Strategic vaccine stockpiles for regional epidemics of emerging viruses: A geospatial modeling framework.

Multinational epidemics of emerging infectious diseases are increasingly common, due to anthropogenic pressure on ecosystems and the growing connectivity of human populations. Early and efficient vaccination can contain outbreaks and prevent mass mortality, but optimal vaccine stockpiling strategies are dependent on pathogen characteristics, reservoir ecology, and epidemic dynamics. Here, we model major regional outbreaks of Nipah virus and Middle East respiratory syndrome, and use these to develop a generalized framework for estimating vaccine stockpile needs based on spillover geography, spatially-heterogeneous healthcare capacity and spatially-distributed human mobility networks. Because outbreak sizes were highly skewed, we found that most outbreaks were readily contained (median stockpile estimate for MERS-CoV: 2,089 doses; Nipah: 1,882 doses), but the maximum estimated stockpile need in a highly unlikely large outbreak scenario was 2-3 orders of magnitude higher (MERS-CoV: ∼87,000 doses; Nipah âˆ¼ 1.1 million doses). Sensitivity analysis revealed that stockpile needs were more dependent on basic epidemiological parameters (i.e., death and recovery rate) and healthcare availability than any uncertainty related to vaccine efficacy or deployment strategy. Our results highlight the value of descriptive epidemiology for real-world modeling applications, and suggest that stockpile allocation should consider ecological, epidemiological, and social dimensions of risk.

Evidence of turmeric adulteration with lead chromate across South Asia.

Food adulteration with toxic chemicals is a global public health threat. Lead chromate adulterated spices have been linked with lead poisoning in many countries, from Bangladesh to the United States. This study systematically assessed lead chromate adulteration in turmeric, a spice that is consumed daily across South Asia. Our study focused on four understudied countries that produce >80 % of the world's turmeric and collectively include 1.7 billion people, 22 % of the world's population. Turmeric samples were collected from wholesale and retail bazaars from 23 major cities across India, Pakistan, Sri Lanka, and Nepal between December 2020 and March 2021. Turmeric samples were analyzed for lead and chromium concentrations and maximum child blood lead levels were modeled in regions where samples had detectable lead. A total of 356 turmeric samples were collected, including 180 samples of dried turmeric roots and 176 samples of turmeric powder. In total, 14 % of the samples (n = 51) had detectable lead above 2 µg/g. Turmeric samples with lead levels greater than or equal to 18 µg/g had molar ratios of lead to chromium near 1:1, suggestive of lead chromate adulteration. Turmeric lead levels exceeded 1000 µg/g in Patna (Bihar, India) as well as Karachi and Peshawar (Pakistan), resulting in projected child blood lead levels up to 10 times higher than the CDC's threshold of concern. Given the overwhelmingly elevated lead levels in turmeric from these locations, urgent action is needed to halt the practice of lead chromate addition in the turmeric supply chain.

WASH interventions and child diarrhea at the interface of climate and socioeconomic position in Bangladesh.

Many diarrhea-causing pathogens are climate-sensitive, and populations with the lowest socioeconomic position (SEP) are often most vulnerable to climate-related transmission. Household Water, Sanitation, and Handwashing (WASH) interventions constitute one potential effective strategy to reduce child diarrhea, especially among low-income households. Capitalizing on a cluster randomized trial population (360 clusters, 4941 children with 8440 measurements) in rural Bangladesh, one of the world's most climate-sensitive regions, we show that improved WASH substantially reduces diarrhea risk with largest benefits among children with lowest SEP and during the monsoon season. We extrapolated trial results to rural Bangladesh regions using high-resolution geospatial layers to identify areas most likely to benefit. Scaling up a similar intervention could prevent an estimated 734 (95% CI 385, 1085) cases per 1000 children per month during the seasonal monsoon, with marked regional heterogeneities. Here, we show how to extend large-scale trials to inform WASH strategies among climate-sensitive and low-income populations.

Perinatal colonization with extended-spectrum beta-lactamase-producing and carbapenem-resistant Gram-negative bacteria: a hospital-based cohort study.

BACKGROUND: Antimicrobial resistance (AMR) is a growing global health threat that contributes to substantial neonatal mortality. Bangladesh has reported some of the highest rates of AMR among bacteria causing neonatal sepsis. As AMR colonization among newborns can predispose to infection with these bacteria, we aimed to characterize the frequency of and risk factors for colonization of mothers and newborns during hospitalization for delivery. METHODS: We enrolled pregnant women presenting for delivery to a tertiary care hospital in Faridpur, Bangladesh. We collected vaginal and rectal swabs from mothers pre- and post-delivery, rectal swabs from newborns, and swabs from the hospital environment. Swabs were plated on agars selective for extended-spectrum-beta-lactamase producing bacteria (ESBL-PB) and carbapenem-resistant bacteria (CRB). We performed logistic regression to determine factors associated with ESBL-PB/CRB colonization. RESULTS: We enrolled 177 women and their newborns during February-October 2020. Prior to delivery, 77% of mothers were colonized with ESBL-PB and 15% with CRB. 79% of women underwent cesarean deliveries (C-section). 98% of women received antibiotics. Following delivery, 98% of mothers and 89% of newborns were colonized with ESBL-PB and 89% of mothers and 72% of newborns with CRB. Of 290 environmental samples, 77% were positive for ESBL-PB and 69% for CRB. Maternal pre-delivery colonization was associated with hospitalization during pregnancy (RR for ESBL-PB 1.24, 95% CI 1.10-1.40; CRB 2.46, 95% CI 1.39-4.37). Maternal post-delivery and newborn colonization were associated with C-section (RR for maternal CRB 1.31, 95% CI 1.08-1.59; newborn ESBL-PB 1.34, 95% CI 1.09-1.64; newborn CRB 1.73, 95% CI 1.20-2.47). CONCLUSIONS: In this study, we observed high rates of colonization with ESBL-PB/CRB among mothers and newborns, with pre-delivery colonization linked to prior healthcare exposure. Our results demonstrate this trend may be driven by intense use of antibiotics, frequent C-sections, and a contaminated hospital environment. These findings highlight that greater attention should be given to the use of perinatal antibiotics, improved surgical stewardship for C-sections, and infection prevention practices in healthcare settings to reduce the high prevalence of colonization with AMR organisms.

Old tools, new applications: Use of environmental bacteriophages for typhoid surveillance and evaluating vaccine impact.

Typhoid-conjugate vaccines (TCVs) provide an opportunity to reduce the burden of typhoid fever, caused by Salmonella Typhi, in endemic areas. As policymakers design vaccination strategies, accurate and high-resolution data on disease burden is crucial. However, traditional blood culture-based surveillance is resource-extensive, prohibiting its large-scale and sustainable implementation. Salmonella Typhi is a water-borne pathogen, and here, we tested the potential of Typhi-specific bacteriophage surveillance in surface water bodies as a low-cost tool to identify where Salmonella Typhi circulates in the environment. In 2021, water samples were collected and tested for the presence of Salmonella Typhi bacteriophages at two sites in Bangladesh: urban capital city, Dhaka, and a rural district, Mirzapur. Salmonella Typhi-specific bacteriophages were detected in 66 of 211 (31%) environmental samples in Dhaka, in comparison to 3 of 92 (3%) environmental samples from Mirzapur. In the same year, 4,620 blood cultures at the two largest pediatric hospitals of Dhaka yielded 215 (5%) culture-confirmed typhoid cases, and 3,788 blood cultures in the largest hospital of Mirzapur yielded 2 (0.05%) cases. 75% (52/69) of positive phage samples were collected from sewage. All isolated phages were tested against a panel of isolates from different Salmonella Typhi genotypes circulating in Bangladesh and were found to exhibit a diverse killing spectrum, indicating that diverse bacteriophages were isolated. These results suggest an association between the presence of Typhi-specific phages in the environment and the burden of typhoid fever, and the potential of utilizing environmental phage surveillance as a low-cost tool to assist policy decisions on typhoid control.

Improved Child Feces Management Mediates Reductions in Childhood Diarrhea from an On-Site Sanitation Intervention: Causal Mediation Analysis of a Cluster-Randomized Trial in Rural Bangladesh.

BACKGROUND: The WASH benefits Bangladesh trial multi-component sanitation intervention reduced diarrheal disease among children < 5 years. Intervention components included latrine upgrades, child feces management tools, and behavioral promotion. It remains unclear which components most impacted diarrhea. METHODS: We conducted mediation analysis within a subset of households (n = 720) from the sanitation and control arms. Potential mediators were categorized into indicators of latrine quality, latrine use practices, and feces management practices. We estimated average causal mediation effects (ACME) as prevalence differences (PD), defined as the intervention's effect on diarrhea through its effect on the mediator. RESULTS: The intervention improved all indicators compared to controls. We found significant mediation through multiple latrine use and feces management practice indicators. The strongest mediators during monsoon seasons were reduced open defecation among children aged < 3 and 3-8 years, and increased disposal of child feces into latrines. The strongest mediators during dry seasons were access to a flush/pour-flush latrine, reduced open defecation among children aged 3-8 years, and increased disposal of child feces into latrines. Individual mediation effects were small (PD = 0.5-2 percentage points) compared to the overall intervention effect but collectively describe significant mediation pathways. DISCUSSION: The effect of the WASH Benefits Bangladesh sanitation intervention on diarrheal disease was mediated through improved child feces management and reduced child open defecation. Although the intervention significantly improved latrine quality, relatively high latrine quality at baseline may have limited benefits from additional improvements. Targeting safe child feces management may increase the health benefits of rural sanitation interventions.

Influence of Temperature and Precipitation on the Effectiveness of Water, Sanitation, and Handwashing Interventions against Childhood Diarrheal Disease in Rural Bangladesh: A Reanalysis of the WASH Benefits Bangladesh Trial.

BACKGROUND: Diarrheal disease is a leading cause of childhood morbidity and mortality globally. Household water, sanitation, and handwashing (WASH) interventions can reduce exposure to diarrhea-causing pathogens, but meteorological factors may impact their effectiveness. Information about effect heterogeneity under different weather conditions is critical to refining these targeted interventions. OBJECTIVES: We aimed to determine whether temperature and precipitation modified the effect of low-cost, point-of-use WASH interventions on child diarrhea. METHODS: We analyzed data from a trial in rural Bangladesh that compared child diarrhea prevalence between clusters (N=720) that were randomized to different WASH interventions between 2012 and 2016 (NCT01590095). We matched temperature and precipitation measurements to diarrhea outcomes (N=12,440 measurements, 6,921 children) by geographic coordinates and date. We estimated prevalence ratios (PRs) using generative additive models and targeted maximum likelihood estimation to assess the effectiveness of each WASH intervention under different weather conditions. RESULTS: Generally, WASH interventions most effectively prevented diarrhea during monsoon season, particularly following weeks with heavy rain or high temperatures. The PR for diarrhea in the WASH interventions group compared with the control group was 0.49 (95% CI: 0.35, 0.68) after 1 d of heavy rainfall, with a less-protective effect [PR=0.87 (95% CI: 0.60, 1.25)] when there were no days with heavy rainfall. Similarly, the PR for diarrhea in the WASH intervention group compared with the control group was 0.60 (95% CI: 0.48, 0.75) following above-median temperatures vs. 0.91 (95% CI: 0.61, 1.35) following below-median temperatures. The influence of precipitation and temperature varied by intervention type; for precipitation, the largest differences in effectiveness were for the sanitation and combined WASH interventions. DISCUSSION: WASH intervention effectiveness was strongly influenced by precipitation and temperature, and nearly all protective effects were observed during the rainy season. Future implementation of these interventions should consider local environmental conditions to maximize effectiveness, including targeted efforts to maintain latrines and promote community adoption ahead of monsoon seasons. https://doi.org/10.1289/EHP13807.

Geographic pair matching in large-scale cluster randomized trials.

Cluster randomized trials are often used to study large-scale public health interventions. In large trials, even small improvements in statistical efficiency can have profound impacts on the required sample size and cost. Location integrates many socio-demographic and environmental characteristics into a single, readily available feature. Here we show that pair matching by geographic location leads to substantial gains in statistical efficiency for 14 child health outcomes that span growth, development, and infectious disease through a re-analysis of two large-scale trials of nutritional and environmental interventions in Bangladesh and Kenya. Relative efficiencies from pair matching are ≥1.1 for all outcomes and regularly exceed 2.0, meaning an unmatched trial would need to enroll at least twice as many clusters to achieve the same level of precision as the geographically pair matched design. We also show that geographically pair matched designs enable estimation of fine-scale, spatially varying effect heterogeneity under minimal assumptions. Our results demonstrate broad, substantial benefits of geographic pair matching in large-scale, cluster randomized trials.

Informing an investment case for Japanese encephalitis vaccine introduction in Bangladesh.

Japanese encephalitis virus (JEV) is a major threat to human health. Bangladesh is considering introducing a JEV vaccine; however, the investment case is hampered by a limited understanding of key aspects of JEV ecology. We conducted a seroprevalence study in a high-incidence region using an assay that limits cross-reactivity with dengue virus. We also trapped mosquitoes and collected information about potential host species. We used mathematical models to recover risk factors for infection and underlying probabilities of severe disease and death. We observed 19.0% [95% confidence interval (CI):17.1 to 21.1] of JEV antibodies. On average, 0.7% (95% CI: 0.2 to 2.0) of the susceptible population gets infected yearly, with pig proximity being the main human infection risk factor. Our traps captured 10 different mosquito species that have been linked with JEV transmission. We estimated that 1 in 1000 infections results in severe disease, 1 in 10,000 results in death, and 76% of severe cases are missed by surveillance.

Is detection of enteropathogens and human or animal faecal markers in the environment associated with subsequent child enteric infections and growth: an individual participant data meta-analysis.

BACKGROUND: Quantifying contributions of environmental faecal contamination to child diarrhoea and growth faltering can illuminate causal mechanisms behind modest health benefits in recent water, sanitation, and hygiene (WASH) trials. We aimed to assess associations between environmental detection of enteropathogens and human or animal microbial source tracking markers (MSTM) and subsequent child health outcomes. METHODS: In this individual participant data meta-analysis we searched we searched PubMed, Embase, CAB Direct Global Health, Agricultural and Environmental Science Database, Web of Science, and Scopus for WASH intervention studies with a prospective design and concurrent control that measured enteropathogens or MSTM in environmental samples, or both, and subsequently measured enteric infections, diarrhoea, or height-for-age Z-scores (HAZ) in children younger than 5 years. We excluded studies that only measured faecal indicator bacteria. The initial search was done on Jan 19, 2021, and updated on March 22, 2023. One reviewer (AM) screened abstracts, and two independent reviewers (AM and RT) examined the full texts of short-listed articles. All included studies include at least one author that also contributed as an author to the present Article. Our primary outcomes were the 7-day prevalence of caregiver-reported diarrhoea and HAZ in children. For specific enteropathogens in the environment, primary outcomes also included subsequent child infection with the same pathogen ascertained by stool testing. We estimated associations using covariate-adjusted regressions and pooled estimates across studies. FINDINGS: Data from nine published reports from five interventions studies, which included 8603 children (4302 girls and 4301 boys), were included in the meta-analysis. Environmental pathogen detection was associated with increased infection prevalence with the same pathogen and lower HAZ (ΔHAZ -0·09 [95% CI -0·17 to -0·01]) but not diarrhoea (prevalence ratio 1·22 [95% CI 0·95 to 1·58]), except during wet seasons. Detection of MSTM was not associated with diarrhoea (no pooled estimate) or HAZ (ΔHAZ -0·01 [-0·13 to 0·11] for human markers and ΔHAZ -0·02 [-0·24 to 0·21] for animal markers). Soil, children's hands, and stored drinking water were major transmission pathways. INTERPRETATION: Our findings support a causal chain from pathogens in the environment to infection to growth faltering, indicating that the lack of WASH intervention effects on child growth might stem from insufficient reductions in environmental pathogen prevalence. Studies measuring enteropathogens in the environment should subsequently measure the same pathogens in stool to further examine theories of change between WASH, faecal contamination, and health. Given that environmental pathogen detection was predictive of infection, programmes targeting specific pathogens (eg, vaccinations and elimination efforts) can environmentally monitor the pathogens of interest for population-level surveillance instead of collecting individual biospecimens. FUNDING: The Bill & Melinda Gates Foundation and the UK Foreign and Commonwealth Development Office.

Influence of hydrometeorological risk factors on child diarrhea and enteropathogens in rural Bangladesh.

BACKGROUND: A number of studies have detected relationships between weather and diarrhea. Few have investigated associations with specific enteric pathogens. Understanding pathogen-specific relationships with weather is crucial to inform public health in low-resource settings that are especially vulnerable to climate change. OBJECTIVES: Our objectives were to identify weather and environmental risk factors associated with diarrhea and enteropathogen prevalence in young children in rural Bangladesh, a population with high diarrheal disease burden and vulnerability to weather shifts under climate change. METHODS: We matched temperature, precipitation, surface water, and humidity data to observational longitudinal data from a cluster-randomized trial that measured diarrhea and enteropathogen prevalence in children 6 months-5.5 years from 2012-2016. We fit generalized additive mixed models with cubic regression splines and restricted maximum likelihood estimation for smoothing parameters. RESULTS: Comparing weeks with 30°C versus 15°C average temperature, prevalence was 3.5% higher for diarrhea, 7.3% higher for Shiga toxin-producing Escherichia coli (STEC), 17.3% higher for enterotoxigenic E. coli (ETEC), and 8.0% higher for Cryptosporidium. Above-median weekly precipitation (median: 13mm; range: 0-396mm) was associated with 29% higher diarrhea (adjusted prevalence ratio 1.29, 95% CI 1.07, 1.55); higher Cryptosporidium, ETEC, STEC, Shigella, Campylobacter, Aeromonas, and adenovirus 40/41; and lower Giardia, sapovirus, and norovirus prevalence. Other associations were weak or null. DISCUSSION: Higher temperatures and precipitation were associated with higher prevalence of diarrhea and multiple enteropathogens; higher precipitation was associated with lower prevalence of some enteric viruses. Our findings emphasize the heterogeneity of the relationships between hydrometeorological variables and specific enteropathogens, which can be masked when looking at composite measures like all-cause diarrhea. Our results suggest that preventive interventions targeted to reduce enteropathogens just before and during the rainy season may more effectively reduce child diarrhea and enteric pathogen carriage in rural Bangladesh and in settings with similar meteorological characteristics, infrastructure, and enteropathogen transmission.

Field Effectiveness of a Typhoid Conjugate Vaccine: The 2018 Navi Mumbai Pediatric TCV Campaign.

Typbar-TCV®, a typhoid conjugate vaccine (TCV), was prequalified by the World Health Organization in 2017. We evaluated its effectiveness in a mass vaccination program targeting children 9 months to 14 years in Navi Mumbai, India, from September 2018 to July 2020. We compared laboratory-confirmed typhoid cases from six clinical sites with age-matched community controls. Of 38 cases, three (8.6%) received TCV through the campaign, compared with 53 (37%) of 140 controls. The adjusted odds ratio of typhoid fever among vaccinated children was 0.16 (95% CI: 0.05-0.55), equivalent to a vaccine effectiveness of 83.7% (95% CI: 45.0-95.3). Vaccine effectiveness of Typbar-TCV in this large public sector vaccine introduction was similar to prior randomized controlled trials, providing reassurance to policymakers that TCV effectiveness is robust in a large-scale implementation.

A cluster-randomized trial of water, sanitation, handwashing and nutritional interventions on stress and epigenetic programming.

A regulated stress response is essential for healthy child growth and development trajectories. We conducted a cluster-randomized trial in rural Bangladesh (funded by the Bill & Melinda Gates Foundation, ClinicalTrials.gov NCT01590095) to assess the effects of an integrated nutritional, water, sanitation, and handwashing intervention on child health. We previously reported on the primary outcomes of the trial, linear growth and caregiver-reported diarrhea. Here, we assessed additional prespecified outcomes: physiological stress response, oxidative stress, and DNA methylation (N = 759, ages 1-2 years). Eight neighboring pregnant women were grouped into a study cluster. Eight geographically adjacent clusters were block-randomized into the control or the combined nutrition, water, sanitation, and handwashing (N + WSH) intervention group (receiving nutritional counseling and lipid-based nutrient supplements, chlorinated drinking water, upgraded sanitation, and handwashing with soap). Participants and data collectors were not masked, but analyses were masked. There were 358 children (68 clusters) in the control group and 401 children (63 clusters) in the intervention group. We measured four F2-isoprostanes isomers (iPF(2α)-III; 2,3-dinor-iPF(2α)-III; iPF(2α)-VI; 8,12-iso-iPF(2α)-VI), salivary alpha-amylase and cortisol, and methylation of the glucocorticoid receptor (NR3C1) exon 1F promoter including the NGFI-A binding site. Compared with control, the N + WSH group had lower concentrations of F2-isoprostanes isomers (differences ranging from -0.16 to -0.19 log ng/mg of creatinine, P < 0.01), elevated post-stressor cortisol (0.24 log µg/dl; P < 0.01), higher cortisol residualized gain scores (0.06 µg/dl; P = 0.023), and decreased methylation of the NGFI-A binding site (-0.04; P = 0.037). The N + WSH intervention enhanced adaptive responses of the physiological stress system in early childhood.

Treatment Heterogeneity of Water, Sanitation, Hygiene, and Nutrition Interventions on Child Growth by Environmental Enteric Dysfunction and Pathogen Status for Young Children in Bangladesh.

Background: Water, sanitation, hygiene (WSH), nutrition (N), and combined (N+WSH) interventions are often implemented by global health organizations, but WSH interventions may insufficiently reduce pathogen exposure, and nutrition interventions may be modified by environmental enteric dysfunction (EED), a condition of increased intestinal permeability and inflammation. This study investigated the heterogeneity of these treatments' effects based on individual pathogen and EED biomarker status with respect to child linear growth. Methods: We applied cross-validated targeted maximum likelihood estimation and super learner ensemble machine learning to assess the conditional treatment effects in subgroups defined by biomarker and pathogen status. We analyzed treatment (N+WSH, WSH, N, or control) randomly assigned in-utero, child pathogen and EED data at 14 months of age, and child LAZ at 28 months of age. We estimated the difference in mean child length for age Z-score (LAZ) under the treatment rule and the difference in stratified treatment effect (treatment effect difference) comparing children with high versus low pathogen/biomarker status while controlling for baseline covariates. Results: We analyzed data from 1,522 children, who had median LAZ of -1.56. We found that myeloperoxidase (N+WSH treatment effect difference 0.0007 LAZ, WSH treatment effect difference 0.1032 LAZ, N treatment effect difference 0.0037 LAZ) and Campylobacter infection (N+WSH treatment effect difference 0.0011 LAZ, WSH difference 0.0119 LAZ, N difference 0.0255 LAZ) were associated with greater effect of all interventions on growth. In other words, children with high myeloperoxidase or Campylobacter infection experienced a greater impact of the interventions on growth. We found that a treatment rule that assigned the N+WSH (LAZ difference 0.23, 95% CI (0.05, 0.41)) and WSH (LAZ difference 0.17, 95% CI (0.04, 0.30)) interventions based on EED biomarkers and pathogens increased predicted child growth compared to the randomly allocated intervention. Conclusions: These findings indicate that EED biomarker and pathogen status, particularly Campylobacter and myeloperoxidase (a measure of gut inflammation), may be related to impact of N+WSH, WSH, and N interventions on child linear growth.

Stress biomarkers and child development in young children in Bangladesh.

BACKGROUND: Hundreds of millions of children in low- and middle-income countries are exposed to chronic stressors, such as poverty, poor sanitation and hygiene, and sub-optimal nutrition. These stressors can have physiological consequences for children and may ultimately have detrimental effects on child development. This study explores associations between biological measures of chronic stress in early life and developmental outcomes in a large cohort of young children living in rural Bangladesh. METHODS: We assessed physiologic measures of stress in the first two years of life using measures of the hypothalamic-pituitary-adrenal (HPA) axis (salivary cortisol and glucocorticoid receptor gene methylation), the sympathetic-adrenal-medullary (SAM) system (salivary alpha-amylase, heart rate, and blood pressure), and oxidative status (F2-isoprostanes). We assessed child development in the first two years of life with the MacArthur-Bates Communicative Development Inventories (CDI), the WHO gross motor milestones, and the Extended Ages and Stages Questionnaire (EASQ). We compared development outcomes of children at the 75th and 25th percentiles of stress biomarker distributions while adjusting for potential confounders using generalized additive models, which are statistical models where the outcome is predicted by a potentially non-linear function of predictor variables. RESULTS: We analyzed data from 684 children (49% female) at both 14 and 28 months of age; we included an additional 765 children at 28 months of age. We detected a significant relationship between HPA axis activity and child development, where increased HPA axis activity was associated with poor development outcomes. Specifically, we found that cortisol reactivity (coefficient -0.15, 95% CI (-0.29, -0.01)) and post-stressor levels (coefficient -0.12, 95% CI (-0.24, -0.01)) were associated with CDI comprehension score, post-stressor cortisol was associated with combined EASQ score (coefficient -0.22, 95% CI (-0.41, -0.04), and overall glucocorticoid receptor methylation was associated with CDI expression score (coefficient -0.09, 95% CI (-0.17, -0.01)). We did not detect a significant relationship between SAM activity or oxidative status and child development. CONCLUSIONS: Our observations reveal associations between the physiological evidence of stress in the HPA axis with developmental status in early childhood. These findings add to the existing evidence exploring the developmental consequences of early life stress.

Measures to prevent and treat Nipah virus disease: research priorities for 2024-29.

Nipah virus causes highly lethal disease, with case-fatality rates ranging from 40% to 100% in recognised outbreaks. No treatments or licensed vaccines are currently available for the prevention and control of Nipah virus infection. In 2019, WHO published an advanced draft of a research and development roadmap for accelerating development of medical countermeasures, including diagnostics, therapeutics, and vaccines, to enable effective and timely emergency response to Nipah virus outbreaks. This Personal View provides an update to the WHO roadmap by defining current research priorities for development of Nipah virus medical countermeasures, based primarily on literature published in the last 5 years and consensus opinion of 15 subject matter experts with broad experience in development of medical countermeasures for Nipah virus or experience in the epidemiology, ecology, or public health control of outbreaks of Nipah virus. The research priorities are organised into four main sections: cross-cutting issues (for those that apply to more than one category of medical countermeasures), diagnostics, therapeutics, and vaccines. The strategic goals and milestones identified in each section focus on key achievements that are needed over the next 6 years to ensure that the necessary tools are available for rapid response to future outbreaks of Nipah virus or related henipaviruses.