems. one of the major barriers has been harmonizing a standard reimbursement policy that is acceptable to all stakeholders and sustainable. we recommend that an integrated framework involving public and private parties could help develop a less complicated and streamlined reimbursement structure. notably, the adoption of a "flip the switch" health insurance strategy in north carolina to reimburse telehealth visits "at parity" with conventional office visits for all healthcare providers and specialists is timely and essential. in the long term, the impact of these strategies on healthcare quality and healthcare costs needs further study. healthcare providers must lead the way here in the covid-19 crisis to explore innovative approaches such as b2b monitoring. certain limitations may act as roadblocks in the uptake, implementation, and scale-up of telemedicine and supporting technologies. considerable training is required to ensure patients can familiarize themselves with video teleconsultations and the use of supportive technologies. physicians also need targeted technical, clinical, and communication training based on their subspecialty needs. issues of limited access to broadband and internet facilities are an area that particularly limits the deployment of telemedicine in remote areas and under-resourced settings. telehealth requires reliable broadband access, which is not always acceptable both for clinics in rural areas and for patients living in such areas. when using telemedicine technology, legal restrictions and a lack of clarity as to what is permitted are possible, and these restrictions force telemedicine providers to proceed with caution. some conditions are not considered in the legislation of health systems. it is still not entirely clear whether virtual consultations and video surveillance will be fully paid in hospitals or will be evaluated as shorter visits so that the rates will be lowered. physician licensing and stability of the telemedicine infrastructures are issues of relevance in under-resourced settings. several critical medical procedures cannot be replaced by telemedicine, nor can it be offered to everyone, and there are many excluded groups of patients, including those with deficiencies (e.g., deaf and blind patients) and elderly patients. the effectiveness of telemedicine relies on the possibilities of the implementation of these tools in the given hospital/healthcare system, preparations/training of physicians/nurses, and awareness of the patients. figure 1 | text, audio, or video means. effective telemedicine has several requirements, including culturally appropriate and available infrastructure; regulatory oversight and privacy compliance such as through the health insurance portability and accountability act of 1996 (hipaa); integration of technologies with existing data such as electronic health records (ehrs), apps, and monitoring devices; and insurance coverage such as medicare or private-payer schemes. credentialing on both sides is essential. the consultation should start with verification of the patient's identity through name, age, phone number, date of birth, and address. the physician should then clearly specify that this is a telemedicine consult and that no audio or video of the communication will be recorded. it is imperative that health record information is protected. the physician should then clearly and explicitly ask for consent, whether that be verbal, text, or video. at the start of the consultation, the physician should assess if acute care is required and make a cursory determination if telemedicine consultation is sufficient. if necessary, the physician should supply an immediate referral or advise the patient to seek immediate medical attention. during a typical consultation, the patient will be evaluated; and specific diagnostics and treatment would be recommended based on the assessment of the healthcare provider; and follow-up could be scheduled either in person or virtually. the physician should go through records, clinical history, and investigations including pathology and diagnostic reports, and obtain any additional information that the patient can provide. a general, non-specialist examination should be obtained, and any vital signs that the patient has the means to measure should be gathered. beyond this, when introducing technologies and measures to overcome gaps in the healthcare system, it is essential not to simply ask, "where are the gaps, " but also to define the standards and ideals of care and continually iterate toward these ideals. as mentioned before, telemedical consultations do not approach the same level of fidelity that an in-person physical exam yields, between physical exams, body language, vocal intonations, and odors. as such, the fidelity of the technology involved with telemedical consults must continually iterate to reach the same level of fidelity and information that an inperson visit might yield. in this vein, virtual and augmented reality technologies, while evolving, hold promise for the future of telemedicine, particularly in envisioning a future in which high-fidelity physician and patient "avatars" may meet in a virtual space for a telemedical consult, replicating aspects of an inperson visit through immersive technologies. covid-19 has expedited the uptake of telemedicine across various specialties. the rapid move by various bodies, associations, and providers to use telemedicine in maintaining patient continuity while limiting covid-19 risks of exposure to patients and healthcare workers will have a long-term impact well-beyond the current pandemic. teleconsultation needs are varied across specialties, and therefore, specialty-specific guidelines and recommendations need to be developed. a scoping list of various telemedicine studies across medical subspecialties (telemedicine vs. standard care) has been provided in table 1 . a comprehensive workflow that critically profiles various telemedicine enablers has been proposed in figure 1 , and recommendations to improve various factors are listed in table 2 . the proposed workflow (figure 1 ) provides a practical telemedicine framework cognizant of relevant requirements and considerations, and a step-by-step pathway to streamlined telemedicine delivery. this could be used as a template (for further customization or adaptation) by individual medical subspecialties. current challenges and recommendations to improve telemedicine include (130) : (i) infrastructure capacity [formation and expansion of dedicated telemedicine units and workforce; cloud-based infrastructure to support telemedicine associated bandwidth traffic; liability, maintenance, and safety of telemedicine platforms; ongoing and regular maintenance and servicing of telemedicine hardware and software; awareness, education, and training to build confidence about telemedicine use among providers and consumers; compulsory telemedicine modules for medical students and continued professional development (cpd) workshops/courses for healthcare providers and medical informaticians/technologists; targeted courses aimed at re-skilling clinicians]; (ii) integration with existing data (standardized patient-specific information and consent form with telemedicine opt-in/out option); (iii) regulatory oversight issues (setup of telemedicine regulatory authority; accreditation/licensing of providers using telemedicine; guidelines for telemedicine use in inter-state and -nation settings; standardization of telemedicine related technologies and services with regulatory oversight, audit, and reporting; appropriate measures and oversight to protect privacy, security, and confidentiality of patient data; legal frameworks for telemedicine-specific information storage, sharing, and access); and (iv) insurance/payers (guidelines for telemedicine insurance; streamlined payment facilities for making and receiving payments; bundled services payments and insurance coverage). another important and emerging area is the use of text messaging [short message service (sms) or multimedia message service (mms)] as a model for service delivery (131) (132) (133) (134) (135) (136) . text messaging has proven efficacious in diabetes self-management, smoking cessation, weight loss, physical activity, and adherence to medication regimens [such as in human immunodeficiency virus infection and acquired immune deficiency syndrome (hiv/aids) patients who are on antiretroviral therapy] (132) . a systematic review on text messaging interventions identified the following issues: identification of intervention characteristics, ensuring intervention effects last over a longer duration of time, and cost-effectiveness of these interventions (132) . issues of privacy and security are also poignant in this context. nevertheless, text messaging offers potential benefit as a public health intervention toward chronic disease management (133) (134) (135) (136) , medication adherence, and secondary prevention (134) . perceptions and experiences/satisfaction, regarding telemedicine services, of the patients and providers is important in improving telemedicine implementation, delivery, and impact (137) (138) (139) (140) (141) . a systematic review on patient satisfaction with telemedicine highlighted methodological deficiencies in published studies (137) . a study on patient and clinician experience with telemedicine found that virtual video visits may provide effective follow-up and increased convenience in comparison to routine in-person visits (139) . another study found a perception of patients with type 2 diabetes that telemedicine can improve their access to care (140) . further studies focusing on communication issues and the quality of interpersonal relationships during telemedicine consultations and how these factors affect healthcare delivery using this medium are required (137, 141) . some specialist examinations, including neurologist consultation, can also be conducted. the american academy of neurology has issued guidelines for telemedicine consultation (142) . physicians can assess mental status; any visual, auditory, or cognitive deficits; comprehensive speech; cranial nerves; apparent tremors; and gait. motor examinations can also be conducted with the aid of a caregiver in order to help ascertain strength, tone, reflexes, dermatome sensation, and cerebellar function. in such a case, consent must be gained from both the patient and the assistor. special considerations may apply for pediatric patients or adults with intellectual disabilities. based on the severity of symptoms, the patient may require a management plan, including specific treatment, health education, and counseling if necessary. patients can be prescribed ongoing prescriptions, specific medications, or add-on medication to optimize regimes, given that there is no ambiguity about diagnosis and the medications are not dangerous. if there is any ambiguity about diagnosis, this must be recognized as a limitation of this mode of telemedicine, and documentation must be made. further tests should be done or referred for in-person consultation if necessary. it should be noted that detailed examination of tone, strength, and reflexes; comprehensive eye examinations; and examinations that require specific maneuvers such as vestibular examinations should be avoided, as examination findings won't be accurate. these recommendations will also need to be adjusted according to individual state or federal legislation. the future of telemedicine beyond the current covid-19 pandemic will depend on how we address existing challenges, building resilient health systems (2) (3) (4) . further randomized controlled trials to evaluate the long-term effects of telemedicine-based interventions in various patient populations should be planned. telemedicine will play a major role as a "safety net" during the pandemic. the covid-19 pandemic is causing an unprecedented public health crisis impacting healthcare systems, healthcare workers, and communities. the covid-19 pandemic health system resilience program (reprogram) consortium is formed to champion the safety of healthcare workers, policy development, and advocacy for global pandemic preparedness and action. sbh devised the project, the main conceptual ideas, including the proposal for a new telemedicine workflow, the proof outline, and coordinated the writing and editing of the manuscript. sbh and sbr wrote the first draft of the manuscript. sbh encouraged sbr to investigate and supervised the findings of this work. all authors discussed the results and recommendations and contributed to the final manuscript. we would like to acknowledge the reprogram consortium members, who have worked tirelessly over the last days in 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of patient satisfaction studies in telehealthcare: a systematic review of the literature telemedicine and covid-19 implementation guide conflict of interest: sp is the vice president of immersive medicine at luxsonic technologies, a medical technology company specializing in virtual/augmented reality for medical education, collaboration, and training. the opinions expressed in this article are those of the authors and do not necessarily represent the decisions, official policy, or opinions of the affiliated institutions.the remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.copyright â© 2020 bhaskar, bradley, chattu, adisesh, nurtazina, kyrykbayeva, sakhamuri, moguilner, pandya, schroeder, banach and ray. this is an open-access article distributed under the terms of the creative commons attribution license (cc by). the use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. no use, distribution or reproduction is permitted which does not comply with these terms. key: cord-343944-nm4dx5pq authors: theys, kristof; lemey, philippe; vandamme, anne-mieke; baele, guy title: advances in visualization tools for phylogenomic and phylodynamic studies of viral diseases date: 2019-08-02 journal: front public health doi: 10.3389/fpubh.2019.00208 sha: doc_id: 343944 cord_uid: nm4dx5pq genomic and epidemiological monitoring have become an integral part of our response to emerging and ongoing epidemics of viral infectious diseases. advances in high-throughput sequencing, including portable genomic sequencing at reduced costs and turnaround time, are paralleled by continuing developments in methodology to infer evolutionary histories (dynamics/patterns) and to identify factors driving viral spread in space and time. the traditionally static nature of visualizing phylogenetic trees that represent these evolutionary relationships/processes has also evolved, albeit perhaps at a slower rate. advanced visualization tools with increased resolution assist in drawing conclusions from phylogenetic estimates and may even have potential to better inform public health and treatment decisions, but the design (and choice of what analyses are shown) is hindered by the complexity of information embedded within current phylogenetic models and the integration of available meta-data. in this review, we discuss visualization challenges for the interpretation and exploration of reconstructed histories of viral epidemics that arose from increasing volumes of sequence data and the wealth of additional data layers that can be integrated. we focus on solutions that address joint temporal and spatial visualization but also consider what the future may bring in terms of visualization and how this may become of value for the coming era of real-time digital pathogen surveillance, where actionable results and adequate intervention strategies need to be obtained within days. genomic and epidemiological monitoring have become an integral part of our response to emerging and ongoing epidemics of viral infectious diseases. advances in high-throughput sequencing, including portable genomic sequencing at reduced costs and turnaround time, are paralleled by continuing developments in methodology to infer evolutionary histories (dynamics/patterns) and to identify factors driving viral spread in space and time. the traditionally static nature of visualizing phylogenetic trees that represent these evolutionary relationships/processes has also evolved, albeit perhaps at a slower rate. advanced visualization tools with increased resolution assist in drawing conclusions from phylogenetic estimates and may even have potential to better inform public health and treatment decisions, but the design (and choice of what analyses are shown) is hindered by the complexity of information embedded within current phylogenetic models and the integration of available meta-data. in this review, we discuss visualization challenges for the interpretation and exploration of reconstructed histories of viral epidemics that arose from increasing volumes of sequence data and the wealth of additional data layers that can be integrated. we focus on solutions that address joint temporal and spatial visualization but also consider what the future may bring in terms of visualization and how this may become of value for the coming era of real-time digital pathogen surveillance, where actionable results and adequate intervention strategies need to be obtained within days. keywords: visualization, phylogenetics, phylogenomics, phylodynamics, infectious disease, epidemiology, evolution despite major advances in drug and vaccine design in recent decades, viral infectious diseases continue to pose serious threats to public health, both as globally well-established epidemics of e.g., human immunodeficiency virus type 1 (hiv-1), dengue virus (denv) or hepatitis c virus (hcv), and as emerging or re-emerging epidemics of e.g., zika virus (zikv), middle east respiratory syndrome coronavirus (mers-cov), measles virus (mv), or ebola virus (ebov). efforts to reconstruct the dynamics of viral epidemics have gained considerable attention as they may support the design of optimal disease control and treatment strategies (1, 2) . these analyses are able to provide answers to questions on the diverse processes underlying disease epidemiology, including the (zoonotic) origin and timing of virus outbreaks, drivers of spatial spread, characteristics of transmission clusters and factors contributing to enhanced viral pathogenicity and adaptation (3) (4) (5) . molecular epidemiological techniques have proven to be important and effective in informing public health and therapeutic decisions in the context of viral pathogens (6, 7) , given that most of the viruses with a severe global disease burden are characterized by high rates of evolutionary change. these genetic changes are being accumulated in viral genomes on a time scale similar to the one where the dynamics of population genetic and epidemiological processes can be observed, which has lead to the definition of viral phylodynamics as the study of how epidemiological, immunological, and evolutionary processes act and potentially interact to shape viral phylogenies (8) . as such, phylogenetic trees constitute a crucial instrument in studies of virus evolution and molecular epidemiology, elucidating evolutionary relationships between sampled virus variants based on the temporal resolution in the genetic data of these fast-evolving viruses that allows resolving their epidemiology in terms of months or years. through the integration of population genetics theory, epidemiological data and mathematical modeling, insights into epidemiological, immunological, and evolutionary processes shaping genetic variation can be inferred from these phylogenies. the field of phylodynamics has generated new opportunities to obtain a more detailed understanding of evolutionary histories-through time as well as geographic space-and transmission dynamics of both well-established viral epidemics and emerging outbreaks (9, 10) . the ability of molecular epidemiological analyses, and phylodynamic analyses in particular, to fully exploit the information embedded in viral sequence data has significantly improved through a combination of technological innovations and advances in inference frameworks during the past decades. from a data perspective, genomic epidemiology is becoming a standard framework driven by high-throughput sequencing technologies that are associated with reduced costs and increasing turnover. moreover, the portability and potential of rapid deployment on-site of these new technologies enable the generation of complete genome data from samples within hours of taking the samples (11). this rising availability of wholegenome sequences increases the resolution by which historical events and epidemic dynamics can be reconstructed. from a methodological perspective, new developments in statistical and computational methods along with advances in hardware infrastructure have allowed the analysis of ever-growing data sets, the incorporation of more complex models and the inclusion of information related to sample collection, infected host characteristics and clinical or experimental status (generally known as metadata) (9, 10, 12, 13) . in contrast to a marked increase in the number of software packages targetting increasingly efficient but complex approaches to infer annotated phylogenies by exploiting genomic data and the associated metadata, the intuitive and interactive visualization of their outcomes has not received the same degree of attention, despite being a key aspect in the interpretation and dissemination of the rich information that is inferred. phylogenies are typically visualized in a rather simplistic manner, with the concept of depicting evolutionary relationships using a tree structure already illustrated in charles darwin's notebook (1837) and his seminal book "the origin of species" (14) . early phylogenetic tree visualization efforts constituted an integral part of phylogenetic inference software packages and as such were restricted to simply showing the inferred phylogenies on a command line or in a simple text file, often even without an accompanying graphical user interface. the longstanding use of phylogenies in molecular epidemiological analyses has however led to the emergence of increasingly feature-rich visualization tools over time. the advent of the new research disciplines such as phylogenomics and phylodynamics necessitated more complex visualizations in order to accommodate projections of pathogen dispersal onto a geographic map, ancestral reconstruction of various types of trait data and appealing animations of the reconstructed evolution and spread over time. tree visualizations resulting from these analyses are also complemented by visual reconstructions of other important aspects of the model reconstructions, such as population size dynamics over time, transmission networks and estimates of ancestral states for traits of interest throughout the tree (15) . across disciplines, adequate visualizations are pivotal to communicate, disseminate and translate research findings into meaningful information and actionable insights for clinical, research and public health officials. the aim to improve datadriven decision making fits within a broader scope to establish a universal data visualization literacy (16) . to this end, enhancing collaborations and dissemination of visualizations is increasingly achieved through sharing of online resources for hosting annotated tree reconstructions (17) , online workspaces (18) and continuously updated pipelines that accommodate increasing data flow during infectious disease outbreaks (19) (see further sections for more information and examples of these packages). given the plethora of options for presenting and visualizing results, and its importance for effectively communicating with a wide audience, choosing the appropriate representation and visualization strategy can be challenging. recent work on this topic focuses on navigating through all the available visualization options by offering clear guidelines on how to turn large datasets into compelling and aesthetically appealing figures (20). a large array of software packages for performing phylogenetic and phylodynamic analyses have emerged in the last decade, in particularly for fast-evolving rna viruses [see (10) for a recent overview]. a more recent but similar trend can be seen for methodologies and applications aimed at visualization of the output of these frameworks. in addition to the need to communicate these outputs in a visual manner, an increasing recognition for the added value of adequate visualization for surveillance, prevention, control and treatment of viral infectious diseases has resulted into the merging of data analytics and visualization, with the visualization aspect being increasingly considered as an elementary component within all-round analysis platforms. this review illustrates the evolution in phylogenetically-informed visualization modalities for evolutionary inference and epidemic modeling based on viral sequence data, evolving from an initial purpose to serve basic interpretation of the results to an in-depth translation of complex information into usable data for virologists, researchers and public health officials alike. novel features and innovative approaches often stem from a community need, which can be translated into a specific challenge to be addressed by current and future software applications. throughout this article, we discuss some of the major bottlenecks for interpretation and visualization of phylodynamic results, and subsequently solutions that have addressed or can address these challenges. a closer inspection of how tools for manipulation, visualization and interpretation of evolutionary scenarios have steadily grown over time reveals different trends of interest. first, visualization needs for phylodynamic analyses are very heterogeneous in nature, driven by the intrinsic objective to better understand viral disease epidemiology. due to the increasing complexity and interactivity of the various aspects that make up phylodynamic analyses, the gradual change in visualization tools has resulted in a wide but incomplete range of solutions provided (illustrated by the wikipedia list of phylogenetic tree visualization software 1 ). software applications for phylodynamic analyses have extended into investigations of population dynamics over time, trait evolution and spatiotemporal dispersal, while still using a phylogenetic tree as their core concept. while we will focus predominantly on the concept of a phylogenetic tree as the backbone of phylodynamic visualization, these analyses also produce other types of output that go beyond visualizing phylogenies, especially when it comes to trait data reconstruction. second, the continuing advances in visualization-which try to keep up with increasing complexities in the statistical models employed-not only result in more features being available for end users to exploit, they may also come at an increased cost in terms of usability and responsiveness. formats for input and output files have increased in complexity, from simple text files to xml specifications and (geo)json file formats for geographical features. reading, understanding and editing such files may prove to be a challenging task for practitioners. however, most visualization tools do not expose these complexities to their users and offer an intuitive point-and-click interface and/or drag-and-drop functionality for customizing the visualization (18) . despite such intuitive interactivity, intricate knowledge and a certain amount of programming/scripting experience is often required for those users who want to customize and/or extend their visualization beyond what the application has to offer. third, visualization goals tend to become context-dependent in that not all phylodynamic analyses deal with the same sense of urgency, with established epidemics requiring different prevention and treatment strategies than outbreak detection and surveillance. for example, in established epidemics (e.g., hiv-1) thefocus may be on identifying (important) clusters within a very large phylogeny (17) , whereas analyses in ongoing outbreaks often determine whether newly generated sequences correspond to strains of the virus known to circulate in a certain region and try to establish spillover from animal reservoirs (21) . finally, despite the major achievements so far, visualization tools are reaching 1 https://en.wikipedia.org/wiki/list_of_phylogenetic_tree_visualization_software the limits of their capacity to comprehensibly present analysis results of large datasets. promising developments and strategies are becoming available that move visualization beyond the goal of communicating and synthesizing results, and actively play an important role in providing analytics to better understand evolutionary and demographic processes fueling viral dispersal and pathogenicity. phylogenetic tree visualizations have played a central role since the earliest evolutionary and molecular epidemiological analyses of fast-evolving viral pathogens. the first computer programs aimed at constructing phylogenies [e.g., paup * ; (22, 23) , and phylip; (24) ] were only equipped with minimal tree drawing and printing facilities, limited by the available operating systems and programming languages of that time. standalone, phylogenetically-oriented programs [e.g., must; (25) and later on treeview; (26)] were specifically developed to interact with tree reconstruction output and to ease tree editing and viewing. even as phylogenetic inference became inherently more sophisticated, for example with the development of bayesian phylogenetic inference and the release of initial versions of mrbayes (27) which contained sophisticated search strategies to ensure finding the optimal set of phylogenetic trees, these software packages still contained their own text-based tree visualization component(s). however, over time a wide range tree visualization software has been released, offering a continuous increase of tree visualization and manipulation functionalities. these packages have been developed as either standalone software packages or have been integrated into larger data management and analysis platforms [e.g., mega (28) ]. the numerous all-round programs available to date offer a range of similar basic tree editing capabilities including the coloring and formatting of tree nodes, edges and labels, the addition of numerical or textual annotations, searching for specific taxa as well as the re-rooting, rotation and collapsing of clades. different tree formats can be imported and again exported to various textual and graphical formats (e.g., vector-based formats: portable document format (pdf), encapsulated postscript (eps), scalable vector graphics (svg), . . . ). a limited set of applications provide more advanced visualization functionalities that enable interactive visualization and management of highly customized and annotated phylogenetic trees. nevertheless, major hurdles still exist that hinder adequate communication and interpretation of phylodynamic analyses. these hurdles mainly relate to the scalability of the visualization, highlighting uncertainty associated with the results and the interactive rendering of available metadata. recent innovative developments attempt to tackle these bottlenecks, although some tools are specifically directed toward addressing a single (visualization) challenge. we here provide an overview of such challenges, along with examples of figures generated by software packages that aim to tackle these challenges. note that all of our visualization examples are shown in the evolving visualization examples section below. first, a major challenge is the ever-increasing size of data sets being analyzed, leading to difficulties with navigating through the resulting phylogenetic trees and to problems with interpreting the inferred dynamics, not only from a computational perspective (e.g., to render large images in a timely manner) but also from the human capability to deal with high levels of detail. software packages that mainly aim to visualize phylogenetic trees as well as those that target more broad analyses have implemented various solutions to accommodate systematic exploration of large phylogenies. dendroscope (29) was one of the first visualization tools aimed at large phylogenies, with its own format to save and reopen trees that had been edited graphically, offering a magnifier functionality to focus on specific parts of the (large) phylogeny. follow-up versions (30) focused on rooted phylogenetic trees and networks, and offered parallel implementations of demanding algorithms for computing consensus trees and consensus networks to increase responsiveness. phylo.io (31) improves the legibility of large trees by automatically collapsing nodes so that an overview of the tree remains visible at any given time. itol [(18), but see below] and icytree (32) also provide intuitive panning and zooming utilities that make exploring large phylogenetic trees of many thousands of taxa feasible. the phylogeotool [(17); also see figure 4 ] eases navigation of large trees by performing an a priori iterative clustering of subtrees according to a predefined diversity ratio, as well as pre-rendering the visualization of those subtrees enabling fluent navigation. pastml (33) allows visualizing the tree annotated with reconstructed ancestral states as a zoomable html map based on the cytoscape framework (34) . pastview (35) offers synthetic views such as transition maps, integrates comparative analysis methods to highlight agreements or discrepancies between methods of ancestral annotations inference, and is also available as a webserver instance. grapetree (36) initially collapses branches if there are more than 20,000 nodes in the tree and then uses a static layout that splits the tree layout task into a series of sequential node layout tasks. with the development of many packages targetting the visualization of large phylogenies in recent years, the question arises whether they will continue to be maintained and extended with novel features. a second challenge lies with the fact that phylogenies represent hypotheses that encompass different sources of error, and the extent of uncertainty at different levels should be presented accordingly. bootstrapping (37) and other procedures are often used to investigate the robustness of clustering in estimated tree topologies,. numerical values that express the support of a cluster are generally shown on the internal nodes of a single consensus summary tree [e.g., figtree; (38) ] or by a customized symbol [e.g., itol; (18) ]. although conceptually different, posterior probabilities on a maximum clade credibility (mcc) tree, majority consensus tree or other condensed trees from the posterior set of trees resulting from bayesian phylogenetic inference can be shown in a similar manner. an informative and qualitative approach to represent the complete distribution of rooted tree topologies is provided by densitree [(39); also see figure 10 ], which draws all trees in a set simultaneously and transparently, and the different output visualizations highlight various aspects of tree uncertainty. for time-scaled phylogenetic trees, uncertainty in divergence time estimates of ancestral nodes (e.g., 95% highest posterior density (hpd) intervals) is usually displayed with a horizontal (node) bar (see figure 1 for an example). additionally, ancestral reconstructions of discrete or continuous trait states at the inner nodes of a tree are increasingly facilitated by various probabilistic frameworks, and these inferences are also accompanied by posterior distributions describing uncertainty. to visualize this uncertainty, pastml (33) inserts pie charts at inner nodes to show likely states when reconstructing discrete traits such as the evolutionary history of drug resistance mutations, while spread3 (40) is able to depict uncertainty of continuous traits, e.g., as polygon contours for (geographical) states at the inner nodes [see (40) for an example]. much like the visualization packages that focus on large phylogenies (see above), the applications listed here have their own specific focus with sometimes limited overlap in functionality. a third challenge consists of the visual integration of metadata with phylogenetic trees-often in the form of either a discrete and/or continuous trait associated with each sequence-which is in part related to the previous challenge concerning uncertainty of trait reconstructions. incorporating virus trait information (e.g., drug resistance mutations, treatment activity scores) or host characteristics (e.g., gender, age, risk group) in phylogenetic inference can substantially facilitate the interpretation for end users and accelerate the identification of potential transmission patterns. tree reconstruction and visualization software generally share a set of basic operations for coloring taxa, branches or clades according to partial or exact label matches. while these annotations can be performed manually using a graphical user interface, this can be timeconsuming and is prone to errors. hence, several software programs offer functionalities to automate the selection and annotation of clades of interest, for example through the use of javascript libraries [e.g., phyd3; (41), spread3; (40) ]also see figure 3 -or python toolkits [e.g., ete; (42), baltic; (43) ]. alternatively, drag-and-drop functionality of plain text annotation files generated with user-friendly text editors facilitate this process, as is for example the case in itol (18) . these scripting visualization frameworks also foster more intense tree editing through their functionalities to annotate inner nodes, clades and individual leaves with charts (pie, line, bar, heatmap, boxplot), popup information, images, colored strips and even multiple sequence alignments. even more advanced integration efforts entail the superimposition of tree topology with layers of information on geographical maps, such as terrain elevation, type of landcover and human population density [e.g., r package seraphim; (44, 45) ]. finally, visualization and accompanying interpretation are a critical component of infectious disease epidemiological and evolutionary analyses. indeed, many researchers use visualization software during analyses for data exploration, identifying inconsistencies, and refining their data set to ensure well-supported conclusions regarding an ongoing outbreak. as such, the visualizations themselves are gradually refined and improved over the course of a research project, with the final figures accompanying a publication often being post-processed versions of the default output of a visualization package or customly designed to attract a wide audience, both through the journal's website and especially social media [see e.g., (5) ]. on the other hand, the advent of one-stop platforms [microreact; (46) and nextstrain; (19, 47) , also see figure 5 ] that seamlessly connect the different steps of increasingly complex analyses and visualization of genomic epidemiology and phylodynamics allows automating this process. applications that are exclusively tailored toward tree manipulation and viewing are starting to offer management services and registration of user accounts [itol; (18) ], while command-line tools (gotree; https://github.com/evolbioinfo/gotree) aimed at manipulating phylogenetic trees and inference methods (pastml; (33) increasingly enable exporting trees that can directly be uploaded to itol, supporting the automation of scripting and analysis pipelines. in the previous sections, we have already covered a wide range of software packages for visualizing phylogenetic trees as well as their associated metadata, which may or may not be used in a joint estimation of sequence and trait data [for an overview of integrating these data types in various inference frameworks for pathogen phylodynamics, we refer to (9) ]. we here organize our visualization examples into different broader categories: different approaches toward visualizing associated trait data with a focus on phylogeography (figures 1-3) , browser-based online applications (figures 4, 5) , applications that use existing libraries such as those available in r, python and javascript for example (figures 6, 7) , non-phylogenetic visualizations typically associated with pathogen phylodynamics (figure 8) , and finally custom-written code or applications that focus on assessing phylogenetic uncertainty (figures 9, 10) . as a first example, we illustrate the development of innovative visualization software packages on the output of a bayesian phylodynamic analysis of a rabies virus (rabv) data set consisting of time-stamped genetic data along with two discrete trait characteristics per sequence, i.e., the sampling location-in this case the state within the united states from which the sample originated-and the bat host type. this rabv data set comprises 372 nucleoprotein gene sequences from north american bat populations, with a total of 17 bat species sampled between 1997 and 2006 across 14 states in the united states (52). we used beast 1.10 (51) in combination with beagle 3 (13) to estimate the time-scaled phylogenetic tree relating the sequences, along with inferring the ancestral locations of the virus using a bayesian discrete phylogeographic approach (53) and, at the same time, infer the history of host jumping using the same model approach. upon completion of the analysis, we constructed a maximum clade credibility (mcc) tree from the posterior tree distribution using treeannotator, a software tool that is part of the beast distribution. this mcc tree contains at its internal nodes the age estimates of all of the internal nodes, along with discrete probability distributions for the inferred location and host traits at those internal nodes. figure 1 shows the visualization of the mcc tree in figtree, with internal nodes annotated according to the posterior ancestral location state probabilities within the mcc tree file. as expected, one can observe that posterior support for the preferred ancestral location decreases from the observed tips toward the root, in other words the further we go back in time, the more uncertain the inferred location states become. all of the information required to make the figtree visualization in figure 1 is contained within a nexus file, containing all of the ancestral trait annotations, which we use as the (only) input for the figtree (38) . the standard newick file format itself does not contain such trait annotations but remains in popular use for storing phylogenetic trees and is hence supported by most (if not all) phylogenetic visualization packages. in general however, newick and other older formats (e.g., nexus) offer limited expressiveness for storing and visualizing annotated phylogenetic trees and associated data, which has lead to extensions for this format being proposed [e.g., the extended newick format; (54) ]. figtree allows users to upload annotation information for the sequences in the analyzed alignment in the form of a simple tabdelimited text file, and a parsimony approach can be used to infer the most parsimonious state reconstruction for the internal nodes from those provided for the tips. itol (18) is another application that can take an mcc tree as its input file and allows annotating branches and nodes of the phylogenetic tree using descriptions provided through the use of simple text files in which custom visualization options can easily be declared (figure 2) . itol is even suited for showing very large trees (with more than 10,000 leaves) with webkit-based browsers-such as chromium/google chrome, opera and safari-offering the best performance. newer input/output file formats for phylogenetic trees and their accompanying annotations, including the xml-based standards phyloxml (55) and nexml (56) , have the benefit of being more robust for complex analyses and easier to process and extend. in particular, applications of phylodynamics aimed at reconstruction and interpretation of spatio-temporal histories have become broadly and increasingly applied in viral disease investigations. the incorporation of geographical and phylogenetic uncertainty into molecular epidemiology dynamics is now well-established (53, 57) , and dedicated developments from a visualization perspective have soon followed to accommodate the outcomes of these models. early attempts include the mapping of geo-referenced phylogenetic taxa to their geographical coordinates [e.g., gengis; (58), cartographer; (59)], while more recent efforts of joint ancestral reconstruction of geographical and evolutionary histories enable visual summaries of spatial-temporal diffusion through the interactive cartographic projection using gis-and kml-based virtual globe software (60) . the latest developments generalize toward interactive web-based visualization of any phylogenetic trait history and are based on data-driven documents (d3) javascript libraries and the json format to store geographic and other tree-related information (40) . as an example, we have created a web-based visualization of our analyzed rabv data set by loading the obtained mcc tree into the spread3 figure 1 | figtree allows visualizing various tree formats, including maximum clade credibility trees from bayesian phylogenetic analyses (38) . external and internal nodes can easily be annotated using the information in the source tree file, and the time information within the tree allows adding a time axis which facilitates interpretation. annotations shown here for the rabv data set are the 95% highest posterior density (hpd) age intervals and the most probable ancestral location state at each internal node, with the circle width corresponding to the posterior support for the internal location state reconstruction. (40) phylodynamic visualization software package (see figure 3 ). spread3 actually consists of a parsing and a rendering module, with the former obtaining the relevant information out of the mcc tree and the latter converting this information into a (geo)json file format, potentially in combination with a geographic map, which can easily be downloaded from websites offering geojson files of different regions of the world and with different levels of detail. the generated output consists of an in-browser animation that allows tracking a reconstructed epidemic over time using a simple slider bar, with the possibility to zoom into specific areas of the map. in figure 3 , we show the reconstructed spread of rabv across the united states at four different time points throughout the epidemic, starting with the estimated location of origin in the state of arizona and tracking the rabv spread as it disperses to all of the 14 states in our data set. the spread3 visualization in figure 3 is an example of an increasing trend toward web-based software tools that can run in any modern browser, making them compatible with all major operation systems, without requiring any additional software packages to be installed by the user. a distinction can be made between browser-based tools that are able to work without internet access [phylocanvas; (http://phylocanvas.org), phylotree.js; (61), icytree; (32), spread3; (40), phylogeotool; (17), see figure 4 ] or that are only accessible online [itol; (18) , phylo.io; (31) ]. web-based visualization platforms enhance figure 2 | interactive tree of life [itol; (18) ] visualization of the mcc tree for rabv. rather than exploiting the annotations within an mcc tree, itol allows importing external text files with annotations through an easy drag-and-drop interface. we have here colored the tip nodes according to the bat host species (outer circle) as well as the sampling location (inner circle) corresponding to each sample. many visual aspects can be set this way and an extensive online help page is available. collaborations and output dissemination in a very efficient and simple manner through their ability to share web links of complex and pre-annotated tree visualizations. transferring genomic data and associated data to an online service may invoke privacy issues which is not the case for tools that execute data processing purely on the client side. by contrast, online accessible visualization tools such as itol (18) offer tree management possibilities to organize and save different projects, annotated datasets and trees for their users. these online packages typically also provide export functionalities to facilitate the production of publication-quality and high-resolution illustrations [see also mrent; (62), mesquite; (59)], directed toward end-users with minimal programming experience. spread3 also illustrates the growing movement toward animated visualizations over time and (geographic) space and as such focuses entirely on the visualization aspect of pathogen phylodynamics. recently, entire pipelines have emerged that include data curation, analysis and visualization components, with nextstrain as its most popular example (19) . on the data side, python scripts maintain a database of available sequences and related metadata, sourced from public repositories as well as github repositories and other (more custom-made) sources of genomic data. fast heuristic tools enable performing phylodynamic analysis including subsampling, aligning and phylogenetic inference, dating of ancestral nodes and discrete trait geographic reconstruction, capturing the most likely transmission events. the accompanying nextstrain website (https://nextstrain.org/) provides a continually-updated view of publicly available data alongside visualization for a number of pathogens such as west nile virus, ebola virus, and zika virus. for the latter virus, we provide the currently available data visualization in nextstrain (at time of submission) in figure 5 , showing a color-coded time-scaled maximum-likelihood tree alongside an animation of zika geographic transmissions over figure 3 | projecting an mcc tree onto a geographic map using spread3 (40) . in a discrete phylogeography setting, as is the case here, the ancestral location states are combined with coordinates corresponding to the states in the us from which the rabv samples were obtained. we use centroid coordinates for the us states to enable this visualization. spread3 animates the reconstructed virus dispersal over time, and we here show four snapshots (starting from the estimated origin of the epidemic at the root node) that capture the reconstructed dispersal over time and geographic space, i.e., in 1860, 1940, 1980, and the "present" (mid 2005) . the transitions between the us states are colored according to the us state of destination for that particular transition, whereas the size of the circles around a location is proportional to the number of lineages that maintain that location. time as well as the genetic diversity across the genome. analysis of such outbreaks relies on public sharing of data, and nextstrain has taken the lead to address data sharing concerns by preventing access to the raw genome sequences, and by clearly indicating the source of each sequence, while allowing derived data-such as the inferred phylogenetic trees-to be made publicly available. we note that these animated visualizations by their very nature do not easily yield publication-ready figures, requiring alternative approaches to be devised. animations resulting from software packages such as spread, spread3 and nextstrain can be hosted on the authors' website or they can be captured into a video file format and uploaded as supplementary materials onto the journal website. alternatively, screenshots of the animation can be taken at relevant time points throughout the visualization and subsequently post-processed to include in the main or supplementary publication text. finally, browser-based packages such as spread3 employ javascript libraries (e.g., d3) to produce dynamic, interactive data visualizations in web browsers, known specifically for allowing great control over the final visualization. custom programs are also typically written in r as a long list of popular r libraries are readily available, with ggplot2 quickly rising to popularity and finding use in both r and python languages. a system for declaratively creating graphics based on the grammar of graphics (63), ggplot2 was built for making professional looking figures with minimal programming efforts. figure 6 shows an example of ggtree, which extends ggplot2 and is designed for visualization and annotation of phylogenetic trees with their covariates and other associated data (48) . a recent software package that is implemented in javascript and python is pastml (33) , which uses the cytoscape.js library (64) for visualizing phylogenetic trees (figure 7) . given that these types of libraries contain many tried-and-tested functions that save substantial time when creating novel software packages, future visualization efforts are likely to see increased usage of readily available visualization libraries in programming languages such as r, python and javascript. phylogenies reconstructed from viral sequence data and their corresponding annotated tree-like drawings and animations lie at the heart of many evolutionary and epidemiological studies that involve phylogenomics and phylodynamics applications. additional graphical output can be generated using visualization packages that focus on other aspects than the estimated phylogeny, but that are however in some manner dependent on the phylogeny. coalescent-based phylodynamic models that connect population genetics theory to genomic data can infer the demographic history of viral populations (65) , and plots of figure 4 | the phylogeotool offers a visual approach to explore large phylogenetic trees and to depict characteristics of strains and clades-including for example the geographic context and distribution of sampling dates-in an interactive way (17) . a progressive zooming approach is used to ensure an efficient and interactive visual navigation of the entire phylogenetic tree. the effective population sizes over time-such as the one shown in figure 8 for our rabv data set, which uses the skygrid model (50) and its accompanying visualization in tracer (49)are commonly used to visualize the inferred past population size dynamics (50, 66, 67) . a variety of other summary statistics computed over the course of a phylogeny also benefit from visual representations, such as for the basic reproduction number and its rate of change as a function through time (68) . closely related are lineage-through-time plots (69) that allow exploring graphically the demographic signal in virus sequence data and revealing temporal changes of epidemic spread. neher et al. (70) plotted cumulative antigenic changes over time by integrating viral phenotypic information into phylogenetic trees of influenza viruses, thereby providing additional insights into the rate of antigenic evolution compared to representations of neutralization titers that are traditionally transformed into a lower-dimensional space (71, 72) . another example relates to reconstructions of phylogeographic diffusion in discrete space, where patterns of migration links are typically projected into a cartographic context, but quantitive measures are additionally computed including the expected number of effective location state transitions (known as "markov jumps"). information on migrations in and out of a location state can be obtained by visualizations of the number of actual jumps between locations as well as the waiting times for each location, either as a total or proportionally over time (73) (74) (75) (76) . the inference of transmission trees and networks ("who infected whom and when") using temporal, epidemiological and genetic information is an application of phylodynamics that has made substantial methodological progress in the last decade (77) (78) (79) . different from phylogenetic trees that represent evolutionary relationships between sampled viruses, transmission trees describe transmission events between hosts and require visualizations that are tailored to the analysis objectives (80) (81) (82) . consensus transmission trees, such as maximum parent credibility (mpc) trees (80) or edmonds' trees (83) , visually alert the user on putative infectors (indicated with arrows), corresponding infection times and potential superspreaders. (80) use the cytoscape framework (34) for drawing the transmission trees, and a similar adaptation of the original biological network-oriented framework has been done by pastml (33) (see above). finally, in order to compare two or more trees that are estimated from the same set of virus samples, but differ in the method used for tree construction or in the genomic region considered, tanglegrams provide insightful visualizations. the most popular use case is the comparison of two trees displayed leaf-by-leaf-wise with differences in clustering highlighted by lines connecting shared tips (84) . alternatively, tanglegrams allow mapping tree tip locations to mapped geographical locations using gengis (58, 85) . the python toolkit baltic (https://github.com/evogytis/baltic) provides functionalities to draw tangled chains, as shown in figure 9 , which are advanced sequential tanglegrams to compare a series of trees (43, 86) . the use of phylogenetic networks, which are a generalization of phylogenetic trees, can also visualize phylogenetic incongruences, which could be due to reticulate evolutionary phenomena such as recombination (e.g., hiv-1) and hybridization (e.g., influenza virus) events (30, 32, 87) . tanglegrams and related visualization of sets of trees [e.g., densitree (39); see figure 10 ] provide a qualitative and illustrative comparison of trees, buy this may prove to be less suited for the interpretation of extremely large trees or sets of trees. recent quantitative approaches allow the exploration and visualization of the relationships between trees in a multidimensional space of tree similarities, based on different treeto-tree distance metrics that identify a reduced tree space that maximally describe distinct patterns of observed evolution [mesquite; (88), r package treespace; (89, 90) ]. we have discussed a wide range of visualization packages for phylogenetic and phylodynamic analyses that allow improving our understanding of viral epidemiological and population dynamics. while these efforts may ultimately assist in informing public health or treatment decisions, visualization needs can differ according to the type of virus epidemics studied and questions that need to be answered. for example, the required level of visualization detail is high for (re-)emerging viral outbreaks when actionable insights should be obtained in a timely fashion in order to control further viral transmissions, figure 6 | r package ggtree (48) visualization of a phylogenetic tree constructed from publicly available zika virus (zikv) genomes. ggtree allows similar advanced customized visualization of phylogenetic trees as e.g., itol, but by means of the traditional r scripting language. in this figure, tree leaves are colored according to continent of sampling, with a size corresponding to the host status and shape indicating the completeness of the cds, using a cutoff of 99% of nucleotide positions being informative. a heatmap was added to denote the presence of amino acid mutations at three chosen genome positions. finally, a particular clade was highlighted in blue based on a given internal node and two additional links between chosen taxa were added. figure 6 . the top-down visualization corresponds to an iterative clustering starting from the root of the tree at the top, with the size of the dot corresponding to the number of taxa in a clade which share the same ancestral state which is indicated on top of the dot. in this type of visualization, a compressed representation of the ancestral scenarios is visualized that highlights the main facts and hides minor details by performing both a vertical and horizontal merge [but see (33) ]. the branch width corresponds to the number of times its subtree is found in the initial tree, and the circle size at a tip is proportional to the size of the compressed (or merged) cluster. with real-time tracking of viral spread and the identification of sources, transmission patterns and contributing factors being key priorities (91) . as a result, software packages that aim to address these questions are typically developed with an explicit emphasis on speed through the use of heuristics, and stress the importance of connectivity and interactivity to quickly respond to the availability of new data in order to develop novel insights into an ongoing epidemic. one-stop and fullyintegrated analysis platforms such as microreact (46) and nextstrain (19) adhere to these needs by providing the necessary visualizations of virus epidemiology and evolution across time and space, and by implementing support for collaborative analyses and sharing of genomic data and analysis outputs. a strategy of interest in these settings is the ability for phylogenetic placement of novel sequence data (92, 93) , for example when updated outbreak information suggests specific cases should be investigated but the reconstruction of a new phylogeny is not desirable, as this may prove too time consuming. to avoid such de novo re-analyses of data sets, software tools such as itol (18) and phylogeotool (17) offer functionalities to visualize placements of sequence data onto an existing phylogeny. a key future challenge of these approaches is to assess and visualize the associated phylogenetic placement uncertainty, or if this information would be unavailable to at least indicate the various stages in which novel sequences were added onto the (backbone) phylogeny. while methodological developments are rigorous in their accuracy assessment-for example through simulation studies-and may even provide visual options for representing the placement uncertainty [see e.g., (92) ], visualization packages themselves do not offer an automated way of assessing or conveying this information and as such may project overconfidence of the power of the phylogenetic placement method used. additionally, other flexible visualization options based on real-time outbreak monitoring can be of great interest such as highlighting locations from which cases have been reported but for which genomic data are still lacking, to clarify the potential impact of these missing data on the currently available inference results. investigations of more established epidemics usually involve much larger sample sizes, are more retrospective-oriented in (49) . this type of output does not directly depend upon the estimated mcc tree, but rather on the estimated (log) population sizes of the skygrid model (50) , which are provided in a separate output file by beast (51) . design and incorporate more heterogeneous information, and therefore benefit from more extended visualization frameworks. for most of these globally prevalent pathogens, clinical and phenotypic information is often available and questions relate to the population-or patient-level dynamics of viral adaptation and the identification of transmission clusters. for example, the selection of the virus strain composition of the seasonal influenza vaccine is informed by analyses and visualizations of circulating strains and their antigenic properties using the nextflu framework (47, 91) . other diverse examples include investigations of the impact of country-specific public health interventions on transmission dynamics (94, 95) , the identification of distinctive socio-demographic, clinical and epidemiological features associated with regional and global epidemics (96) (97) (98) (99) and large-scale modeling of epidemiological links among geographical locations (100) (101) (102) . in these settings, relevant software packages should consider the scalability of large phylogenies and allow user-friendly exploration of heterogeneous and customized annotations. overall, it is anticipated that future work on visualization tools, accompanying analysis and visualization software developments as described above, will result in a merging of these two epidemic perspectives, with the development of context-independent visualization software tools that can handle both scenarios equally well. viral pathogens, in particular rna viruses, have been responsible for epidemics and recurrent outbreaks associated with high morbidity and mortality in the human population, for a duration that can span from hundreds of years [e.g., hcv (103) and denv (104) ] to decades [e.g., hiv-1 (3)]. rna viruses are known for their potential to quickly adapt to host and treatment selective pressure, but their rapid accumulation of genomic changes also provides opportunities to study their population and transmission dynamics in high resolution. consequently, the fields of phylogenomics and phylodynamics play a pivotal role in studies on epidemiology and transmission of viral infectious diseases, and have advanced our understanding of the dynamical processes that govern virus dispersal and evolution at both population and host levels. compared to the tremendous achievements in the performance of evolutionary and statistical inference models and hypothesis testing frameworks, software packages and resources aimed at visualizing the output of these studies have experienced difficulties to handle the increasing complexity and sizes of the analyses, for example to display levels of uncertainty and to integrate associated demographic and clinical information. accurate and meaningful visual representation and communication are however essential tools for the interpretation and translation of outcomes into actionable insights for the design of optimal prevention, control and treatment interventions. with a plethora of applications for phylodynamics having been introduced in the last decades, in particular tailored toward reconstructions of spatiotemporal histories-which start to become useful in public health surveillance-visualization has substantially grown as an elementary discipline for investigations of infectious disease epidemiology and evolution. an extensive array of software and tools for the manipulation, editing and annotation of output visualizations in the field of pathogen phylodynamics is available to date, characterized by varying technical specifications and functionalities that respond to heterogeneous needs from the research and public health communities. the increasing recognition for visualization tools in support of viral outbreak surveillance and control has stimulated the advent of more complex and fully integrated frameworks and platforms, all the while focusing on user experience and ease of customisation. we anticipate that future visualization developments will take further leaps in this ongoing trend by tackling remaining challenges to display increasing amounts of dense information in a human-readable manner and introducing concepts from new disciplines such as visual analytics. in particular, high expectations are stemming from the ensemble of visualization methods that allow users to work at, and move between, focused and contextual views of a data set (105) . large scientific data sets with a temporal aspect have been the subject of multi-level focus+context approaches for their interactive visualization (106) , which minimize the seam between data views by displaying the focus on a specific situation or part of the data within its context. these approaches are part of an extensive series of interface mechanisms used to separate and blend views of the data, such as overview+detail, which uses a spatial separation between focused and contextual views, and zooming, which uses a temporal separation between these views (105) . phylogenetic trees can be interactively visualized as three-dimensional stacked representations (107). the field of phylogenomics and phylodynamics visualizations will increasingly implement and adapt technologies from other disciplines, as already illustrated by tools and studies using the network-oriented cytoscape package (33, 34, 78) , or through the use of virtual reality technologies including customizable mapping frameworks and high-performance geospatial analytical toolboxes. as such, concomitant to the ongoing developments figure 9 | tanglegrams are typically shown in a side-by-side manner, in order to easily and visually identify differences in clustering between two or more phylogenetic trees, for example when inferred from different influenza proteins (pb1, pb2, pa, ha, np, na, m1, and ns1). such a series of trees can also be visualized in a circle facing inwards with a particular isolate highlighted in all plotted phylogenies (left figure) , or with all isolates interconnected between all proteins (right figure). figure 10 | bayesian phylogenetic inference software packages generate a large number of posterior trees, potentially annotated with inferred ancestral traits. this collection of trees is often summarized using a consensus tree, allowing to plot a single tree with posterior support values on the internal nodes. densitree enables drawing all posterior trees in the collection; areas where a lot of the trees agree in topology and branch lengths show up as highly colored areas, while areas with little agreement show up as webs (39) . we refer to figure 2 for the color legend of the host species, as the legend drawn by densitree was not very readable and could not be edited (in terms of its textual information). in sample collection and sequencing, the design of more complex analytical inference models and powerful hardware infrastructure will be complemented by a new era in visualization applications that will collaboratively foster visualizations that track virus epidemics and outbreaks in real-time and with high resolution. an initial but already comprehensive list of publications was compiled from backward and forward citation searches of the various visualization software packages the authors have (co-)developed, as well as those packages that the authors have used throughout their academic career. complementing this already extensive list, we searched pubmed and google scholar, which keeps track of arxiv and biorxiv submissions and hence decreased the risk of missing potential publications. additional supplementary searches have been performed by backward and forward citation chasing of all of the included references throughout the writing process of writing the manuscript for the initial submission on april 7th 2019. no date restrictions were applied, but only visualization packages and publications written in english were considered. kt wrote the manuscript. pl helped with the interpretation and writing. a-mv gave the idea, helped with the interpretation and writing. gb wrote the manuscript and prepared the visualizations. phylodynamic applications in 21st century global infectious disease research. glob health res policy phylodynamic assessment of intervention strategies for the west african ebola virus outbreak hiv epidemiology. the early spread and epidemic ignition of hiv-1 in human populations genomic and epidemiological monitoring of yellow fever virus transmission potential virus genomes reveal factors that spread and sustained the ebola epidemic science forum: improving pandemic influenza risk assessment enhanced use of phylogenetic data to inform public health approaches to hiv among men who have sex with men unifying the epidemiological and evolutionary dynamics of pathogens emerging concepts of data integration in pathogen phylodynamics recent advances in computational phylodynamics realtime, portable genome sequencing for ebola surveillance adaptive mcmc in bayesian phylogenetics: an application to analyzing partitioned data in beast beagle 3: improved performance, scaling and usability for a highperformance computing library for statistical phylogenetics on the origin of species by means of natural selection fast, accurate and simulation-free stochastic mapping data visualization literacy: definitions, conceptual frameworks, exercises, and assessments phylogeotool: interactively exploring large phylogenies in an epidemiological context interactive tree of life (itol): an online tool for phylogenetic tree display and annotation nextstrain: real-time tracking of pathogen evolution fundamentals of data visualization metagenomic sequencing at the epicenter of the nigeria 2018 lassa fever outbreak a fast method for approximating maximum likelihoods of phylogenetic trees from nucleotide sequences phylogenetic analysis using parsimony (*and other methods) phylip -phylogeny inference package (version 3.2) tree view: an application to display phylogenetic trees on personal computers mrbayes 3.2: efficient bayesian phylogenetic inference and model choice across a large model space mega7: molecular evolutionary genetics analysis version 7.0 for bigger datasets dendroscope: an interactive viewer for large phylogenetic trees dendroscope 3: an interactive tool for rooted phylogenetic trees and networks io: interactive viewing and comparison of large phylogenetic trees on the web icytree: rapid browser-based visualization for phylogenetic trees and networks a fast likelihood method to reconstruct and visualize ancestral scenarios cytoscape: a software environment for integrated models of biomolecular interaction networks pastview: a user-friendly interface to explore evolutionary scenarios grapetree: visualization of core genomic relationships among 100,000 bacterial pathogens confidence limits on phylogenies: an approach using the bootstrap densitree: making sense of sets of phylogenetic trees spread3: interactive visualization of spatiotemporal history and trait evolutionary processes phyd3: a phylogenetic tree viewer with extended phyloxml support for functional genomics data visualization ete 3: reconstruction, analysis, and visualization of phylogenomic data seraphim: studying environmental rasters and phylogenetically informed movements explaining the geographic spread of emerging epidemics: a framework for comparing viral phylogenies and environmental landscape data microreact: visualizing and sharing data for genomic epidemiology and phylogeography nextflu: real-time tracking of seasonal influenza virus evolution in humans two methods for mapping and visualizing associated data on phylogeny using ggtree posterior summarization in improving bayesian population dynamics inference: a coalescent-based model for multiple loci bayesian phylogenetic and phylodynamic data integration using beast 1.10 host phylogeny constrains cross-species emergence and establishment of rabies virus in bats bayesian phylogeography finds its roots extended newick: it is time for a standard representation of phylogenetic networks phyloxml: xml for evolutionary biology and comparative genomics nexml: rich, extensible, and verifiable representation of comparative data and metadata phylogeography takes a relaxed random walk in continuous space and time gengis: a geospatial information system for genomic data cartographer, a mesquite package for plotting geographic data spread: spatial phylogenetic reconstruction of evolutionary dynamics js -a javascript library for application development and interactive data visualization in phylogenetics mrent: an editor for publication-quality phylogenetic tree illustrations the grammar of graphics (statistics and computing) js: a graph theory library for visualisation and analysis origins of the coalescent genie: estimating demographic history from molecular phylogenies smooth skyride through a rough skyline: bayesian coalescent-based inference of population dynamics birth-death skyline plot reveals temporal changes of epidemic spread in hiv and hepatitis c virus (hcv) inferring population history from molecular phylogenies prediction, dynamics, and visualization of antigenic phenotypes of seasonal influenza viruses mapping the antigenic and genetic evolution of influenza virus dengue viruses cluster antigenically but not as discrete serotypes unifying viral genetics and human transportation data to predict the global transmission dynamics of human influenza h3n2 counting labeled transitions in continuoustime markov models of evolution global migration dynamics underlie evolution and persistence of human influenza a (h3n2) phylodynamics of h1n1/2009 influenza reveals the transition from host adaptation to immune-driven selection bayesian reconstruction of disease outbreaks by combining epidemiologic and genomic data using genomics data to reconstruct transmission trees during disease outbreaks inferring hiv-1 transmission networks and sources of epidemic spread in africa with deep-sequence phylogenetic analysis epidemic reconstruction in a phylogenetics framework: transmission trees as partitions of the node set relating phylogenetic trees to transmission trees of infectious disease outbreaks a bayesian approach for inferring the dynamics of partially observed endemic infectious diseases from space-time-genetic data simultaneous inference of phylogenetic and transmission trees in infectious disease outbreaks reassortment between influenza b lineages and the emergence of a coadapted pb1-pb2-ha gene complex host ecology determines the dispersal patterns of a plant virus mers-cov recombination: implications about the reservoir and potential for adaptation tanglegrams for rooted phylogenetic trees and networks mesquite: a modular system for evolutionary analysis mapping phylogenetic trees to reveal distinct patterns of evolution treespace: statistical exploration of landscapes of phylogenetic trees real-time analysis and visualization of pathogen sequence data pplacer: linear time maximumlikelihood and bayesian phylogenetic placement of sequences onto a fixed reference tree a format for phylogenetic placements tracing the impact of public health interventions on hiv-1 transmission in portugal using molecular epidemiology the effect of interventions on the transmission and spread of hiv in south africa: a phylodynamic analysis the global origins of resistanceassociated variants in the non-structural proteins 5a and 5b of the hepatitis c virus the global spread of hepatitis c virus 1a and 1b: a phylodynamic and phylogeographic analysis hiv-1 infection in cyprus, the eastern mediterranean european frontier: a densely sampled transmission dynamics analysis from 1986 to 2012 sub-epidemics explain localized high prevalence of reduced susceptibility to rilpivirine in treatment-naive hiv-1-infected patients: subtype and geographic compartmentalization of baseline resistance mutations phylogenetic analysis reveals the global migration of seasonal influenza a viruses the impact of migratory flyways on the spread of avian influenza virus in north america spatiotemporal characteristics of the largest hiv-1 crf02ag outbreak in spain: evidence for onward transmissions evolutionary analysis provides insight into the origin and adaptation of hcv the origin, emergence and evolutionary genetics of dengue virus a review of overview+detail, zooming, and focus+context interfaces a four-level focus+context approach to interactive visual analysis of temporal features in large scientific data we are grateful to gytis dudas for providing a figure from his baltic visualization package (https://github.com/evogytis/baltic). we thank simon dellicour for fruitful discussions. the authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.copyright â© 2019 theys, lemey, vandamme and baele. this is an open-access article distributed under the terms of the creative commons attribution license (cc by). the use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. no use, distribution or reproduction is permitted which does not comply with these terms. key: cord-259178-2opfkm7l authors: gao, ya; yang, kelu; liu, ming; chen, yamin; shi, shuzhen; yang, fengwen; tian, jinhui title: research collaboration and outcome measures of interventional clinical trial protocols for covid-19 in china date: 2020-09-02 journal: front public health doi: 10.3389/fpubh.2020.554247 sha: doc_id: 259178 cord_uid: 2opfkm7l background: research collaboration of registered clinical trials for coronavirus disease 2019 (covid-19) remains unclear. this study aimed to analyze research collaboration and distribution of outcome measures in registered interventional clinical trials (icts) of covid-19 conducted in china. methods: the international clinical trials registry platform, china clinical trials registry, and clinicaltrials.gov were searched to obtain covid-19-registered icts up to may 25, 2020. excel 2016 was used to perform a descriptive statistical analysis of the extracted information. vosviewer 1.6.14 software was used to generate network maps for provinces and institutions and create density maps for outcomes. results: a total of 390 icts were included, and the number of daily registrations fluctuated greatly. from 29 provinces in china, 430 institutions contributed to the registration of icts. the top three productive provinces were hubei (160/390, 41.03%), shanghai (60/390, 15.38%), and beijing (59/390, 15.13%). the top three productive institutions were tongji hospital, tongji medical college, huazhong university of science and technology (30/390, 7.69%), zhongnan hospital of wuhan university (18/390, 4.62%), and wuhan jinyintan hospital (18/390, 4.62%). collaborations between provinces and institutions were not close enough. there were many interventions, but many trials did not provide specific drugs and their dosage and treatment duration. the most frequently used primary outcome was chest/lung ct (53/390, 13.59%), and the most frequently used secondary outcome was hospital stay (33/390, 8.46%). there was a large difference in the number of outcomes, the expression of some outcomes was not standardized, the measurement time and tools for some outcomes were not clear, and there was a lack of special outcomes for trials of traditional chinese medicine. conclusions: although there were some collaborations between provinces and institutions of the current covid-19 ict protocols in china, cooperation between regions should be further strengthened. the identified deficiencies in interventions and outcome measures should be given more attention by future researchers of covid-19. the severe acute respiratory syndrome coronavirus 2 (sars-cov-2), a novel enveloped rna betacoronavirus, has the characteristics of fast spread and strong infectivity (1) (2) (3) . in late december 2019, the coronavirus disease 2019 (covid-19) caused by sars-cov-2 first appeared, and it then quickly spread to various countries (4) (5) (6) . on march 11, 2020 , the world health organization (who) declared the outbreak of sars-cov-2 as a pandemic (7) . as of july 12, 2020, a total of 12,552,765 confirmed cases were reported worldwide, including 561,617 deaths (8) . to find an effective drug to treat covid-19, medical workers and scientific researchers actively carry out research and have registered numerous clinical trials. recently, scholars have assessed the characteristics and status quo of registered covid-19 clinical trials (9, 10) . however, no research has focused on the research collaboration of these registered clinical trials. this study was designed to evaluate the cooperation between institutions and the distribution of outcome measures in registered interventional clinical trials (icts) of covid-19 conducted in china, to provide a reference for future researchers to register and carry out covid-19 clinical trials. we included registered icts of covid-19 that conducted in china without restricting the types of interventions, comparisons, and outcomes. we excluded trials conducted outside china. studies of basic science, diagnostic test, and epidemiological research as well as duplication and retracted records were also excluded. two researchers (y.g. and k.l.y.) independently reviewed the records and screened out eligible icts according to the inclusion and exclusion criteria, and then proceeded to a cross-check. (y.g., k.l.y., or m.l.) extracted data from the included icts using the pre-defined form and a second reviewer (f.w.y, or j.h.t.) checked the extracted data. the detailed data included: registration number, registration time, title, inclusion criteria, exclusion criteria, gender and age of the population, sample size, provinces, institutions, interventions, primary outcomes, and secondary outcomes. for institutions, interventions, and outcomes with different expressions, we have processed them, leaving only a standardized name. microsoft excel 2016 (microsoft corp, redmond, wa, www.microsoft.com) was used to perform descriptive statistical analysis of the extracted information. vosviewer 1.6.14 (leiden university, leiden, netherlands) software was utilized to extract provinces and institutions and generate corresponding cooperation network maps. furthermore, we created density maps for high-frequency primary and secondary outcome measures. in this study, the nodes in the network map represented the analyzed elements (provinces and institutions), the size of the nodes reflected the frequency of elements, the colors of nodes and lines represented different clusters, and the links between nodes indicated the relationship of cooperation or co-occurrence (11) (12) (13) (14) . the parameters of the vosviewer were as follows: counting method (fractional counting), ignore documents with many authors (maximum number of authors per document is 25). a total of 3,541 records were retrieved through the systematic literature search, and 1,159 were non-interventional trials. after reading the detailed registration information, we further excluded 1,992 records for the following reasons: trials conducted outside china (n = 1,336), duplicate records (n = 609), retracted/terminated trials (n = 47). finally, 390 icts were included for analysis. the flowchart of the screening process is provided in figure s1 . the number of daily covid-19 ict registrations fluctuated considerably, and the maximum number of registrations per day was 13 (figure 1) . six (1.54%) icts incorporated only males, and the remaining 384 (98.46%) icts included both males and females. a total of 74.87% of icts included adults (18 years and older), but 59 (15.13%) icts did not report the age of the included population. the total sample size of the 390 icts was 109,372, and the smallest sample size was only four; the maximum was 20,000, and the median was 100. a total of 29 provinces participated in the registration of covid-19 icts. the number of icts conducted by one, two, three, four, five, and six provinces were 304/390 (77.95%), 61/390 (15.64%), 12/390 (3.08%), 4/390 (1.03%), 6/390 (1.54%), and 3/390 (0.77%), respectively. the top five productive provinces were hubei . the remaining provinces participated in the registration of fewer than six icts, the detailed information is presented in table 1 . a social network analysis of provinces revealed that 26 provinces formed a cooperative relationship. hubei, located in the center of the network, had more collaborations with other provinces. shanxi, fujian, hainan, and guizhou were situated on the edge of the network and had little cooperation with other provinces. xinjiang, jilin, and hong kong did not cooperate with other provinces (figure 2 ). a total of 430 institutions contributed to the registration of covid-19 icts. the number of icts conducted by one, two, three, four, five, six, seven, eight, nine, and more than nine institutions were 228/390 (58.46%), 78/390 (20.00%), 27/390 (6.92%), 15 table 2 . a cluster analysis was performed for institutions that participated in more than four icts. a total of 32 institutions have established cooperative relations and formed six clusters (figure 3) . the largest cooperative team consisted of nine hospitals and research institutions. the smallest team only included three institutions. there was relatively more cooperation between institutions within the team. however, collaboration between different teams was sparse. there were various types of interventions. commonly used western medicines included lopinavir/ritonavir (34 times), mesenchymal stem cells (21 times), interferon α (18 times), chloroquine phosphate (15 times), favipiravir (14 times), sars-cov-2 inactivated/convalescent plasma (10 times), arbidol (10 times), thymosin (eight times), tocilizumab (seven times), hydroxychloroquine sulfate (six times), and arbidol hydrochloride (six times). other western medicines were used less than six times, such as azvudine, hydroxychloroquine, ritonavir, and remdesivir. a total of 125/390 (32.05%) icts focused on traditional chinese medicine or integrated traditional chinese and western medicine, of which 55/390 (14.10%) icts mentioned traditional chinese medicine treatment, traditional chinese medicine syndrome differentiation treatment, or integrated traditional chinese and western medicine treatment, but they did not provide specific names of medicine. among icts that provided the specific chinese medicine, drugs that appeared more than once included honeysuckle decoction/oral liquid (four times), xiyanping injection (four times), shuanghuanglian oral liquid (three times), lianhua qingwen capsules/granules (figure 4 ). figure 5 shows the primary outcome measures with frequencies greater than two times, which includes 51 outcomes on the map. as shown in figure 5 and table 3 of the 390 icts, 279 (71.54%) icts have secondary outcomes. figure 6 shows the secondary outcome measures with frequencies greater than two times, which includes 49 outcomes on the map. a total of 29 provinces from china contributed to the registration of covid-19 icts, of which 55.17% provinces participated in < 10 icts, while hubei province participated in 160 icts, indicating that icts registrations were mainly concentrated in a few provinces. through the network analysis of provinces, we found that hubei and beijing had more collaborations with other provinces, but the collaborations between the remaining provinces were not close. a total of 430 institutions participated in the registration of covid-19 icts, but only 26 institutions participated in the registration of more than five icts, and 80.93% of the institutions contributed to only one or two icts. the productive institutions formed six cooperative teams and the number of institutions within the teams did not exceed nine. the cooperation between institutions within each team was relatively close, but cooperation between different teams was sparse. therefore, future researchers should strengthen more comprehensive and extensive cooperation between different provinces and different regions. through the analysis of the sample size, we found that the sample size of 26.67% icts was lower than 50. some icts only included 10 patients, which were inadequate. 12.82% of icts had a sample size > 300, with the maximum sample size up to 20,000, but the sample size of some icts was too large to be performed in just one institution, as the sample size far exceeds the total number of patients in their region. however, they did not carry out cross-institutional and cross-regional cooperation. besides, patients before the trial should be ruled out, which shows that it is difficult to complete the trial according to the research protocol. this also shows that it is necessary to strengthen cooperation and exchanges and carry out multi-center research. in clinical trials, many strategies have been tried to treat covid-19. although there is no specific drug for covid-19 (15), the drug used in clinical trials should also be carefully chosen to avoid additional damage to the patient's health. the commonly studied western medicines included lopinavir/ritonavir, mesenchymal stem cells, interferon α, chloroquine phosphate, hydroxychloroquine sulfate, favipiravir, and arbidol. however, the sample sizes of many trials were insufficient, and the usage, dosage, and treatment course of drugs were unclear, which may lead to a lack of credibility in the results of the research. therefore, future researchers should conduct large-scale, multi-center clinical trials, rather than repeating trials for an intervention, to avoid wasting resources. of the 125 icts concerned with traditional chinese medicine or integrated traditional chinese and western medicine, about 45.00% of the trials did not provide specific names and usages of traditional chinese medicine. besides, the most commonly used control was the usual treatment, but most icts did not provide specific content of the usual treatment. future trial registers and reviewers of registry platforms should pay more attention to these aspects to promote the registration of covid-19 clinical trials more standardized. some icts only adopted one primary outcome measure, and some icts had more than 12 primary outcome measures, which indicated that there was a considerable difference in the number of primary outcomes. chest/lung ct, time of viral nucleic acid turning negative, the incidence of adverse events, clinical improvement time, mortality, and hospital stay were among the top 10 primary outcomes, as well as among the top ten secondary outcomes, indicating that these six outcome measures were key outcomes in this field. future researchers can use these measures when conducting covid-19 clinical trials. this study found that there are some problems with the outcome measures: (1) there were too many types of indicators and lack of main outcome measures, which added difficulties to the development of systematic reviews and guidelines; (2) the expression of outcome measures was not standardized, and there were multiple expression terms for the same measure; (3) the definitions of outcome measures were not clear, and many outcome measures were ambiguous; (4) most icts did not clarify the time of follow-up and the measurement time of the outcomes; (5) the selected outcome measures cannot fully reflect the expected research results; (6) regarding outcomes that need to be measured, most icts did not provide measurement tools; and (7), considering icts that focused on the traditional chinese medicine and integrated traditional chinese and western medicine, there was a lack of outcome measures with characteristics of traditional chinese medicine. these shortcomings need to be further improved for future clinical trials of covid-19. we conducted a comprehensive analysis of the registered icts of covid-19 conducted in china using the bibliometric analysis method and presented collaborations of provinces and institutions, and the distribution of outcome measures by using visual network maps and density maps. however, this study also has some limitations. firstly, only icts from china were included, and many clinical trials will be registered in the future, which cannot fully reflect the status of all clinical trials and may not apply to icts in other countries. secondly, since some institutions, interventions, and outcomes have different expressions, although we have standardized them, bias may still exist. thirdly, some registered icts may not provide all participating institutions, resulting in the results of this study may differ from the actual situation. finally, since this study was based on data of registered icts, we did not explore the effectiveness of the interventions and outcome measures. further studies are needed to assess whether the registered icts have been completed and whether the interventions and outcome measures studied are effective. during the covid-19 pandemic, we are very pleased that scholars from all over the world are actively conducting clinical trials to explore effective drugs for the treatment of covid-19. however, our study found that the registered icts had many defects in methods and results. therefore, future researchers should optimize the methods of these trials and ensure the transparency of their methods to produce high-quality evidence. otherwise, it will not only result in a waste of resources and property, but more importantly, mislead the measures to deal with covid-19 and delay treatment for patients. furthermore, researchers should facilitate the completion of these clinical trials and translate the results of these trials into practices and policies. clinical characteristics of coronavirus disease 2019 in china clinical characteristics of 113 deceased patients with coronavirus disease 2019: retrospective study early transmission dynamics in wuhan, china, of novel coronavirus-infected pneumonia clinical and microbiological effect of a combination of hydroxychloroquine and azithromycin in 80 covid-19 patients with at least a six-day follow up: a pilot observational study a novel coronavirus from patients with pneumonia in china nowcasting and forecasting the potential domestic and international spread of the 2019-ncov outbreak originating in wuhan, china: a modelling study who-director-general-s-opening-remarks-at-the-mediabriefing-on-covid coronavirus disease (covid-2019) situation reports clinical trial analysis of 2019-ncov therapy registered in china analysis on clinical study protocols of traditional chinese medicine for coronavirus disease global trends and future prospects of e-waste research: a bibliometric analysis bibliometric analysis of global research on pd-1 and pd-l1 in the field of cancer global hotspots and future prospects of chimeric antigen receptor t-cell therapy in cancer research: a bibliometric analysis study of acupuncture for low back pain in recent 20 years: a bibliometric analysis via citespace a review of sars-cov-2 and the ongoing clinical trials the authors thank all investigators and supporters involved in this study. the supplementary material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fpubh. 2020.554247/full#supplementary-material figure s1 | the flowchart of the screening process. the authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.copyright © 2020 gao, yang, liu, chen, shi, yang and tian. this is an open-access article distributed under the terms of the creative commons attribution license (cc by). the use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. no use, distribution or reproduction is permitted which does not comply with these terms. key: cord-356314-mhkhey2w authors: alyami, mohammad h.; naser, abdallah y.; orabi, mohamed a. a.; alwafi, hassan; alyami, hamad s. title: epidemiology of covid-19 in the kingdom of saudi arabia: an ecological study date: 2020-09-17 journal: front public health doi: 10.3389/fpubh.2020.00506 sha: doc_id: 356314 cord_uid: mhkhey2w objectives: considering the transmissible nature of covid-19 it is important to explore the trend of the epidemiology of the disease in each country and act accordingly. this study aimed to examine the trend of covid-19 epidemiology in the kingdom of saudi arabia in term of its incidence rate, recovery rate, and mortality rate. material and methods: we conducted an observational study using publicly available national data taken from the saudi ministry of health for the period between 3 march and 7 june 2020. the number of newly confirmed cases, active cases, critical cases, percentage of cases stratified by age group [adults, children, and elderly] and gender were extracted from the reports of the saudi ministry of health. results: during the study period, the total number of confirmed cases with covid-19 rose from one on 2 march 2020 to 101,914 on 7 june, representing an average of 1,039 new cases per day, [trend test, p < 0.000]. despite the increase in the number of newly confirmed daily cases of covid-19, the number of reported daily active cases started to stabilize after 2 months from the start of the pandemic in the country and the overall recovery rate was 71.4%. the mortality rate decreased by 6.4% during the study period. covid-19 was more common among adults and males compared to other demographic groups. conclusion: the epidemiological status of covid-19 in the kingdom of saudi arabia showing promising improvement. males and adults accounted for the majority of covid-19 cases in the ksa. further studies are recommended to be conducted at the patient level to identify other patient groups who are at higher risk of getting infected with covid-19, and for whom the best pharmacological intervention could be provided. the novel coronavirus disease 2019 (covid-19) was first isolated from biological samples in wuhan, china, in december 2019. the virus was identified as a member of the genus betacoronavirus, grouping it with severe acute respiratory syndrome (sars) and middle east respiratory syndrome (mers) (1) . the virus spread internationally within 1 month of first being identified, being transmitted via close human-to-human contact (2) . the world health organization (who) declared covid-19 (sars-cov-2) a public health emergency of international concern on 1 february 2020. over 200 countries have confirmed cases to date, including countries from asia, europe, north america and the middle east. the ongoing explosive spread of covid-19 and the new hotspots beyond the first city of wuhan, especially in the united states (us), russia, united kingdom (uk), italy, spain, brazil, and its introduction to the middle eastern countries calls for additional regional actions to stem its further spread (3) . for the first time in the eight decades of the muslim pilgrimage to the holy sites in the kingdom of saudi arabia (ksa), on 27 february 2020, ksa placed restrictions on inbound umrah pilgrimage, placed a ban on inbound travel of persons coming from covid-19-affected countries and restrictions on travel of gulf cooperation council (gcc) citizens who have traveled to covid-19-affected countries. by 7 june 2020, the number of persons infected by the virus in the ksa has reached more than 100,000 and saudi authorities have reported 283 deaths from the virus, most of which were in the main cities including mecca, riyadh, jeddah, and medina (4) . the global outbreak of covid-19 has been a matter of international concern as the disease is spreading very fast. considering the transmissible nature of the disease, which has had a massive impact worldwide, there is a crucial need to explore the trend of the epidemiology of the disease in the ksa. this will help clinicians to establish risk stratification of covid-19 patients as early as possible, calling on the community to pay more attention to defending the more susceptible groups from the virus in order to decrease its prevalence. due to differences in the physiological structure of women and men, gender differences play an indisputable role in the pandemic of the disease (5) . also, aging is connected with a number of variations in pulmonary physiology, pathology and function, throughout the period of lung infection. the age-related alterations in sensitivity and tolerance may lead to an increased rate of death in aged people (6) . to the best of our knowledge, there is no previous study that has investigated the characteristics of the epidemiology of covid-19 in the ksa. this study aimed to examine the trend of covid-19 epidemiology in the ksa in term of its incidence rate, recovery rate, and mortality rate. in addition, this study aimed to explore the gender and age differences in term of the epidemiology of the disease, and the trend of covid-19 mortality. this was a secular trend study using publicly available national data taken from the saudi ministry of health for the period between 2 march and 7 june 2020 (7, 8) . the saudi ministry of health provided detailed data on the incidence of covid-19 in the kingdom daily, with the following details: (a) the number of newly confirmed cases, (b) number of active cases, (c) number of critical cases, (d) percentage of cases stratified by age group [adults, children, and elderly] (available from 2 may until 25 may), and (e) percentage of cases stratified by gender (available from 2 may until 25 may). in addition, the number of newly confirmed cases stratified by city is available starting from 25 march onwards. the saudi ministry of health report on covid-19 cases is based on real-time (rt)-pcr obtained through nasopharyngeal swabs, which were processed and validated through a regional lab. confirmed covid-19 case is defined as a case with positive real-time (rt)-pcr sample obtained through nasopharyngeal swabs. active case is defined as a covid-19 case that is still under medical supervision without two negative real-time (rt)-pcr samples. critical case is defined as a covid-19 case which required intensive care unit (icu) admission. the trend of the epidemiology of covid-19 was presented graphically, showing the number of daily confirmed cases during a period of 98 days (between 2 march and 7 june 2020). the same procedure was followed to present the total number of confirmed cases and number of active cases. covid-19 recovery rates, with 95% confidence intervals (cis), were calculated using the number of daily recovered cases divided by the total number of active cases in the same day. the same procedure was followed to calculate the mortality rate and the rate of critical cases daily. the chi-squared test was used to assess the difference between the recovery rates on 2 march and 7 june 2020. similarly, the chisquared test was used to assess the difference in the mortality rate and the rate of critical cases during the study period. the trends in the epidemiology of covid-19 were assessed using a poisson model. spss (statistical package for the social sciences) version 25.0 software was used to perform all statistical analysis. the total number of confirmed cases with covid-19 rose from one on 2 march 2020 to 101,914 on 7 june, representing an average of 1,039 new cases per day, [trend test, p < 0.000]. compared to 2 march (the date of the first reported covid-19 case) the number of new daily cases on 7 june had reached 3,045 cases. the number of daily active cases showed a continuous increase for a duration of 76 days until 16 may, then it started decreasing until 29 may; from this date the number of daily active cases started to increase again to peak on 6 june (figure 1) . despite the increase in the number of newly confirmed daily cases of covid-19, the number of reported daily active cases started to stabilize from 8 may onwards, fluctuating between (figure 1 ). as we can see in figure 2 , the epidemiological patterns of covid-19 in the five main cities in the ksa (riyadh, jeddah, mecca, medina, and damam) were not similar throughout the study period. the highest percentage of new daily cases was in riyadh (average 24.2%), followed by mecca (17.7%) and jeddah (16.2%). in addition, medina contributed an average of 12.1%, and damam 6.1% of the daily new cases. during the study period, a total of 72,817 patients have recovered from covid-19 as of 7 june, out of a total of 101,914 confirmed cases, representing a recovery rate of 71.4%. the recovery rate during the study period increased 2-fold from 1 (figure 3) . mortality rates due to covid-19 have been fluctuating, starting from 2 march, reaching the peak rate of deaths on 1 april (0.417 per 100 patients), which was followed by nonlinear reduction until 26 april (0.020 per 100 patients). starting from 29 april, the mortality rate remained relatively constant, fluctuating between 0.027 per 100 patients and 0.028 per 100 patients on 18 may. this was followed by another increase in the mortality rate, which reached 0.127 per 100 patients on 7 june. despite that, the number of daily deaths showed a constant increase during the study period, starting from one death reported on 24 march to 36 daily deaths by 7 june (712 deaths in total), with an average of seven deaths per day. the mortality rate decreased by 6. during the 24 days of the study period (between 2 may and 25 may, the period for which the data were available stratified by gender), covid-19 was clearly more prevalent among males compared to females. on average, males contributed to 79.0% of the cases, compared to 21.0% for females. the percentage of males in the total reported daily cases decreased by 18.0% (from 89.0% on 2 may to 73.0% on 25 may). on the other hand, the percentage of females in the total reported daily cases increased by 1.5 times, from 11.0 to 27.0% (figure 6) . during the same period of the study, covid-19 was clearly more prevalent among adults compared to children and the elderly population. on average adults contributed to 89.0% of the daily reported cases, followed by children and the elderly, with 8.0 and 3.0%, respectively. the percentage of adults in the total reported daily cases decreased by 10.5% (from 95.0% on 2 may to 85.0% on 25 may). on the other hand, the percentage of children and the elderly in the total reported daily cases doubled and trebled, respectively (figure 7) . our study explored the trend of covid-19 epidemiology in the ksa in term of its incidence rate, recovery rate, and mortality rate. the key findings were: (1) the epidemiological status in ksa reached a steady level after 2 months from the beginning of the pandemic, due to the implementation of successful healthcare and treatment protocols, (2) the international travel restrictions and household quarantine were effective ways to control the epidemic of covid-19 the ksa, (3) the rates of critical cases and mortality in ksa are at a low level, due to the younger population in saudi arabia compared to european and asian countries, and the effective control measures taken by the government, and (4) in the ksa, covid-19 was more common among adults and males compared to other demographic groups. despite the high number of preventive and control measures that have been taken by the saudi arabian government, the results of this study demonstrate an exponential increase in the total number of newly confirmed cases. the results confirm the rapid spread of the disease among the citizens in the ksa during the first 2 months of the pandemic (until 8 may). the rate of active covid-19 cases showed an exponential increase during the first 2 months, which started to stabilize and increase less sharply from 8 may onwards, probably due to the continuous increase in the recovery rate from the disease. this could be explained by advances in the saudi healthcare system, which provides advanced medical care for the patients that decreases the probability of life-threatening complications, or increases in citizens' adherence to personal protective measures. despite applying the same restrictions and preventive measures across all the cities in the ksa, the incidence of covid-19 was not similar across different cities. this may be due to differences in citizens' adherence to government restrictions. in addition, there are many differences between these five main cities in term of population density and diversity in the nationality of their inhabitants. diversity in the culture between the individuals lead to different implications on the epidemiology of diseases as it affects their attitudes, knowledge and practices toward the disease (9-12). the current study suggests potential risk factors among covid-19 infected cases. adults contributed to the highest proportion (on average 89.0%) of the daily reported new covid-19 cases, compared to children and elderly. therefore, they are considered the most vulnerable individuals to get infected with covid-19. this was confirmed by earlier studies which showed that mortality of covid-19 is linked with age: 80% of reported deaths in china were of individuals aged over 65 years old, and up to 15% of the deaths in the us were among adults over 70 years (13, 14) . similarly, in another large database study that included data from 17 million patients in the uk, the authors of the study highlighted that patients aged >60 years were at higher risk of hospital mortality due to covid-19, specifically patients aged >80 hr 12.64 (95% ci 11.19-14.28) (15) . several recent studies have speculated on the reasons for age being a risk factor of covid-19. for instance, the response of the immune system in adults may undergo several changes over the years, including the production of t and b lymphocytes, and the coordination of the immune system (16) , which may lead to excessive immune response and further complications such as hypercoagulability and endotheliopathy (17) . chronic illnesses have been linked with poorer outcome in patients with covid-19, and comorbidities are more common among the elderly compared to younger populations (15, 18, 19) . besides this, older populations tend to have a higher risk of mortality associated with influenza and other respiratory viruses which are similar to documented in sars-cov2 (20) . however, confirmed cases within the child population are usually less severe than for adults (14, 21) . more than 90% of infected children are asymptomatic or have mild to moderate disease (21) . covid-19 cases for infants are few, with mild illness (22) . similar findings have stated that sars-cov-2 preferentially infects older adult males, with rare cases reported in children (3, 6, 23) . these are all in line with our study findings. another suggested risk factor that emerged from our study is that there is a gender difference in term of covid-19 epidemiology, with males more susceptible to covid-19 infection than females. our study found that the highest proportion of covid-19 cases were among the male population (on average 79% of the cases) compared to only 21% for females. various epidemiological and population-based studies from other countries supported these findings. the incidence of covid-19 was found most commonly among adult males (median age between 34 and 59 years) (3, 24, 25) . furthermore, the highest proportion of severe cases is reported among adult patients ≥60 years of age, especially those suffer from one or more disorders such as cardiovascular and cerebrovascular diseases and diabetes (5, 6) . although the reason is not yet understood, some researchers speculate that sars-cov-2 is more likely to infect people with chronic comorbidities such as cardiovascular diseases (cvd) and cerebrovascular diseases and diabetes. co-infections of bacteria and fungi may also contribute to severe manifestations (6) . males more commonly have cvds, also more men are smokers, and their lifestyle is different (26) . despite the 130% increase in the rate of daily reported critical covid-19 cases during the study period, the mortality rate was not high in the ksa, and it decreased by 6.4% during the study period. our estimates for the rates of critical cases of people infected with covid-19 who need special care are considered extremely low compared to those published in the literature from other countries, where about 20% of all cases usually need to be hospitalized (3) . in fact, this could be due to several reasons such as saudi arabian demographics, as the saudi population is younger compared to european and asian countries (27) . this was also observed in other middle eastern countries, such as qatar and the united arab emirates, where the mortality rates were low (28) . in addition, the saudi government implemented strict rules in the fight against covid-19 including travel restrictions and lockdown of cities (29) , and these measures may have helped the country to contain the spread of the virus and helped in the process of providing early recognition and treatment of cases, and therefore better outcomes (30) . this study found that the number of new covid-19 cases decreased sharply during the period of complete lockdown (between 22 and 29 may), and started to increase again after ending the lockdown, reaching its peak on 6 june with 3,121 newly confirmed covid-19 cases. the saudi government eased some of the strict rules of lockdown and quarantine for the period between 22 and 29 may in order to re-open the country and minimize the socioeconomic effects of covid19 (31) , and this may have led to the pattern observed at the end of study period. in addition, this can be seen in the number of incident cases by city (figure 2) , where riyadh and jeddah had a doubling in the number of cases from the end of may until the end of the study period, while mecca city, which remains under lockdown, had a more stable curve throughout the same period. however, it is important to highlight that this study is ecological and therefore, it is difficult to conclude any association or causality. this study outlined that the epidemiological status in the ksa is getting better, which can be seen from the stable rate of active cases, specifically after 2 months from the beginning of the pandemic (12 march 2020) onwards (32). this reflects implementation of successful healthcare practices and treatment protocols. in addition, the application of international travel restrictions and household quarantine helped to slow down the spread of covid-19 in the ksa. this study examined the trend of covid-19 in the ksa in terms of recovery rates, mortality rates and rates of critical cases. in addition, we presented trends of covid-19 incidence stratified by age and gender. however, this study has some limitations. despite the fact that this study was a population-level study at the national level, it was ecological and therefore we were unable to access data on patient level to identify other risk factors such as the presence of comorbidities, or other factors associated with covid-19 infection. the age and gender distribution of the death cases with covid-19 was not available in our study as this type of data was not mentioned in the saudi ministry of health reports. in conclusion, the results of this study showed that males and adults accounted for the majority of covid-19 cases in the ksa. moreover, our study suggests that the epidemiological status in saudi arabia is getting better, specifically while applying restrictive measures. further studies are recommended to be conducted at the patient level to identify other patient groups who are at higher risk of getting infected with covid-19, and for whom the best pharmacological intervention could be provided. the original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author/s. the study was based on publicly available data and did not involve any new studies of human or animal subjects performed by any of the authors. ethical approval was obtained for this study from the research ethics committee at najran university, kingdom of saudi arabia (ref. no: 10 -05 -03 -2020 ec). ma, an, and haly: conceptualization, methodology, validation, writing-review and editing, and funding acquisition. an and halw: software, formal analysis, data curation, writing-original draft preparation, visualization. ma, an, mo, halw, and haly investigation. ma, an, and haly: resources and supervision. ma, an, halw and haly: project administration. all authors agreed to be accountable for the content of the work. this study was supported by the deanship of scientific research-najran university-kingdom of saudi arabia for their financial and technical support under code number (nu/mid/18/002). a novel coronavirus from patients with pneumonia in china the sars, mers and novel coronavirus (covid-19) epidemics, the newest and biggest global health threats: what lessons have we learned? clinical 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(covid-19): a review the authors would like to express their gratitude to the ministry of education and the deanship of scientific research-najran university-kingdom of saudi arabia for their support. key: cord-321835-qn33sx8x authors: bailey, emily s.; fieldhouse, jane k.; choi, jessica y.; gray, gregory c. title: a mini review of the zoonotic threat potential of influenza viruses, coronaviruses, adenoviruses, and enteroviruses date: 2018-04-09 journal: front public health doi: 10.3389/fpubh.2018.00104 sha: doc_id: 321835 cord_uid: qn33sx8x during the last two decades, scientists have grown increasingly aware that viruses are emerging from the human–animal interface. in particular, respiratory infections are problematic; in early 2003, world health organization issued a worldwide alert for a previously unrecognized illness that was subsequently found to be caused by a novel coronavirus [severe acute respiratory syndrome (sars) virus]. in addition to sars, other respiratory pathogens have also emerged recently, contributing to the high burden of respiratory tract infection-related morbidity and mortality. among the recently emerged respiratory pathogens are influenza viruses, coronaviruses, enteroviruses, and adenoviruses. as the genesis of these emerging viruses is not well understood and their detection normally occurs after they have crossed over and adapted to man, ideally, strategies for such novel virus detection should include intensive surveillance at the human–animal interface, particularly if one believes the paradigm that many novel emerging zoonotic viruses first circulate in animal populations and occasionally infect man before they fully adapt to man; early detection at the human–animal interface will provide earlier warning. here, we review recent emerging virus treats for these four groups of viruses. | the geographical location of first detections (with known reservoirs) for recently emerged adenoviruses (ads), enteroviruses (evs), coronaviruses, and influenza viruses. zoonotic (coronaviruses and influenza viruses) and non-zoonotic viruses (ads and evs) are shown. for zoonotic viruses, the hosts range from cattle, bats, chickens, camels, wild birds, cats, ferrets, goats, and humans (from left to right). the different sizes of the circles represent the number of human cases during the first outbreaks of the emerging respiratory viruses. human cases of adenoviral infections are shown in blue; human cases of enteroviral infections are shown in yellow; human cases of coronaviral infections are shown in green; and human cases of influenza viral infections are shown in red. zoonotic influenza introduction and epidemiology influenza viruses are rna viruses that are members of the orthomyxovirus family and classified into four types: a, b, c, and d (2) . as shown in table 1 , these four types of viruses are characterized by their immunologically distinct nucleoprotein and matrix protein antigens. influenza a and b viruses consist of hemagglutinin (ha), which binds a sialic acid receptor, allowing the virus to enter the host cell, and neuraminidase (na), which cleaves the sialic acid to release the virus. similarly, influenza c and d viruses contain ha-esterase fusion glycoproteins that also allow for the attachment of viral and cellular membranes. antigenic shifts (influenza a only) in ha, na, and the ha-esterase proteins contribute to the generation of novel viral strains. the host range of influenza viruses includes humans, birds, pigs, bats, and other livestock animals such as cattle and goats. the network of the influenza viral transmission is complex with both inter-and intraspecies transmission. as the viruses continue to change in their genetic sequences, ongoing research is imperative in investigating the ecology of these viruses at the human-animal interface to control further spread of infections and prevent the risk of future pandemics. influenza a virus h3n2 subtypes are frequently reported in swine, avian, and canine hosts that are responsible for highly infectious respiratory diseases in pigs and have been examined as a potential cause of influenza in humans. one study, examining the role of iav in pigs at usa agricultural fairs, reported an average influenza a prevalence of 77.5% among 161 swine across all seven fairs (3) . the genomic sequences of the viruses isolated from the swine were ≥99.89% similar to the h3n2 viruses isolated in humans. at these fairs, iavs were detected at least 1 day before symptoms of the virus were observed in humans, indicating that h3n2 was transmitted from pigs to humans in this case. since 2009, h1n1 virus has posed a significant threat to livestock workers and the greater community and has now become a seasonal influenza virus which circulates in humans. to explore the role of swine production facilities in the development of new swine-like influenza viruses, the spatiotemporal association between weekly influenza-like illnesses (ilis) in humans and the location of pig farms was investigated in north carolina over four influenza seasons (4) . analyses showed that the years of h1n1 pandemic, 2009-2010 and 2010-2011, were closely related with earlier peaking of ili cases. these findings suggest that increased exposure to pigs was associated with earlier observations of the greatest number of human h1n1 cases. in china, the transmission of influenza a between humans and pigs in six farms is being examined using a one health approach, taking into consideration the interconnectedness of humans, animals, and the environment (5) . findings suggest that both a(h1n1)pdm09-like and swine-lineage h1n1 and swine-lineage h3n2 viruses are circulating in swine workers and that these viruses likely reassort and cross species within the pig farms; as such, additional research is needed to understand the relationship between cross species transmission of viruses in humans and pigs. avian influenza viruses are the largest group of influenza a viruses reservoired in aquatic birds or poultry. although infrequently transmitted to humans, many cases have now been reported. human infection with avian influenza can lead to serious health conditions, including death. the first outbreak of an iav strain, h5n1, in humans occurred in hong kong sar, china, in 1997, infecting 18 humans (6). the first identified cases of human infection with h7n2, another avian influenza, occurred in north america with two human cases reported in 2002 (7) . another variation of the virus, h7n7, was the first avian influenza strain reported in europe; it infected 89 humans in 2003. in 2004, the first human cases of h10n7 infections were observed in africa (8) . it is important to note that h5n1 virus outbreak occurred again in 2004, 7 years after its first outbreak in humans, infecting more than 650 humans and causing more than 386 deaths worldwide (9) . the avian influenza viruses have continuously evolved, causing serious infections among humans across the world. h7n9 virus, a sporadic subtype of an avian influenza a virus, was first reported in humans in china in 2013. since the first outbreak, china has been experiencing epidemics annually, with a cumulative number of 1,562 reported cases, 40% of which have led to deaths as of september 2017 (10) . the incidence of the h7n9 infections has been increasing in both humans and poultry and in 2017 alone 764 infections have been reported (11). although h7n9 was first recognized as a low pathogenic avian influenza, two divergent lineages were detected in 2016-including a highly pathogenic avian influenza variant (12). according to the center for disease control and prevention (cdc), h7n9 is now recognized as the virus with the greatest potential to cause a pandemic due to its rapid genetic changes over the last 5 years. this further supports the need to improve disease control strategies and increase efforts to develop an effective vaccination strategy in the future as the spread of the h7n9 infection poses a threat to the poultry business. influenza d virus (idv) is a novel influenza virus that is structurally different from the other influenza viruses. idv was first isolated in 2001 from pigs in usa and since the first report, viral infection has been reported in various locations in usa, europe, and asia. in a serological study, cattle workers and non cattleexposed adults in florida were screened for idv antibodies (13) . of the cattle workers, 97% of idv seroprevalence was observed, while less than 20% was observed in non-cattle-exposed adults, suggesting a greater risk of idv infection for cattle workers. during a swine respiratory disease outbreak in northern italy in 2015, the idv genome was detected and isolated in both pigs and cattle herds (14) . the viral genome isolated from the pigs was closely related to the viral genome isolated in usa in 2011. additionally, the archived serum samples from 2009 had lower idv antibody titers compared to the serum samples collected in 2015. these findings suggest that the incidence of idv infections in pigs may have increased over time, and therefore, idv may pose a public health threat to the community. (17, 18) . recently, it has also been suggested that bats may play a role in the direct human transmission as bat sars-like coronaviruses have been identified in some species (19) . in the past decade, teams from the sabin vaccine institute and baylor college of medicine have been working toward the development of a vaccine for sars-cov. although initial reports indicated that a vaccine may be ready for human clinical trials in 2017, progress has been slow and few human sars vaccine trials have been conducted to date. middle east respiratory syndrome was first recognized in saudi arabia in 2012. many cases were linked to travel to or residence in countries in and near the arabian peninsula. symptoms include severe acute respiratory illness with fever, cough, and shortness of breath. there is limited human-to-human transmission of mers-cov, but exposure to camels is a risk factor for infection, with seroprevalences 15-23 times higher in camel exposed individuals (20) . despite this, major health care-associated transmission of mers-cov was reported in the middle east and korea, with outbreaks characterized by interhospital spread related to overcrowding and a lack of personal protective equipment (21) . the total number of worldwide cases reported to the who as of january 9, 2017 was 2,067 mers-cov cases (22). the cocirculation of covs in its animal reservoirs (camels and bats) raises important questions about the evolution of mers-cov. in a study conducted between 2014 and 2015 in saudi arabia, researchers found that dromedary camels share three cov species with humans, including betacoronavirus 1, mers-cov, and a cov 229e-related virus (23) . with the aim of reducing mers-cov transmission to humans, haagmans et al. developed a vaccine for camels using a poxvirus vehicle (24) . this vaccine has significantly reduced virus excretion among camels and conferred cross-immunity to camelpox infections (25) . enteroviruses are small, positive-sense, single-stranded rna viruses in the picornaviridae family. there are 12 species of evs found globally, including ev a-j (ev-a, b, c, d, e, f, g, h, and j) and rhinovirus a-c (rv-a, b, and c). with low replication fidelity and frequent recombination, evs have viral genetic diversity and a potential for cross-species infection. in february 2013, the international committee on taxonomy of viruses (ictv) approved changes to ev and rhinovirus species names after many of the human ev species were identified and isolated in nonhuman hosts. based on an analysis of picornaviridae hosts listed in the ictv database and subsequent studies of ev infection in non-human primates, there is growing evidence to indicate a potential for future zoonotic transmission between animals and humans (26, 27) . among the most important emerging respiratory viruses are ev68, ev71, coxsackieviruses, echoviruses, rhinoviruses, and polioviruses. enterovirus transmission occurs year-round, with seasonal peaks occurring in the summer and fall (june-october). infants less than 1 year of age are most susceptible to infection, and males are at an increased risk for infection until the age of 20 years (28) . the predominant mode of transmission is through a direct or indirect fecal-oral route; however, certain serotypes are transmitted via the respiratory route, in tears, and via fomites (29) . immunity to evs is serotype specific with most causing mild respiratory infections. rhinoviruses are small, single-stranded rna viruses in the picornavirus family that are responsible for more than half of all upper respiratory tract infections. in addition to exacerbating asthma and chronic obstructive pulmonary disease, rhinoviruses have also been associated with acute respiratory hospitalizations among children (30) . in a large prospective study of us pneumonias, rhinoviruses have been identified as the second most prevalent etiology of pneumonia in children after respiratory syncytial virus and the first most common etiology among adults (31) . there are more than 150 unique types of rhinoviruses. among the three genotypes (a, b, and c) types a and c are most often associated with increased morbidity and bacterial secondary infection. in animals, rhinovirus type c has been associated with morbidity in chimpanzees (32) . with an array of unique serotypes no vaccines or approved antiviral therapies have been commercially produced; however, experiments have suggested that vaccines and antiviral therapy may be possible (33, 34) . enterovirus d68 has caused sporadic respiratory disease outbreaks across asia, europe, and usa since 1960s; however, in 2014, a nationwide outbreak of d68 was associated with severe respiratory illness in usa, resulting in 14 deaths out of a known 1,150 cases (35) . the cdc found 36% of all evs tested during this outbreak were d68 and that patients with a history of asthma were found to be at a disproportionately increased risk of infection (36). one study of the 2014 outbreak found 59% of patients seen with ev-d68 in hospitals across missouri, illinois, and colorado were admitted to intensive care units and 28% received ventilator support (35) . in a study evaluating evs in non-human primates, ev-d68 was detected as a recombinant zoonotic strain (37) . while there are several strains of coxsackievirus and evs that can cause hand-foot-and-mouth disease (hfmd), ev71 is most commonly associated with severe disease outcomes. hfmd predominantly affects young children and is found worldwide but especially in the asia-pacific region. although ev71 is not typically detected in animals, recent research has indicated that it infects non-human primates (38) . various antiviral therapies are currently under study, including small molecules, monoclonals, and antivirals. vaccine candidates are also in development, with two vaccines currently available in china, which involve recombinant proteins, attenuated strains, inactivated whole-virus and virus-like particles, and dna vaccines (39) . first discovered in 1953 by rowe et al., ads are non-enveloped, double-stranded dna viruses with 57 unique serotypes, some of which are specific for attacking the respiratory track, conjunctiva, or gastrointestinal track (40) . key features of ad infections include various symptoms of disease, including rhinorrhea, nasal congestion, cough, sneezing, pharyngitis, keratoconjunctivitis, pneumonia, meningitis, gastroenteritis, cystitis, and encephalitis. illnesses may be asymptomatic, mild, or severe; however, immunocompromised patients and infants are at increased risk of severe morbidity and death. outbreaks of respiratory ad infection are common in both military recruits and other large training groups, such as police trainees. large persistent epidemics of ad type 4-associated respiratory disease have been documented in various military trainees (41) (42) (43) . in response to the increased disease burden from ad4 and ad7 in military recruits, teva has made a vaccine available to military recruits in usa (42) . despite a 12-year hiatus from use, in late 2011 oral ad4 and ad7 vaccines were reintroduced as an infection control measure for military recruits (42) . after reintroduction, military recruits experienced a 100-fold decline in ad disease burden, which accounted for the prevention of approximately 1 death, 1,100-2,700 hospitalizations, and 13,000 febrile ad cases per year among trainees (44) . outbreaks of ad in the general population have been characterized by infection due to novel viruses such as ad7h, ad7d2, ad14a, and ad3 variants. these novel viruses are sometimes associated with high attack rates and a high prevalence of pneumonia. severe mortality is also prevalent among patients with chronic disease and in the elderly. one of the most important novel serotypes, ad14, previously rarely reported, is now considered as an emerging ad type causing severe and sometimes fatal respiratory illness in patients of all ages (45) . beginning in 2005, ad14 cases were suddenly identified in four locations across usa (46) ; the strain associated with this outbreak was different than the original ad14 strain isolated in 1950s. the novel strain, ad14a, has now spread to numerous us states and is associated with a higher rate of severe illness when compared to other ad strains. novel ad species have also been recently detected in crossspecies infections from non-human primates to man in usa and between psittacine birds and man in china (47) . these cross-species infections indicate that ads should be monitored for their potential to cause cross-species outbreaks. in a recent review of the risks of potential outbreaks associated with zoonotic ad (48) , it was noted that intense human-animal interaction is likely to increase the probability of emergent cross-species ad infection. additionally, the recombination of advs with latent "host-specific" advs is the most likely scenario for adaptation to a new host, either human or animal. currently, there are no fda approved antivirals for ad infection; however, the best antiviral success has been seen with ribavirin, cidofovir, and most recently brincidofovir an analog of cidofovir (49) . as it is clear that many emerging respiratory viruses have zoonotic reservoirs, the design and implementation of effective control strategies are increasingly important. it has been suggested that avoiding direct contact with animals known to be zoonotic reservoirs for these viruses is one potential strategy (50); however, in populations where contact at the human-animal interface is common this may not be an acceptable solution. complex disease problems cannot be solved by one institution or one discipline; as such, this presents opportunities to incorporate the one health approach of working across disciplines to incorporate human, animal, and environmental health to solve complex problems. although some of the respiratory viruses described here are found almost exclusively in humans (ad strains), many of the most important emerging respiratory viruses are found at the human/animal interface. this suggests that strategies for novel virus detection should incorporate global surveillance at the human-animal interface to detect potentially emerging zoonotic viruses. this surveillance will require collaboration and cooperation among many stakeholders in order to address emerging and novel viral diseases. eb, jf, and jc conducted the literature review and wrote the manuscript; gg conceived the idea of the review and helped revise the manuscript to add important scientific content and refine the interpretation of the results. all the authors reviewed the final version of the manuscript and agreed to its submission. this work was supported in part by nih/niaid grant r01ai108993-01a1 (gregory gray pi). current infectious disease challenges centers for disease control and prevention. types of influenza viruses influenza a(h3n2) virus in swine at agricultural fairs and transmission to humans are people living near modern swine production facilities at increased risk of influenza virus infection? evidence for cross-species influenza a virus transmission within swine farms, china centers for disease control and prevention. h7n2 questions & answers avian influenza virus a (h10n7) circulating among humans in egypt global and local persistence of influenza a(h5n1) virus food and agriculture organization of the united nations serologic evidence of exposure to influenza d virus among persons with occupational contact with cattle influenza d in italy: towards a better understanding of an emerging viral infection in swine update: outbreak of severe acute respiratory syndrome -worldwide factors associated with nosocomial sars-cov transmission among healthcare workers in hanoi isolation and characterization of viruses related to the sars coronavirus from animals in southern china severe acute respiratory syndrome coronavirus-like virus in chinese horseshoe 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renewed use of adenovirus vaccines acute respiratory disease associated with adenovirus serotype 14 -four states severe pneumonia due to adenovirus serotype 14: a new respiratory threat? a novel psittacine adenovirus identified during an outbreak of avian chlamydiosis and human psittacosis: zoonosis associated with virus-bacterium coinfection in birds do nonhuman primate or bat adenoviruses pose a risk for human health brincidofovir is highly efficacious in controlling adenoviremia in pediatric recipients of hematopoietic cell transplant emerging viral respiratory tract infections -environmental risk factors and transmission simultaneous determination of ace activity with 2 substrates provides information on the status of somatic ace and allows detection of inhibitors in human blood human infections with influenza a(h3n2) variant virus in the united states the severity of pandemic h1n1 influenza in the united states novel influenza a (h6n1) virus that infected a person in taiwan human illness from avian influenza h7n3, british columbia genome analysis of south american adenovirus strains of serotype 7 collected over a 7-year period outbreak of adenovirus genome type 7d2 infection in a pediatric chronic-care facility and tertiary-care hospital the 1998 enterovirus 71 outbreak in taiwan: pathogenesis and management human infection with influenza virus a(h10n8) from live poultry markets, china avian influenza a virus (h7n7) associated with human conjunctivitis and a fatal case of acute respiratory distress syndrome in vitro susceptibility of adenovirus to antiviral drugs is speciesdependent key: cord-332108-6riu44fw authors: alanezi, fahad; aljahdali, anan; alyousef, seham; alrashed, hebah; alshaikh, wyam; mushcab, hayat; alanzi, turki title: implications of public understanding of covid-19 in saudi arabia for fostering effective communication through awareness framework date: 2020-09-18 journal: front public health doi: 10.3389/fpubh.2020.00494 sha: doc_id: 332108 cord_uid: 6riu44fw background: participation of the public is an important and most effective approach for controlling the spread of novel coronavirus. however, considering its novel nature, it is important to create awareness among the public to be able to take timely preventive measures. on the contrary, misinformation and myths from online communities result in severe damages in mitigation of this novel disease. objective: focusing on these aspects, this manuscript reviews public awareness about covid-19, myths surrounding it, its symptoms, treatment, transmission, importance of information sources, types of information to be considered in awareness campaigns, promotional channels, and their implications in saudi arabia. methods: an online questionnaire-based survey was used for collecting data related to five major aspects related to covid-19 and awareness creation process. the survey was accessed by 1,881 people, out of whom 741 people participated in the survey. however, 150 dropouts left the survey in between, as a result of which a final sample of 591 was achieved, indicating the response rate of 39.3% and a completion rate of 79.76%. results: awareness levels of the participants related to covid-19, its means of transmission, preventive measures, symptoms, and treatment were identified to be moderate to high (60–80%). however, reliance on a few myths and violation of certain preventive measures were identified with majority of the participants (more than 60%). the ministry of health was identified to be the most reliable source of information followed by family and friends. moreover, 15 types of information were identified to be highly relevant and important, which need to be effectively disseminated among the public through effective communication channels. conclusions: lack of awareness can result in serious outcomes in relation to covid-19. effective awareness campaigns including relevant information from reliable sources can improve the knowledge of people, and they must be effective in developing positive attitudes among the public toward adopting preventive measures. creating public awareness about infectious diseases which are caused by new pathogens is one of the effective approaches for controlling the spread of diseases such as covid19 . as the information about the disease, its symptoms, precautionary methods, diagnosis, and treatment may vary with other infectious diseases and it may take considerable amount of time, it is important for timely updates about the pandemic and the preventive care to be disseminated among the public in order to contain the transmission of infection. lack of public awareness about covid-19 was observed in different places in the initial days of the pandemic, and people roamed freely without following precautionary methods such as social distancing, and wearing masks (1) (2) (3) . while the nature of the pandemic changes, it is important that the information and advice remain constant. therefore, it is very important that accurate and reliable information must be disseminated to the public through verified sources, and spread of any misinformation must be effectively contained to prevent any loss. therefore, various reliable sources including the world health organization (who) and united nations sister organizations, along with governments of various countries, have been providing regular updates and the necessary information to prevent covid-19 through various channels (4) (5) (6) . another important factor of creating awareness is to prevent the spread of myths and misinformation. it is evident that perceptions and myths such as drinking raw alcohol can cure covid-19 by people in iran (7) , that 5g towers are the cause for covid-19 by people in the uk (8) , and eating garlic or mint can cure covid-19, as well as many others (9) , can lead to serious damage and may increase the chances of contamination. a recent study has identified that there is a positive correlation between the increase in the number of covid-19 cases and the relative search volumes of terms related to covid-19 (10) . in addition, public awareness about covid-19 varied across sub-regions in different countries, and the immediate need for strengthening the publicity regarding covid-19 by the governments was identified. however, the concerns about the transmission and the number of infected persons is growing at alarming rates in the past few months compared to other diseases like sars, mers-cov, and influenza. a recent review (11) of various studies in china and other countries related to covid-19 has indicated that the reproductive rate (it is an indication of the transmissibility of a virus, representing the average number of new infections generated by an infectious person in a totally naive population) of covid-19 is very high compared to other infectious diseases. in addition, children and old-aged people are identified to be at high risk of contamination with the novel coronavirus if necessary precautionary methods were not taken. studies have identified that infection was mainly identified in family clusters and workplaces (12) , reflecting the transmission by direct or close contact in the environment of those with infection. on the other hand, the governments are adopting various approaches (12) such as containment and mitigation activities to delay the major surges in number of patients and level the demand for healthcare resources such as hospital beds, testing kits, medicines, and other medical equipment and also to protect the most vulnerable from infection, including elderly people and those with health complexities or other critical diseases (13, 14) . considering these approaches by the governments, it is important that people are provided with accurate and timely information in relation to these approaches. focusing on the aspect of public awareness, this paper investigates the level of public awareness in saudi arabia and analyzes the types of information to be communicated from the reliable sources and its implications on the public by proposing a conceptual framework. the purpose of this study was to investigate the level of public awareness about covid-19 in saudi arabia and the importance of information sources, information types, and communication/promotional channels for creating awareness among the people in saudi arabia. as an approach for achieving this objective, an online questionnaire-based survey was adopted. the questionnaire was designed with various aspects related to covid-19 and level of awareness. it included various sections, including questions related to general awareness of covid-19 (four items), its symptoms (six items), transmission (three items), preventive care (10 items), treatment options (two items), myths (eight items), types of information (15 items), communication/promotional channels (nine items), and sources of information (five items). multiple-choice answers and fivepoint likert scale ratings (15) were used by the participants to answer the questions. the questionnaire was initially designed in english and was then translated to arabic by two professional arabic translators. the arabic version of the questionnaire was designed using questionpro application. a pilot study was conducted with 12 randomly selected people for evaluating the questionnaire. based on the feedback from the pilot study participants, few changes were made in relation to the questions' formulation and grammatical errors in arabic. in addition, cronbach's alpha for all items in the questionnaire was identified to be >0.88, revealing good consistency and reliability. the general public living in saudi arabia were recruited for the survey using the survey link generated using questionpro application. the survey link was initially forwarded to the general public by posting the link on community groups and other platforms on social media platforms. moreover, the survey was conducted for a period of 4 weeks from 23 march to 19 april 2020. considering the purpose and objective of the study, which was to collect the data from the general population of saudi arabia, the participants were randomly selected. however, the targeted sample population was composed of adults aged 18 years or above. as an approach to reach maximum samples in a short time, snowball sampling technique (16) was adopted, in which a request is made while forwarding the survey link, whereby participants were requested to forward the message to their friends and colleagues. accordingly, the survey link was initially forwarded to 439 people through various modes. as a result of using snowball sampling technique, the link was accessed by 1,881 people, out of which 741 people participated in the survey. however, 150 dropouts were identified who left the survey in between; as a result a final sample of 591 was achieved, indicating a response rate of 39.3% and a completion rate of 79.76%. in addition, the average time taken by the participants to complete the survey was 7 min. the survey was developed using questionpro application and conducted for a period of 4 weeks. the data were analyzed and discussed using four themes, which included sources of information, types of information, communication/promotional channels, and implications of good public awareness. relative frequencies for each item under these themes are used for analyzing the data, which are presented in the following section. the final sample achieved in this study was 591. the demographic information of the participants is presented in table 1 . among the total participants, 65.31% were male and 34.69% were female. considering the age groups, 59.05% were aged between 25 and 34 years followed by 16.07% between 45 and 54 years, 13.36% between 35 and 44 years, 9.47% between 18 and 24 years, and only 12 participants aged more than 54 years. focusing on the education levels of the participants, 57.39% have bachelor's degrees, followed by 14.25% who have master's degrees, 12.89% have diploma, 11.13% have ph.d., and 21 participants have secondary education. focusing on the professions of the participants, a diverse scenario can be observed with 20.81% government employees, 19.79% private sector employees, 26.90% business professionals, 10.65% students, 14.45% unemployed, and 7.27% retired individuals. majority of the participants belonged to three regions: 33.52% from medina, 28.73% from riyadh, 18.33% from mecca, and 19.42% belonged to other regions of saudi arabia. it is important to note that 85.78% of the participants' educational background (degree education) was not related to healthcare and 84.44% of the participants were not working in healthcarerelated organizations. working in healthcare organizations or having a qualification related to healthcare may increase the possibility that the participants were more aware of the infectious diseases/healthcare aspects compared to other participants. focusing on the general awareness of covid-19, majority of the participants, 86.31%, identified incubation period (the time between catching the virus and beginning to have symptoms of the disease) to be ranging from 5 to 14 days, while 12.68% of the participants stated they do not know, and six participants stated 21 days. in addition, 83.6% of participants were aware that covid-19 is a disease caused by novel coronavirus, and 91.5% of participants believed it was identified in wuhan region, china. while 36.25% of other regions 115 is your education background related to healthcare practices/healthcare management? no 507 are you working in any healthcare related organization? no 499 participants believed that the source of the novel coronavirus is "bats, " 14.35% believed the source is "chinese man;" 49.4% stated that the source is not yet identified. in addition, there are various myths being circulated online, and the participants' awareness levels in relation to these myths are presented in table 2 . the findings reflected that 18% of the participants believed various myths circulating online, which are not officially confirmed or declared by the governments or healthcare organizations. public awareness about covid-19 symptoms is presented in table 3 , which has revealed that majority of the participants (84.26%) identified fever, dry cough, and breathing difficulties as the general symptoms of covid-19, and prolonged illness or symptoms in severe cases as identified by 86.63% of the participants may include pneumonia, acute respiratory syndrome, and organ failure. similarly, public awareness about the transmission risks is presented in table 4 . majority of the participants (76.48%) identified different possibilities of transmission by not adopting social distancing measures. in relation to the possibility of cure and treatment, it was acknowledged by 83.65% of the participants that most of the affected persons may recover on their own, and only a small proportion of patients who have severe pre-medical conditions, are old-aged, and are children may need intensive care. it is interesting to note that 74.79% of the participants were aware that people with chronic acute respiratory disease can be severely affected if they are infected with novel coronavirus. in addition, 69.43% of the participants were aware that there is no treatment available for covid-19, but about 30% believed that there is a treatment available, which may be an issue of concern, as they may not seriously adopt preventive measures. focusing on the public awareness of preventive measures, table 5 indicated good awareness levels, as 70-99% of participants acknowledged different preventive measures. however, only 78.85% of the participants stated that they always followed precautionary methods, while 12.96% stated they followed sometimes, and 8.19% stated that they did not follow any precautionary methods. however, 97.6% of the participants believed that quarantine and staying at home is an effective approach toward preventing the spread of novel coronavirus. in addition, only 32.29% of the participants stated that they did not leave home during lockdown/curfew, while 54.2% stated they left home as it was necessary, and 13.51% stated that they left home without any reason. accordingly, 30.64% stated they left home once (1 day) a week, 12.03% 2 days per week, 6.75% 3 days per week, 3.95% 4 days per week, 1.98% 5 days per week, and 2.80% 6 days per week; 32.62% stated they did not leave the house. in relation to the reliable sources of information, participants were asked about various sources which they would prefer, and the results are presented in table 6 , which indicates that majority of the participants relied on the ministry of health, friends, and family. in addition, the participants were asked to rate the importance and effectiveness of various types of information which need to be promoted, and the findings are presented in table 7 . although all types of information were important, few types such as access to care, helpline and support, health insurance, and access to medicine were highly important. similarly, participants were asked to rate the importance and effectiveness of various channels/modes of communication, and the responses are presented in table 8 , which indicated online government portals and mobile [calls/sms (short message service)] were identified to be important. the findings related to public awareness have revealed some important aspects related to the information known by the public and the implications especially in adopting preventive measures. in addition, the information flow, reliable sources, types of information, and modes of promotions can be assessed in the context of saudi arabian lifestyle. firstly, focusing on the general awareness about covid-19, participants exhibited good understanding about the disease, the pathogen causing the disease, its sources, and the incubation period. though the source of covid-19 is yet to be identified, there are a considerable number of participants who believed the source of the virus might be bats or transmitted through chinese people. in relation to the awareness about myths circulating online and the truth in them, most of the participants reflected good understanding of the myths, which were verified by the world health organization (9) and turned out to be false. however, in relation to few myths, there are a considerable number of participants (∼30% of the participants) who believed them to be true, such as using alcohol, hand dryers, and eating garlic can kill the virus. these can have serious outcomes, as it is evident from the recent incidents such as drinking raw alcohol in iran (7) and burning down 5g towers in the uk (8) . therefore, the spread of such myths must be targeted by effectively promoting awareness campaigns through various channels. focusing on the symptoms, participants reflected good understanding, as they stated fever, dry cough, and breathing difficulties as general symptoms which were identified by various reliable organizations (17) (18) (19) . one of the important aspects of covid-19 awareness is related to the various means of transmission from an infected person. in relation to these factors, most of the participants reflected good understanding, as they identified that the main cause of virus spread is through the droplets released by an infected person through sneezing or coughing, which can rest on different places for a considerable amount of time. however, one of the concerns is that about 24% of the participants were not aware of these factors. unlike other infections, the importance of awareness and preventive measures is very important in containing the spread of covid-19, as there is a high risk of contamination from a single person which can easily lead to the infections across the community or region if proper precautionary methods are not implemented (20, 21) . focusing on awareness of preventive measures, participants exhibited good understanding, especially in relation to social distancing, covering mouth and nose while coughing or sneezing, avoiding close contact with symptomatic (flu, cough) persons, and seeking medical help in case the symptoms prolong after incubation period during quarantine. however, other preventive measures such as washing hands regularly and using hand sanitizers were only recognized by ∼75% of the participants. these two approaches are among the important measures which need to be considered on a daily basis to prevent being infected and contain the spread of the virus (22) . in relation to the reliable sources of information about covid-19, majority of the participants relied more on the saudi ministry of health, friends, and relatives than on the recognized bodies such as who and healthcare experts. it is important that the public should rely on reliable sources of information, as unreliable sources increase the chances of contamination and other challenges related to healthcare and social challenges as a result of vast misinformation available on various channels (23, 24) . in relation to the types of information to be considered during covid-19 outbreak, there has been no consensus among the organizations. however, information related to preventive measures, symptoms, and self-care were the most promoted (10, (25) (26) (27) ; there is a need for considering the additional information in order to prevent the spread of mis-information, enable people to manage their activities during lockdown/quarantine, and manage their lifestyles and other aspects such as finance, basic needs, and other necessary aspects. therefore, various types of information were reviewed, and 15 different types of information (presented in table 7 ) were perceived to be highly important by most of the participants. focusing on the channels/modes of promotion, it is essential to consider that information must be disseminated to a large section of the population within a short time, and it is also essential that regular updates can be easily accessed by the public. social media and mobile phones (sms/calls) can be effective in reaching a large section of the population in a short time. therefore, approaches such as passing messages and information about covid-19 before connecting a call on mobiles by the mobile services companies and daily sms and mobile applications launched by the government to create awareness and track diseases and vulnerability of the users having an infection are proving to be effective in different regions (28) (29) (30) (31) (32) . however, majority of the participants preferred online government portals and press releases compared to social media platforms. in addition, mobiles and television were considered by the participants to be effective platforms for creating awareness. it is interesting to note that newspapers were least preferred compared to other channels, as the risk of contamination may be high. by effectively creating public awareness, the spread of covid-19 can be minimized, and the risk of infections, death, and losses can be prevented. it can also result in effective health outcomes, improve quality of life during lockdowns, survival, and proper planning of work, business and finances, etc. based on these findings, a framework (figure 1) for creating public awareness with components including information sources, types of information, communication channels, and the outcomes is formulated especially considering saudi arabian lifestyle. this framework can also be used as conceptual framework for future studies focusing on evaluating public awareness related to pandemics/infectious diseases. there are a few limitations in this study. the first is the methodological approach based on survey questionnaire for collecting and analyzing the public awareness data related to covid-19; a mixed method approach such as observations and interviews could have gathered more qualitative and behavioral data which can be used to analyze the public reactions and lifestyle changes in relation to covid-19 outbreak. in addition, the survey was conducted over a period of 4 weeks, which could have been increased to achieve a large sample population and response rates. a major limitation of this study is the online questionnaire due to the lockdown situation that reduced the reachability to boarder communities with good sample pool. various implications can be drawn from the study. firstly, this study contributes to the literature by providing the relationship between awareness and self-care practices adopted by the public considering the covid-19 outbreak, reflecting the people's attitudes toward the pandemic and preventive measures. the findings from the survey can prove to be a valuable source of information for the government, based on which it can update its awareness creation strategies and also tract peoples' attitudes toward the pandemic. in addition, the proposed framework can also be used as a conceptual framework in other research studies focusing on public awareness about pandemic/infectious diseases. this study analyzed the public awareness about covid-19, its precautionary measures, and its implications on the lifestyles of the people in saudi arabia. an online survey was conducted, considering the prevailing situation of lockdown to reach maximum participants. a total of 591 respondents participated in this survey. overall, the findings revealed that public awareness about covid-19 in saudi arabia varied between moderate to high, and its implications reflected that a few measures were not adopted by the public, such as staying at home, which resulted in increased number of positive cases. though they were aware of the precautionary measures of staying at home during lockdowns, most of the participants frequently went out of their homes, which might increase the risk of contamination. therefore, it is very much essential that strict measures and an effective approach for creating awareness are to be adopted, to ensure the success of the lockdown strategy in order to limit the spread of covid-19. the original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author/s. how brazilian favela journalists are raising awareness about covid-19. open democracy covid-19 awareness among healthcare students and professionals in mumbai metropolitan region: a questionnaire-based survey covid-19 requires a coordinated public information campaign. the guardian. (2020) pass the message: five steps to kicking out coronavirus covid-19): awareness resources-canada.ca. canada.ca off-label use of medicines for covid-19 methanol poisoning emerging as the result of covid-19 outbreak; radiologic perspective the perception of covid-19 as a fear factor in the preparation for the pandemic aftermath. nairobi: researchgate available online at more effective strategies are required to strengthen public awareness of covid-19: evidence from google trends the reproductive number of covid-19 is higher compared to sars coronavirus covid-19: towards controlling of a pandemic fair allocation of scarce medical resources in the time of covid-19 statement-older people are at highest risk from covid-19, but all must act to prevent community spread a technique for the measurement of attitudes snowball sampling: a purposeful method of sampling in qualitative research available online at covid-19)-symptoms and causes cdc. coronavirus disease 2019 (covid-19)-symptoms presumed asymptomatic carrier transmission of covid-19 early dynamics of transmission and control of covid-19: a mathematical modelling study interventional radiology and covid-19: evidence-based measures to limit transmission community responses during early phase of covid-19 epidemic, hong kong covid-19) situation report-−80 are patients with hypertension and diabetes mellitus at increased risk for covid-19 infection? more awareness is needed for severe acute respiratory syndrome coronavirus 2019 transmission through exhaled air during non-invasive respiratory support: experience from china defining the epidemiology of covid-19-studies needed covid-19-related knowledge, attitudes, and practices among adolescents and young people in bihar and uttar pradesh, india: study description whatsapp messenger as a teledermatology tool during coronavirus disease (covid-19): from bedside to phone-side bluetooth phone apps for tracking covid-19 available online at you will hear a person coughing and that is annoying. india today available online at the studies involving human participants were reviewed and approved by the institutional review board of the imam abdulrahman bin faisal university. the patients/participants provided their written informed consent to participate in this study. all authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication. key: cord-346138-ip42zcld authors: zhurakivska, khrystyna; troiano, giuseppe; pannone, giuseppe; caponio, vito carlo alberto; lo muzio, lorenzo title: an overview of the temporal shedding of sars-cov-2 rna in clinical specimens date: 2020-08-20 journal: front public health doi: 10.3389/fpubh.2020.00487 sha: doc_id: 346138 cord_uid: ip42zcld coronavirus disease 2019 quickly spread in china and has, since march 2020 become a pandemic, causing hundreds of thousands of deaths worldwide. the causative agent was promptly isolated and named sars-cov-2. scientific efforts are related to identifying the best clinical management of these patients, but also in understanding their infectivity in order to limit the spread of the virus. aimed at identifying viral rna in the various compartments of the organism of sick subjects, diagnostic tests are carried out. however, the accuracy of such tests varies depending on the type of specimen used and the time of illness at which they are performed. this review of the literature aims to summarize the preliminary findings reported in studies on covid-19 testing. the results highlight how the pharyngeal swab is highly sensitive in the first phase of the disease, while in the advanced stages, other specimens should be considered, such as sputum, or even stool to detect sars-cov-2. it highlights that most patients already reach the peak of the viral load in the upper airways within the first days of displaying symptoms, which thereafter tend to decrease. this suggests that many patients may already be infectious before symptoms start to appear. coronavirus disease 2019 (covid-19) quickly spread in china was declared a became pandemic in march 2020, causing hundreds of thousands of deaths worldwide. the causative agent, a virus from the coronavirus family, was promptly isolated and named sars-cov-2 (1). the characteristics that make this virus highly dangerous for the population are represented by a very high transmission capacity, as well as by its complex interaction with the host's organism which in a variable, but high percentage of cases, can lead to death (2) . transmission through respiratory droplets, indirect contact, as well as airborne transmission of the virus has been confirmed and the diagnosis is made combining clinical, radiographic (chest computer tomography), and laboratory evaluations. in particular, the presence of viral rna in the pharyngeal swab is analyzed using the real-time reverse transcription-polymerase chain reaction (rt-pcr) (3) (4) (5) . regarding the molecular targets that can be used for pcr assays, some structural proteins were identified, among which: spike (s), envelope (e), transmembrane (m), helicase (hel), and nucleocapsid (n). furthermore, other genes that are required for viral replication, like rna-dependent rna polymerase (rdrp), hemagglutinin-esterase (he) , and open reading frames (orf1ab) may be targeted for virus detection by rt-pcr (4, 6) . there are different recommendations among countries regarding the choice of target (4, 7) , nevertheless, to obtain a reliable result, at least two molecular targets should be included in the assay (8) . the result of rt-pcr, expressed in cycle threshold (ct) provides an answer about the presence or absence of the viral rna and also estimates the viral load in the sample, where the ct is inversely proportional to the quantity of the viral rna. even if so, it seems that positivity diagnosed with rt-pcr is not indicative of the contagiousness of the patient (1) . scientific efforts at this time are directed on multiple fronts: on the one hand, researchers are studying the best clinical management of infected patients; on the other hand, they are trying to define the infectious aspects of these patients. in particular, it is necessary to understand when the sars-cov-2 positive subject is capable of infecting others or when this possibility is greater? in which biological materials is the virus present and in what quantities? how do these values change during the course of the disease? are they related to the symptoms? partial answers to these questions come from an increasing number of studies that have reported the clinical and virological data of patients, observed in various parts of the world. however, these data often relate to a few patients or only focus on some aspects and not others. this review aims to summarize the findings of the studies published until now regarding the trend of temporal shedding of sars-cov-2 rna in various clinical specimens. the electronic database pubmed was screened in order to select studies suitable for inclusion in this review. the following strategy of search was used: [("sars-cov-2" or "2019-ncov" or "covid-19") and (load or samples or specimens)]. in addition, bibliographies of the included studies were read, and suitable references researched separately. the results were screened by title and abstract, selecting the records fulfilling the following inclusion criteria: -studies published in english; -studies reporting data on sars-cov2 rna evaluation in clinical specimens with chronological reference to the illness course. no restrictions on the study design were applied. the established exclusion criteria consisted of: -studies written in languages other than english; -studies evaluating treatment options; -non-original studies; -studies without a clear reference to the onset of the disease (onset of symptoms). in case of insufficient information after abstract reading, the full-text publication was examined. the selected papers were full-text evaluated and, if meeting the inclusion criteria, were included in the review. an ad hoc datasheet containing queries was prepared and the following data, if available, was extracted and inserted into the datasheet: -author's names; -number of patients; -type of specimen analyzed and results of rt-pcr with the corresponding days of illness from symptom onset to which they refer; -molecular target used in the rt-pcr analysis. the results of the examined specimens reported for every day of patients' illness were collected. if the result of the test was positive, according to the parameters established in the original paper, a "+" was assigned, while a "-" was assigned if the test result was negative. no distinction was made on the methodology used in the various studies, nor on the unit of measure, only a dichotomous result (+ or -) was reported. the total percentage of positives and negatives was thus determined day by day, for each type of sample. the cases for which the ct values of rt-pcr were reported for every single test were included in this analysis. the data were grouped by type of target (i.e., orf1ab, e, s, rdrp etc.) used for virus rna detection in every type of specimen. the mean and standard deviation of ct values were calculated for each day of patients' illness. the descriptive results that could not be included neither in a quantitative nor in a qualitative analysis, were also collected. a total of 243 records were found, applying the search strategy on electronic databases. after the title and abstract examination, 25 abstracts fulfilled the inclusion criteria and were selected for a full-text reading. of these, 21 (7, (9) (10) (11) (12) (13) (14) (15) (16) (17) (18) (19) (20) (21) (22) (23) (24) (25) (26) (27) were deemed suitable for inclusion in the review. generic information about the included studies are reported in table 1 . the discarded articles were focused on the evaluation of some treatments and therefore considered misleading for the purposes of our evaluation (29) (30) (31) . one study was only a descriptive report and was also excluded (32) . a flowchart representing the selection process is reported in figure 1 . due to a large variability among studies in methodology and presentation of results, only six studies were included in the quantitative evaluation, while for others a qualitative or discursive consideration was performed. in the final qualitative analysis 68 patients were included. of these, complete temporal data, with reference to the -most patients had a positive pharyngeal swab result for the first 10 days of illness. after this term, the percentage of patients whose pharyngeal swab result was negative increased, and then even exceeded the positive ones around day 12 of illness ( figure 2) ; -viral rna was not detected in the blood of most patients. in <15% of patients, viremia was registered in the second week of illness (figure 3) ; -sputum contains viral rna throughout the duration of the disease (figure 4) ; -the virus is eliminated in the stool of sick patients. toward the end of the first week of the disease, viral rna was found in approximately 40% of patients ( figure 5) ; -the urine of covid-19 patients was almost always negative for the presence of the virus (figure 6 ). the figure 7 summarizes the percentages of positivity observed for each type of specimen during the patients' illness. data other results reported in the included studies which were not considered in the quantitative and qualitative analyses, affirm as follows: pharyngeal viral load is highest in the early phase of illness (12, 16, (20) (21) (22) (23) 25) , showing high levels already in the first 24 h from the onset of symptoms (14) with the peak on the 5-6th day of illness (16) . according to wolfel et al., in this period the detection rate was 100%, decreasing substantially after day 5, with a detection rate that more than halves (39.93%) (23) . furthermore, the study of subgenomic messenger rnas (sgrna) suggested that the first 5 days of illness are characterized by an active replication of sars-cov-2 in the upper respiratory tract, while after the 5th day, no sgrna was detected in pharyngeal samples (23) . in the advanced stage of the disease (second-third week), the virus can be intermittently detectable in nasopharyngeal swabs (9, 20) . some authors reported a positive correlation between the severity of clinical conditions and upper respiratory tract viral load (25, 27) . regarding the comparison of naso-and oropharyngeal swabs, the opinions are discordant: wölfel et al. (23) state that no differences in viral loads or detection rates were revealed when comparing naso-and oropharyngeal swabs, while zou et al. (25) and yang et al. (26) noticed higher viral loads and detection rates in the nose swabs. yu et al. (21) , contrariwise, found a higher mean viral load in the throat (2,552 vs. 651 copies/test, p < 0.001). blood positivity rates reported among covid-19 patients vary between 0 and 22% (10, 12, 14, (18) (19) (20) (21) 23) . chen et al. affirm that the detection of viral rna in the blood is a strong indicator of illness severity (10) . stool content of viral rna was detected in a great percentage of patients enrolled in various studies (11, 14, 19, 20, 23, 24) . wolfel et al. noted that the viral load in the stool seemed to reflect the sputum viral content (23) . several authors therefore suppose an infection of the gastrointestinal tract by the virus (11, 24) , with its continuous elimination with the feces which has been reported to last from 1 to 12 days (24) and in some cases, viral rna were detected in feces or anal swabs even after the respiratory tests became negative (11, 22, 24) . zhang et al. also report that during the first days of illness, the most positive swabs were the oral ones, whereas in the following days more and more anal swabs were positive, and oral ones negative (22) . sputum samples appear to contain the maximum viral load (16, 21, 23) , reaching the peak on the 5-6th day after symptoms onset (16) and remain positive for a maximum duration over time, compared to swabs of the upper respiratory tract (23) . they also show one of the highest positivity rates (53.42-100%) among the tested samples (19, 21, 23, 24, 26) , giving positive results for a long time, even when the pharyngeal samples are negative for the presence of the sars-cov-2 rna (15), sometimes even after symptoms have ended (23) . some authors state that the sputum viral load seems to be significantly correlated to the pharyngeal one (12, 16) . all patients, except one in kim's report (12) and four reported by liu et al. (27) had negative viral detection in urine. results on viral rna detection in saliva are reported in two papers (17, 18) . the detection rate in the initial samples is estimated to be around 90% (17, 18) . the serial daily sampling revealed that the viral load was highest during the first week of symptoms and declined in the following days. on day 20 after symptoms onset, 33% of patients had viral rna detected in the saliva specimens (18) . the main findings of the included studies are summarized in the table 2 . the pandemic spread of coronavirus infection sars-cov-2 forced many countries to take strong containment measures (33, 34) . to avoid an uncontrolled broadcast of the disease, it is fundamental to understand the manner and timing of disease transmission. then, a reliable test is needed to identify infected subjects, to take appropriate isolation measures for a period sufficient enough to avoid contagion of other individuals. the reference method for testing positivity to sars-cov-2 infection is represented by the pharyngeal swab that is taken from the patient's nasopharynx or oropharynx and, through an rt-pcr analyzed for the presence of viral rna (8) . this method has been reasonably chosen, as it has already been used for other viruses affecting the airway tract, such as sars-cov (35) . the wide use of such protocol is due to its multiple advantages. it is simple to perform, relatively inexpensive, and fast. however, as has emerged from recent studies, and confirmed by our cumulative analysis, the accuracy in the diagnosis of this swab seems to be excellent in the first phase of the disease, losing sensitivity in the following days (16, (20) (21) (22) (23) 25) . this can be linked to a reduction in the viral load present in the upper respiratory tracts starting from the second week of the disease (14, 16, 20, 23) . these data reveal two aspects to reflect on. the first one concerns the initial phase of the disease, that is, when the symptoms arise and the viral load in the upper airways is already almost at the peak, as suggested by several authors (14, 16, 23) . this implies that many patients may be infectious for days before they show signs of disease. the second reflection concerns the terminal phase of the disease. in particular, attention should be paid to patients who test negative for the pharyngeal swab in the advanced stages of the disease, since young et al. (20) and lan et al. (9) show that the swab may be positive intermittently in this phase. therefore, it is fundamental to understand whether the virus can be transmitted in this stage of disease. the presentation of the results of the rt-pcr analysis, however, remains only for a diagnostic purpose, without being able to provide indications on the contagiousness of the positive subject. other methods like isolation and culture of the virus, are needed for this estimate (8) . for diagnostic proposes, it should be considered, as stated by yu et al., that the performance of a droplet digital pcr (ddpcr) in sars-cov-2 detection may be significantly better compared to the traditional rt-pcr, especially for low viral loads (21) . in addition, according to some authors, there seems to be a difference between nasopharyngeal and oropharyngeal swabs (21, 25) . in particular, one study with a high overall number of performed swabs (250 throat and 490 nasal swabs) state that the nasal swabs have a significantly higher positive rate than the oropharyngeal ones (73.3% vs. 60% in the first 7 days and 72.3% vs. 50.0% during the second week of illness) (26) . among the investigated samples, saliva seems to be a promising specimen for detection of sars-cov-2 (17, 18) . authors found a positivity rate in the initial saliva samples of 87%, with a median viral load of 3.3 × 10 6 copies per ml, values that seem to be similar to the pharyngeal swabs (ranging between 104 and 107 copies per ml) (16) . the temporal course of the viral load in the saliva seems to follow that of the pharynx (18), even if it was not possible to refer data to the symptoms onset, but only to the hospitalization timing. the sputum, seems to possess the highest positive rate among all the specimens (26), except for bronchoalveolar lavage fluid (balf) (19, 26) , and persists throughout the course of the disease (21, 23, 24, 26) . the study investigating the active viral replication in the cells using sgrna, found that the active replication of sars-cov-2 in the sputum samples persisted until days 10/11 of the illness, unlike pharyngeal swabs, where sgrnas were no longer detectable at the end of the first week of symptoms (23) . as suggested by lo et al. (15) the sputum could be useful in the diagnosis of some suspected cases that are negative with repeated pharyngeal swabs. regarding the advanced stages of the disease, a fair rate of sars-cov-2 positivity was found in the stool of infected patients. in studies investigating the presence of viral rna in the feces, more than half [and up to 90% reported by lo et al. (15) ] of the patients tested positive (11, 24) . furthermore, sometimes the fecal specimen remained positive, even after the pharyngeal specimen became negative (11, 22, 24) . we do not know what implications this data has on the transmission or on the course of the disease, however, fecal examination should be considered to complement the diagnosis of covid-19 patients. the presence of viral rna in the blood has also been investigated. however, few patients appear to have viremia during the course of the disease (14, 18, 19) . although, this event appears to be positively correlated with the severity of the symptoms (10) . no viral rna was detected in breast milk (13) , nor in vaginal fluids (28) of infected women. an attempt was made in this overview to compare the ct values of the main specimens that were found in the various studies during the course of the disease. surely this result may be affected by a bias due to the difference in the methods and targets used in the various studies, even if there are universally accepted cut-offs (ct-value < 40) that give us a reference in the interpretation of the results (8) . another important aspect regarding the sars-cov-2 genome, and thanks to the availability of the newest sequencing methods and highly organized databases, several researchers are investigating genetic characteristics of the virus, subtype evolution, as well as geographic and temporal changes in the virus genome. major attention has been focused on homoplasies, that is mutations that have emerged multiple times and may represent the sign of ongoing adaptation of the virus to the new human host. several mutations in different regions of the viral genome have been found. these include sites in the orf1ab region, spike protein (36, 37) , as well as the n gene (38) . the implications of such mutations are not completely known. some of them can be neutral (39) , but it can be supposed that the changes in surface glycoprotein can influence the interaction between the virus and the host cell, as well as the anti-genicity of the virus (36, 40, 41) . a great part of knowledge about the genomic stability of sars-cov2 is still in evolving. it is still unclear if some sequence differences found in samples coming from different continents represent a temporal rather than a geographic signal. further studies are needed to better define the behavior of the virus, in order to develop efficient treatments. a comprehensive approach of this overview was chosen in order to include as much data as possible in the final analysis, making it possible to analyze the data related to 889 patients, while all data reported the results differently. the results in the included studies were reported unevenly. some were reports of a few patients, others presented data for many patients, but in a synthetic way. for this reason, the homogeneous data have been grouped together as far as possible and others treated discursively. however, some important conclusions emerged: -the sputum, together with the bronchoalveolar lavage fluid, closely reflect the course of the infection; -the pharyngeal swabs have a high accuracy in the initial phase of the disease, while their positivity rate drops suddenly in the following phases; -viral rna could be eliminated in the stool even for prolonged periods and their examination could supplement the pharyngeal swab. further studies with standardized protocols and an equally large number of samples for all types of specimens would be needed to draw more precise conclusions. publicly available datasets were analyzed in this study. the data can be found in papers cited in the references. a new coronavirus associated with human respiratory disease in china escalating infection control response to the rapidly evolving epidemiology of the coronavirus disease 2019 (covid-19) due to sars-cov-2 in hong kong molecular diagnosis of a novel coronavirus (2019-ncov) causing an outbreak of pneumonia detection of 2019 novel 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covid-19 infection hydroxychloroquine and azithromycin as a treatment of covid-19: results of an open-label non-randomized clinical trial patients of covid-19 may benefit from sustained lopinavir-combined regimen and the increase of eosinophil may predict the outcome of covid-19 progression renin-angiotensin system inhibitors improve the clinical outcomes of covid-19 patients with hypertension transmission of 2019-ncov infection from an asymptomatic contact in germany only strict quarantine measures can curb the coronavirus disease (covid-19) outbreak in italy 2020 the positive impact of lockdown in wuhan on containing the covid-19 outbreak in china emergence of genomic diversity and recurrent mutations in sars-cov-2 genetic diversity and evolution of sars-cov-2 genomic characterization of a novel sars-cov-2 computational inference of selection underlying the evolution of the novel coronavirus, severe acute respiratory syndrome coronavirus 2 human coronavirus: host-pathogen interaction measures for diagnosing and treating infections by a novel coronavirus responsible for a pneumonia outbreak originating in wuhan the supplementary material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fpubh. 2020.00487/full#supplementary-material key: cord-343347-guciupc8 authors: hajj hussein, inaya; chams, nour; chams, sana; el sayegh, skye; badran, reina; raad, mohamad; gerges-geagea, alice; leone, angelo; jurjus, abdo title: vaccines through centuries: major cornerstones of global health date: 2015-11-26 journal: front public health doi: 10.3389/fpubh.2015.00269 sha: doc_id: 343347 cord_uid: guciupc8 multiple cornerstones have shaped the history of vaccines, which may contain live-attenuated viruses, inactivated organisms/viruses, inactivated toxins, or merely segments of the pathogen that could elicit an immune response. the story began with hippocrates 400 b.c. with his description of mumps and diphtheria. no further discoveries were recorded until 1100 a.d. when the smallpox vaccine was described. during the eighteenth century, vaccines for cholera and yellow fever were reported and edward jenner, the father of vaccination and immunology, published his work on smallpox. the nineteenth century was a major landmark, with the “germ theory of disease” of louis pasteur, the discovery of the germ tubercle bacillus for tuberculosis by robert koch, and the isolation of pneumococcus organism by george miller sternberg. another landmark was the discovery of diphtheria toxin by emile roux and its serological treatment by emil von behring and paul ehrlih. in addition, pasteur was able to generate the first live-attenuated viral vaccine against rabies. typhoid vaccines were then developed, followed by the plague vaccine of yersin. at the beginning of world war i, the tetanus toxoid was introduced, followed in 1915 by the pertussis vaccine. in 1974, the expanded program of immunization was established within the who for bacille calmette–guerin, polio, dtp, measles, yellow fever, and hepatitis b. the year 1996 witnessed the launching of the international aids vaccine initiative. in 1988, the who passed a resolution to eradicate polio by the year 2000 and in 2006; the first vaccine to prevent cervical cancer was developed. in 2010, “the decade of vaccines” was launched, and on april 1st 2012, the united nations launched the “shot@life” campaign. in brief, the armamentarium of vaccines continues to grow with more emphasis on safety, availability, and accessibility. this mini review highlights the major historical events and pioneers in the course of development of vaccines, which have eradicated so many life-threatening diseases, despite the vaccination attitudes and waves appearing through history. vaccines constitute one of the greatest success stories within the health sector. they form part of a multifaceted public health response to the emergence of pandemics. this review is general in nature. it highlights the major historical cornerstones in the development and progress of various types of vaccines since the beginning and through the ages until today. it recognizes the major pioneers whose work has made a difference in the advancement of this vital health field, despite all the anti-vaccination movements that appeared through the ages. multiple reviews were encountered during our literature search; however, each of those reviews dealt with a specific aspect of vaccination like effectiveness of a particular vaccine, or side effects of another or even attitudes toward vaccines. consequently, this work tried to put together the major achievements through history stressing the importance, continuous vital role, and the need for immunization for health prevention and protection as well as its impact on human experience. the physiological mechanisms behind vaccination are well established. vaccination activates the immune system and induces both innate and adaptive immune responses thus leading to the production of antibodies, in the case of a humoral response, or to the generation of memory cells that will recognize the same antigen, if there is a later exposure. periodic repeat injections can improve the efficacy and effectiveness of inoculations (1) . the approval of a vaccine abides by a set of well-established international rules and regulations. prior to their approval by the respective health authorities, scientists test vaccines extensively in order to ensure their efficacy, safety, and effectiveness. next to antibiotics, vaccines are the best defense that we have to date against infectious diseases; however, no vaccine is actually 100% safe or effective for everyone. this is attributed to the fact that each body reacts to vaccines differently (2) (3) (4) . significant progress has been made over the years to monitor side effects and conduct research relevant to vaccine safety. in addition, vaccine licensing is a lengthy process that may take 10 years or longer. the food and drug administration (fda) and the national institute of health (nih) require that vaccines undergo the required phases of clinical trials on human subjects prior to any use in the general public. this process is becoming more complex as more caution and care is being allocated to the quality of the market product. furthermore, vaccines can be divided into different categories depending on the way that they are prepared including liveattenuated vaccines, inactivated vaccines, subunit vaccines, conjugate vaccines, and toxoids. live-attenuated vaccines are used more frequently for viruses rather than bacteria, since the former contain a lesser amount of genes and can be controlled more easily (5) . the most common method in formulating live-attenuated vaccines involves passing the virus through successions of cell cultures to weaken it. this will produce a form of the virus that is no longer able to replicate in human cells. however, it will still be recognized by the human immune system, hence protecting the body from future invasions. examples of such vaccines are measles, rubella, mumps, varicella (more commonly known as chickenpox), and influenza. the disadvantage of using this technique is that the virus may transform into a more virulent form due to a certain mutation and cause illness once injected into the body. although this rarely occurs, it must always be taken into consideration (6) . by using heat, radiation, or certain chemicals, one can inactivate a microbe. the microbe will no longer cause illness but can still be recognized by the immune system. poliovirus and hepatitis a are common examples of inactivated vaccines. this type of vaccine has the disadvantage of being effective for a shorter period of time than live-attenuated vaccines. multiple boosters of the vaccine are sometimes required to improve effectiveness and sustainability (6) . a subunit vaccine contains only portions of the microbe that can be presented as antigens to the human immune system instead of the microbe as a whole. the antigens or the microbe portions that best activate the immune response are usually selected. an influenza vaccine in the form of shots is an example. in addition, a recombinant subunit vaccine has been made for the hepatitis b virus. hepatitis b genes are injected into maker cells in culture. once these cells reproduce, the desired antigens of the virus are produced as well, and these can be purified for use in vaccines (6) . conjugate vaccines are designed from parts of the bacterial coat. however, these parts may not produce an effective immune response when presented alone. hence, they are combined with a carrier protein. these carrier proteins are chemically linked to the bacterial coat derivatives. together, they generate a more potent response and can protect the body against future infections. vaccines against pneumococcal bacteria used in children are an example of conjugate vaccines (6) . some bacteria release harmful toxins that cause illness in infected individuals. vaccinations against such types of bacteria are prepared by inactivating or weakening the toxin using heat or certain chemicals. this will help prepare the immune system against future invasion. the vaccine against tetanus caused by the neurotoxin of clostridium tetani is a good example of a toxoid (6) . the generation of vaccine-mediated protection is a complex challenge. effective early protection is conferred primarily by the induction of antigen-specific antibodies. the quality of such antibody responses has been identified as a determining factor of efficacy. efficacy requires long-term protection, namely, the persistence of vaccine antibodies and/or the generation of immune memory cells capable of rapid and effective reactivation upon subsequent microbial exposure (7) . the exponential development of new vaccines raises many questions about their impact on the immune system. such questions related to immunological safety of vaccines as well as triggering conditions such as allergy, autoimmunity, or even premature death (7) . such issues were always looked for and monitored and some vaccines were even stopped because of these issues. recent vaccine models rely on both a cell-mediated response and a humoral immune response with highly specific antibodies and have shown an adequate amount of success. this, however, has not been the case for a few diseases such as tuberculosis where the humoral immunity mounted by the bacille calmette-guerin (bcg), the only currently used human vaccine, is inefficient in conferring proper immunization (8) . however, t cells do take part indirectly in the production of antibodies and of secreted biological molecules (e.g., interferon) for protection. it seems that a proper mounted immunity is better achieved by vaccineinduced antibodies, whereas a t cell immune response is needed for disease attenuation. hence, a robust understanding of b and t cell function is needed for proper immunization (9) . multiple determinants modulate the primary vaccine antibody response in healthy individuals; they include the vaccine type, live versus inactivated, protein versus polysaccharide, and use of adjuvants (10) . they also include the nature of the antigen and its intrinsic immunogenicity (11) , the dose of the antigen, the route of administration, the vaccine schedule, and the age at administration (12) . in addition, genes play a direct role in the body's response to vaccination even in healthy individuals (13, 14) . for each of the above determinants, there might be a particular mechanism involved and is further influenced by other factors including extremes of life, acute or chronic diseases, immunosuppression, and nutrition status (12) . early life immune responses are limited by (1) limited magnitude of antibody responses to polysaccharides and proteins, (2) short persistence of antibody responses to protein, (3) influence of maternal antibodies, and (4) limited cd8+ t cell and interferongamma responses. such factors are difficult to study in human infants due to neonatal immune immaturity and the inhibitory influence of maternal antibodies, which increase with gestational age and wane a few months post-natal (7) . on the other hand, in elderly persons, the immune system undergoes characteristic changes, termed immunosenescence, which leads to increased incidence and severity of infectious diseases and to insufficient protection following vaccination (15) . vaccines induce both innate (non-specific) and adaptive (specific) immune responses, which decline substantially with age thus leading to the decreased efficacy of vaccines in elderly persons. in the elderly, the innate immune response will witness a reduced phagocytic capacity of neutrophils and macrophages, a decrease in their oxidative burst, and impairment in the up-regulation of mhc class ii expression among other parameters (16) . in addition, persistent inflammatory processes occur with increasing age and may reduce the capacity to recognize stimuli induced by pathogens or vaccines. for the elderly, improved special antigen delivery systems are needed to overcome these limitations (12) . furthermore, the adaptive immune response is functionally defective in the elderly. the involution of the thymus with aging leads to a decrease in content and in output of mature naïve t cells into the periphery, which hampers the induction of adaptive immune responses to neoantigens. in the context of primary vaccination, this causes reduced response rate (7) (8) (9) (10) (11) (12) . b cells also undergo age-related changes that aggravate the functionality of b cells colonies. as effector b cells accumulate, naïve b cells decrease in number and this leads to a reduction in the diversity of antibody responses. in brief, vaccines tailored to the needs of the elderly will have to be developed, taking into consideration these limitations in order to improve protection in this population. in 2010, weinberg and szilagyl eloquently approached the issues of efficacy and effectiveness clarifying the road to correctly answer the relevant but complex question: "how well does the candidate vaccine prevent the disease for which it was developed?" they highlighted clearly the distinction between efficacy (individual level) and effectiveness (population level), which are often confused terms that fit well into the new paradigm of translational research (15) . at about the same time, curns et al. elaborated on the distinction between the epidemiologic concepts of vaccine efficacy and effectiveness within the context of translational research (17) . such concepts were also addressed earlier, but slightly differently, by clemens and co-workers in two separate publications in 1984 and 1996, and also by orenstein et al. in 1989 (18-20) . accordingly, vaccine efficacy is measured as the proportionate reduction in disease attack rate when comparing vaccinated and unvaccinated populations. vaccine efficacy studies always have rigorous control for biases through randomized prospective studies and vigilant monitoring for attack rates (15) . in addition to proportionate reduction in attack rates, these studies can furthermore assess outcomes through hospitalization rates, medical visits, and costs. despite the complexity and expenses that arise from the initial trials, they are needed to establish vaccine efficacy (15) . on the other hand, the related but distinct concept of vaccine effectiveness has always been compared to a "real world" view of how a vaccine reduces disease in a population. as such, it can evaluate risks versus benefits behind a vaccination program under more natural field conditions rather than in a controlled clinical trial. vaccination program efficiency is proportional to vaccine potency or efficacy in addition to the degree and success of immunization of the target groups in the population. in brief, it is influenced by other non-vaccine-related factors that could influence the outcome. the "real world" picture provided by vaccine effectiveness data is desirable in planning public health initiatives, an advantage that makes these studies attractive. translating research data into real public health application are a process that has been reengineered by the nih as part of a road map for future research. consequently, a new expanded definition of translational research, consisting of four steps was proposed, which fits nicely within the continuum of vaccine research (21) . in this new process of phase i to phase iv clinical trials, safety, immunogenicity, efficacy, and post-licensure effectiveness of a particular vaccine are assessed ending up in phase iv with the burden of the disease (15) . vaccines stood the test of time and many techniques have been introduced into the world of vaccination. practitioners used to write articles about their vaccinating instruments and techniques. according to john kirkup, vaccinators and physicians used various instruments and techniques to inject the vaccinating material into the human body. more than 45 different vaccinating instruments have been recorded in british, american, german, and french catalogs between the years 1866 and 1920; most of them are out of use nowadays (22) . there are multiple major landmarks in the history of vaccines. it was reported that the origin goes as far back as hippocrates, the father of modern medicine, 400 b.c. he described mumps, diphtheria, and epidemic jaundice among other conditions (23) . the earliest methods of immunization and protection against smallpox date back to about 1000 a.d., and are attributed to the chinese. it has been said that the son of a chinese statesman was inoculated against smallpox by blowing powdered smallpox sores into his nostrils (24) . another method used for inoculation was the removal of fluid from the pustules of an infected individual and subsequently rubbing it into a skin scratch of a healthy individual. this procedure was later introduced into turkey around 1672, long before reaching europe (25) . it took six centuries for variolation to be introduced to great britain, in 1721 (26) . the eighteenth century was marked by several major events that started with the spread of variolation from turkey and china to england and america, followed, in the late eighteenth century, by edward jenner's breakthrough of vaccination. variolation, derived from the latin word varus, meaning "mark on the skin, " or inoculation, derived from the latin word inoculare, meaning "to graft, " are two words that were used interchangeably in describing the aforementioned immunization process. by 1715, variolation was introduced to england after the pursuit of an english aristocrat, lady mary wortley montague, who had been personally inflicted with an episode of smallpox. after being informed of the method of variolation, she made the embassy surgeon, charles maitland, perform the procedure on her 5year-old son in 1718 in turkey. in 1721, dr. charles maitland performed the first english variolation on lady montague's 4year-old daughter after their return to london (27) . lady montague became a great proponent of the procedure and worked thoroughly on advocating this process for its ability to protect against the spread of smallpox. data from the u.s. national library of medicine and the nih showed that 1-2% of those variolated died as compared to 30% of those who contracted the disease naturally. correspondingly, rev. cotton mather and dr. zabdiel boylston introduced variolation in america and were also great advocates of this procedure especially since, in the same year, there was a smallpox epidemic in boston that killed hundreds (28) . however, lady montague, rev. mather, and dr. boylston faced great opposition regarding their promotion of variolation even with the presentation of the comparative analysis of fatality rates, which reached 2% for those variolated compared to 14% for the naturally occurring disease (27) . despite some variolation-related deaths, the word of inoculation kept spreading along with data suggesting that variolation was still the safeguard against the spread of smallpox. in addition, benjamin franklin, who lost his son in 1736, wrote: "i long regretted that i had not given it to him by inoculation, which i mention for the sake of parents who omit that operation on the supposition that they should never forgive themselves if a child died under it; my example showing that the regret may be the same either way, and that therefore the safer should be chosen" (24) . in 1759, dr. william heberden, at his own expense and with the support of benjamin franklin, wrote a pamphlet entitled "some account of the success of inoculation for the small-pox in england and america: together with plain instructions by which any person may be enabled to perform the operation and conduct the patient through the distemper" (29) . toward the late eighteenth century came jenner's breakthrough in finding a safer immunizing technique than variolation, which is vaccination. the method of variolation had low yet significant death rates; therefore, physicians were on the quest of finding a new and more secure method of immunization with minimal or no death rates. on this basis, an english physician named edward jenner (1748-1823) searched for a cure for smallpox, a debilitating disease that rendered the world helpless. jenner became interested in certain individuals who were immune to smallpox because they had contracted cowpox in the past. he personally witnessed this when he learned of a dairymaid that was immune to smallpox due to her previous infection with the cowpox virus, usually transmitted from infected cattle. during that time, an english farmer named benjamin jesty personally took charge of inoculating his wife and children with fresh matter from a cowpox lesion in one of his cows out of fear of having his wife and children become victims of the smallpox epidemic. he applied this method after having contracted cowpox himself and believing he was immune to smallpox. he never published his results even though his wife and children did not show symptoms after being exposed to smallpox (27) . during these years, there were still outbreaks of smallpox. george washington, after surviving smallpox, ordered mandatory inoculation for his troops in 1777 (27) . after many speculations on the role of cowpox and its immunizing effect against smallpox, jenner, in 1796, inoculated an 8-year-old boy named james phipps using matter from a fresh cowpox lesion on the hands of a dairymaid named sarah nelms who caught them from her infected cattle. after several days, jenner inoculated the boy again but this time with fresh matter from a smallpox lesion and noted that the boy did not acquire the disease proving that he was completely protected (27) . a few years later, word of his success circulated among the public, and jenner wrote "an inquiry into the causes and effects of the variolae vaccinae, a disease discovered in some of the western counties of england, particularly gloucestershire and known by the name of cowpox, " after adding several cases to his initial achievement with the boy phipps. at first, his publication and achievement did not stir any interest in his community, but with time, word of jenner's breakthrough began spreading (27) . the late eighteenth century was characterized by the implementation of the new process of immunization, vaccination, which required the inoculation of fresh matter from cowpox lesions into the skin of healthy individuals. the nineteenth century was a major landmark in the history of vaccines since it witnessed discoveries made by louis pasteur, the father of microbiology, and robert koch, the scientist who discovered the germ responsible for tuberculosis (26) . in the beginning of the nineteenth century, the term "vaccination" was introduced by richard dunning from the latin word for cow "vacca. " after becoming aware of the fact that vaccination was more secure than variolation, several physicians initiated movements against the use of variolation and advocated for its eradication. dr. jean de carro, for example, aided in the elimination of variolation and its substitution with vaccination. some of the major efforts implemented in america were initiated by dr. benjamin waterhouse, who received the vaccine from edward jenner and vaccinated his own family. he later proved that they acquired immunity when they remained asymptomatic after he infected them with smallpox. waterhouse worked effectively on making vaccination universal in the u.s. unfortunately, like any other medical breakthrough, problems arose both because waterhouse aimed at making profit and the public was not ready to implement these procedures. however, after breaking his initial monopoly, waterhouse accepted to share his vaccines and made the supplies available to other physicians (24) . despite all these efforts, smallpox epidemics continued to occur and jenner stated in a pamphlet that he wrote, "the annihilation of the small pox, the most dreadful scourge of the human species, must be the final result of this practice. " eradication was finally achieved 176 years later. the time it took could be attributed to the fact that jenner did not think of the necessity of revaccination nor of the instability of vaccines, which made them unable to handle different environmental conditions, including countries other than england (30) . the late nineteenth century was distinguished by pasteur's achievements that made him the father of vaccines after creating the first laboratory vaccine. louis pasteur (1822-1895), a french chemist and microbiologist, was the first to propose the "germ theory" of disease in addition to discovering the foundations of vaccination (26) . he studied chicken cholera and received strains of bacteria causing anthrax and septic vibrio. pasteur started his experiments by intentionally infecting chickens by feeding them cholera-polluted meals and then recording the fatal progression of the illness. at first, pasteur was using fresh cultures of the bacteria to inoculate the chickens, most of which did not survive. during that time, pasteur had to go on a holiday, so he placed his assistant in charge of injecting the chickens with fresh cultures. however, his assistant accidentally forgot to perform the injections, and the bacterial cultures were left in a medium that was exposed to room air for about a month. later, the attendant injected the chickens with the now "attenuated" strain of bacteria resulting in mild, nonfatal symptoms. pasteur later re-injected these chickens, but this time with fresh bacteria. to his surprise, they did not get ill. ultimately, pasteur reasoned that what made the bacteria less deadly was exposure to air, mainly oxygen. pasteur used the french verb "vacciner" during the years 1879 and 1880 to describe how he was able to provide total body immunity through vaccination by inoculation of an attenuated virulence which was the first vaccine made by a human in the laboratory (31) . pasteur also developed the anthrax vaccine in his laboratory, not long after performing his studies on chicken cholera. in 1881, pasteur used his own anthrax vaccine, which contained attenuated live bacterial cultures in addition to carbolic acid, and demonstrated that all vaccinated animals survived while the control group died (32) . during the same year, louis pasteur in france and george miller sternberg in the u.s. almost simultaneously and independently isolated and grew the pneumococcus organism. later in 1884, pasteur successfully fought rabies that was endangering the european livestock by using his attenuated rabies vaccine obtained from desiccated brain tissue inactivated with formaldehyde, which provided immunity to dogs against rabies in his experiments (26) . he reported his success to the academy of sciences in france, and a year later, he applied his original vaccine 60 h after a 9-year-old boy was bitten several times by a rabid dog. the boy survived after being first inoculated with the most attenuated organisms, then subsequently with less attenuated organisms each day for 10 days (33) . in 1888, the pasteur institute was established as a rabies treatment center as well as an infectious diseases research and training institute. after pasteur's successful live vaccines, a new type of vaccine was introduced in the last few years of the nineteenth century. these were killed vaccines, which were directed against three chief bacterial causes of human morbidity: cholera, typhoid, and the plague. the first cholera vaccine used to immunize humans was actually a live vaccine developed by jaime ferran (1852-1929), which provided a high level of protection during the 1884 epidemic in spain. however, the first killed vaccine for cholera was developed in 1896 by wilhelm kolle (1868-1935) and was used in japan in 1902 with over 80% efficiency. the credit for developing the killed typhoid vaccine during the 1890s goes to both richard pfeiffer and almroth wright who made great contributions. wright was later credited for carrying out the "first large-scale vaccination using a killed typhoid vaccine" (34) . finally, the killed vaccine for plague was first developed in 1896 by haffkine, who was one of pasteur's followers, when an epidemic struck bombay. during this period, vaccine production was taken over by factorytype laboratories, which formed the precursors of the biological products supply houses. many types were produced. paul ehrlich (1854-1915), a german physician and scientist who worked under a contractual collaboration with behring, noted the existence of toxoids in the late 1890s. he also promoted enrichment and standardization protocols. these protocols enabled the exact determination of quality of the diphtheria antitoxins. in 1907, it was demonstrated that toxoids could be used to durably immunize guinea pigs. it is crucial to briefly address the historical background of the bacterial infections that led to some of the earliest and most successful use of toxoids, inactivated forms of bacterial toxins, for the purpose of immunization. until the twentieth century, diphtheria, tetanus, and pertussis proved to be significant causes of illness and death with no effective treatments or prevention in sight. fortunately, advances in 1890 improved the prognosis of numerous future patients (35) . at the end of the nineteenth century, especially in 1896 and 1897, the cholera and typhoid vaccines were developed, followed by the introduction of the plague vaccine. the latter was preceded by the preparation of anti plague horse serum at the pasteur institute by alexandre yersin. yersin demonstrated disease protection in animals. later, he went to china to try his vaccine on humans during a plague epidemic (26) . diphtheria is a potentially fatal disease that primarily involves tissues of the upper respiratory tract and kills its victims slowly by suffocation. in 1884, a german physician, edwin klebs (1834-1913), was able to successfully isolate the bacteria that proved to be the etiological agent of the disease. it was later proved that toxin production is initiated only after the bacteria are themselves infected by a specific virus or a bacteriophage carrying the toxin's genetic instructions (35) . in france, during the year 1888, emile roux discovered the diphtheria toxin. his discovery led to the development of passive serum therapies through the scientific contributions of many, including emil von behring and paul ehrlich (26) . similarly, the etiological agent of pertussis, commonly known as the "whooping cough, " was found to be a bacterium isolated from infected patient tissues in 1906 (36) . tetanus was similarly a significant cause of mortality usually resulting from dysfunction of the autonomic nervous system or the respiratory muscles (37) . in 1884, another german scientist, arthur nicolaier (1862-1942), correlated tetanus with an anaerobic soil bacterium found in wounds. a few years later, the japanese investigator shibasaburo kitasato (1853-1931) was able to isolate this bacterium (35) . at the beginning of world war i in 1914, the tetanus toxoid was introduced following the development of an effective therapeutic serum against tetanus by emil von behring and shibasaburo kitasato. the rabies and typhoid vaccines were then licensed in the u.s. as the etiology of these destructive diseases was slowly being uncovered, by shibasaburo kitasato along with emil von behring (26) . they discovered that the serum of animals that had been exposed to sub-lethal doses of the bacteria involved in tetanus and diphtheria was protective against the lethal effects associated with these pathogens by having an antitoxin effect when injected into another animal. additionally, this discovery, which earned behring the inaugural nobel prize for physiology and medicine in 1901, was the concept of passive transfer in addition to serum therapy. he proved that serum could be acquired from immune animals and transferred to others as protection (38) . once this concept made its way to clinical practice in 1891, technical problems were faced while developing the right antitoxin concentration and potency. as a result, in the early twentieth century, the u.s. congress enacted the biologics control act legislation "to regulate the sale of viruses, serums, toxins, and similar products" to ensure medication quality control. nevertheless, with the increasing use and popularity of antitoxins derived from animal serum, scientists began to observe a syndrome now called serum sickness, or a reaction to immune-complexes formed from combining high concentrations of antigens with antibodies. this eventually led to the use of human rather than animal serum in order to decrease the frequency of adverse events; still, serum therapy was not perfect in preventing disease due to the frequency of adverse events and its brief duration of action. later on, combining diphtheria toxin and antitoxin in the same syringe proved much more effective in decreasing mortality rate. this combination became commercially available in 1897. this was the first step in the shift from passive to active immunization (35) . in 1923, gaston ramon (1886-1963), a french veterinarian working at the pasteur institute, used a diphtheria toxoid produced by formalin and heat inactivation without the use of antitoxin to safely induce active immunity in humans. this product, termed anatoxine, was the basis for the novel and clinically effective toxoid vaccine against diphtheria. experiments followed to improve the durability of the protective response of the vaccine, and in 1926, the importance of aluminum salts as an adjuvant added to the vaccine to augment the immune response to the antigen, became apparent (38) . this was discovered by alexander thomas glenny (1882-1965) who proved that toxoid alone produced a lower level of antibody and immunity than desired, whereas better immunity was achieved when an inflammatory reaction was triggered. with these significant improvements, tetanus and diphtheria toxoids became routinely used across america and europe in the 1930s and 1940s (35) . since then, refinements have been made to these vaccines to yield higher purity and reduce the number of booster doses. nowadays, widespread childhood vaccination is reducing the burden of these diseases. while this is a huge advantage, vaccines may potentially produce adverse effects that can discourage their acceptance by some populations. this has led to numerous safety movements which culminated in the congressionally legislated national childhood vaccine injury act in the 1980s created to compensate families for selected adverse events potentially related to mandatory childhood vaccinations (37) . nevertheless, global recommendations continue to call for routine immunization of children against diphtheria, tetanus, and pertussis with the combined dtp vaccine to sustain immunity in childhood and adolescence. dtp has, therefore, become one of the most widely used vaccines to achieve widespread immunity across age groups (35) . tuberculosis, otherwise known as the "great white plague, " is another disease that started spreading as an epidemic once industrialization began. this disease caused approximately 15% of deaths in the eighteenth and nineteenth centuries across all socioeconomic groups (39) . a french physician named jean antoine villemin (1827-1892) demonstrated that the mode of transmission of disease is through the respiratory system. robert koch (1843-1910) , known as the founder of modern bacteriology, revealed in 1882 that the causative agent of the disease is mycobacterium tuberculosis, which later became known as koch's bacillus (40) . following this discovery, koch created what later came to be known as koch's postulates, which listed the criteria necessary for proof of bacterial causality: "the organism must be present in diseased tissues; it must be isolated and grown in pure culture; and the cultured organisms must induce the disease when inoculated into healthy experimental animals" (39) . in 1908, two bacteriologists working in the pasteur institute in lille, albert calmette (1863-1933) and camile guerin (1872-1961), announced their discovery of mycobacterium bovis, which is a strain of tubercle bacilli that could be used to create a vaccine against tuberculosis. this occurred after it became evident that different forms of the bacterium were required to prevent or treat tuberculosis, including non-pathogenic, attenuated, or killed tubercle bacilli from different sources, including human, bovine, and equine. this strain had an attenuated virulence while maintaining its antigenicity and became known as bcg (40) . bacille calmette-guerin vaccinations proved to be successful in animal studies in 1921 and were soon used as an oral vaccine to immunize humans against tuberculosis. in 1927, the bcg vaccine, constituted by the live-attenuated m. bovis, was first used in newborns. it has become the most widely administered of all vaccines in the who expanded program for immunization, but has been estimated to prevent only 5% of all potentially vaccinepreventable deaths due to tuberculosis (26) . despite its imperfections, bcg remains the only effective vaccination for protection against human tuberculosis (39) . yellow fever is a highly fatal infection caused by a small, enveloped, single-stranded rna virus and results in renal, hepatic, and myocardial injury, along with hemorrhage and shock (41) . unlike previously mentioned diseases, the history of yellow fever is highly uncertain and filled with misconceptions. early work on immunization against the disease began with carlos finlay in the 1870s and 1880s when koch's postulates were becoming increasingly accepted. finlay proposed that mosquitos carried the yellow fever "germ. " he attempted to prove it by feeding mosquitos that had fed on yellow fever patients. however, it was later revealed that his process failed due to the lack of an incubation period within the mosquito, which is a transmission requirement that finlay was unaware of (42). since 1900, significant advances have been made in creating a vaccine by the yellow fever commission, which was originally led by walter reed (1851-1902) along with jesse lazear, aristedes agramonte, and james carroll. reed's experiments took finlay's discovery one step further by adding an incubation period of approximately 2 weeks and achieved the same positive results. when mosquitos bite non-immune individuals after feeding on individuals who had yellow fever, none of the non-immune subjects died and very few suffered disease. this led the commission of investigators to a major discovery, namely, the identification of the asibi strain, which is the parent strain of the present 17d vaccine, obtained via continuous indirect passage through the aegypti mosquitos and direct passage through monkeys. in addition to identifying the etiological agent of the disease, the commission also identified rhesus monkeys as susceptible hosts, hence providing a means for testing future vaccine attempts. this paved the way for max theiler and other rockefeller foundation scientists to develop a successful live-attenuated vaccine for yellow fever in 1937. "the most important experimental passage seriesdesignated 17d -used a virus that had been subcultured eighteen times in whole mouse embryos, followed by 58 passages in wholeminced chick embryo cultures, after which the virus was passed in minced chick embryo depleted of nervous tissue. " theiler himself was actually one of the first individuals to be successfully vaccinated. the vaccine was quickly implemented, and alternative vaccines shown to be more dangerous were discontinued (42) . influenza has proved to be very difficult to trace back in history due to its non-specific symptoms and features. it was not until the early twentieth century that influenza outbreaks began to be systematically studied due to well-documented clinical descriptions and epidemiological data. in 1918, the "spanish flu" influenza pandemic was responsible for 25-50 million deaths worldwide and more than one-half million in the u.s. this virus was unusual because it spread so quickly, was so deadly (26) . richard e. shope (1901-1966) , a physician who conducted his research in the department of animal pathology at the rockefeller institute in princeton, was the first to isolate influenza virus; a member of the orthomyxovirus family, from a mammalian host in 1931 (43) . he was able to induce the syndrome of swine influenza in pigs by applying respiratory secretions intranasally. he also isolated a bacterium from the respiratory tract of infected pigs called haemophilus influenzae suis. when this bacterium was combined with a filterable agent and inoculated, the pigs developed the clinical manifestations of swine influenza. these two agents seemed to act synergistically with the virus to damage the respiratory tract hence creating the suitable environment needed for the virus to exercise its pathological effects. in 1933, scientists from the british national institute for medical research including christopher andrews, wilson smith, and patrick laidlaw successfully isolated and transmitted the influenza virus from humans. throughout this year, "burnet has successfully cultivated the organism in chick embryos; other influenza types had been recognized; neutralizing antibodies had been identified and quantitated; and viral surface glycoproteins, h and n had been described" (43) . these discoveries led scientists to introduce the inactivated vaccine in the mid-1940s that is still used to this day (44) . the influenza a/b vaccine was initially presented to the armed forces epidemiological board in 1942. it was licensed following the war and used for civilians in 1945 in the u.s. starting 1985, a series of vaccines were licensed for haemophilus influenza type b (hib) polysaccharide vaccines. these vaccines are recommended routinely for children at 15 and 24 months of age. the vaccine was, however, not consistently immunogenic in children <18 months of age. in 1987, the protein-conjugated hib vaccine was licensed and in the next 2 years, it became available. during 1996, a combined vaccine hib conjugate and hepatitis b was licensed. later on, in 2003, the first nasally administered influenza vaccine was licensed. this live influenza a and b virus vaccine was indicated for healthy, non-pregnant persons ages 5-49 years. the contracts to develop vaccine against the h5n1 avian influenza virus were awarded to aventis pasteur and to chiron in 2004. during the following year, an inactivated, injectable influenza vaccine was licensed. it was indicated for adults 18 years of age and older. during the same year, the fda approved afluria, a new inactivated influenza vaccine, for use in people aged 18 years and older. two years later in 2009, the department of health and human services, supported the building of a facility to manufacture cellbased influenza vaccine. it also directed toward development of a vaccine for novel influenza a (h1n1). during the same year, the fda approved four vaccines against the h1n1 influenza virus high-dose inactivated influenza vaccine (fluzone high-dose) for people aged 65 years and older. in 2012, the fda approved several vaccines: hibmency a new combination of meningococcal and hib vaccine for infants; flucelvax, which is the first seasonal influenza vaccine, manufactured using cell culture technology and a quadrivalent formulation of fluarix (26) . unfortunately, one of the difficulties in dealing with influenza is the continuous mutability of the viral genome necessitating annual reassessments and reformulations of the vaccine. this has led to a suboptimal effectiveness of influenza vaccines, which are only successful against strains included in the vaccine formulation or strains of homogenous subtype. several pandemics were caused by the influenza virus: during the years 1957-1958, the "asian" influenza pandemic caused by h2n2 influenza virus resulted in an estimated 70,000 deaths in the u.s. alone and in the years 1968-1969, the "hong kong" influenza pandemic caused by an h3n2 influenza virus induced roughly 34,000 deaths in the u.s. (26) . future studies should focus on producing vaccines protective against variant strains and creating surveillance systems to detect novel strains in time to formulate the proper vaccines. poliomyelitis, or polio, is an intestinal infection spread between humans through the fecal-oral route. it is a disease of the developed nations striking younger individuals most frequently in warmer weather. one of the most famous polio victims, president franklin d. roosevelt, founded the national foundation for infantile paralysis in 1938, later known as the march of dimes (26) . it is well established that better hygiene decreases childhood exposure to the disease, when infection would usually be milder since protective maternal antibodies are present (45) . in 1954, the nobel prize in medicine was awarded to john enders, thomas weller, and fredrick robbins for their discovery of the ability of poliomyelitis viruses to grow in tissue cultures (26) . two major lifelong competitors were involved in the race for the polio vaccine, jonas salk and albert sabin . salk took a more traditional route using a killed-virus approach, which did not involve natural infection in acquiring immunity. instead, his approach involved a fully inactivated virus that still had the ability to induce protective antibodies. sabin, on the other hand, set out to create a live-virus vaccine based on the belief that this would trigger natural immunity and provide a lasting protection. salk had speed, simplicity, and safety on his side since a killedvirus did not have the ability to revert to virulence, whereas the live-virus vaccine could be given orally, establish longer lasting immunity, and offer passive vaccination through the excreted weakened virus potentially immunizing a large portion of nonvaccinated communities (46) . not surprisingly, salk's vaccine was the first to make it to the population. following successful clinical trials in 1954, six companies began mass production of the vaccine. unfortunately, salk's vaccines were soon suspended and recalled when contaminated samples were found in the market due to poor monitoring and control in some laboratories leading to serious health consequences and national panic. the first cutter polio vaccine incident was reported on april 25, 1955 with 5 more cases reported just a day later with the number eventually rising to 94 of those vaccinated and in 166 of their close contacts. on april 27, the laboratory of biologics control requested that cutter laboratories recall all vaccines and the company did so immediately. on may 7, the surgeon general recommended that all polio vaccinations be suspended pending inspection of each manufacturing facility and thorough review of the procedures for testing vaccine safety. the investigation found that live polio virus had survived in two batches of vaccines produced by cutter laboratories. large-scale polio vaccinations resumed in the fall of 1955 (26) . at the same time, sabin had been making great advances with his live-virus vaccine since 1951. after successful clinical trials conducted in the soviet union that left polio virtually wiped out with no safety issues, it soon became the vaccine of choice in the west. the polio vaccination assistance act was enacted by congress and was the first federal involvement in immunization activities. it allowed congress to appropriate funds to the communicable diseases center [later the centers for disease control and prevention (cdc)] to help states and local communities acquire and administer vaccines. at the beginning of the 1960s, the oral polio vaccine types 1, 2, and 3 as well as the trivalent product were licensed in the u.s. the first 2 were developed by sabin and grown in monkey kidney cell culture, while the trivalent oral polio was developed to improve upon the killed salk vaccine (26) . as a result, in the late 1990s, the cdc recommended switching back to salk's killedvirus polio vaccine, while the who also advocated the switch for polio-free nations and the continued use of the favored live-virus vaccine for routine immunization (45) . the last two cases of wild type polio were reported in an unvaccinated amish in 1979 and in a 5-year-old boy from peru in 1991 (26) . in 1990, the enhanced-potency inactivated poliovirus vaccine was licensed. following successful developments in the polio vaccine, attention soon shifted to three other common viral diseases of childhood: measles, mumps, and rubella. the measles virus is an rna virus from the genus morbillivirus belonging to the paramyxooviridae family. it causes an acute illness that includes fever, cough, malaise, coryza, and conjunctivitis, in addition to a maculopapular rash. in general, measles is a mild disease but, like many others, has the potential to cause serious complications. in addition, measles is known to be one of the most contagious human diseases causing major outbreaks to occur very often. until the year 2000, measles was still the leading cause of vaccine-preventable childhood deaths worldwide (47) . john enders (1897 enders ( -1985 , known as the "father of modern vaccines" had a particular interest in revealing the virus responsible for measles. he isolated the edmonston strain of the virus in 1954, which was named after the child from whom it was isolated. a formalin-inactivated measles virus vaccine derived from this strain was subsequently licensed in the u.s. in 1963. however, following the discontinuation of this vaccine in 1967 due to short-lived and incomplete immunity, over 20 further attenuated vaccines were developed and used throughout the world, most of which were also derived from the edmonston strain (48) . the first live-virus measles vaccine, rubeovax, was licensed in 1963. other live-attenuated virus measles vaccines were eventually licensed in the u.s. in 1965. the recommended age for routine administration was changed from 9 to 12 months of age. the first national measles vaccine campaign was launched in 1966. the world recorded a 90% decreased incidence compared to the pre-vaccination years. in 1968, a second live, further attenuated measles virus vaccine was also licensed. in 1989, both the advisory committee on immunization practices (acip) and the american academy of pediatrics (aap) issued recommendations for a routine second dose of the measles vaccine. during the midto-late 1980s, a high proportion of reported measles cases were in school-aged children (5-19 years) who had been appropriately vaccinated. these vaccine failures led to new national recommendations of a second dose of measles-containing vaccine (26) . mumps is another acute viral illness. it is the only virus known to cause epidemic parotiditis in humans accompanied by fever, anorexia, headache, and malaise. k. habel and john enders isolated the virus in 1945 (26) , and trials of formalin-inactivated mumps vaccine in humans began the same year by joseph stokes and colleagues and by enders. this approach was abandoned in the 1950s due to short-lived immunity, and work began to develop live-attenuated mumps vaccines in 1959 by the vaccinologist maurice hilleman (1919 hilleman ( -2005 and colleagues (48) . hilleman isolated the wild type virus from his daughter, jeryl lynn, who contracted the virus at the age of 5 and was recovering from it. it became known as the jeryl lynn strain of mumps virus. the mumps livevirus vaccine was licensed in december 28, 1967 (26) . trials with this attenuated virus resulted in 100% protective efficacy and the vaccine was licensed in the u.s. in 1967. this strain is still used to produce mumps vaccines until this day. it is given as part of the measles, mumps, and rubella (mmr) vaccine (49) . rubella is a rash disease in children and adolescents caused by a filterable virus. it poses a severe threat to pregnant women and their children by potentially causing congenital deafness and cataracts. in 1964, a rubella epidemic swept the u.s. resulting in 12.5 million cases of rubella infection, with an estimated 20,000 newborns having congenital rubella syndrome (crs), along with fetal and neonatal deaths in the thousands (26) . the rubella virus was detected and isolated by two groups of scientists, thomas weller and franklin neva at harvard medical school, in addition to paul parkman and colleagues at the walter reed army institute of research (wrair). similar to measles and mumps, inactivated whole virus vaccines proved ineffective, so efforts turned to discovering a live-attenuated vaccine (26) . in 1963, paul parkman left wrair and joined harry meyer jr. at the nih division of biological standards, and the pair developed the first live-attenuated rubella vaccine in 1966, hpv-77, which was subsequently included in the initial mmr vaccine used in the u.s. in the 1970s (26) . maurice hilleman discovered the superior ra 27/3 vaccine that became the only vaccine used outside of japan starting in the late 1970s. this vaccine maintained its preference due to many factors including increased durability and harmlessness to fetuses of inadvertently vaccinated pregnant women (47) . in 1969, three rubella virus strains were licensed in the u.s.: hpv-77 strain grown in dog-kidney culture, hpv-77 grown in duck-embryo culture, and cendehill strain grown in rabbit-kidney culture. a decade later, in 1979, the ra 27/3 (human diploid fibroblast) strain of rubella vaccine (meruvax ii) by merck was licensed. all other strains were discontinued. merck's combined trivalent mmr as well as the combined measles and rubella vaccine (m-rvax) developed by maurice hilleman and colleagues, was licensed by the u.s. government in 1971 (26) , and is still in use today. moreover, the age for routine vaccination with mmr vaccine was changed from 12 to 15 months in the year of 1976. the next vaccine that combined measles, mumps, rubella, and varicella antigens (proquad) was licensed in 2005. it was indicated for use in children 12 months to 12 years. in response to the association of this vaccine with autism, in 2004, the eighth and final report of the immunization safety review committee was issued by the institute of medicine concluded that the body of epidemiological evidence favors rejection of a causal relationship between the mmr vaccine and autism (26) . combination vaccines hold many advantages including reduced need for several injections, therefore, reducing the incidence of vaccination site reaction (48) . the etiological agent of clinical hepatitis, identified by its distinguishing yellow jaundice, was found to be infectious in the early 1900s. the different hepatitis strains, a and b, were first differentiated in 1942 (26) . in the mid-1960s, blumberg and coworkers and prince discovered hepatitis b surface antigen in the circulating blood of carriers of the infection. deinhardt et al. soon followed this discovery with that of the hepatitis a virus (49) . provost et al. successfully prepared a killed hepatitis a vaccine in 1986, which proved to be safe and highly effective in extensive clinical trials. the first inactivated hepatitis a vaccine (havrix) was licensed in 1995. the following year, a second inactivated vaccine (vaqta) also became available (50) . hepatitis b, on the other hand, rarely causes any severe risk as a primary infection. however, those who develop a chronic persistent infection may continue to have severe disease for the rest of their lives. this may even lead to cirrhotic destruction of the liver due to host immune response to the virus. the discovery of the surface antigen particles of the hepatitis b virus by blumberg and colleagues in the plasma of human carriers was followed by attempts to create a vaccine. in 1968, a killed hepatitis b vaccine was developed and clinical trials began in 1975 proving the safety and efficacy of the vaccine. merck and pasteur institute subsequently independently licensed the plasma-derived vaccine in 1981 (50). on july 23rd 1986, the recombinant hepatitis b vaccine (recombivax hb) was licensed. using recombinant dna technology, merck scientists developed a hepatitis b surface antigen subunit vaccine. three years later, on august 28th 1989, the recombinant hepatitis b vaccine (engerix-b) was licensed. a decade later in 1999, the fda approved a two-dose schedule of hepatitis b vaccination for adolescents 11-15 years of age using recombivax hb (by merck) with the 10-μg (adult) dose at 0 and 4-6 months later. at the beginning of the new millennium, in 2001, a combined hepatitis a inactivated and hepatitis b (recombinant) vaccine, twinrix was licensed. the following year, a vaccine combining diphtheria, tetanus, acellular pertussis, inactivated polio, and hepatitis b antigens (pediarix) was licensed (26) . in conclusion, fortunately, both hepatitis a and b are now preventable due to the discovery of these highly effective vaccines that proved to maintain long-term immunity in vaccinated individuals (50) . in 1966, the world health assembly called for global smallpox eradication, which was launched the following year. during the first year of the program 217,218 cases of polio were reported in 31 countries that were endemic to smallpox. four years later, the cdc recommended discontinuation of routine vaccination for smallpox in the u.s. following a greatly reduced risk of disease (26) . during the 70s, especially in 1974, the expanded program on immunization was created within who, in response to poor immunization levels in developing countries (<5% of children in 1974). the following vaccines were used by the expanded program on immunization: bcg, polio, dtp, measles (often mmr vaccine), yellow fever (in endemic countries), and hepatitis b. three years later, in october 1977, the last case of naturally acquired smallpox occurred in the merca district of somalia. in the same year, the first pneumococcal vaccine was licensed, containing 14 serotypes (of the 83 known serological groups) that composed 80% of all bacteremic pneumococcal infections in the u.s. (26) . on may 8 1980, the world health assembly declared the world free of naturally occurring smallpox. on the other hand, in july 1983, two enhanced pneumococcal polysaccharide vaccines (pneumovax 23 and pnu-imune 23) were certified. these vaccines included 23 purified capsular polysaccharide antigens of streptococcus pneumoniae and replaced the 14-valent polysaccharide vaccine licensed in 1977. a few years later, in 1988, the world health assembly passed a resolution to eradicate polio by the year 2000 (26) . later on, in 1992, the japanese encephalitis (je) inactivated virus vaccine (je-vax) was licensed. during the year 1994, the expanded program for vaccine development and the vaccine supply and quality program were merged creating the global program for vaccines and immunization. during the same year, the western hemisphere was finally labeled as "polio-free" by the international commission for the certification of polio-eradication. the 1996 was another monumental year with the launching of the international aids vaccine initiative (iavi) that called for the speedy development of a human immunodeficiency virus (hiv) vaccine for use worldwide. this in turn led to the introduction of the scientific blueprint for aids vaccine development. iavi was funded by several ngos and foundations. it is a collaborating center of the joint united nations program on hiv/aids (unaids) whose efforts led finally lead to the first possible vaccine against hiv (aidsvax) which reached phase iii trials, the largest recorded human hiv vaccine trial at that time. the trial involved 5400 volunteers from the u.s., canada, and the netherlands, the majority of whom were men who have sex with men (26) . preliminary results from the trial of aids vax (vaxgen) vaccine were reported in early 2003. while the vaccine was shown to be protective amongst non-caucasian populations, especially african-americans, the same effect was not reproducible in caucasians (26) . during the same year, the children's vaccine program was established at who's program for appropriate technology in health (path). the program's goal was to provide vaccines to children in the developing world and to accelerate research and development of new vaccines. the first vaccines purchased were hib, hepatitis b, rotavirus, and pneumococcal, which were not commonly used in the developing world (26) . at the beginning of the new millennium, the western pacific region of the world was certified as polio-free. during the next 2 years, the european region also became certified as polio-free. in 2006, the fda licensed the first vaccine developed to prevent cervical cancer (gardesil), precancerous genital lesions and genital warts due to human papillomavirus (hpv) types 6, 11, 16, and 18. the first smallpox vaccine for certain immune-compromised populations was delivered under project bioshield on july 10th 2010. the following year 2010, the who declared the "decade of vaccines" and in 2012, the united nations foundation launched shot@life campaign (26) . varicella ("chickenpox") is caused by the varicella zoster virus (vzv). michiaki takahashi, professor of virology at the research institute for microbial diseases at osaka university, successfully produced the oka vaccine strain of live, attenuated varicella vaccine in the 1970s. takahashi was able to make this remarkable advance at a time when very few viruses had been attenuated to produce efficacious live-virus vaccines including yellow fever, polio, measles, mumps, and rubella as previously mentioned. the vzv vaccine is the first and only licensed live, attenuated herpesvirus vaccine in the world. numerous trials in the early 1970s continued to prove the safety and efficacy of the vaccine in both healthy and immunocompromised, high-risk individuals. as a result of these successful trials, the live varicella virus vaccine (varivax) was licensed in 1995 for the active immunization of persons 12 months of age and older (51) . about 10 years later, in 2006, varizig, a new immune globulin product for post-exposure prophylaxis of varicella, became available under an investigational new drug application expanded access protocol (26) . as a herpesvirus, vzv possesses the unique ability to establish latent infection subsequent to primary infection. zoster results from reactivation of latent vzv that spreads through nerves to the skin. therefore, one fear associated with this vaccination was the possibility that it could increase the incidence and/or severity of zoster when compared to natural disease. conversely, it was actually shown that following vaccination, zoster is less common than after natural infection (51) . in 2006, the fda licensed a new vaccine to reduce the risk of shingles in the elderly. the vaccine, zostavax was approved for use in people aged 60 years of age and older (26) . rotavirus is the leading cause of severe diarrhea and vomiting (severe acute gastroenteritis) among young infants and children worldwide. no significant difference was found in the incidence of rotavirus in industrialized and developing countries, suggesting that vaccination may be the only way to control the impact of this severe disease. dr. ruth bishop and colleagues were the first to describe rotavirus in humans in 1973. it was clear, early on, that a naturally acquired first infection, whether symptomatic or asymptomatic, was the most effective defense against severe reinfection, and subsequent infections progressively created greater protection. therefore, the goal was to create a vaccination that mimicked the effectiveness of naturally acquired immunity following infection. the development of live, attenuated, oral, safe, and effective rotavirus vaccines was then attempted starting in the mid-1970s. dr. albert kapikian and colleagues, at the nih, developed the rrv strain that was subsequently used to develop the rrv-tv, or the rotashield, live oral, and tetravalent vaccine licensed in 1998 to be used in infants at 2, 4, and 6 months of age (26) . however, due to several reported cases of vaccine-associated intestinal intussusception, rotashield was pulled off the market in the u.s. 14 months after its introduction on the 16th of october, 1999. in 2004, the national institute of allergy and infectious diseases (niaid), part of the nih, awarded a new license agreement for rotashield to biovirx, inc. of minneapolis, mn, usa, which planned its global commercialization. in 2011, history of intussusception was added as a contraindication for rotavirus vaccination (26) . clark, offit, and plotkin then produced the rotateq vaccine by merck based on their bovine strain wc3 in 1992, which was licensed in 2006 by the u.s. fda. this vaccine, live oral and pentavalent, is destined for use in infants ages 6-32 weeks (26) . another vaccine, rotarix, was also licensed in 2008. it is a liquid given in a two-dose series to infants from 6 to 24 weeks of age. before being licensed, both vaccines were shown to be safe and effective in rigorous clinical trials (52) . during the past two decades, improvements in environmental health have contributed tremendously to disease vector control. however, substantial challenges remain in dealing with the newly emerging diseases such as severe acute respiratory syndrome (sars), h1n1, h7n9, and h5n1 influenza, middle east respiratory syndrome (mers-cov), rotavirus, ebola virus, and a variety of other viral, bacterial, and protozoal diseases (53) . the role of vaccines in the control and protection from the above mentioned emerging diseases cannot be overemphasized. actually, the importance of inducing protective immunity through vaccination came out to be the most powerful tool and effective strategy to prevent the spread of emerging viruses among populations, in particular, among people that are immunologically naïve and susceptible hosts. such emerging diseases represent a major public health concern; they affect livestock and humans thus threatening the world's economy and public health. vaccine strategies for emerging pathologies are limited by sudden appearance of the pathogen and the delayed time consuming traditional vaccine development process. novel methods to rapidly develop vaccine are being experimented, whereby investigators are working to achieve a better understanding of the nature of the interactions between the immune system and a panel of novel harmful microbes. on this basis several novel strategies have been developed and applied. such strategies included the use of (1) recombinant proteins, or nanoparticles like in sars-cov and mers-cov, (2) synthetic peptides like the case of influenza virus, in managing or even in preventing the emergence of new infectious diseases, a plan should be developed to strengthen surveillance and promote a multi-partners response within local, national, and global programs. with the high burden of emerging infectious diseases (eid) it becomes an essential part to find an effective method of either preventing or controlling their spread, that is where the role of vaccines prevails. it is significant to mention that the average case fatality rate for ebola is around 50% and outbreaks are affecting both developed and developing countries. another emerging disease, mers-cov, has caused the death of around 36% of people reported to have contracted the disease. another disease with high health and economic burden would be rotavirus which was estimated to have annual direct and indirect costs of around $1 billion with "more than 400,000 physician visits, more than 200,000 emergency department (ed) visits, 55,000 to 70,000 hospitalizations, and 20 to 60 deaths each year in children younger than 5 years" (cdc, 2015) . these are few of the facts regarding the affliction of eid most of which have no approved vaccine yet. on the other hand, the influenza virus which was estimated to cause an average of 23,607 deaths annually with a $12 billion cost of an epidemic, showed that with the introduction of its vaccine, studies proved it to be 80% effective in preventing death (55) . these figures have managed to influence many governmental and non-profit organizations to intervene either through governmental funding of vaccines where the congress provides yearly international eid funding to several u.s. governmental agencies or through international non-profit organizations which are the leaders in global health innovation (56). vaccines remain among the most reliable and effective medical interventions in providing the means to fight debilitating and preventable diseases thus ensuring the continuity of mankind and saving lives. through reviewing the factsheets provided by the world health organization, which provide statistical data on the mortality and morbidity percentages before and after the introduction of the vaccines, one can comprehend the vital role vaccines have played up till this day. some of the figures that depict the impact of vaccines in decreasing mortality and morbidity include more than 99% decrease in polio cases since 1988, with cases reaching 350,000 from over 125 endemic countries down to 359 cases as reported in 2014 with only 2 endemic countries, measles vaccine has prevented the death of around 15.6 million children during 2000-2013, in general vaccines prevent around 6 million deaths annually worldwide (57) . this success in providing better public health does not negate the economic burden of vaccination. vaccination programs require excessive funding to ensure proper handling and maintenance of vaccines, adequate staffing and ongoing provision over efficacy and safety of vaccines and the development of newer vaccines (58) . nevertheless, the economic and social burden related to the expenses in hospitalizing affected unvaccinated people still outweighs the aforementioned burden. moreover, better health in the society would promote economic growth and productivity. consequently, public awareness and public efforts agree on the importance of vaccination and the implementation of policies regarding mandatory vaccinations as a way to decrease outbreaks of preventable diseases and improve global health and prosperity. as early as the introduction of vaccines, campaigns against vaccination were raging. as with any new medical intervention there are safety concerns that arise which might be deleterious to the public health. concerns regarding vaccines often follow a path that starts with the hypothesis of a potential adverse event that is impulsively announced to the public without having reproducible studies to confirm this hypothesis, and thus it would take the public several years to regain trust in the vaccine. a notable example in the recent history would be of the paper published by andrew wakefield in the british medical journal the lancet in 1998, linking the mmr vaccine to autism. however, his research was discredited and the paper was retracted from the journal after it was proven that actually there is no link between mmr vaccine and autism as per the systemic review by the cochrane library (59) . the battle against vaccines did not reach a halt, and there are still ongoing campaigns that come from religious, political, community-based, and even individual-based grounds raising even ethical issues regarding the mandatory vaccinations proposed by the government. according to the cdc, this year 95% of the children were vaccinated in the u.s., leaving 5% unvaccinated due to religious and philosophical exemptions or even parental refusal due to the fear of vaccine's side effects and concerns regarding autism from vaccines (60); this is still a critical number since the unvaccinated would pose risk of outbreaks even among the immunized, which necessitates the need for additional awareness campaigns regarding the importance of vaccination since vaccines remain the only plausible measure of protection against preventable diseases. actually, a trend was reported in the health news lately, in the u.s., that pediatricians refuse to offer medical care for children whose parents declined their vaccination. vaccination has been of great importance throughout centuries (tables 1 and 2 ). people started with inoculation techniques dating back to 1000 a.d. with the chinese, turks, and asians. with every century and with every curious physician, inoculation techniques improved gradually giving rise to newer vaccination techniques with edward jenner and later on, louis pasteur and others. however, there is still plenty of room for improvement with the presence of ongoing epidemics and the spread of newly emerging diseases. one important goal is to strengthen the science base for vaccine development and for public health action and disease prevention. despite the common belief that infectious diseases were virtually eliminated by the middle of the twentieth century, new and reemerging infections are appearing along with drug resistant infections in the past two decades in the various parts of the world and whose incidence threatens to increase in the near future, due to changes in human demographics and behavior, immigration, and speed of international travel among other things (61) (62) (63) . the importance of vaccine safety continued to grow throughout the twenty-first century, with the development and licensure of new vaccines added to the already robust immunization armamentarium. scientists also perfected new ways of administering immunizations including edible vaccines and needleless injections. however, formulated or delivered, vaccines will remain the most effective tool we possess for preventing disease and improving public health in the future. despite the antivaccination campaign and the association of vaccines with some side effects, vaccines continue to remain a cornerstone in global health. the distinctions between national and international health problems are losing ground and could be misleading, the "world is a village. " clinicians and public health workers need to interact on regular basis with veterinarians and veterinary public health. actually, good examples of the necessity of such collaboration is the emergence of sars-cov and mers-cov, it shows clearly how coronaviruses can spillover from animals into humans at any time, causing lethal diseases. foodborne diseases could lead to regional and international outbreaks which might constitute a threat to national and global security. centers for disease control and prevention. vaccines and immunizations: the basics epidemiology of vpds, vaccine safety the complicated task of monitoring vaccine safety vaccine safety: current and future challenges niaid. topics: vaccines the college of physicians of philadelphia. articles -different types of vaccines general aspects of vaccination the immune response to bcg vaccination of newborns the methodology for determining the efficacy of antibodymediated immunity aluminum hydroxide adjuvant induces macrophage differentiation towards a specialized antigen presenting cell type twin studies of immunogenicity-determining the genetic contribution to vaccine failure biology of immune responses to vaccines in elderly persons the influence of genetic factors on the immune response as judged by pneumococcal vaccination of mono-and dizygotic caucasian twins genetic regulation of immune responses to vaccines in early life vaccine epidemiology: efficacy, effectiveness, and the translational research roadmap the aging innate immune system reduction in acute gastroenteritis hospitalizations among us children after introduction of rotavirus vaccine: analysis of hospital discharge data from 18 us states resolving the pneumococcal vaccine controversy: are there alternatives to randomized clinical trials? evaluating new vaccines for developing countries. efficacy or effectiveness? assessing vaccine efficacy in the field. further observations translational research and pediatrics the evolution of surgical instruments the history of pediatric infectious diseases the college of physicians of philadelphia. history of vaccines timelines. the college of physicians of philadelphia (1885) surgeons, smallpox, and the poor: a history of medicine and social conditions in nova scotia the immunization action coalition. vaccine timeline. the immunization action coalition jenner and the history of smallpox and vaccination experience in massachusetts and a few other places with smallpox and vaccination the medical side of benjamin franklin history of vaccine development (smallpox eradication: the vindication of jenner's prophesy chapter history of vaccine development. (pasteur and the birth of vaccines made in the laboratory chapter the history of anthrax vaccines: a biography (rabies) vaccines: a biography (killed vaccines: cholera, typhoid, and plague) vaccines: a biography (toxoid vaccines) historical review of pertussis and the classical vaccine preventing tetanus, diphtheria, and pertussis among adolescents: use of tetanus toxoid, reduced diphtheria toxoid and acellular pertussis vaccines recommendations of the advisory committee on immunization practices (acip) a brief history of vaccines and vaccination vaccines: a biography (tuberculosis and bcg chapter the history of tuberculosis yellow fever: a disease that has yet to be conquered vaccines: a biography (yellow fever chapter a history of influenza vaccines: a biography (influenza chapter vaccines: a biography (polio chapter a brief history of polio vaccines vaccines: a biography (measles, mumps, and rubella chapter the history of vaccines and immunization: familiar patterns, new challenges vaccines in historic evolution and perspective: a narrative of vaccine discoveries history of vaccine development (three decades of hepatitis vaccinology in historic perspective. a paradigm of successful pursuits chapter vaccines: a biography (varicella and zoster chapter vaccines: a biography (rotavirus chapter pandemic preparedness and response -lessons from the h1n1 influenza of 2009 emerging infectious diseases: a cdc perspective vaccination greatly reduces disease, disability, death and inequity worldwide historical comparisons of morbidity and mortality for vaccinepreventable diseases in the united states vaccines for measles, mumps and rubella in children vaccination coverage among children in kindergarten -united states historic dates and events related to vaccines and immunization ih is the first author. she provided the idea and followed along with aj the execution of the work and final editing. nc and sc did the literature search for the eighteenth and nineteenth century and the respective preliminary writing about this period. ss and rb did the literature search for the twenty-first century, and about general aspects of vaccination and the respective preliminary writing about this period.mr did the literature search regarding vaccine efficacy and effectiveness in the context of the transnational research map and regarding vaccination instruments and inoculating techniques. ag did the literature search and the preliminary writing for the early history of vaccination and wrote a draft of a manuscript about this period. al edited thoroughly and commented on the final manuscript. aj supervised the whole process from inception to the final submission and edited the whole manuscript. the authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. no use, distribution or reproduction is permitted which does not comply with these terms. key: cord-331375-tbuijeje authors: villalobos, carlos title: sars-cov-2 infections in the world: an estimation of the infected population and a measure of how higher detection rates save lives date: 2020-09-25 journal: front public health doi: 10.3389/fpubh.2020.00489 sha: doc_id: 331375 cord_uid: tbuijeje this paper provides an estimation of the accumulated detection rates and the accumulated number of infected individuals by the novel severe acute respiratory syndrome coronavirus 2 (sars-cov-2). worldwide, on july 20, it has been estimated above 160 million individuals infected by sars-cov-2. moreover, it is found that only about 1 out of 11 infected individuals are detected. in an information context in which population-based seroepidemiological studies are not frequently available, this study shows a parsimonious alternative to provide estimates of the number of sars-cov-2 infected individuals. by comparing our estimates with those provided by the population-based seroepidemiological ene-covid study in spain, we confirm the utility of our approach. then, using a cross-country regression, we investigated if differences in detection rates are associated with differences in the cumulative number of deaths. the hypothesis investigated in this study is that higher levels of detection of sars-cov-2 infections can reduce the risk exposure of the susceptible population with a relatively higher risk of death. our results show that, on average, detecting 5 instead of 35 percent of the infections is associated with multiplying the number of deaths by a factor of about 6. using this result, we estimated that 120 days after the pandemic outbreak, if the us would have tested with the same intensity as south korea, about 85,000 out of their 126,000 reported deaths could have been avoided. this paper provides an estimation of the accumulated detection rates and the accumulated number of infected individuals by the novel severe acute respiratory syndrome coronavirus 2 (sars-cov-2). worldwide, on july 20, it has been estimated above 160 million individuals infected by sars-cov-2. moreover, it is found that only about 1 out of 11 infected individuals are detected. in an information context in which population-based seroepidemiological studies are not frequently available, this study shows a parsimonious alternative to provide estimates of the number of sars-cov-2 infected individuals. by comparing our estimates with those provided by the populationbased seroepidemiological ene-covid study in spain, we confirm the utility of our approach. then, using a cross-country regression, we investigated if differences in detection rates are associated with differences in the cumulative number of deaths. the hypothesis investigated in this study is that higher levels of detection of sars-cov-2 infections can reduce the risk exposure of the susceptible population with a relatively higher risk of death. our results show that, on average, detecting 5 instead of 35 percent of the infections is associated with multiplying the number of deaths by a factor of about 6. using this result, we estimated that 120 days after the pandemic outbreak, if the us would have tested with the same intensity as south korea, about 85,000 out of their 126,000 reported deaths could have been avoided. governments and policymakers dealing with the covid-19 pandemic will fail in their objectives if their actions are guided by misleading data or subsequent misinformation. the authorities should have reliable estimations of the number of sars-cov-2 infected individuals. however, there are few attempts to estimate the total amount of infections (1) (2) (3) (4) (5) . consequently, health systems face enormous challenges since an unknown and probably a high proportion of all sars-cov-2 infections remains undetected. moreover, data suggest that infected individuals can be highly contagious before the onset of symptoms and sars-cov-2 can be also highly contagious in individuals who will never develop any symptoms (6) (7) (8) (9) (10) . undetected infections are dangerous because infectious individuals spread the coronavirus in unpredictable ways. undetected infections consist of non-pcr-tested individuals with symptoms and asymptomatic individuals (non-covid-19 patients) that are likely to remain undetected over all phases of the infection. however, non-pcr-tested individuals with symptoms would tend to auto-select themselves, depending on the severity of their symptoms (from mild to severe), toward treatment and late detection. for this reason, it is important to know the proportion of the infected population which is asymptomatic or has such mild symptoms that self-select them into the group of non-pcr-tested individuals (11) (12) (13) (14) (15) . here, regarding the estimation of the number of infections, and for purposes of public health, i advocate the view by amartya sen and martha nussbaum that is preferable to be vaguely right than precisely wrong. the public health problem is that undetected asymptomatic individuals, as well as late-detected sars-cov-2 infected individuals, increase the risk for vulnerable groups 1 . since there is a transmission channel between the level of detection and the number of deaths, the early detection of asymptomatic infections, pre-symptomatic, and mild covid-19 cases is a public health concern. moreover, undetected cases also are responsible for the collapse of the health system by numerous aggravated and sometimes unexpected covid-19 patients requiring treatment in a short period. overwhelmed health care systems reduce the recovery prospects of patients by the lack of treatment, undertreatment, increased risk of mistreatment of all patients, including those with covid-19, and also put at unnecessarily risk the health workforce (21, 22) . the problem is that many governments formulate their strategies and responses to the pandemic based on figures that they can control. this problem of reverse causality produces contra-productive incentives for governments since public opinion tends to negatively react to the report of the cumulative and the marginal numbers of detected (reported) cases. the contradiction is that something good, such as the increase in the testing efforts by governments can be perceived by the public opinion as something bad (due to the increase in detections). worldwide, the media communicates confirmed cases and deaths as the relevant parameters to take into consideration when assessing the evolution of the pandemic. this is a mistake since this emphasis discourages governments from decidedly pushing for mass testing with the obvious consequence of an increased number of detected cases (although, as shown in this paper, there is a theoretical mechanism relating more testing with saving lives). more sophisticated observers would use the crude and adjusted case fatality ratios to assess the pandemic evolution. however, international comparisons show that crude and adjusted case fatality ratios are highly heterogeneous and their use can be misleading (23, 24) . for instance, the simple division of the cumulative number of deaths by the cumulative number of confirmed cases underestimated the true case fatality ratio in past epidemics (24, 25) . although nowadays many case fatality ratios have been estimated in this pandemic correcting many of the observed past biases (26) (27) (28) , they are still depending on testing efforts made by countries. the problem with heterogeneous case fatality ratios (different proportions of all cases that will end in death due to methodological differences on the denominator) is that they are not anchored at any exogenous information that allows researchers to perform international or territorial comparisons based on credible, and transparent assumptions. consequently, to rely on the number of confirmed cases makes international comparations impossible since governments have shown to implement highly heterogeneous sars-cov-2 testing strategies ending up in different levels of location-based under-ascertainment. in an attempt to solve the mentioned problem, we anchor our analysis in the cumulative number of deaths, which is a statistic much more difficult to alter, in free societies, than the number of sars-cov-2 tests 2 . we use this information together with the newest and sound estimates of the age-stratified infection fatality ratios (ifrs) provided in the recent sars-cov-2 related literature. in particular, we base our analysis on the ifr of 0.657% reported in verity et al. (26) . this ifr is very close to the 0.75% reported in a meta-analysis of 13 ifr estimates from a wide range of countries, and that were published between february and april of 2020 (30) . we also assume orthogonal attack rates of the infection which is also supported by recent literature (16) . by weighting the age-stratified ifrs by the country population agegroups shares in each country, it is possible to obtain countryspecific ifrs. the relevance of this study is 3-fold: firstly, the estimation of the true number of infections includes not only confirmed cases but covid-19 undetected cases, as well as sars-cov-2infected individuals without the disease, or in a pre-symptomatic stage. therefore, to provide an estimation of the true number of sars-cov-2 infections is of more utility than to be only informed about the number of confirmed infections. this is because confirmed cases depend on the testing efforts that can be altered or even manipulated by governments. moreover, one can compare the true estimate of infections with the number of covid-19 patients that require hospitalization. such ratios can contribute to predicting, with exogenousto-government information, shortages of the health systems. secondly, the estimation of the true number of sars-cov-2 infections allows us to estimate the detection rate of the infection, which is a measure of the performance of health systems and governments while facing the pandemic. one can expect that higher levels of detection of sars-cov-2 infections, which includes asymptomatic population, and those in their early stages of the infection (which are more infectious) can reduce the risk exposure of the susceptible population with relatively a high risk of death, that is, the elderly and those individuals with preexisting conditions (17) . accordingly, a highly neglected statistic, such as the detection rate should be considered highly relevant from the public health point of view. thirdly, in this paper, we test the hypothesis that higher detection rates can save lives while providing a measure of this impact (having in mind that is preferable to be vaguely right than precisely wrong). thus, this study aims to quantify the importance of testing while providing empirical support to the utility of implementing massive sars-cov-2 tests. overall, this study argues that it is crucial to compute the evolution of the cumulative number of estimated sars-cov-2 infected individuals, and subsequently, the cumulative detection rates. this information would provide public health managers and governments the incentives to improve detection rates, rather than to the opposite. moreover, the identification strategy can be used at lower levels of aggregation, such as regions, provinces, and municipalities to improve responses to the pandemic, including the planning of selective lockdowns or spatial-selective enhancements of the installed critical care units. in summary, this study proposes a baseline estimation of the number of sars-cov-2 infections and detection rates based on current information and transparent assumptions. however, the assumptions discussed later in this paper can be later modified to match the current scientific available evidence and countryspecific developments and contexts. for this research, we use the cumulative number of deaths and confirmed cases in the world and by country, published by ourworldindata.org, a project of the global change data lab with the collaboration of the oxford martin programme on global development at the university of oxford 3 . age-stratified demographic proportions of the population were obtained from the un population data 4 (26) , the estimated ifrs correct for many types of bias. the infection fatality ratios were obtained after combining adjusted case fatality ratios with data on infection prevalence amongst individuals returning home from wuhan in repatriation flights. and death. since this number is unknown, we approach to this number using the sum of the median incubation period as reported in lauer et al. (31) , and the mean number of days between the onset of symptoms and death as reported in verity et al. (26) . for our empirical exercise, we rely on world development data by the world bank (gdp per capita and health expenditure as a share of the gdp) 6 and in world health organization data for bcg vaccination 7 . in this study, our regression analysis relies on data for 91 countries covering above 86% of the world population. the remaining countries were excluded because they either do not have significant mortality figures (for instance uruguay, monaco, bermuda, etc.), or full data. in this study, we rely on a very simple rationale. at a given point in time, the cumulative number of deaths should be a proportion of the cumulative number of infections somewhat in the past. but how many days in the past? the answer lies in the sum of the number of days of incubation and the number of days between the onset of symptoms and death. this rationale follows a report focusing on the 40 most-affected countries by the pandemic in the world (32) . however, in this paper, we deviated from the mentioned report by using the key parameters in a different way, which translated into a different estimation of the number of infected individuals. on average, deaths occur ∼18 days (17.8 days with 95% credible interval [cri] 16.9-19.2) after the onset of covid-19 symptoms (26) , while the incubation period of covid-19 has been estimated in about 5 days (5.1 days with 95% ci, 4.5-5.8) as reported in lauer et al. (31) . thus, by comparing the cumulative number of deaths at time t in country i (cdeaths (i,t) ) with the country-specific infection fatality ratio (ifr i ), which is assumed constant over time, it is possible to obtain a rough approximation of the cumulative number of sars-cov-2 infections 23 days (18 days + 5 days) in the past (cinfected (i,t −23 ) ) 8 . 6 https://data.worldbank.org/indicator/ (accessed april 24, 2020). 7 https://apps.who.int/gho/data/node.main.a830?lang=en (accessed april 24, 2020). 8 differently to bommer and vollmer (32), we include the incubation period while avoiding the subtraction of the number of days between the onset of symptoms and detection to the relevant lag period. these differences explain the discrepancies between both set of estimates. moreover, by combining the cumulative distribution function of the sars-cov-2 incubation period as reported in lauer et al. (31) and an approximation of the gamma distribution with correction for epidemic growth of the days between the onset of symptoms to death as reported in verity et al. (26) , one can calculate a vector of probabilities to weight the cumulative number of deaths required in equation 1. the weighting vector goes from t −2 (representing the proportion of deaths of those who experienced 1 day between infection and the onset of symptoms, plus one day from the onset of symptoms to death) to t −72 (representing the proportion of deaths of those who experienced 12 days between infection and the onset of symptoms and 60 days between the onset of symptoms to death). the smoothed approach produces almost an identical estimation of the cumulative number of infected individuals. given that and for the sake of simplicity, we prefer to use the non-smoothing approach. additionally, we use the ratio between the cumulative number confirmed (detected) cases at time t −23 in country i (cconfirmed (i,t −23 ) ) and the cumulative number of infected individuals (cinfected (i,t −23 ) ) at time t −23 in country i as a rough measure of the cumulative rate of detection of sars-cov-2 infections at time t − 23 . in order to estimate the country-specific infection fatality ratio for country i used in equation 1, we weight the agestratified infection fatality ratios reported in verity et al. (26) , by the age-group population shares of country i. the calculation of the age-stratified infection fatality ratios relies on two assumptions that can be modified when producing point estimates of the number of individuals affected by a sars-cov-2 infection. firstly, it assumes that there are no crosscountry differences in the average overall health status of the population, comorbidity, or in the soundness of the different health systems. in absence of standardized country-specific information of these variables, this assumption is convenient although, at first sight, it can be considered a restrictive one. however, it is quite the opposite since, in richer countries with higher proportions of elderly populations, the estimated infection mortality ratios are likely to be overestimated. if so, our estimates of the infected population represent a lower limit of the true number of infections. the second assumption is that the attack rate of the coronavirus is unrelated to the age and sex of susceptible individuals. this is in concordance with the evidence in respiratory infections in previous pandemic processes (26, 33) . then, the distribution of ifrs across countries reflects the "fixed" lethality of the virus associated to a varying demographic structure of the population across the world. figure 1 presents the calculated infection fatality ratios for the world, and for 50 countries in which the lethality of the pandemic has been more significant. recently, a cross-sectional epidemiological study with a super-spreading event in the county of heinsberg in germany offered the opportunity to estimate the infection fatality ratio in the community (34) . the estimated infection fatality ratio was 0.36%. although this number is surprisingly low when compared with other estimations, for instance, the used in this study for germany (1.3%), it is not evident that the true infection fatality ratio is closer to 0.36% rather than 1.3%. this is because there can be local factors that explain the discrepancy as pointed out in the heinsberg study. amongst these factors, it might be mentioned comorbidity gaps, ethnic differences, the quality and coverage of the health systems, climatic differences, immunization levels, etc. 9 . consequently, it might be necessary to assess the consequences of using an overestimated infection fatality ratio (that is, an ifr closer to the one reported in the heinsberg study, or others inferred from seroprevalence data (36). the answer is that the number of infections would be underestimated, and that detection rates would be overestimated (since the infection fatality ratio is on the denominator). an overestimation of the detection rates reduces the validity of international rankings based on this figure. however, from the public health point of view, this would be irrelevant since, as discussed later, all countries should increase their detection rates of sars-cov-2 infections as much as possible. to investigate whether improving the detection rates of sars-cov-2 infections is potentially associated to save lives, we use a parsimonious synchronic cross-country multiple linear regression 10 . that is, we use the information reported 15, 60, and 105 days after the confirmation of the first 100 sars-cov-2 infections, which corresponds to the pandemic outbreak (po). at a given pandemic phase, we regress the natural logarithm of the cumulative number of deaths in country i, ln deaths i , on their estimated detection rates (dr i ) and its squared to assess whether there is a non-linear relationship of this conditional correlation 11 . the four parsimonious regressions have a demographic control that corresponds to the estimated country-specific infection fatality ratio (ifr i ). this is a non-endogenous control since it only captures the impact of demography (population shares by age-groups) on the number of deaths and not the reverse. the regressions control for the population size of the country i in its natural logarithmic form ln(pop i ). this control is necessary because the share of the susceptible population remains persistently at relatively higher levels in more populated countries when compared with the less populated ones. we also include the natural logarithm of the number of confirmed sars-cov-2 infections in each country ln(confirmed i ). this is a measure of the persistence of the mortality process while controlling for cross-country differences in their absolute testing number of days since the pandemic outbreak. on the contrary, a non-synchronic estimation neglects the pandemic phases but considers as reference period the calendar day. 11 output tables without the square of the detection rates are available in the supplementary material. performances. the regressions also control for the economic performance of a country by means of the natural logarithm of the per capita gross domestic product ln(gdppc i ) 12 . we also include the current health expenditure as share of gdp in 2017 (healthshare i ). this control is needed to account for relative resource-dependent differences in the coverage/quality of the health systems around the globe. finally, we use available data to explore a possible association between bcg vaccination and aggravated cases of covid-19, and deaths [a relationship which is being investigated in some clinical trials (37)] 13 . the evidence is still inconclusive because the argued existence of uncontrolled confounders (38) (39) (40) (41) (42) . however, if these confounders exist, they can bias the relationship between sars-cov-2 detections rates and the cumulative number of deaths. based on this argument, we include a raw of dummies capturing the degree of bcg vaccination coverage as follows: bgc group 1: no mandatory vaccination (up to 49.9% coverage), bgc group 2: 50 to 79.9% coverage, bgc group 3: 80 to 89.9%, bgc group 4: 90 to 98.9%, and bgc group 5: 99 to 100%. the reference category is bcg 12 in constant 2017 international dollars with the same purchase power. 13 https://apps.who.int/gho/data/node.main.a830?lang=en (accessed april 24, 2020). group 1. an alternative approach is used to indirectly investigate the conditional association between detection rates and sars-cov-2 related deaths. instead of using the detection rates and its square, we use the natural logarithm of the estimated number of infections ln(infections i ) while dropping from the equation the natural logarithm of the number of confirmed (detected) sars-cov-2 infections as follows: regarding the statistical inference, significance tests rely on a heteroscedasticity consistent covariance matrix (hccm) type hc3 which is suitable when the number of observations is small (43) . although in the presence of heteroscedasticity of unknown form, ordinary least square estimates are unbiased, the inference can be misleading due to the fact that the usual tests of significance are generally inappropriate (43) . additionally, we estimate the same set of equations (the main specification and the robustness specification 15, 60, and 105 days after the pandemic outbreak) using robust regressions. we do this because we have the concern that parameter estimates may be biased if, in some countries (outliers), the report of the cumulative number of deaths has been involuntarily altered or even manipulated. robust regression resists the effect of such outliers, providing better than ols efficiency when heavytailored error distributions exist as it can be likely the case (44) . on july 20, the estimated infected population reaches about 160 million individuals (figure 2a) . this number is about 19 times larger than the reported number of confirmed cases (about 8.6 million represented by the dashed line). note that the number of infections is estimated based on detection rates calculated 23 days in the past. thus, for the period t −23 to t, the number of sars-cov-2 infected individuals are estimated using the estimation rate as in t −23 . therefore, the estimation of sars-cov-2 infected individuals can be biased if detection rates deteriorate or improve considerably within this time span. the accuracy of our estimations can be assessed by contrasting them against to those provided by population-based seroepidemiological studies. there are some studies of this type focusing on restricted geographical areas, for instance, in germany and switzerland (34, 45) . however, to the best of our knowledge, there is only one country level and large scale population-based seroepidemiological study performed in spain (46) . the ene-covid study in spain finds that, on 11 may, 5% of the population would test igg positive against sars-cov-2. it implies that about 2.35 million individuals were infected by sars-cov-2. similarly, in our study we estimated on 11 may an infected population of about 2.25 million individuals. this evidence suggests that our method can be a suitable alternative when population-based seroepidemiological studies are not available, which is frequently the case. here, it is important to recognize that, from the public health point of view, it is preferable to be vaguely right than precisely wrong. on 11 may, spain confirmed only 246,504 cases (about 10% of all estimated infections). at that time, it would have been convenient that public health authorities and the public opinion would have the information that, for each confirmed case, there were significantly much more individuals spreading the infection in unpredictable ways. back to the global estimates, by comparing the cumulative number of estimated infections with the cumulative number of confirmed (detected) cases, we obtain, at the end of june 2020, a global detection rate of about 9% ( figure 2b) . the global detection rate curve shows an u-shape with a minimum at the beginning of the third week of march reaching only 1.1%. the last data suggest that detection rates are steadily increasing. moreover, the semi-logarithmic plot in figure 2a suggests that the infection stopped spreading at its maximum pace approximately during the third week of march, but unfortunately, it increased its speed again around the last week of june. the world distribution of the number of deaths, the estimated number of sars-cov-2 infections, and the detection rates of sars-cov-2 infections across the world are displayed in figures 3-5 , respectively. since the global estimates are no more than an aggregation of the trajectories made by the different countries in the world, we investigate how heterogeneous the detection rates across countries are. table 1 presents this information in a synchronic way. the rankings compare countries in the same phase of their respective pandemic processes, that is after 15, 30, 45, 60, 75, and 90 days after the confirmation of the first 100 sars-cov-2 infections (pandemic outbreak). this approach allows us to perform such an international comparison. at a first sight, it is noteworthy the fact that each of the first 24 countries ranked on the top by the initial detection rate (15 days after the beginning of the pandemic outbreak) does not accumulate more than 500 deaths 45 days after initiating their pandemic processes. thus, it seems to exist a strong correlation between detection rates and the cumulative number of deaths for a given stage of the pandemic process. countries with high counts of deaths ranked very badly in their initial detection rates. for example, the us, spain, italy, uk, france, and belgium ranked in place 90, 82, 81, 89, 87, and 85, out of 91 countries listed in the ranking. a second conclusion is that the relative improvement of detection rates over time, that is, 30, 45, 60, 75, and 90 days after the beginning of the pandemic processes, does not alter the fact that those countries are still ranked the worst in terms of deaths. that is, improving detection over time has declining returns to scale when comes to save lives. the depicted relationship between detection rates and the cumulative number of deaths remains almost unchanged when using non-synchronic data as of 20 may in table 2 . this table mixes information of countries at different stages from their pandemic processes. so, it must be interpreted with caution. although efforts to increase detection have been significative in in table 3 , we present the non-synchronic ranking as of 22 june. the us is in place 35, spain 49, italy 53, belgium 63, uk 61, and france 67. it is noteworthy that, except for russia, none of the first 16 countries in this ranking have accumulated more than 2,000 fatalities on 22 june. more importantly and despite the incredible efforts to increase the tests amongst the more developed countries, none of them were able to detect more than 16% of the estimated infections (the us detected 15.7% on 22 june). it implies that testing efforts need to be deployed at the first stages of the pandemic process due to its cumulative nature. countries are ranked by the detection rates of sars-cov-2 infections as of 20 may. source: own elaboration. frontiers in public health | www.frontiersin.org countries are ranked by the detection rates of sars-cov-2 infections as of 22 june. source: own elaboration. frontiers in public health | www.frontiersin.org table 1a ). (b) contains all 61 countries (in table 1a ) whose pandemic processes have more than 120 days since the po. the dashed fitted line excludes south korea (kr). source: own elaboration. show that moving over time from relatively low to relatively high cumulative detection rates is unlikely and probably very expensive. this is due to the over proportional efforts needed to expand testing relative to the exponentially growing infections at the early stages of the pandemic. consequently, from the public health point of view, it is much more advantageous, technically, and economically feasible, to implement mass testing from the very beginning of the pandemic process. to achieve this goal, health authorities and governments would require understanding the linkages between the cumulative detection rates and the minimization of the pandemic related fatalities and economic damage. in this analysis, we show the unconditional relationship between detection rates and deaths. the fitted lines in figure 6 are obtained after regressing the natural logarithm of the cumulative number of deaths in the country i on their estimated cumulative detection rates (dr i ). the results strongly suggest a negative relationship between detection rates and the cumulative number of deaths. this strong negative slope is in concordance with the hypothesis that, by detecting a higher proportion of the sars-cov-2 infected population, many lives can be saved, in particular, the lives of the elderly and those individuals with preexisting conditions. the strong association between the number of deaths and the estimated cumulative detection rates remains significant 15, and 120 days after the po. these associations are shown in figures 6a,b , respectively. figure 7 shows the relationship between detection rates (15 and 120 days after the po) and deaths 120 days after the po. this descriptive result is of interest since it suggests that, unconditionally, early detection is associated with death outcomes 120 days after the po to a greater extent than the contemporary detection rates, that is, 120 days after the po. although this information suggests the existence of a strong relationship between detection rates and the cumulative number of deaths, this slope may be confounded by the variables mentioned before. thus, in the next section, we show the results of our conditional analysis as described earlier. our results in table 4 show that higher detection rates are associated with a reduction in the number of deaths after controlling for demography (age-structure of the population and population size), economic performance (gdp per capita), and table 1a ) whose pandemic processes have more than 120 days since the pandemic outbreak. source: own elaboration. the relative resources that the economies devote to their health systems. over time, the cross-sectional regressions increase in explanatory power, from a r-squared of 0.71 in model 2 to 0.95 in model 8. based on these results, figure 8 shows a strong conditional gradient between detection rates and the cumulative number of deaths. for instance, for a hypothetical country with average and constant endowments, the cost in terms of deaths of detecting 5% vs. 35% is about 1.81 natural logarithm points which corresponds to exp 1.81 = 6.13. that is, the average country detecting 5% is associated with a number of deaths about 6.1 times higher when compared with the same country detecting 35% of all sars-cov-2 infections. to put this result in perspective, let us simulate what would be the number of deaths in the u.s., if instead of detecting 16.02% 120 days after the pandemic outbreak, the country would have detected with the same intensity as south korea (41.01%). evaluating the number of deaths at the endowments of the u.s, the country would have fewer deaths by 1.14 natural logarithm points. it means that the current u.s deaths are now 3.13 times higher than they would be if the country would have tested with similar intensity as south korea. since the number of deaths 120 days after the pandemic outbreak reached 126,140, detecting at the rate of south korea would have saved about 85,794 lives in the u.s. at that time. finally, looking at the regression coefficients in table 3 , it is noteworthy the fact that during the pandemic outbreak, a 1% higher detection rate is associated with more lives saved than a 1% increase in the health expenditure over the gdp. our results also suggest that the number of deaths, rather than depending on the relative solvency of the health system, could depend in a greater extent on the size and opportunity of the testing efforts. the conclusion is the more tests the better. although in this study we employed an economics inspired approach to figure out the importance of testing, our findings are also endorsed by recent medical literature on coronavirus as well as by another economics inspired models providing support to a causal relationship between detection and saving lives (47) (48) (49) (50) . robust regressions provide estimates that are close to the ones reported in table 4 . consequently, it is unlikely that the results reported in this study are outlier driven. additionally, results are robust to heteroscedasticity of unknown form for small samples. nevertheless, results should be interpreted with caution. the few observations available for the regressions and lack of data does not allow to rule out the possibility that there are omitted variables that have the potential to bias the results. it is important to keep in mind that results can be biased if omitted variable problem exists. that is, there are variables that are correlated with the explained outcome but at the same time they are also correlated with the explanatory variables of interest. for instance, one can think in countries implementing lockdowns because lower detection rates standard errors in parentheses. significance levels: ***p < 0.01, **p < 0.05, *p < 0.1. source: own elaboration. (argentina), or relaxed social distancing rules because higher detection rates (australia). nevertheless, these non-observed variables yield to an underestimation of the true association between detection rates and the cumulative number of deaths. thus, detection matters. in this study, we have proposed a method to estimate the number of sars-cov-2 infections for the globe and also for all 91 major countries covering more than 86% of the world population. on june 22, we find that, worldwide, about 160 million individuals have been infected by sars-cov-2. moreover, only about 1 out of 11 these infections have been detected. we find that detection rates are very unequally distributed across the globe and that they also increased over time from about 1% during the second and third weeks of march to about 9% on june 22. in an information context in which population-based seroepidemiological studies are not available, this study shows a parsimonious alternative to provide estimates of the number of sars-cov-2 infected individuals. by comparing our estimates with those provided by the ene-covid study in spain, we confirm the utility of our approach keeping in mind that from the public health point of view, it is preferable to be vaguely right than precisely wrong. in order to provide reliable estimates of the number of sars-cov-2 infections and of the cumulative detection rates, it is necessary that governments provide real-time information about the number of covid-19 deaths. this study supports the view that an accurate communication of the fatality cases can have consequences on the development of the pandemic itself. thus, it is also a call for allowing international comparison following who international norms and standards for medical certificates of covid-19 cause of death and international classification of diseases (icd) mortality coding. additionally, in our empirical analysis, we have presented parsimonious evidence, that higher detection rates are associated with saving lives. our conditional analysis shows, for example, that if the us would have had the same detection rate trajectory as south korea, about two-thirds of the reported deaths could have been avoided (about 85,000 lives). we find that detection rates at the very early stages of the pandemic seem to explain the great divergence in terms of deaths between countries. moreover, we showed evidence that moving from relatively low to high cumulative detection rates (and thus saving lives) is unlikely and difficult. this is probably due to the high level of efforts needed to expand testing relative to the exponentially growing infections at the early and middle stages of the pandemic. thus, from the public health point of view, it is better to deploy testing efforts at the first stages of the pandemic process. to do this would be much more advantageous, in terms of saved lives, but also it would be technically, and economically feasible. already, many developed countries with well-developed health sectors were not able to avoid unnecessary deaths by their inaction in terms of promoting mass testing to counter the pandemic outbreak at early stages. to achieve the goal of implementing mass testing from the very beginning of the pandemic outbreak, governments need to understand the consequences of not doing that. thus, the evidence presented in this paper offers a rigorous macro-level linkage between detection rates and the cumulative number of deaths which may be useful in future pandemics. this evidence also supports the implementation of mass testing in the likely coming secondary pandemic outbreak (so-called second waves). further research should be devoted to understanding why the detection capacity in many advanced countries was too weak, late, and also so weakly correlated (if correlated) with the income levels. in this paper, we claim that governments have incentives against test because the public opinion tends to primarily react to the report of the cumulative and the marginal numbers of detected (reported) cases. the contradiction is that something good, such as the increase in the testing efforts by governments, can be perceived by the general public as something negative (due to the increase in detections). in consequence, are low detection rates in developed countries simply a management failure, or are there long-run incentives that promoted this behavior among many rich countries? it is clear that during the ongoing pandemic, improving detection rates is a race against time, but are there institutional and/or technological constraints that hamper detection improvements that can save lives? all these questions are relevant for this and future pandemics. this study claims that all countries in the world should be able to respond to a pandemic outbreak with massive testing in the very short run. this would be an efficient approach since it is also likely that higher detection rates are also associated with a lesser impact of the pandemic on the economy. the raw data supporting the conclusions of this article will be made available by the authors, without undue reservation. cv conceived this research, performed the background work, collected the data, performed all statistical analyses, and wrote the paper. substantial undocumented infection facilitates the rapid dissemination of novel coronavirus (sars-cov2) inferring the number of covid-19 cases from recently reported deaths fundamental principles of epidemic spread highlight the immediate need for large-scale serological surveys to assess the stage of the sars-cov-2 epidemic estimating the number of sars-cov-2 infections in the united states estimating the effects of non-pharmaceutical interventions on covid-19 in europe salivary glands: potential reservoirs for covid-19 asymptomatic infection sars-cov-2 viral load in upper respiratory specimens of infected patients investigating the impact of asymptomatic carriers on covid-19 transmission. medrxiv covid-19: identifying and isolating asymptomatic people helped eliminate virus in italian village presumed asymptomatic carrier transmission of covid-19 clinical characteristics of 24 asymptomatic infections with covid-19 screened among close contacts in nanjing characteristics of covid-19 infection in beijing asymptomatic novel coronavirus pneumonia patient outside wuhan: the value of ct images in the course of the disease asymptomatic carrier state, acute respiratory disease, and pneumonia due to severe acute respiratory syndrome coronavirus 2 (sars-cov-2): facts and myths gender differences in patients with covid-19: focus on severity and mortality sars-cov-2: virus dynamics and host response the origin, transmission and clinical therapies on coronavirus disease 2019 (covid-19) outbreak-an update on the status clinical characteristics of coronavirus disease 2019 in china review of the clinical characteristics of coronavirus disease 2019 (covid-19) practical recommendations for critical care and anesthesiology teams caring for novel coronavirus (2019-ncov) patients covid-19: protecting health-care workers potential biases in estimating absolute and relative case-fatality risks during outbreaks assessing the severity of the novel influenza a/h1n1 pandemic epidemiological determinants of spread of causal agent of severe acute respiratory syndrome in hong kong estimates of the severity of coronavirus disease 2019: a model-based analysis real-time estimation of the risk of death from novel coronavirus (covid-19) infection: inference using exported cases real-time tentative assessment of the epidemiological characteristics of novel coronavirus infections in wuhan, china medical certification, icd mortality coding, and reporting mortality associated with covid-19 a systematic review and meta-analysis of published research data on covid-19 infection-fatality rates the incubation period of coronavirus disease 2019. 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in prevalence of sars-cov-2 in spain (ene-covid): a nationwide, population-based seroepidemiological study asymptomatic transmission during the covid-19 pandemic and implications for public health strategies prevalence of sars-cov-2 infection in residents of a large homeless shelter in boston covid-19 epidemic in switzerland: on the importance of testing, contact tracing and isolation an economic model of the covid-19 epidemic: the importance of testing and age-specific policies. crc tr 224 discussion paper series crctr224_2020_175 the author would like to thank and acknowledge dr. carlos chavez for comments of a very early version of this paper. i would also like to thank m.sc. andrea torres for their comments on the implications of this research. the author also would like to recognize the suggestions and comments provided by the participants at the doctoral seminar at facultad de economía y negocios, universidad de talca. the author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.copyright © 2020 villalobos. this is an open-access article distributed under the terms of the creative commons attribution license (cc by). the use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. no use, distribution or reproduction is permitted which does not comply with these terms. key: cord-354678-tlba8flz authors: westgard, christopher; fleming, w. oscar title: the use of implementation science tools to design, implement, and monitor a community-based mhealth intervention for child health in the amazon date: 2020-08-19 journal: front public health doi: 10.3389/fpubh.2020.00411 sha: doc_id: 354678 cord_uid: tlba8flz it is essential to analyze the local context and implementation components to effectively deliver evidence-based solutions to public health problems. tools provided by the field of implementation science can guide practitioners through a comprehensive implementation process, making innovations more adaptable, efficient, and sustainable. it is equally important to report on the design and implementation process so others can analyze, replicate, and improve on the progress made from an intervention. the current study reports on the design and implementation of an mhealth intervention to improve child health in the amazon of peru. the study aims to provide insight into how an implementation science tool can be used to improve implementation and reporting of an evidence-based intervention in a global health setting. methods: implementation of a community-based mhealth intervention is analyzed and reported through the lens of the active implementation frameworks (aif). the aif is used to analyze the design, implementation, adaptation, and monitoring of the intervention. the implementation process is categorized in the four stages of implementation. the results of the analysis and subsequent implementation activities are reported. results: the exploration stage was used to learn about the local context in the amazonian communities and identify an evidence-based solution to address poor child health. several potential solutions were combined to create an innovative mhealth tool. during the installation stage, the stakeholders worked together to improve the intervention and plan for implementation through human-centered design. the providers in the field were trained and data was gathered to monitor implementation. during initial implementation stage, electronic tablets were distributed to community health agents and continuous quality improvement activities allowed for rapid improvements to be implemented. the intervention moved on to full implementation stage as acceptance and fidelity approached 100%. conclusion: the aif highlighted several potential barriers to implementation that may have been overlooked without the guidance of a science-based implementation tool. reporting on the implementation process shows how implementation science tools can be used to foresee and address potential threats to successful implementation. the results of this study provide insight into the components of implementation in amazonian communities, as well as the process of using implementation science tools in any global health setting. many public health interventions that have been proven to be effective in controlled settings are not creating the expected impact when replicated in community settings (1) (2) (3) (4) (5) (6) . there are interventions that have been effective at improving child health and development in low-resource community settings, however, replicating and scaling these interventions have been challenging (7, 8) . for example, home visits by health promotors have been shown to be effective, though outcomes vary greatly (9) (10) (11) (12) . progress to improve and scale evidence-based interventions to address poor childhood development has been slow, partly due to difficulty adapting interventions to diverse contexts and a lack of reporting on the implementation process conducted by researchers (5, 6, 13) . the implementation process is complex and influenced by diverse factors. prior to implementing an innovative program in a new context, it is essential to determine if it can be effective and if adaptations are needed to enhance its potential impact. understanding the context helps to improve the fit of the innovation and implementation strategies, thus improving feasibility, acceptability, and sustainability (1, 14) . implementation science proposes various theories, models, and frameworks (called tools henceforth) that can be used to improve diffusion of evidence-based interventions, adapt innovations to local contexts, better understand the implementation setting, and evaluate the implementation process (2, (15) (16) (17) (18) . however, few studies have been conducted that report on the use of the tools in global health settings and the resulting implementation process (13) . the current study reports on the design and implementation of an mhealth intervention to improve child health in the amazon of peru. the study aims to provide insight into how an implementation science tool can be used to improve implementation and reporting of an evidence-based intervention in a global health setting. reporting on the implementation process is expected to show how implementation science tools can be used to foresee and address potential threats to successful implementation. this report addresses the need for critical reflections from practice-based settings to give insight into the barriers and facilitators of effective implementation in community-based settings (3) . the current study utilizes an implementation science tool to systematically design, implement, monitor, adapt, and report on a community-based mhealth intervention for child health. the study utilizes a systematic method for choosing the most appropriate implementation science tool for the initiative. the tool is used to ensure the key components to effective implementation are considered and supported. the tool is also used to guide reporting of the implementation process to ensure all relevant activities are described here. the implementation process is categorized into four stages of implementation to display the challenges to implementation and the solutions that were provided. the analysis focuses on the use of information gathering to identify and improve an intervention and the implementation process, the implementation outcomes (fidelity, acceptability, adoption) and training for quality improvement. the analysis of the process and outcomes are reported in the results. this article describes the implementation of an intervention to improve the impact of community health agent (chas) programs on child health and development outcomes. the study took place in the northern amazon region of peru, in the department of loreto. in loreto, 57% of children under 3 have anemia, 20% under 5 have chronic malnutrition (2018), and infant mortality rate is 30 deaths per 1,000 live births (19) (20) (21) . delay in early childhood development was reported to be experienced by 26 .7% of children in the region (2017) (22) . many of the illnesses can be mitigated by better practices in the household that lead to better sanitation practices, nutrition, and disease prevention (23, 24) . however, caregiver's knowledge of practices to maintain a healthy family are limited as they transition from traditional practices to modern medicine (25) (26) (27) (28) . to improve health in the communities, the population must understand the causes, consequences, and treatments of poor nutrition and infection (24, (29) (30) (31) . in peru, cha programs are widely used but greatly fragmented, with each level of government (national, regional, local) operating distinct programs. although they share the objective of improving maternal and child health, each program has a different system of operations, incentives, supervision, material, etc. while some communities have cha programs from all three levels of government, others have none. the cha programs often lack effective job aids to guide health education and data collection. to address these concerns, elementos, a peruvian research organization, used an implementation science tool to guide the process to identify a potential solution, co-create the design, and implement the innovation. the objective was to improve child health and development, by improving the capacity of cha programs to conduct health promotion and surveillance. during the pilot study, which is the focus of the current paper, the innovation was tested in a randomized control trial, in 6 communities, with 20 chas, serving 230 children. it was provided to established cha programs for them to use during their regularly scheduled home visits with caregivers of children 0-3 years of age. the communities are only connected by rivers, approximately 6 h by boat (1.5 h by speed boat) from the department capitol of iquitos. each community has a population between 500 and 2,000 people. the communities have sporadic cell phone signal and at least 3 h of electricity per day. the study protocol is described in westgard et al. (32) . the first step for the implementation process was to choose the appropriate implementation science tool. a list of potential tools and their level of analysis is included in the online tool, dissemination and implementation models in health research and practice (33) . the list is extensive with little information on how each tool can be used. previous knowledge of implementation science and its tools or additional reading is necessary for the list to be meaningful. the authors of the current study utilized their knowledge of implementation science, along with additional study of the various tools, to select the five most promising tools for the project. the five tools were: (1) active implementation frameworks (aif) (18); (2) consolidated framework for implementation research (cfir) (15); (3) the exploration, preparation, implementation, sustainment framework (epis) (2); (4) interactive systems framework for dissemination and implementation (isf) (34); and (5) the theoretical domains framework (tdf) (35) . to compare the tools and select the most appropriate for the project objectives, the theory, model, and framework comparison and selection tool (t-cast) was used (36, 37) . the t-cast helped the authors systematically think about the strengths of each tool as they relate to each criterion that is important for successful implementation. the criteria were chosen from a list, based on the project's objectives. the tools were scored across the following 7 criteria: the tool includes relevant constructs, provides a step-by-step approach for applying it, provides an explanation for how constructs influence implementation, focuses on relevant implementation outcomes, addresses a relevant analytic level, proposes testable hypotheses, and contributes to an evidence base. based on the score of each criterion, the authors were able to differentiate the most appropriate tool. the aif scored the highest in the evaluation with an average score of 1.57. it was therefore selected to be the tool utilized to guide the implementation research and practice. the average score of each tool is in table 1 . the aif is comprised of five distinct frameworks. the 5 active implementation frameworks include; (1) usable innovations, (2) implementation stages, (3) implementation drivers, (4) implementation teams, (5) improvement cycles. through the application of the 5 aifs, users are guided through the stages and key activities for successful implementation, supporting careful consideration of the implementation setting and components of the intervention [see figure 1 ; (38, 39) ]. the stages of implementation include (1) exploration of the local context and identification of innovations that can create positive change, (2) installation of the capacity and resources needed to introduce, improve and sustain an innovation; (3) initial implementation, during which performance data is used to rapidly improve both the innovation and implementation supports and strategies; and (4) full implementation, where high quality implementation and program outcomes are realized and sustaining performance is a core focus. the current study reports on the process used to move from exploration to full implementation of the innovation in the communities. the implementation stages framework, of the aif, is used to organize the description of the evolving implementation process. the other components of the aif are presented within the various stages of implementation (18, 40) . the implementation process during each stage is described with the aim of reporting on the key components addressed to accomplish implementation. key challenges that arose and the decisions that were taken to address them are presented. the results of the analysis of the implementation process is presented in the sections below, representing the four stages of implementation. the authors explore the critical components of project implementation as they relate to each stage of implementation. the exploration stage involved understanding the needs of the communities, identifying evidence-based practices that can address their needs, and determining the right fit between potential solutions and the local context. the work done during this stage improved the chances for success of the program by checking to ensure the local population wanted the intervention and believed it could work within their reality (41, 42) . the research team conducted formative research in the communities to better understand the needs and priorities of the families. this involved the following activities: • interviewed regional health directors, program coordinators of municipalities, and community leaders to learn about their most pressing health issues, their priorities, and key barriers to progress. a common consensus among all stakeholders was the problem of child malnutrition and poor early childhood development. • conducted a social determinants study to better understand the drivers of poor child development in the communities. the study found that poor sanitation and nutritional practices were associated with an increase in developmental delay, and contact with a chas was associated with a decrease in developmental delay (22) . • conducted a study to better understand the barriers to utilization of local health services for maternal and child health. the study identified key reasons why some mothers do not attend health-checkups for their child nor give micronutrient supplements. long wait times, closures, and a mistrust of health center personal were among the top reasons (26) . • conducted a performance evaluation of chas in the communities. through observations of home visits by chas, the study found that many chas lacked the capacity and material to transmit the knowledge needed by the caregivers to conduct healthy maternal and child health practices (43) . the studies and informant interviews identified poor health behaviors within the household as a key driver for child health and development. unhealthy behaviors that were taking place included: drinking untreated water; early cessation of breast feeding; poor diet; poor handwashing practices; unsanitary toilets; and low use of nutrient supplements and deworming medication (22, 44, 45) . caregivers often lacked a good understanding of the causes, consequences, and treatment of common childhood illnesses. the local stakeholders agreed that health promotion and education were greatly needed, and that chas are a strong potential mechanism to provide that service. evidence from the studies suggested that improved performance of chas could improve the knowledge and practices of caregivers, and thus improve the child health and development outcomes. following the decision to focus on chas to address poor child development, additional research was conducted on the policies and operations of the cha programs in the region. the research team conducted interviews with representatives of cha programs at the national, regional, and local level. it was soon discovered that representatives at each level operated a distinct cha program. the programs share the objective of improving maternal and child health, however, each program has a different system of operations, incentives, supervision, recruitment, and material. while some communities have chas from all three levels of government, others have none. the research team studied the operations of the cha programs to better understand how an intervention could be designed and implemented to improve cha performance and impact. the research revealed several of the barriers expressed above: chas struggle to remember and transmit the knowledge needed to teach caregivers, they lack direction to choose which health messages should be shared at each home visit, and they lack material to help transmit the information. additionally, there is a lack of supervision and any control of the quality of the home visits. fidelity of the cha program suffers from a lack of a responsive supervisory system. the supervisors and representatives of the health centers and ministry of health have little way of determining if home visits are being conducted as intended. a landscape analysis was conducted to identify evidencebased interventions with the potential to improve cha performance in the amazonian communities. potential interventions were identified by reading scientific literature, expert interviews, and assessing the tools shared by chw central 1 and the community health worker assessment and improvement matrix (46) . a list of potential interventions was evaluated through a policy analysis to determine which best satisfied the selection criteria and showed most promise to be successful in the low-resource community setting. the search for potential interventions and the comparison process was dynamic, with new interventions being added and deleted over several months. the analysis revealed that multiple interventions had the potential to create positive impact in the cha setting. by utilizing mobile information and communication technology (ict), several of the intervention components could be combined into one innovative intervention. several studies have shown that mobile icts can improve the performance of chas in their ability to perform health promotion, collect and report timely information regarding family health, provide health services such as vaccines, and refer families to appropriate local health services (3, (47) (48) (49) (50) (51) (52) (53) . additionally, when a mobile ict tools are used by a cha, the device can increase the confidence the caregivers have in the messages being transmitted and increase the confidence the chas have in their own work (47, 48, 51, 52, (54) (55) (56) . through implementation science, innovations in mobile icts and strategies for child health and development can be extended to low resource settings to empower local actors and spread the benefits of advancements in technology (3, 50) . the evidence-based interventions that showed promise to improve cha performance included: conducting surveillance of maternal and child health indicators with a mhealth tool, utilizing animated videos to deliver health messages to encourage behavior change, harnessing health behavior theory for the creation of health messages, and improve self-efficacy of chas by providing dynamic tool (24, 30, 31, 47-49, 51-53, 55, 57, 58) . the intervention components were combined to create an innovative tool that supports cha programs. the innovative tool was titled, the child health education and surveillance tool application (the chest app). a video of the app can be viewed online (59) . the chest app is an android-based application downloaded onto an electronic tablet. the chest app provides the steps for the cha to follow to conduct an effective home visit with caregivers. it was designed to improve the capacity of chas to transmit knowledge of healthy child-rearing practices and conduct disease surveillance. the chest app provides the following functions: (1) collect child health indicators at the household level and upload the data to the server; (2) select appropriate health messages to deliver during the home visit based on the age of the child; (3) share animated videos, images, and statements that reinforce the health messages; (4) calculate and display the anthropometric and nutritional status of children; and (5) organize the case load of children and maintain schedules for home visits and health check-ups (32) . a full description of the intervention can be seen in the study protocol that was published in 2019 (32) . the theory of change for the intervention is displayed in appendix 1 in supplementary material. once the chest app intervention was defined, it needed to be assessed to determine fit and feasibility for success in the local context. the intervention was assessed alongside the implementation setting to determine the probability of success. the exercise was supported by the hexagon exploration tool, of the aif. the hexagon exploration tool guides selection and evaluation of potential interventions for an implementation setting by promoting the consideration of key program and implementation site indicators [appendix 2 in supplementary material (63)]. the chest app was assessed with the hexagon exploration tool by considering the six key components for successful implementation, as displayed in table 2 . the exercise confirmed the potential for success of the intervention in the communities and promoted further consideration of important components of implementation. after exploration, efforts shifted to preparing for implementation. an implementation team at elementos was created to assist the actors in the field. the implementation team created the initial plan for implementation, prepared the local actors, and readied the tools, and material for the intervention. they conducted the training, monitoring, and quality improvement cycles. the team consisted of an implementation scientist, nurse, nutritionist, and anthropologist. before going to the field to prepare the local actors, the implementation team was trained on the use of the chest app, how to coach the chas, how to conduct an effective home visit with the tool, and how to identify and report challenges experienced by the chas. the chest app was developed throughout the 6 months of the installation phase. a prototype was needed to show the local actors what the intervention would look like. however, the final form of the app was unknown at the beginning of development because the design needed the input from the end-users and the implementation team needed to further understand the workflow of the chas. the multidisciplinary team designed and created the app, the health messages and images, and animated videos to include in the app. to prepare for implementation, the team needed to determine where and when implementation would take place. to determine the location of the pilot, meetings were conducted with directors of cha programs at the 3 levels of government (national, regional, and local) to present the chest app, document the system of operations of each cha program, and assess interest multiple studies have shown that mhealth tools can improve cha performance in similar low-resource community settings, including health education with videos and digital surveillance tools (47) (48) (49) (51) (52) (53) (54) (55) usability previous studies and stake-holder interviews suggested that the technology could be used in the local context. additionally, the acceptability and usability of the chest app was confirmed through informal interviews with the local populations. the chas and local supervisors expressed their preferences for how the tool should be designed to fit the needs of their program. elementos had the resources to design and implement the chest app thanks to funding from grand challenges canada, saving brains grant (60) . elementos created the capacity to conduct the project by hiring a multidisciplinary team of specialists; an implementation scientist, nutritionist, anthropologist, community psychologist, epidemiologist, nurse, communicator, and software engineer. together they developed the material (a guidebook of health messages and animated videos), the app, and the implementation protocol. the chest app was developed from open source code from opensrp, (61) which includes code and forums for support. technical assistance and development was also provided by the unc chai core team (62) capacity to implement the communities have established cha programs that have the capacity and interest to receive and integrate the chest app into their normal activities. the cha programs are supported by funding from their municipality, which includes pay for a program supervisor. additional implementation support was provided by elementos by providing an implementation team that visits the communities for continuous training and support for 1 year. fit with current initiatives the tool was created to integrate within the established cha programs with minimal interruption of their current activities. the tool was expected to improve the ease and effectiveness of their current initiatives. multiple studies by the research team identified the need; reflected by the high rates of malnutrition, misunderstanding of health topics by caregivers, and poor performance of chas. in receiving the intervention. the cha program coordinated by the regional ministry of health has little formal structure or supervision. the chas conduct occasional campaigns (such as malaria prevention) and some conduct home visits as their own independent initiative. the chas did not receive incentives or regular supervision. their home visits are thus infrequent and unpredictable, making their program a poor fit to receive the chest app. at the national level, the cha program, "cuna mas, " conducts home visits in areas of extreme poverty (64) . the chas receive a modest stipend for their work, close supervision, and continuous training. based on the structure of the program, they were an excellent fit to receive the chest app. the directors of the program were excited to receive the chest app. however, working with the national government provided difficult. significant turnover of staff in the ministry delayed communications and the formulation of a formal agreement. ultimately, the team was not able to formulate a formal agreement with the ministry in time to implement. they decided to implement the intervention with the local government cha programs. the district-level municipalities operate their own cha program, which vary by districts. all include home visits with children under 4, an incentive package (stipend or gift baskets), and a program supervision. the 5 districts that were approached by the implementation team (amazon, indiana, las amazonas, fernando lores, and punchana) were enthusiastic to receive the chest app intervention. they established communications with each district and began learning about the specific activities of the cha program in each district. to determine when implementation should take place, the implementation process had to adapt to the political activities in each district. the districts had recently conducted elections, so their new representatives were adjusting programs and budgets, including the cha program. many were replacing chas and supervisors with their own contacts, freezing the program until a new budget could be released, or changing specific activities of the chas. therefore, installation and initial implementation had to be delayed for the programs to stabilize. continuous communication with the program coordinators and policy makers in the districts made it possible to continue to improve the intervention and implementation process during the delay. although this created delay for the start date of the chest app intervention, it helped troubleshoot and avoid several potential issues that may have arose. in each community, leaders were selected to head the initiative in their group. the program supervisor was included as a leader and the supervisor choose one cha to join the leadership. the supervisor was the primary person of contact in each community. the cha leader helped lead group discussions, trainings, and share the opinions of the chas to the implementation team. the cha leaders also played an important role in setting the general mood of the group. when the leader decided to accept the intervention and dedicate themselves to learning the new skills, the rest of the group followed even if they were initially hesitant. to prepare for the evaluation of the intervention and to adjust the program to the local setting, extensive data collection was conducted. the data provided a baseline for adaptive monitoring, evaluation, and learning. process data was collected on the procedures of the chas and supervisors to be able to monitor changes that may occur after implementation of the intervention. the indicators included the number of home visits conducted, number of children visited by each cha, the reporting procedures of the cha and supervisors, the health indicators they reported, time delay for the indicators to be reported to the health authorities, and acceptability expressed by all stake-holders. this information allowed the implementation team to later assess acceptability, adoption, and fidelity of the new intervention. this helped determine if doses and quality are changing overtime and identify opportunities to adapt the intervention to achieve greater effectiveness. an assessment form was created for the implementation team to measure acceptability of the intervention. acceptability was measured by interviewing the chas, supervisors, and caregivers. during each visit to the communities by the implementation team, an interview was conducted with one of each actor. the implementation team filled out the acceptability assessment form with each. the questions pertained to what they liked and disliked about the intervention and suggestions to improve it. the chest app includes a method to track adoption of the tool into the cha program. the cha records child health indicators with the app during the home visits. the supervisor connects the tablet to a wifi hotspot and uploads the data from the app to the server. the server can be accessed by the supervisor, health center personal, municipality, and implementation team. they can see if the chas are conducting the appropriate number of home visits with the tool and collecting the required information. the supervisor was trained to upload the data from the tablets and interpret the data to determine if the frequency of home visits by the chas matches what is expected of them. in this way, adoption can be tracked by all parties. fidelity of the intervention was accessed by the supervisor through observations of home visits by the chas. an assessment form was created by the implementation team and supervisors to assess fidelity. the fidelity assessment form included the steps needed for a quality home visit and scoring system for each step. the supervisor kept a record of fidelity scores for each cha and scheduled trainings with the chas based on their scores. data was collected on the intermediary/mediator variables to test the theory of change of the intervention. the information was gathered from household surveys conducted by the implementation team. the intermediary variables included; performance of chas, knowledge of caregivers, childrearing practices, and use of health services. testing for change along each step of the theory of change helped to determine opportunities to adjust and improve the intervention or implementation process. data was also collected on the primary outcome indicators; hemoglobin levels, anthropometrics to estimate malnutrition, and early childhood development scores. the data was collected to determine the effective size of the intervention and report the implementation outcomes. the chas and program supervisors were trained on how to use the chest app to support their work. the training was designed to teach them how to operate the tablet and application, how to use the tool to improve the interaction with caregivers during home visits, and how to use the information gathered by the tablet to improve their impact. the training lasted 3 days. the first day was focused solely on the use of the app. the implementation team sat down with groups of chas to show them how to use the app. then, the chas spent the day practicing, working in groups to help each other resolve problems and remember the steps. the cha leaders were the first to answer questions from the others before a member of the implementation team stepped in to help. the second day of training included simulations of home visits. one cha conducted the home visits with the chest app while another cha pretended to be a caregiver in her home. the implementation team conducted several simulations for others to watch to show how the home visits could be more dynamic with the use of the tool. the chas mimicked the behaviors of the implementation team and greatly improved how they conduct home visits. the third day of training was one-on-one with a member of the implementation team and each cha. the member of the implementation team accompanied the cha on a home visit with a caregiver in their community. the implementation team member gave advice to the cha after the home visit on how it could be improved to better transmit the knowledge displayed in the app. at times, the supervisor joined home visits with the cha and implementation team member. at this time, the supervisor was trained in how to assess fidelity with the fidelity assessment form. before and after the home visits, the implementation team showed the supervisor how to score the home visit on the fidelity assessment form, creating a common standard for a quality home visit. through the conversations and observations of quality home visits, the supervisor learned how the intervention is intended to be delivered. the chas were initially nervous to use the new tool, albeit excited by the novelty. many of the chas had never used a touchscreen device before. at the end of the 3-day training, all chas were able to conduct a home visit on their own with the chest app. however, ∼20% of the cha needed additional practice with the app to become faster and more comfortable. a total of 20 chas were training, in groups with an average size of 6 chas. during the workshops, the implementation team worked together with the chas and supervisors to identify opportunities to further adapt the chest app to match their needs. the team conducted human centered design exercises to surface challenges they anticipated from using the new tool and elicit suggestions for how it can be improved. the research team noted the difficulties and suggestions that were expressed and took them back to the developers so they could make quick, incremental improvements. for example, the language used in the app needed to be updated to include more localized terminology. also, the images used to indicate if a child has chronic or acute malnutrition were removed because they caused confusion. the option in the app to record the child's id number was made optional because we learned some children do not have a government-issued id. the initial implementation stage began by distributing the tablets with the chest app to the chas and supporting the integration of the new tool into their normal activities. a total of 20 chas in five communities received a tablet. the chas immediately began using the tool to help choose which child to visit and guide them through their home visits. they collected data on child health indicators while in the homes and coordinated with the implementation team to upload the data to the server. this stage of implementation was about testing and improving the functionality of the chest app and the implementation process. the implementation team continued to work with the chas to conduct improvement cycles on the intervention, further train the chas in the use of the chest app, support the program supervisors on downloading the data and making data-based decisions, and communicate with the authorities of the municipalities to share the advancements and value of the chest app for their program. the cha leaders agreed to meet with the chas that were struggling to use the app comfortably. initially, all chas in each community met 1-3 times per week to practice using the app. the cha leaders and supervisor organized the meetings and assisted those that needed help. the meetings became less frequent as they mastered the new tool. members of the implementation team from elementos visited each community bi-weekly during the first 2 months following implementation, and then once a month thereafter during the first year of implementation. the cha leaders played an important role during the meetings with the implementation team. they voiced the concerns they had about the tool, requested changes, and gave feedback about the general mood of the chas in using the tool. the mood was very positive, as the chas liked the new tool and the prestige it gave them when they visited the homes. the families that receive visits from a cha with the chest app were the ultimate recipients of the intervention. their experience with the chas changed due to the new tool. they now have the opportunity to see the health status of their child displayed in the app with stop-light indicators (red or blue), view images and videos that explain topics of health and development, and hear the cha give guided messages to promote behavior change. to measure the effectiveness of the chest app intervention, implementation outcomes were tracked and evaluated throughout implementation. the implementation outcomes represented how well the intervention was delivered and received. the outcomes that were tracked included adoption, fidelity, and acceptability. the implementation team and local authorities used the chest app as a decision-support data system to assess adoption. adoption was accessed by analyzing the number of children the chas visited and the number of home visits conducted per month. the number of home visits per month was consistently rising or staying consistent (depending on the community), over the first 4 months of implementation. at month 5 of implementation, the implementation team noticed a sharp drop in number of children visited with the chest app in a community. the change signaled a reduction in adoption of the intervention and the need for the implementation team to visit the community to troubleshoot the situation. the team found that several of the chas were released from the cha program due to budget cuts. the team worked with the supervisor and municipality to adapt their program to work with fewer chas, prioritizing the children with poor nutrition status, and visiting the healthy children less frequently. this allowed the chas that remained to continue to visit all the children in the program. identifying the problem was possible due to the integrated mechanism in the chest app to monitor use of the tool. the fidelity assessments conducted by the supervisors provided the information needed for targeted training and quality improvements. by observing random home visits with the chas, the supervisor identified which chas were having problems conducting the home visits as intended. the chas that scored poorly on parts of the fidelity assessment form received support from the supervisor and cha leader to improve their performance on those specific steps of the home visit. the assessment allowed the supervisor to identify which aspects of the home visit were not being delivered with fidelity and focus on those aspects during the on-going training. the information gathered during the fidelity assessments also improved quality improvement efforts. the supervisor and implementation team found that many chas were having trouble remembering to gather child health indicators during the visit. they conducted the educational portion without conducting the surveillance portion of the home visit. with this information, the team made adjustments to the chest app, making it required to click through the surveillance section of the app before advancing to the educational section. this proved to be effective at ensuring the surveillance was conducted and that the intervention maintained high fidelity. the implementation team evaluated acceptability of the intervention immediately after implementation and during the following months. the information recorded in the acceptability assessment form provided valuable information to continuously improve the quality of the intervention. overall acceptability of the intervention increased over time. most of the suggestions for improvement occurred during the first 4 weeks of implementation. after adjusting the program based on their suggestions, acceptance, and positive feedback were expressed by all chas and supervisors. evaluation of acceptability by the caregivers revealed that the families found the home visits to be more appealing with the chest app. caregivers, children, and other family members became more interested and attentive during the home visit than before. the chest app made the caregivers feel more confident in the information the cha presented and could more easily understand the messages. the suggestions gathered during the acceptability assessments provided opportunities to improve the quality of the intervention. the team synthesized the requests for changes and adjusted the chest app when appropriate. a change was made to the app because some communities were not able to upload the data from the tablet to the server due to insecure assess to cell phone data. the developers added to the chest app the ability to transfer data directly from the tablet to a local computer with a cable. by adding a direct transfer function, the program coordinators were able to extract the data as they needed, without cell phone signal or direct assistance from the implementation team. additionally, a function to erase a case/child from the caseload was added to the chest app interface. the chas expressed the need for the function due to children frequently aging out of their program or moving away. the chas needed the ability to delete cases without the assistance of the implementation team. the solution seemed obvious once the chas explained the need, however, the problem did not occur to the design team until then. once a high level of acceptability, adoption, and fidelity were reached and maintained, the program began the full implementation stage. after 10 months of implementation support, the intervention was operating with 100% adoption across all active cha programs involved in the pilot. when a cha conducted a home visit, they used their chest app. also, acceptability and fidelity were high, and supervisors continued fidelity checks and quality improvement efforts without outside support. one community canceled their cha program, and thus stopped using the chest app. the municipality canceled support for the program due to budget restrictions. they anticipate re-activating the program in the coming months. this is an important detail when assessing sustainability of the intervention when implemented at the district level. after 10 months, the research team ended their monthly visits to the communities. the chas and supervisors did not need ongoing training outside of their own local support. elementos was able to scale-back resources (staff and travel expenses) invested to support the chest app program on the ground. however, elementos was not yet able to stop all involvement in the programs. the supervisors in three of the communities were not yet able to upload, download, organize, and interpret the data obtained with the chest app. a member of the implementation team continued communication with the supervisors of each program to assist with the task of data management. on a monthly basis, the supervisors connected the tablets to a cell phone hot spot or directly to a computer to upload the data to the server. they signaled to the team at elementos that new data was uploaded. at elementos, the data was then downloaded and organized in a user-friendly report and sent back to the supervisors. the supervisors then shared the report with the municipality and local health post. to determine if the chest app program (intervention and implementation process) is cost-effective and should be sustained and scaled, an evaluation of the process and impact is needed. follow-up surveys were planned to be conducted and compared to baseline to determine impact after 12 months of operation. the follow-up surveys were delayed due to the covid-19 pandemic, still pending at the time of writing this manuscript. assessment will include measurement of the performance of the chas, knowledge evaluations, and surveys of household practices to measure the impact of the chest app on chas and caregivers. the improvements in knowledge and practices of caregivers are expected to reduce anemia, reduce chronic malnutrition, and increase early childhood development scores. sustainability of the intervention has been measured by tracking the adoption and fidelity scores over time. both adoption and fidelity were high during the first phase of implementation and has maintained after external support from the research team was withdrawn. sustainability will be tracked for an additional year to ensure the intervention can be further maintained before scaling. an important component to assess sustainability of the intervention is the cost. the primary expense of the chest app intervention is the cost of the tablets. for the pilot project, the tablets were provided by elementos. the municipalities committed to buying new tablets for the intervention to scale to additional communities in their district and to replace old tablets as they become unusable. their commitment to dedicate sufficient budget to the cha program to buy tablets is necessary for the intervention to be sustained. therefore, sustainability of the program is determined by state actors, and not outside support or funding. the program is expected to be continued as long as child health and development remain a top priority. the cha program with the chest app is expected to be scaled to additional districts and regions of peru once sustainability is confirmed. the intervention and implementation process were created so they can be replicated and expanded without a decrease in impact (voltage drop) (65) . training chas in new communities can be done with trainers of relatively low expertise. the cha leaders of past intervention communities can take a lead role in training new communities. the data support can be conducted by a central supporting agency, such as the regional ministry of health or a non-governmental organization. each municipality can manage the supervision and evaluation of adoption and fidelity. therefore, the program can replicate with little additional cost and demand for outside support. the educational material that is included in the chest app was created to match the reality of the amazon region. the food sources, infections, sanitation challenges, etc., matches the experience of amazonian communities. to scale the program, the educational material will need to be adapted to match the diverse contexts in peru, such as the high mountains and coastal plains, and include messages in local languages. with the chest app, modifying the material to match the local reality is feasible and economical. once the material is developed and translated, it can be uploaded to the tablets remotely. additionally, new educational material can be added to the chest app as the program advances or to match diverse health challenges that arise. the updates can be distributed without purchase or deliver of new material, only adjust the app's code and connect the tablets. this is the first study to examine the use of the aif to analyze and report on the implementation process of a global health intervention for child health and development. by reporting on the process, the reader can learn about the implementation context in the amazon of peru and how the tool can be applied to analytically assess key components of implementation. the aif guided the research team to focus on important components of implementation, thus further dedicating resources and analytical consideration during implementation to increase probability of successful of the intervention. the key components of the implementation process included information gathering to conduct improvement cycles, the implementation outcomes (fidelity, acceptability, adoption) to monitor progress and sustainability, and training for continuous quality improvement. analyzing the various components gave great insight into the behavior of the participants and local system. understanding the perspectives and behaviors of the providers, end users, and program coordinators on the ground is a valuable part of the implementation science approach, and essential to create longlasting behavior change (66) . the chest app innovation and the implementation strategy went through several adaptations to better fit with the local context. the implementation science approach was extremely beneficial to guide the multiple design iterations and rapid-cycle problem solving. the results were greatly improved promotional material, app design, and implementation process. it is important that researchers specify and report on the process used to design, adapt, and implement an intervention (5) . details of the implementation process are needed for others to evaluate, replicate, improve, and scale the intervention (6, 13) . this study reports on the implementation process and key components that were assessed during the design and implementation of the intervention. the consolidated advice on reporting ecd guidelines (c.a.r.e guidelines) describe which implementation components should be reporting when conducting implementation research on early childhood development interventions (13) . this study reports on those components, including previous evidence of intervention, rational, context of implementation, description of recipients, adaptations that occurred, personnel, methods to assess fidelity, and others. an additional study will be published following the final evaluation of the chest app intervention that reports on process and clinical. the study contributes to the knowledge base by demonstrating how an implementation tool can be applied in practice in global health. the scientific community has indicated the need for greater reporting on the delivery of public health interventions, especially those in global health (1) (2) (3) (4) (5) (6) . activities conducted during the design, implementation, and evaluation of an intervention should be reported so the scientific community can learn what works and what does not. this study provides information on the implementation of a child health and development intervention in a community-based setting. the chest app intervention was analyzed and reported through the lens of the aif. the aif assisted the research team to consider components of implementation that are often neglected, such as choosing the right solutions that fits local context, information gathering for data driven decision making and adaptations, and monitoring implementation outcomes. the analysis and activities that took place during each stage of implementation are described so others implementing a similar intervention can reflect on the experience and improve their own implementation process. this report contributes to the pool of knowledge needed to improve impact and scale of global health, communitybased interventions. publicly available datasets were analyzed in this study. this data can be found here: https://figshare.com/articles/indiana_ resultados_xlsx/12056100/1. cw was involved in the design, implementation, data collection, data analysis, and writing of the manuscript. wf was involved in the analysis and writing of the manuscript. all authors contributed to the article and approved the submitted version. the supplementary material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fpubh. 2020.00411/full#supplementary-material diffusion theory and knowledge dissemination, utilization, and integration in public health advancing a conceptual model of evidence-based practice 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