However, this literature has not adequately controlled for the implicit discrimination processes that sort girls into different types of families  and at earlier parities. To better address the endogeneity associated with implicit discrimination processes, we explore the association between child sex and postneonatal under-5 mortality using a sample of mixed-sex twins from four waves of the Indian National Family Health Survey. Mixed-sex twins provide a natural experiment that exogenously assigns a boy and a girl to families at the same time, thus controlling for selectivity into having an unwanted female child. We document a sizable impact of explicit discrimination on girls’ excess mortality in India, particularly compared with a placebo analysis in sub-Saharan Africa, where girls have a survival advantage. We also show that explicit discrimination weakened for birth cohorts after the mid-1990s, especially in northern India, but further weakening has stalled since the mid-2000s, thus contributing to understandings of how the micro-processes underlying the female mortality disadvantage have changed over time.Son preference has been linked to excess female under-5 mortality in India, and considerable literature has explored whether parents invest more resources in sons relative to daughters—which we refer to as The online version of this article (10.1007/s13524-020-00909-0) contains supplementary material, which is available to authorized users. Furtheres Clark . If techIt is empirically difficult to measure explicit discrimination net of implicit discrimination because prenatal sex selection remains unobserved at the family level and because other forms of differential selection, such as family size or birth order, are endogenous to mortality and parental son preference. It is further complicated to explore how explicit discrimination has changed over time given that the implicit processes that might sort girls into qualitatively different households have also changed with diffusion of ultrasound technology, fertility declines, improvements in women’s education, and other social and economic changes. Nonetheless, it is fundamental for our understanding of son preference in India to understand whether explicit discrimination underpins observed mortality disadvantage for girls. Furthermore, accurately documenting explicit discrimination is essential from a policy perspective because the policy responses implied by parents’ differential resource allocation to boys versus girls within families are different than if girls’ mortality disadvantage accrues primarily from selection into different families. If there is intrahousehold discrimination against girls, then policies targeting health and welfare investments in girls specifically within families will be necessary. However, if girls fare worse, on average, because of selection into larger and/or poorer families, then policies addressing generalized poverty reduction will be better motivated.To better address the endogeneity of implicit discrimination processes, we use a large sample of mixed-sex twins to investigate the association between child sex and postneonatal under-5 mortality with data from four waves of the Indian National Family Health Survey . Mixed-sex twins provide a natural experiment that exogenously assigns both a boy and a girl to families at the same time, thus allowing us to control for differential family selectivity into having an unwanted female child and other implicit discrimination processes. To validate our estimates of explicit discrimination, we conduct a placebo analysis using a large sample of twins from sub-Saharan Africa, a region that does not have a history of female mortality disadvantage. We also explore heterogeneity in explicit discrimination by stratifying by region and number of older female siblings. Finally, we investigate whether explicit discrimination has declined over subsequent birth cohorts, thus providing important insight into how the micro-processes that contribute to the female mortality disadvantage have changed over time in contemporary India.Patterns of excess female infant and child mortality arising from a strong preference for male offspring have been long noted in India. Sex ratios  of infant and child mortality in India have remained under 1.00, which is indicative of a female mortality disadvantage that is attributable to social (gender) discrimination processes because males are biologically more vulnerable to mortality in infancy and, to a lesser extent, in early childhood. Particularly in the age group 1–4 years, India has the most anomalous levels of excess female mortality in the world  or nutrition  that are relevant for survival  and compared boys and girls between different families, usually in a regression framework. However, in a context where son preference shapes fertility behaviors and family sex composition is not random, girls are likely to be selected into different types of families. This differential selection—which we term For example, studies have found that son-preferring fertility rules result in girls being born into larger families—that is, having larger siblingship sizes relative to boys  is weakened as a result of the uptake of prenatal discrimination via sex-selective abortion  Goodkind . EvidencA standard approach for measuring the mortality attributable to explicit discrimination would be to estimate the association between child sex and mortality controlling for birth order, family size, family socioeconomic status (SES), and other measures related to the implicit discrimination processes that sort girls and boys into different families. However, with this approach, it would be difficult to appropriately control for implicit discrimination processes because the intensity of son preference and prenatal sex selection are unobserved at the family level, and variables such as completed family size and birth order are endogenous to mortality and parental son preference. Controlling for variables such as family size or sex composition would allow us to compare outcomes of boys and girls in families of the same size. However, as Barcellos et al.  noted, iOne approach for addressing the endogeneity of family size, as followed by Rosenblum , has beeWe propose a novel strategy to better address the endogeneity associated with implicit discrimination processes by leveraging mixed-sex twins as a natural experiment in which both a boy and a girl are assigned to a family at the same time, thus allowing us to control for implicit discrimination processes, such as differential family selectivity into having an unwanted female child. Mixed-sex twins, exposed to the same prenatal environment and born at the same time, are exposed to the same family environment . Because the principal difference in mixed-sex twins is child sex—and not family size, birth order, maternal age, family wealth at birth, and so on—elevated female mortality among mixed-sex twins should be more readily attributable to differential parental behaviors based on child sex . This is particularly the case given that biologically male children are more vulnerable to death in infancy and early childhood . The NFHS collects cross-sectional microdata on key demographic and health outcomes that are nationally representative of all women ages 15–49 and follows the format and structure of the Demographic and Health Surveys (DHS). The NFHS is collected by the Indian Ministry of Health and Family Welfare and International Institute for Population Sciences, with input from ORC Macro International.We identify a sample of mixed-sex twins using the NFHS birth recode, which provides detailed information on all children born to women in the sample. Respondents are queried about whether each child is still alive and, if not, at what age in months the child died. For each birth, respondents are also asked whether it is a multiple birth , the birth order, and the sex. Combining this information allows us to identify which births are mixed-sex twins. We exclude households with multiple sets of twins and households with triplets and quadruplets given the exceptional nature of these events, which suggests that these household might be categorically different from others in the sample in their potential genetic predisposition to twinning. Our analytical sample includes 6,200 mixed-sex twins from 3,100 families.Our main outcome is a dichotomous indicator of whether the birth resulted in death in infancy or early childhood . We exclude mortality in the first month of life because we are interested in capturing social rather than biological processes that impact mortality, and previous literature on son preference has shown that its mortality manifestations in under-5 mortality are most apparent in the postneonatal ages  captures all observed and unobserved factors  shared between the twin pair. For an individual j in twin pair i, the within-twin fixed-effects model of sex of the child on mortality can be expressed as follows:We use a within-twin fixed-effects model that allows us to compare boy-girl differences in mortality within twin pairs born into the same family. The fixed effect  capFirst, we use the within-twin fixed-effects model in Eq.  to estimTo validate our measure, we also conduct a placebo analysis using a large sample of sub-Saharan African (SSA) twins. The SSA data come from the Demographic and Health Surveys (standardized with the NFHS), with multiple survey waves occurring over the same period as the NFHS  and youngest  birth cohorts, twins were increasingly born into smaller families at earlier birth orders, which corresponds with overall fertility declines in India in recent history. Mothers in the sample are increasingly better educated and have children at older ages, which also makes sense given that these are key correlates of fertility declines. Mother’s stated ideal number of boys and girls also both significantly declined over subsequent birth cohorts of twins, which may reflect a preference for increasingly smaller family sizes. There are also significant declines over birth cohorts in mother’s ideal sex ratio of boys to girls , which does suggest some lessening of stated son preference over time. Nonetheless, even in the most recent birth cohort, mother’s ideal sex ratio is still skewed toward boys (0.54).p < .01)  mortality. Unlike past estimates of the female mortality disadvantage, this specification allows us to control for implicit discrimination processes by accounting for unobserved twin-level confounders that do not vary between twins . We find that females experience a 2 percentage point higher probability of postneonatal under-5 mortality than males (1) Table , panel Cp < .001) (Table p < .05). The female coefficient in the earliest birth cohort  is significantly higher than the female coefficients in the latter two birth cohorts, thus providing evidence of the female mortality disadvantage attributable to explicit discrimination weakening between the first cohort and the two subsequent ones. The coefficient between the second and third cohort are similar in magnitude and indicate a stagnation of improvements after the mid-2000s. Respecifying the birth cohorts by decades   Table . Upon dip < .10), the size of this effect for 12–59 months is 3.6 percentage points (150% higher) (p < .05).We disaggregate our main outcome into postneonatal infant mortality (1–11 months) and child mortality (12–59 months). Fig. p < .001)  higher probability of postneonatal under-5 mortality than males in northern India (1) Table , panel Bp < .001) (Table p < .05). Post-estimation tests of significance indicate the female coefficient in the earliest birth cohort in the northern region is significantly different from the female coefficients in the latter two birth cohorts in the northern region, which is indicative of weakening explicit discrimination over time in the region where son preference was historically strongest. However, we see a stalling of improvements in the cohorts after the mid-2000s compared with the mid-1990s in the northern region. Here, the female coefficient increases slightly between the second and third cohort, although the differences between the two cohorts are not statistically significant at p < .05. On the other hand, among cohorts born after the mid-2000s in the other regions, there is indication of the emergence of a female mortality advantage as the coefficient becomes negative, although the female coefficients in the other regions are not statistically significantly different by birth cohorts , we find a sizable impact of explicit discrimination in the northern region, with girls experiencing a 9.1 percentage point (or 76%) higher probability of mortality than males   and 8.5 (127%) percentage point higher probability of postneonatal under-5 mortality among twins with two and three older sisters, respectively (1) Table , panel A1) Table , panel BAlthough twin studies have widely been used to account for unobserved heterogeneity in demographic research (Guo and Tong both singletons and twins are changing. This is further confirmed in Table As Table p < .001), net of controls for family and child characteristics, respectively. Although we are hesitant to directly compare these OLS results with those generated by the within-twin fixed effects, we cautiously note that the female disadvantage in mortality, both in absolute and relative measures, indicated by the magnitude of the coefficient on the pooled OLS models is smaller than those on the within-twin fixed-effects models. This difference is especially so for cohorts born prior to 1995. Although they used a different estimation strategy than ours to exploit random variation in the sex of the child, Barcellos et al.  regression analysis regressing mortality on child sex for a large sample of singleton children and using within-family fixed-effects , but our indicator of firstborn twin likely captures whether the twin had higher or lower birth weight because of the correlation between twin birth order and birth weight. We nevertheless perform sensitivity tests with imputed birth weight and rerun our analyses; results are unchanged  twins, who share 100% of their genetic material, mixed-sex twins are fraternal (dizygotic) and share 50% of their genetic material . Thus, it is plausible that there are unobservable genetic differences between twins that lead to differential parental care and attention, net of child sex. Another biological mechanism that may operate distinctively among mixed-sex twins is intrauterine hormonal exposure  and occur in ways that are not easily captured in survey instruments such as the NFHS. This may also help explain why female mortality disadvantage in studies is more consistently found whereas evidence for differential allocation is more mixed. Parents might also be prone to reporting bias when describing allocation of resources, particularly for children born several years prior to the survey, and may also be reluctant to report differential investments in children. Even for children born in the last five years, the NFHS data do not have information on key measures  for deceased children. Furthermore, children who have died will likely differ in key characteristics  than children who survived through early childhood, and it would not be possible to know whether these differences led to death  or instead early death led to these differences . Finally, if a child died, the surviving twin may have received better treatment because of the death . Ultimately, because mortality is the strongest benchmark of discrimination—one that is least prone to recall bias—and it is what our data best allow us to measure, it is the focus of our research presented here.explicit discrimination—this literature has not adequately controlled for what we term implicit discrimination processes that sort girls into different types of families  and at different birth orders than boys. It is conceptually important to recognize these two distinctive micro-level mechanisms of discrimination because the family-level processes implied by each are different, as are the policy responses they require. To better address the endogeneity associated with implicit discrimination processes, we explore the association between child sex and postneonatal under-5 mortality using a sample of mixed-sex twins. We argue that mixed-sex twins provide a natural experiment that exogenously assigned a boy and a girl to families at the same time, thus controlling for family selectivity into having an unwanted female child, birth order, and other implicit discrimination processes.One of the most striking demographic manifestations of son preference in India is the persistence of excess female under-5 mortality. Although considerable literature has attributed the under-5 female mortality disadvantage to parents differentially investing more resources in boys versus girls within families—Our within-twin fixed-effects models show that female children experienced a significantly higher probability of postneonatal under-5 mortality. This provides strong evidence of the important role of explicit discrimination in the female mortality disadvantage observed in our data because our models control for implicit discrimination processes that resulted in the differential sorting of boys and girls into different kinds of families and birth orders. The Indian estimates for explicit discrimination are particularly striking when compared with a placebo analysis conducted in sub-Saharan Africa, where female twins actually had a survival advantage; this finding corresponds with literature showing that males have a biological disadvantage in early life.Using our novel measure, we find that that the role of explicit discrimination underlying the female mortality disadvantage weakened for cohorts born after the mid-1990s relative to those born prior to mid-1990s. Subsequent analyses also show that our temporal results are largely driven by northern India, and explicit discrimination declined over time in this region, which has historically been characterized by high son preference. Nevertheless, our results do not indicate the disappearance of a mortality disadvantage attributable to explicit discrimination in India, and indeed the cohorts born after the mid-2000s in northern India appear to show stalling improvements.Although we are not able to test them directly, we anticipate that a combination of contextual changes—weakening son preference, policy initiatives aimed at improving girls’ status, fertility decline, and the ability to realize son preference at lower parities due to the practice of sex-selective abortion—underpin weakening explicit discrimination in India since the mid-1990s. Compared with the pre-1995 period, we find that later cohorts of mixed-sex twins are born into smaller families with lower indicators of stated son preference. Although these results refer to stated preference indicators, it is plausible that son preference has weakened through socioeconomic development , rather than generalized poverty policies targeting all children, are still necessary. These policies, combined with indirect measures to weaken son preference through media advocacy as well as measures to improve women’s outcomes in political, legal, and economic domains are needed to further reduce explicit discrimination.Although the approach presented here does not provide an all-encompassing measure of son preference , we provide a conceptual contribution by distinguishing between explicit and implicit discrimination processes, and we demonstrate a quasi-experimental approach to better estimate explicit discrimination effects using a novel sample. It is fundamental for our understanding of son preference to explore whether the effects of son preference arise from parents’ actively investing more in their boys than their girls or instead they accrue as a result of changing patterns of implicit discrimination. A significant contribution of our approach is that it allows for the temporal analysis of the impact of explicit discrimination on the female mortality disadvantage in India over four decades.Although our analysis is focused on India, the points we raise about the different processes behind both explicit and implicit discrimination can also be applied to other contexts in South, East, and Central Asia with high son preference. This distinction may become particularly important as wider changes such as fertility decline and technology diffusion continue across countries with historically strong son preference, implying that changing family selectivity—as opposed to differential resource allocation within families—could become a particularly important mechanism through which the mortality manifestations of son preference emerge. Future research should explore the mechanisms of both explicit and implicit discrimination and better understand the interrelationship between changing son preference, fertility decline, and excess female mortality.ESM 1(PDF 478 kb)


Access to primary healthcare is crucial for the delivery of Kenya’s universal health coverage policy. However, disparities in healthcare have proved to be the biggest challenge for implementing primary care in poor-urban resource settings. In this study, we assessed the level of access to primary healthcare services and associated factors in urban slums in Nairobi-Kenya.The data were drawn from the Lown scholars’ study of 300 randomly selected households in Viwandani slums , between June and July 2018. Access to primary care was measured using Penchansky and Thomas’ model. Access index was constructed using principal component analysis and recorded into tertiles with categories labeled as poor, moderate, and highest. Generalized ordinal logistic regression analysis was used to determine the factors associated with access to primary care. The adjusted odds ratios (AOR) and 95% confidence intervals were used to interpret the strength of associations.p < .05). Households with an average quarterly out-of-pocket healthcare expenditure of ≥USD 30 had significantly lower odds of being in the highest versus combined categories of lowest and moderate access tertile compared to those spending ≤ USD 5 . Households that sought primary care from private facilities had significantly higher odds of being in the highest versus combined categories of lowest and moderate access tertiles compared to those who sought care from public facilities .The odds of being in the highest access tertile versus the combined categories of lowest and moderate access tertile were three times higher for males than female-headed households (AOR 3.05 [95% CI 1.47–6.37]; In Nairobi slums in Kenya, living in a female-headed household, seeking care from a public facility, and paying out-of-pocket for healthcare are significantly associated with low access to primary care. Therefore, the design of the UHC program in this setting should prioritize quality improvement in public health facilities and focus on policies that encourage economic empowerment of female-headed households to improve access to primary healthcare. Access to primary healthcare is widely acknowledged as key to reducing the global burden of morbidity and mortality –3. In 19Kenya typifies urban growth and slumization in sub-Saharan Africa. The majority (60–80%) of urban slum dwellers in Kenya live in informal settlements characterized by poor sanitation and hygiene, overcrowding and poor housing, and inadequate public healthcare services , 10. StuThe objective of this study was to assess the factors associated with access to primary healthcare in urban slums in Nairobi, Kenya. Our study contributes to existing knowledge in two major ways. First, access to essential healthcare services is a critical indicator in the evaluation of UHC. Therefore, knowledge of healthcare services accessibility and associated factors in resource-poor urban settings may be used in the planning and delivery of evidence-based interventions to optimize health service delivery and achieve sustainability. Second, using Penchansky and Thomas’ model of access to healthcare , we consThe data for this study are drawn from the Lown scholars’ survey on healthcare gaps in informal settlements conducted between June 2018 and July 2018 in Viwandani slums . A total of 300 randomly selected households from the Nairobi Urban Health Demographic Surveillance System (NUHDSS) were surveyed in the Lown scholars’ study. The respondents comprised adults aged 18 years and over who were either household heads or permanent household members. The design of the Lown scholars’ study has been previously published ; In this study, we assessed the level of access to primary healthcare services and associated factors in urban slums in Nairobi-Kenya. Our findings revealed that seeking care from a public primary care facility, living in a household headed by a female, and paying out-of-pocket for healthcare services are significantly associated with low access to primary care.Our results suggest a systematic disadvantage of female versus male-headed households in access to primary care. Previous studies have also consistently revealed widespread gender differences in access to primary care –28. SeveOur finding that paying out-of-pocket for healthcare services was significantly associated with low access to primary care is consistent with evidence from a number of recent studies –36. In pSimilar to previous studies –44, our Our findings have three key policy implications. First, within the healthcare system in Viwandani slums in Nairobi, Kenya, there is an urgent need for implementation of policies and programs that take into account the gender disparity in access to primary care. Second, there is a need to scale up efforts for expanding health insurance coverage in the slum communities to cushion households against OOP expenditures. Third, proper mechanisms should be developed to regularly monitor the quality of healthcare services offered by public facilities in urban slums by the relevant authorities. Technical support is also required for them to improve the quality of healthcare services.The respondents for this study comprised adults aged 18 years and over who were either household heads or permanent household members, therefore, the possibility of recall bias or slight variations in the responses provided by the household heads, their spouses, or other credible adult household members cannot be overemphasized. The study did not disaggregate health expenditure into the various components of direct and indirect healthcare spending. There is therefore little room to draw conclusive arguments on costs such as transport to access healthcare, time lost from work and other informal costs which households may incur in the process of seeking access to care. In addition, the fact that the study was conducted in one urban slum settlement may have a bearing on its generalizability to other urban slums in Kenya. Despite these limitations, our study findings provide useful insights on the level of access to primary healthcare services and associated factors in urban slums in Nairobi, Kenya and serve as a basis for more rigorous investigations in other urban slum settings in Kenya and sub-Saharan Africa.This study shows that access to primary healthcare services for slum residents is poor and varies by the gender of the household head, source of primary care and OOP healthcare expenditure. Our study provides important results particularly highlighting the lower access to primary healthcare among female-headed households. Multiple approaches to primary healthcare access are needed to address this issue among slum residents. Therefore, policies that encourage economic growth in female-headed households are likely to create economic empowerment and improve access to primary healthcare in these settings. Similarly, public programs that offer protection against out-of-pocket spending are likely to improve access to primary healthcare. In addition, public health facilities need to improve the quality services provided.


Although much of the health emergency and disaster risk management  literature evaluates methods to protect health assets and mitigate health risks from disasters, there is a lack of research into those who have taken high-risk behaviour during extreme events. The study’s main objective is to examine the association between engaging in high-risk behaviour and factors including sociodemographic characteristics, disaster risk perception and household preparedness during a super typhoon. A computerized randomized digit dialling cross-sectional household survey was conducted in Hong Kong, an urban metropolis, two weeks after the landing of Typhoon Mangkhut. Telephone interviews were conducted in Cantonese with adult residents. The response rate was 23.8% and the sample was representative of the Hong Kong population. Multivariable logistic regressions of 521 respondents adjusted with age and gender found education, income, risk perception and disaster preparedness were insignificantly associated with risk-taking behaviour during typhoons. This suggests that other factors may be involved in driving this behaviour, such as a general tendency to underestimate risk or sensation seeking. Further Health-EDRM research into risk-taking and sensation seeking behaviour during extreme events is needed to identify policy measures. Asia is particularly at risk of tropical cyclones, also known as typhoons in the western Pacific, with around half of worldwide tropical cyclones recorded and more than 90% of cyclone-related deaths being from this region . TyphoonHealth emergency and disaster risk management  is a field which involves the systematic analysis and management of health risks surrounding emergencies and disasters. By reducing risk and vulnerabilities and improving preparedness, response and recovery measures, the impact of disasters can be minimised . Health-A previous study on urban disaster preparedness in Hong Kong discovered that only 20.6% of respondents chose the correct action to take while major disaster warnings were in force (such as staying in a safe place until heavy rain has passed) . HoweverThis article is an extension of the cross-sectional study investigating risk perception, household preparedness, and self-reported short-term impacts of typhoons after Typhoon Mangkhut . Our preA computerized digit dialling population-based household telephone survey was conducted from 17 September 2018 to 2 October 2018, right after the date of Typhoon Mangkhut landing in Hong Kong. Random digit dialling and the last birthday method  intervi. The resThis study investigates the associations between non-essential RBDT and the sociodemographic factors of education and income; indicators of risk perception including perception of Hong Kong being susceptible to disasters, perception of the impact of Typhoon Mangkhut compared to expectations and concern for the safety of oneself and family members; indicators of household preparedness including food and water reserves prepared routinely or specifically for Typhoon Mangkhut.This paper considers the act of going outside during the strongest typhoon winds as risk-taking (RBDT) or high-risk behaviour, regardless of the reasoning. Those who go outside for work or emergency related purposes would be considered as engaging in socially acceptable or understandable risk-taking behaviour. This article focuses on active risk-taking behaviour, where individuals remove themselves from areas of safety to head into areas posing health risks, and does not investigate passive risk-taking behaviour, such as failure to act, evacuate or engage in other safety-seeking behaviour. This is because there are potentially different motivating factors, rationale and mechanisms involved in these two types of behaviour and research has found that passive risks are associated with a lower risk perception than equivalent active risks . PreviouTo clarify, the respondents were asked whether they left their homes to go outside during Typhoon Mangkhut while the typhoon warning signal T8 or above was in force. Those who left their home to address any perceived urgent and unexpected situations that required immediate action to prevent further deterioration, such as “due to injury or disease”, were classified as having ‘emergency’ reasons. Those who did not have to manage such pressing issues or work-related duties but left their home for other reasons, such as “eating a meal or watching a movie”, were categorized as having ‘non-emergency’ reasons. This paper will hence refer to RBDT due to ‘non-emergency’, also referred to as non-emergency and non-occupational reasons in our previous published paper, as non-essential reasons. Verbal informed consent was obtained at the beginning of the interview. The ethical approval of this study was obtained from the Survey Behavioural Research Committee at the Chinese University of Hong Kong (SBRE-18-075).2) tests were used to compare the study population and the respondents who reported going outdoors during Typhoon Mangkhut. We conducted univariate analyses to identify associations between sociodemographic characteristics, risk perception, disaster preparedness factors and the risk-taking behaviour. Multivariable logistic regression was performed to identify factors related to going outdoors during strong typhoon winds for ‘non-emergency’ reasons, using variables with at least marginal statistical association in the univariate analysis (p < 0.10). Age and gender were covariates for the multivariable model base. All odds ratios (OR) present in this paper were adjusted odds ratios from the multivariable models. Statistical analyses were performed using IBM SPSS 24  [Descriptive chi-square   and statData were collected from 17 September 2018 to 2 October 2018. The final sample size constituted 521 valid respondents . The study population were comparable with the Hong Kong 2016 census data, except the study population were proportionally more middle age (age 45–64), more at the post-secondary education level and had higher income. Please refer to the previous paper [p = 0.006). There were no significant associations between RBDT and marital status, income, and respondents with chronic disease. Of the respondents with occupations which require emergency work while typhoon No. 8 or higher was in force, 72.2% reported staying home during Typhoon Mangkhut when the typhoon was at the height of strength. In addition, respondents who had occupations relating to “Sales and services” and “Elementary occupation” were more likely to leave their homes for emergency or work reasons. Respondents who participated in RBDT for emergency or work reasons were found to be more likely to obtain their weather-related information during this typhoon through television and newspapers and less likely through websites and mobile apps.For the descriptive comparison , it was In the multivariable logistic regressions , the relThe current study is an extension of the previous published paper , which iHousehold preparedness and risk-taking behaviour may be negatively associated, as household preparedness represents active protective behaviour, while non-essential RBDT involves potentially injurious active behaviour. Although this study did not find any significant negative association between higher educational level, higher risk perception and routine emergency preparedness with non-essential RBDT, the previous published paper  found a Although there was no association between perceived impact of Typhoon Mangkhut compared to expectations and non-essential RBDT, 80.9% of all respondents thought the impact of the typhoon was similar or less than expected. This may suggest that fewer people underestimate the risks of typhoons, even after the recent typhoon influence, given that Typhoon Mangkhut was objectively one of the strongest typhoons in Hong Kong to date. The literature on sensation seeking involving demographics  has alsoThis study found food and potable water reserves, whether prepared regularly or specifically for this typhoon, were not associated with respondents going outside for non-essential reasons at the height of the storm. In addition to being markers of household preparedness, the reserves and the lack thereof may indicate situations of non-essential character, which could motivate individuals to leave their homes under the rationale of necessity. The results suggest that seeking these two necessities were not primary reasons for non-essential RBDT.News outlets have documented a case of an elderly man in Hong Kong stranded at sea and requiring rescue after swimming during Typhoon Haima while the typhoon signal No. 8 was in force , highligThere is also an ethical argument on the duty of firefighters who bear personal risk and danger to help those engaging in sensation seeking behaviour. A fireman in Hong Kong died in 2017 after sustaining a cliff fall while rescuing a pair of hikers , highligOne of the major gaps found in this study is that education, disaster risk perception and disaster preparedness were not found to be associated with whether respondents engaged in unexplained risky behaviour. Common understanding would suggest that those with better understanding of the risks presented and especially those concerned about the safety of themselves and their family members during the typhoon would practice less risk-taking or sensation seeking. This suggests that knowledge-based interventions may not be as effective in deterring individuals from engaging in non-essential RBDT.As younger aged males were found to be more likely to engage in non-essential RBDT, health promotion targeting this group may be more effective, possibly through official government websites/apps or well-placed advertisements in social media platforms. Legislation limiting accessibility to areas of higher risk during typhoons, such as waterfronts and beaches, may also have a beneficial effect on warding off risk-taking behaviour. Numerous provinces and cities in the Philippines have imposed liquor bans during typhoons to prevent inebriated individuals from hindering relief operations ,31,32, bAs some respondents were found to engage in RBDT for work purposes, the updated “Code of Practice in Times of Typhoons and Rainstorms”, published by the Hong Kong Labour Department , is a crThe main limitation of the analysis is that the results do not demonstrate a causative effect since this study used descriptive analysis and logistic regression as a cross-sectional study. There may also be reporting bias as respondents may present with higher social desirability response bias due to telephone interviews . In addiFuture studies can directly investigate the reasons or rationale behind RBDT and explore the extent of such behaviour in detail. The sensation seeking trait and relevant factors could also be examined to determine its association and relevance to RBDT by using a modified version of the sensation seeking scale. Research into interpersonal perspectives through injunctive safety norms  and motiWhile age and gender were associated with risk-taking behaviour during natural disasters, other sociodemographic characteristics (such as education) and measures of disaster risk perception or disaster preparedness were not found to be correlated with non-essential RBDT. Despite the lack of literature investigating this phenomenon, media outlets in Hong Kong have reported several cases of sensation seeking behaviour during typhoons. Future studies are necessary to investigate the scope of risk-taking behaviour during disasters and the reasons driving this behaviour. Although there have been limited reports of injuries caused by risk-taking behaviour, relevant policy makers should begin to discuss and implement solutions to prevent any accidents and reduce potential extra burden on the emergency response system.


A growing number of cancer patients use complementary and alternative therapies during and after conventional cancer treatment. Patients are often reluctant to discuss these therapies with their oncologist, and oncologists may have limited knowledge and confidence on how to advise patients on the appropriate use. Integrative oncology is a patient-centered, evidence-informed field that utilizes mind–body practices, lifestyle modifications and/or natural products interwoven with conventional cancer treatment. It prioritizes safety and best available evidence to offer appropriate interventions alongside conventional care. There are few opportunities for oncologists to learn about integrative oncology. In this commentary, we highlight the Integrative Oncology Scholars (IOS) program as a means to increase competency in this growing field. We provide an overview of several integrative oncology modalities that are taught through this program, including lifestyle modifications, physical activity, and mind–body interventions. We conclude that as more evidence is generated in this field, it will be essential that oncology healthcare providers are aware of the prevalent use of these modalities by their patients and cancer centers include Integrative Oncology trained physicians and other healthcare professionals in their team to discuss and recommend evidence-based integrative oncology therapies alongside conventional cancer treatments to their patients. Many cancer patients and survivors use complementary and alternative therapies during and after cancer treatment. A recent meta-analysis of 32 surveys of cancer patients in North America found a point prevalence of 46% (95% CI 35–56%) of complementary medicine use and showed that rates of use have been growing steadily in the past few decades . PatientOne approach to address these various concerns comes from the relatively new discipline of Integrative Oncology. Integrative Oncology, is a patient-centered, evidence-informed approach that utilizes mind–body practices, lifestyle modifications and/or natural products interwoven with conventional cancer treatment . IntegraDr. Karim, the first author and a trained Medical Oncologist recently had the opportunity to participate in the Integrative Oncology Scholars (IOS) Program at the University of Michigan. This year long program is supported through a grant from the National Cancer Institute, and aims to train 100 integrative oncology (IO) leaders and to facilitate partnerships with IO leaders and complementary practitioners within their communities . In the Below is a brief summary of reflections and important learnings from this program:Lifestyle modifications, including diet, physical activity and sleep hygiene have been shown to have numerous benefits for people with cancer .Many cancer patients inquire about the “best diet” for cancer and whether changes in their diet can have an impact on their cancer outcomes. Between 3–48% of cancer patients pursue “special diets” during their cancer treatment ,15. UnfoSedentary behavior has been linked to the development of numerous cancers and is associated with increased cancer mortality, recurrence and treatment-related side effects . UnfortuMind-body therapies are a group of techniques that enhance the mind’s interaction with bodily function, to induce relaxation and to improve overall health and well-being . These tThere are several different forms of meditation that have been studied in patients with cancer. The most studied and those with the best evidence are interventions derived from mindfulness based stress reduction (MSBR) or mindfulness based cognitive therapy (MBCT) ,35,36,37Yoga is a mind–body therapy which combines physical poses (asanas) with breathing and meditation . There aTai Chi and Qigong (TCQ) integrate elements of traditional Chinese medicine, martial arts conditioning, and lifestyle philosophy. These mind–body interventions incorporate elements of slow gentle movement, awareness and breath regulation in addition to intentional direction of thoughts, attention, imagery and sensation . A recenAcupuncture is a non-pharmacologic modality that arises from traditional Chinese medicine. It involves inserting thin needles through the skin in specific locations called acupoints to stimulate energy flow in the body. Acupressure involves stimulating the acupoints using the thumbs or fingers, without the insertion of needles. Acupuncture and acupressure have been studied for a variety of cancer-related side effects. Acupuncture has been shown to reduce aromatase inhibitor-associated joint symptoms ,44. AcupNatural Health Products Regulations and require a product license and specific labeling requirements [Natural health products (NHP) supplement the diet and consist of one or more of the following ingredients: vitamin, mineral, herb or botanical, or amino acid . In Canairements . Concernirements ,57. Addiirements . Severalirements , and actirements . On the irements . OncologCommunication with patients regarding complementary and integrative therapies, and with complementary providers is an important part of patient-centered cancer care. Several studies indicate that the reason for non-disclosure of these therapies among patients include anticipation of doctor disapproval or doctor disinterest . On the Integrative oncology is growing field that uses the best available evidence, which incorporates safe and effective complementary therapies along conventional cancer treatment in a patient-centered approach. It is imperative that as more individuals with cancer use complementary and integrative therapies and as more research in this field emerges, oncologists should routinely ask their patients about the use of these therapies and include Integrative Oncology-trained team members who are equipped with the communication skills and competencies to guide patients in their decision making. It is important to recommend evidence-based integrative oncology therapies and separate them from those without adequate evidence to improve multiple aspects of cancer care. Evidence-based integrative therapies have the potential to improve quality of life of cancer patients and several studies have highlighted that an integrative approach is cost effective ,65,66.Since completing the IOS program in June 2020, Dr. Karim reports much more confidence in discussing complementary therapies with patients, and recommending evidence-based modalities for their specific concerns. We highly recommend that oncology healthcare providers build their knowledge in the field of integrative oncology, either through a formal program like the IOS program or through continuing medical education activities .


The Randomized Embedded Multifactorial Adaptive Platform (REMAP-CAP) adapted for COVID-19) trial is a global adaptive platform trial of hospitalised patients with COVID-19. We describe implementation in three countries under the umbrella of the Wellcome supported Low and Middle Income Country (LMIC) critical  care network: Collaboration for Research, Implementation and Training in Asia (CCA). The collaboration sought to overcome known barriers to multi centre-clinical trials in resource-limited settings. Methods described focused on six aspects of implementation: i, Strengthening an existing community of practice; ii, Remote study site recruitment, training and support; iii, Harmonising the REMAP CAP- COVID trial with existing care processes; iv, Embedding REMAP CAP- COVID case report form into the existing CCA registry platform, v, Context specific adaptation and data management; vi, Alignment with existing pandemic and critical care research in the CCA. Methods described here may enable other LMIC sites to participate as equal partners in international critical care trials of urgent public health importance, both during this pandemic and beyond. With steroids and possibly IL6 receptor antagonists the exceptions, survival from severe COVID-19 remains dependent on providing the best possible supportive care. Recommendations for supportive therapies are derived mainly from resource-rich settings, whereas recommendations for resource-poor settings in low- and middle-income countries (LMICs), or for rich countries with health systems overwhelmed by the pandemic, are largely lacking2.A truly global pandemic, the COVID-19 pandemic has placed unprecedented strain on national health systems globally, with demand for intensive care beds and mechanical ventilators rapidly outstripping their availability, even in relatively highly resourced settings. The consequences for low- and middle-income settings, where the quality and availability of health care and related resources  is typically poorer and where limited pre-pandemic data is available to inform priorities for research, are potentially devastating1. High quality clinical research, codesigned and conducted in low SDI countries and in resource constrained LMICS is required in order to discover or verify both the efficacy and effectiveness of treatments in diverse settings. Despite this, LMICs remain severely underrepresented in clinical research - and specifically in clinical trials3. Those stakeholders from LMICs seeking to undertake research often face barriers to successful trial participation; limited expertise or infrastructure to conduct research, lack of financial and human resources and lack of peer to peer support, and complex ethical and regulatory processes- which to navigate costs both time and energy for already overburdened clinicians4.Developing countries represent the majority of the world’s population and host nearly 90% of the worldwide burden of disease, with communicable diseases including lower respiratory tract infections the prevailing causes for loss of life and disability in low socio-demographic Index (SDI) countriesREMAP-CAP, the Randomised Embedded Multifactorial Adaptive Platform Trial in Community-Acquired Pneumonia , is a trial that studies multiple interventions simultaneously and sequentially for patients with severe community acquired pneumonia (CAP) admitted to the intensive care unit (ICU). Its adaptive statistical methods including response-adaptive randomisation enable rapid uptake of study results, meaning patients may benefit from the accruing data. Following the COVID-19 outbreak, REMAP-CAP activated its pandemic mode to focus on treatments for COVID-19 disease in the most critically ill patients. Since the global pandemic in March 2020 REMAP has increased its sites five-fold, internationally.5. Its goal is to improve outcomes for critically ill patients, using near real-time high-quality data captured through a cloud-based registry platform to enable setting prioritised improvement, training and research. At its core, the CCA brings together clinical, research, data science and quality improvement stakeholders, who together work to support fledgling acute and critical care registries7. The CCA connects over 95 intensive care units from institutions to provide diverse high-quality data to generate evidence and feedback in near real time for service improvement and research, akin to the foundations of a learning health system (LHS)8.Wellcome - Mahidol Oxford Tropical Medicine Research Unit supported CCA is a LMIC-led collaborative spanning nine Asian countriesWe leveraged the CCA registry platform and existing infrastructure to operationalise REMAP-CAP for COVID and non COVID domains in LMIC ICUs. We sought to overcome the known barriers to operationalising clinical trials in LMICs. Six key aspects of this process are described: i) strengthening an existing community of practice; ii) enabling remote study site recruitment, training and support; iii) harmonising the REMAP trial with existing care processes; iv) embedding REMAP into the existing CCA registry platform; v) providing context specific adaptation and data management, vi) aligning with existing pandemic and critical care research in the CCA.7.We leveraged existing knowledge and expertise within the CCA and adopted a “learning by doing” approach. Stakeholders who included clinicians, researchers, microbiologists, policy makers and laboratory/ procurement services met online to discuss the REMAP-CAP vision and the feasibility of specific trial domains. The national leads and REMAP-CAP International Trial Steering Committee (ITSC) jointly designated the CCA registry team as the central hub for site recruitment training and data coordination in the network sites, providing local ownership and engagement. A regional management committee (CCA RMC) was proposed, consisting of national Principal Investigators (PIs) and members of the CCA from three CCA countries  where CCA supported critical care registries are now well established and where governance pathways for data collection and sharing as part of the CCA is already establishedNational PIs then together with the CCA RMC and ITSC reviewed the trial protocols and identified potential country and site specific ethical and regulatory bottlenecks. Network members with expertise in navigating ethical and regulatory approval for trials in Asia, provided templates for ethical applications, along with past reviewer questions and the corresponding responses, enabling system memory, shared learning and reducing the burden/ duplication of work for local investigators. Existing REMAP-CAP core protocol documentation and appendices for each domain provided modular, stepwise resources that were presented to national regulatory committees, providing context and precedent for the REMAP trial. The iterative approach process allowed for learning a great deal about trial implementation in diverse regions while ensuring local ownership and engagement was a major focus.9, and analysis, worked closely with the international REMAP trial team to train the multidisciplinary site level study teams in patient recruitment, consent and study monitoring protocols. The training was delivered online using audiovisual communication mechanisms and leveraged existing international REMAP-CAP resources of training videos. Following training, the central CCA team monitors ongoing trial recruitment and reporting from each site, providing remote support for troubleshooting for technical or research issues. Weekly meetings with the national coordinators using the logs (as described above) offers an opportunity to feedback site level learning and monitor protocol deviations, which are reported through the registry platform. Leveraging existing CCA remote support and communication channels for trial coordination has been especially important given both current COVID pandemic and the geographic distance that the CCA covers.The already-established CCA registry team—project coordinators, research assistants and data analysts, in partnership with national PI’s, clinical leads, site level data collectors and clinical research nurses—were essential to operationalize REMAP. Stakeholders in existing CCA sites keen to participate in the trial were approached. Previous trial participation was not a requirement, but an established track record of registry data capture for evaluating existing care was. The CCA team, who already provide support to sites in the network with data quality, curationThe REMAP design is that the trial research activities and existing clinical care are synergistic. This design aims to streamline research processes and embed them within existing care. This design approach is especially important both in resource constrained health care settings, and during pandemics where trial coordination and research specific activities can at best place additional burden on already exhausted healthcare providers and at worst distract or divert clinicians away from front line care. Two domains; anticoagulation for COVID-19 patients and Vitamin C for severe respiratory illness patients were selected based on their synergy with population specific research priorities, their existing use in clinical care of critically ill COVID and non-COVID respiratory illness patients, and existing availability of the therapeutic agents. National leads and the CCA RMC then worked with site level stakeholders to ensure trial therapeutics and bioclinical sampling within existing supply chain and laboratory services. Trial domains and data points were reviewed, and all (currently 12) recruited centers selected have the necessary laboratory services in place, removing the need for additional trial-specific laboratory resources. Treatments within the two selected domains are already available in the participating centers, meaning additional drug procurement, shipping and storage for the trial was not needed.The REMAP-CAP and CCA teams have integrated the REMAP trial domain specific Case Report Forms (CRF) into the CCA registry, ensuring interoperability of data through harmonisation with existing REMAP data structure and CRF logic . To achi10, embedded in the CCA registry platform, provides a seamless transition for the bedside research team. Consent forms, study protocols, and participatory information leaflets including contact information for the local, national, and international study teams are all available to view, download and print by registered users from the CCA registry platform. Consent forms, once signed are then photographed and uploaded to the CCA platform, placing all study resources and documentation in a central location, where issues pertaining to enrollment and consent can also be reported to and monitored by the central REMAP CCA team, ensuring Good Clinical Practice criteria are met 12 as part of the CCA platform’s commitment to the FAIR principles of data management13 and creating the potential for sites to contribute to other international observational pandemic research.The COVID-19 pandemic has resulted in unprecedented mobilisation of ministries, policy makers and clinicians to engage in research. In partnership with ISARIC and led by collaborating registry PRICE14. Known barriers to trials in resource constrained health systems; technological challenges including internet bandwidth, navigating institutional firewalls, device availability and human computer interaction were mitigated by the infrastructure already established by the CCA. Similarly, the strong partnership of support for real-time troubleshooting already present between the CCA implementation team and collaborating registries was invaluable during initial recruitment and training. Embedding the REMAP trial domain CRF’s into the existing registry platform has reduced the burden of data capture for frontline clinical staff; essential in resource constrained settings, where failure to optimise and reuse data results in at best poor quality of data and at worst misdirects resources from clinical care. The CCAs upfront investment in a codesigned platform, developed in partnership with frontline clinicians and iterated within the diverse health systems in the CCA, has mitigated against known challenges of data availability and quality. In addition, leveraging the cloud-based platform with inbuilt data audit and feedback mechanisms has enabled hospitals within the geographically wide network to be supported by a centralised research team. Data generated through the CCA will enable evaluation and benchmarking of existing care practices for patients with pneumonia in intensive care and may inform quality improvement projects to implement and share best practices within the community of practice; the hallmarks of a learning health system. Nine sites in three countries are now actively recruiting patients to pandemic related REMAP trial domains; India, Nepal and Pakistan. Other sites in the CCA network are seeking collaboration and will be supported.The CCA’s and collaborating registries shared expertise, track record in remote working and a prior knowledge of overcoming technical and training barriers to registry adaption was a central tenet of overcoming known barriers to trials described aboveWhilst the pandemic has accelerated opportunities for international clinical trial collaboration, particularly amongst clinicians, ethics committees, data sharing committees and research review boards are faced with unprecedented numbers of applications for review. Such committees in many LMICs rely heavily on volunteers, and members may have themselves face rising clinical obligations, which coupled with limited experience of complex trials such as REMAP or of navigating international data sharing- may lead to opportunities to engage in research being rejected or delayed. Collaborations such as CCA, along with grant making bodies, have a duty to further Invest in building capacity for such services and in promoting greater compatibility of governance structures.Implementation of the REMAP-CAP for COVID trial in the CCA is feasible and facilitated by multidisciplinary collaboration. This investment establishes important groundwork for future learning health system endeavors. This operationalisation of a randomized controlled platform trial in a registry-embedded manner in three countries of a nascent critical care network can be the stimulus for further democratisation of international trial participation.No data are associated with this article. This article focuses on an important topic in clinical research - the underrepresentation of LMICs in clinical research/trials. This article describes the implementation of the REMAP-CAP study and CCA collaboration as impressive examples of how to promote equitable and context-relevant research. Overall the manuscript is excellent though could benefit from some additional copyediting. Please find additional minor comments for consideration and revision below: Introduction:The terms low SDI and LMIC are both used independently and in combination - consider streamlining terminology.May be helpful to make the point that interventions designed/implemented for respiratory failure in well-resourced settings have the potential to cause harm when applied in LMICs  without other considerations in place.Consider expanding on the reference/origin for 'known barriers' to operationalising clinical trials in LMICs or expanding on the process that identified the 'six key aspects' of the process.When discussing REMAP-CAP trial design, consider further clarifying how study patients benefit from the response-adaptive randomization in near real time.Second sentence in Collaboration for Research, Implementation and Training (CCA) section needs clarification.  Approach:Strengthening an existing community of practice section: Consider expanding on the lasting positive effects of this endeavor. Specifically, what was learned/gained during this process that will facilitate future inclusion of LMIC sites in international clinical trials.Consider expanding on how the CCA model of remote onboarding/monitoring can be replicated elsewhere.Harmonisation with existing care processes section: consider clarifying the message in the first sentence.  Context specific adaptation and data management section: Consider additional citations to specify the “already proven registry data collection practices.” Impact:First paragraph: Could you present quantifiable data such as percent completeness, any audit data as available, to underscore the degree of impact.Remaining challenges section: Consider clarifying the wording of the first sentence, as we do not know which groups are faced with accelerated opportunities vs unprecedented numbers of applications.Please expound upon remaining challenges, as bottlenecks at ethics/regulatory committees are likely not the only remaining challenges for this type of work. Conclusions: Could consider also highlighting the scientific merit to include LMIC sites in international critical care clinical trials.Figure/Tables:Figure 2. Please consider including figure legend to specify the significance of dotted lines, red circles in “academic community” box, greyed-out boxes, and lines which have arrows in opposite directions .Figure 3. Consider color coding to further delineate data flow in the direction of national registries to CCA database from reports/analytics flow in the direction of CCA data to national registries.Define “ETL” in legend.Does the article adequately reference differing views and opinions?YesAre all factual statements correct, and are statements and arguments made adequately supported by citations?YesIs the Open Letter written in accessible language?YesWhere applicable, are recommendations and next steps explained clearly for others to follow?YesIs the rationale for the Open Letter provided in sufficient detail?YesReviewer Expertise:ARDS, research in HIC-LMIC collaborationsWe confirm that we have read this submission and believe that we have an appropriate level of expertise to confirm that it is of an acceptable scientific standard. Major comments This is a really important and well-structured manuscript, providing a detailed description of how a regional international ICU registry was used to make international trial participation feasible for three LMICs. The detail provided is incredibly helpful as readers think about applying the lessons learned by this group. In particular the following descriptions were helpful: use of the community of practice for IRB navigation; using the CCA structure and REMAP resources to onboard remote sites; choosing interventions that are feasible for the resources at the sites in question; embedding every part of the CRF and consent into the CCA registry; and a very detailed description of the data management processes. One barrier I would love to see addressed is compensation for time spent, including both PIs as well as data collectors. Often international trials expect sites to provide leadership (PIs) and data collection, with little or no compensation. This is far less feasible in LMICs, where clinicians are already stretched, as noted in the manuscript. A description of how time is compensated (or not) for the baseline registry, and whether the REMAP-CAP trial added resources to this, would be very helpful. If the answer is that compensation is largely not provided, this is also interesting information – and would suggest that the registry is so useful to clinicians that the time spent entering data is considered part of clinical care time. Any detail that can be provided on this would be a welcome addition. However, the authors are certainly not required to add comments on this, as it may not be a relevant learning point from their experience. Overall the manuscript could benefit from copy editing, particularly in shortening some lengthy sentences, and adding and deleting commas to improve clarity.Minor commentsIf allowed by Wellcome formatting rules, I would add the acronym (REMAP-CAP) after the full name in the title, as this is a well-known trial group, recognized more easily by its acronym name. Title:It is not obvious how CCA is the acronym for the group as spelled out .A dash is not needed between centre-clinical. Instead, there could be a dash in multi-centre.Would say “Methods described focus” rather than “Methods described focused”.Would use usual numbering: 1) or i) rather than i,No need to capitalize the implementation areas described Abstract:I would provide citations for: 1) the statement of scarcity of resources even in highly-resourced areas and 2) the mention of steroids and IL-6 inhibitors as evidence-based treatments for COVID-19.Would say “bear …” rather than “host …”“High quality clinical research … in low SDI countries and in resource constrained LMICs” … are the authors meaning say that low SDI countries and LMICs are distinct from one another? If not, it would be better to use only one of these as the descriptor of resource-limited settings.“successful trial participation” should be followed by a colon rather than a semicolon.“Those stakeholders from LMICs seeking to undertake …” is a long sentence, and would benefit from shortening, particularly the last parenthetical about the time and energy required for regulatory processes.“REMAP: a platform trial”: I would cite the description noted in the first sentence; even citing the REMAP-CAP website would be sufficient.“CCA”: I would start the first sentence of this section with “The” before “Wellcome-Mahidol …”.“CCA”: I would add a citation for the sentence describing CCA; the website for CCA would be sufficient. IntroductionThis would be even more useful if REMAP-CAP were mentioned, diagramming at what point in the process the data goes to the REMAP-CAP group. Figure 3:Does the article adequately reference differing views and opinions?YesAre all factual statements correct, and are statements and arguments made adequately supported by citations?PartlyIs the Open Letter written in accessible language?PartlyWhere applicable, are recommendations and next steps explained clearly for others to follow?YesIs the rationale for the Open Letter provided in sufficient detail?YesReviewer Expertise:global health, resource-poor settings, critical care, ARDS, sepsisI confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard. This is a very clear account of an important and impressive piece of work implementing a complex global trial within an existing registry.  It provides a blueprint for future efforts to involve LMICs in international critical care trials. The article is scientifically sound and I have no suggestions for changes except that "data is" should be changed to "data are" because the singular form of data is datum.Does the article adequately reference differing views and opinions?YesAre all factual statements correct, and are statements and arguments made adequately supported by citations?YesIs the Open Letter written in accessible language?YesWhere applicable, are recommendations and next steps explained clearly for others to follow?YesIs the rationale for the Open Letter provided in sufficient detail?YesReviewer Expertise:intensive care medicineI confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard.


Prior to 1961, there were six known cholera pandemics. In each case, after 6–24 years of global spread cholera appears to have died out Past experience with smallpox, polio and malaria has taught us that such disease elimination efforts not only call for expanded control activities, but also substantial improvements in surveillance – from its essential role in allocating resources to how case finding, and case definitions, must change as we come closer to reaching our goals. However, cholera’s specific epidemiology poses unique challenges that must be addressed to move forward. Here, building on lessons from historical efforts, we propose three pillars for success in setting priorities and measuring progress in the fight against cholera: consistent reporting across time and space, appropriate indicators and matching interventions to populations.Fighting cholera and documenting progress comes with a number of cholera-specific challenges due to its diverse transmission dynamics, the lack of highly cholera-specific symptoms, that laboratory confirmation has little bearing on appropriate treatment and that no intervention alone can sustainably control cholera.Unlike malaria and measles, cholera exhibits a spectrum of transmission dynamics ranging from epidemic, where countries report zero cases in some years and large outbreaks in other years, to endemic, where cases occur regularly with seasonal peaks. The substantial lull periods of cases in many countries combined with non-specific cholera symptoms, make it difficult for surveillance to maintain focus on consistently tracking cholera with high specificity. Furthermore, reporting cholera has historically been thought to affect tourism and exports within a country, leading to underreporting or no reporting at all.Unlike smallpox and polio, there is no ‘silver bullet’ to protect people and halt transmission. While OCVs have moderate medium-term effectiveness a patient ≥ 5 years [who] develops severe dehydration or dies from acute watery diarrhea,’ whereas during outbreaks, all acute watery diarrhea patients ≥ 5 years are counted Assessing progress requires that we quantify the burden of cholera. However, only a small fraction of suspected cholera cases are laboratory confirmed. The World Health Organization (WHO) does not recommend exhaustive confirmation, in part because confirmation rarely influences clinical care The true proportion of suspected cases that would be confirmed cases varies from place-to-place and season-to-season, thus location-specific sentinel surveillance with routine confirmation of suspected cases is key to estimating the true number of cases from suspected case counts. We suggest this is done in endemic and epidemic settings during both low and high-transmission periods and across the urban/rural gradient. These estimates can then be combined with routinely collected acute watery diarrhea incidence data from a larger geographic area  to produce high resolution estimates of cholera burden. Understanding the etiology and seasonality of other diarrheal pathogens across all ages can help further refine this picture.Consistent reporting of cholera cases across time and space is a critical first step in estimating the burden of cholera. Currently, countries are asked to report suspected cholera cases each year to the WHO, although reports tend to be aggregated annually and over the country The WHO should ask that countries provide data disaggregated by week and district  and explicit case definitions should be provided for each location. As with other diseases like malaria, an assessment of the quality of reporting can be made using simple indicators like the proportion of health facilities reporting each week Given the dynamic nature of cholera, especially in areas that exhibit more epidemic dynamics, assessing incidence or mortality rates in a single year can be misleading. For example, Lusaka, Zambia Time-averaged incidence rates can be slow to change, meaning annual updates may provide little new information on progress. We propose the development of location-specific hypothesis tests that would yield the probability of data from that current year (or N-years) being indicative of a true reduction in the risk of cholera at a specific location, as compared to expected year-to-year random incidence variation. As more locations report zero cases each year, this could evolve into using statistical methods to estimate the probability that cholera is truly eliminated in a location. This type of location-specific definition can guard against false declarations of elimination, which may occur frequently if a simple definition  is used across all areas, irrespective of the local cholera epidemiology.Estimating cholera mortality can be extremely challenging given that in some places many cases lack access to care Other potential indicators include the outbreak recurrence frequency, proportion of months with active cholera transmission, the age distribution of cases, and measures of the geographic expansion of an outbreak after a confirmed case. Global efforts to map appropriate indicators of water and sanitation use Focusing cholera control efforts on entire countries is not feasible, thus identification of high-risk populations is essential for guiding the optimal intervention targets and types. Ongoing efforts to map historical mean incidence rates of reported cholera cases may provide one avenue for identifying those at-risk While the numerical cutoffs for indicators used to classify areas may vary by settings, the classifications can be used to prioritize interventions. For example, in incidence hotspots, both short-term and long-term approaches are needed, combining the use of OCV and preparations for appropriate case management with long-term behavior change and infrastructure programs. In epidemic-prone areas, preemptive OCV use may be less appropriate given the year-to-year variation in risk and the short-term vaccine protection, unless the periodicity of risk is well understood. However, as these areas may be prone to large but infrequent outbreaks, plans for rapid reactive OCV use should be put in place. In lower burden settings, while the mean annual incidence may be low, similar investments in infrastructure and behavior change can ensure they do not act as gateways of transmission to other neighboring areas and that they do not transition into epidemic prone or incidence hotspots, perhaps after a complex emergency. This system is simple enough to apply across all cholera-prone countries although it neglects many potentially important local features of cholera epidemiology. Thus, location-specific epidemiologic knowledge should supplement any broad intervention prioritization system.While the fights against smallpox and polio had broad impacts in building international health systems and local expertise, the tools used in each primarily impact a single disease. Success in fighting cholera would have broad impacts on health, far beyond those specific to cholera. Though an essential tool for control, OCV protection is impermanent and the bacteria may persist in the environment. Hence, the only long-term solution is access to safe water and improved sanitation and behavior change. Sustained improvements here, though focused on cholera, would allow people to enjoy broad health benefits, such as access to clean drinking water. Cholera is then not just a goal itself, but a rallying point for a broader fight against water-related pathogens and an essential indicator of our progress. That every previous pandemic came to an end tells us the fight against cholera can be successful, and success would be a general public health win, not simply related to cholera.Bill & Melinda Gates Foundation, Seattle, WA [OPP1171700], [OPP1191944] and National Institutes of Health (R01 AI135115).This work was supported by the We declare no conflicts of interest.