Search

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.

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

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.

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.

OBJECTIVES: (1) Assess and compare the perceptions of pet owners and veterinary professionals pertaining to the extent of veterinary workforce and access to care challenges in 2023 in Colorado, and (2) Assess what programs, policies, and resources veterinary professionals and pet owners believe would be most effective at addressing access to care and workforce challenges in Colorado. SAMPLE: 736 veterinarians, veterinary technicians, or practice/owner manager (veterinary professionals) in Colorado. A total of 1,209 pet owners (919 from an online survey and 290 from in-person surveying). PROCEDURES: Distribution of an online anonymous survey to veterinary professionals in Colorado. Pet owners were surveyed both online and in-person at pet pantry or shelter events. RESULTS: Veterinary professionals reported significant workforce challenges, including having to frequently divert clients, clients forced to decline medical care or having to euthanize their pets due to cost. Veterinary professionals were especially supportive of policy efforts to enhance recruitment and retention of technicians, including through mechanisms such as clarifying their scope of practice, loan repayment programs, and enhancing career pathways. Colorado pet owners responses pertaining to the scope of access to care challenges were similar to prior national research. Pet owners reported particularly needing low-cost emergency clinics in their community as well as resources to reduce the cost of care. Pet owners were generally supportive of expanding veterinary care access through telemedicine; indicating they would feel comfortable seeing a veterinarian via telemedicine, even for the first time, and that expanded use of telemedicine would increase their ability to obtain care. CONCLUSIONS AND CLINICAL RELEVANCE: Colorado pet owners and veterinary professionals both identified numerous access to care challenges as well as indicated support for the development of several potential initiatives to address the problem. Low-cost clinics that provide sick and emergency care was the resource rated as being most helpful among pet owners. Further exploration of grants, voucher programs, expansion of telemedicine, increased utilization and title protection for CVTs, and the creation of the veterinary professional associate position are all initiatives that were noted to be worthy of further exploration.

Language represents a framework used to organize the things we experience. Redundant linguistic category labels facilitate category learning at a faster rate than category learning without labels (Luypan et al., 2007) suggesting language is also meaningfully involved in forming new categories. However, labels are not exclusively advantageous. Brojde et al., (2011) demonstrates that labels can be detrimental to category learning dependent on attending to historically agnostic dimensions over historically diagnostic ones (i.e., learning texture-based categories while ignoring shape). To separate historical experience from novel category learning, we task participants with classifying stimuli based on perceptual dimensions with less historical precedence as diagnostic cues for categorizing objects in everyday life (i.e., orientation and spatial frequency). Our results reveal a labeling advantage as well as slower overall learning in the orientation condition compared to spatial frequency-based learning. We discuss implications involving the historical use of these dimensions and the relationship between diagnostic and non-diagnostic dimensions.

Growth faltering in children (low length for age or low weight for length) during the first 1,000 days of life (from conception to 2 years of age) influences short-term and long-term health and survival1,2. Interventions such as nutritional supplementation during pregnancy and the postnatal period could help prevent growth faltering, but programmatic action has been insufficient to eliminate the high burden of stunting and wasting in low- and middle-income countries. Identification of age windows and population subgroups on which to focus will benefit future preventive efforts. Here we use a population intervention effects analysis of 33 longitudinal cohorts (83,671 children, 662,763 measurements) and 30 separate exposures to show that improving maternal anthropometry and child condition at birth accounted for population increases in length-for-age z-scores of up to 0.40 and weight-for-length z-scores of up to 0.15 by 24 months of age. Boys had consistently higher risk of all forms of growth faltering than girls. Early postnatal growth faltering predisposed children to subsequent and persistent growth faltering. Children with multiple growth deficits exhibited higher mortality rates from birth to 2 years of age than children without growth deficits (hazard ratios 1.9 to 8.7). The importance of prenatal causes and severe consequences for children who experienced early growth faltering support a focus on pre-conception and pregnancy as a key opportunity for new preventive interventions.

Sustainable Development Goal 2.2-to end malnutrition by 2030-includes the elimination of child wasting, defined as a weight-for-length z-score that is more than two standard deviations below the median of the World Health Organization standards for child growth1. Prevailing methods to measure wasting rely on cross-sectional surveys that cannot measure onset, recovery and persistence-key features that inform preventive interventions and estimates of disease burden. Here we analyse 21 longitudinal cohorts and show that wasting is a highly dynamic process of onset and recovery, with incidence peaking between birth and 3 months. Many more children experience an episode of wasting at some point during their first 24 months than prevalent cases at a single point in time suggest. For example, at the age of 24 months, 5.6% of children were wasted, but by the same age (24 months), 29.2% of children had experienced at least one wasting episode and 10.0% had experienced two or more episodes. Children who were wasted before the age of 6 months had a faster recovery and shorter episodes than did children who were wasted at older ages; however, early wasting increased the risk of later growth faltering, including concurrent wasting and stunting (low length-for-age z-score), and thus increased the risk of mortality. In diverse populations with high seasonal rainfall, the population average weight-for-length z-score varied substantially (more than 0.5 z in some cohorts), with the lowest mean z-scores occurring during the rainiest months; this indicates that seasonally targeted interventions could be considered. Our results show the importance of establishing interventions to prevent wasting from birth to the age of 6 months, probably through improved maternal nutrition, to complement current programmes that focus on children aged 6-59 months.

Globally, 149 million children under 5 years of age are estimated to be stunted (length more than 2 standard deviations below international growth standards)1,2. Stunting, a form of linear growth faltering, increases the risk of illness, impaired cognitive development and mortality. Global stunting estimates rely on cross-sectional surveys, which cannot provide direct information about the timing of onset or persistence of growth faltering-a key consideration for defining critical windows to deliver preventive interventions. Here we completed a pooled analysis of longitudinal studies in low- and middle-income countries (n = 32 cohorts, 52,640 children, ages 0-24 months), allowing us to identify the typical age of onset of linear growth faltering and to investigate recurrent faltering in early life. The highest incidence of stunting onset occurred from birth to the age of 3 months, with substantially higher stunting at birth in South Asia. From 0 to 15 months, stunting reversal was rare; children who reversed their stunting status frequently relapsed, and relapse rates were substantially higher among children born stunted. Early onset and low reversal rates suggest that improving children's linear growth will require life course interventions for women of childbearing age and a greater emphasis on interventions for children under 6 months of age.

BACKGROUND: Poor immune function increases childrens risk of infection and mortality. Several maternal factors during pregnancy may affect infant immune function during the postnatal period. OBJECTIVES: We aimed to evaluate whether maternal micronutrients, stress, estriol, and immune status during the first or second trimester of pregnancy were associated with child immune status in the first two years after birth. METHODS: We conducted observational analyses within the water, sanitation, and hygiene (WASH) Benefits Bangladesh randomized controlled trial. We measured biomarkers in 575 pregnant women and postnatally in their children. Maternal biomarkers measured during the first and second trimester of pregnancy included nutrition status via vitamin D (25-hydroxy-D [25(OH)D]), ferritin, soluble transferrin receptor (sTfR), and retinol-binding protein (RBP); cortisol; estriol. Immune markers were assessed in pregnant women at enrollment and their children at ages 14 and 28 mo, including C-reactive protein (CRP), alpha-1-acid glycoprotein (AGP), and 13 cytokines (including IFN-γ). We generated a standardized sum score of log-transformed cytokines. We analyzed IFN-γ individually because it is a critical immunoregulatory cytokine. All outcomes were prespecified. We used generalized additive models and reported the mean difference and 95% confidence intervals at the 25th and 75th percentiles of exposure distribution. RESULTS: At child age 14 mo, concentrations of maternal RBP were inversely associated with the cytokine sum score in children (-0.34 adjusted difference between the 25th and 75th percentile [95% confidence interval -0.61, -0.07]), and maternal vitamin A deficiency was positively associated with the cytokine sum score in children (1.02 [0.13, 1.91]). At child age of 28 mo, maternal RBP was positively associated with IFN-γ in children (0.07 [0.01, 0.14]), whereas maternal vitamin A deficiency was negatively associated with child AGP (-0.07 [-0.13, -0.02]). Maternal iron deficiency was associated with higher AGP concentrations in children at age 14 mo (0.13 [0.04, 0.23]), and maternal sTfR concentrations were positively associated with child CRP concentrations at age 28 mo (0.18 [0, 0.36]). CONCLUSION: Maternal deficiencies in vitamin A or iron during the first 2 trimesters of pregnancy may shape the trajectory of a childs immune status.

BackgroundSanitation interventions typically result in modest increases in latrine access, and any gains in latrine access and use are often not sustained over time. Sanitation programs also rarely include child-focused interventions such as potties. We aimed to assess the sustained effect of a multi-component sanitation intervention on access to and use of latrines and child feces management tools in rural Bangladesh.MethodsWe conducted a longitudinal substudy nested within the WASH Benefits randomized controlled trial. The trial provided latrine upgrades, child potties and sani-scoops for feces removal, along with behavior change promotion to encourage use of the delivered hardware. Promotion visits to intervention recipients were frequent during the first 2 years after intervention initiation, decreased in frequency between years 2-3, and ceased after 3 years. We enrolled a random subset of 720 households from the sanitation and control arms of the trial in a substudy and visited them quarterly between 1 and 3.5 years after intervention initiation. At each visit, field staff recorded sanitation-related behaviors through spot-check observations and structured questionnaires. We assessed intervention effects on observed indicators of hygienic latrine access, potty use and sani-scoop use and investigated whether these effects were modified by duration of follow-up, ongoing behavior change promotion and household characteristics.ResultsThe intervention increased hygienic latrine access from 37% among controls to 94% in the sanitation arm (p

BackgroundWater, sanitation, and hygiene (WASH) improvements are promoted to reduce diarrhoea in low-income countries. However, trials from the past 5 years have found mixed effects of household-level and community-level WASH interventions on child health. Measuring pathogens and host-specific faecal markers in the environment can help investigate causal pathways between WASH and health by quantifying whether and by how much interventions reduce environmental exposure to enteric pathogens and faecal contamination from human and different animal sources. We aimed to assess the effects of WASH interventions on enteropathogens and microbial source tracking (MST) markers in environmental samples.MethodsWe did a systematic review and individual participant data meta-analysis, which included searches from Jan 1, 2000, to Jan 5, 2023, from PubMed, Embase, CAB Direct Global Health, Agricultural and Environmental Science Database, Web of Science, and Scopus, of prospective studies with water, sanitation, or hygiene interventions and concurrent control group that measured pathogens or MST markers in environmental samples and measured child anthropometry, diarrhoea, or pathogen-specific infections. We used covariate-adjusted regression models with robust standard errors to estimate study-specific intervention effects and pooled effect estimates across studies using random-effects models.FindingsFew trials have measured the effect of sanitation interventions on pathogens and MST markers in the environment and they mostly focused on onsite sanitation. We extracted individual participant data on nine environmental assessments from five eligible trials. Environmental sampling included drinking water, hand rinses, soil, and flies. Interventions were consistently associated with reduced pathogen detection in the environment but effect estimates in most individual studies could not be distinguished from chance. Pooled across studies, we found a small reduction in the prevalence of any pathogen in any sample type (pooled prevalence ratio [PR] 0·94 [95% CI 0·90-0·99]). Interventions had no effect on the prevalence of MST markers from humans (pooled PR 1·00 [95% CI 0·88-1·13]) or animals (pooled PR 1·00 [95% CI 0·97-1·03]).InterpretationThe small effect of these sanitation interventions on pathogen detection and absence of effects on human or animal faecal markers are consistent with the small or null health effects previously reported in these trials. Our findings suggest that the basic sanitation interventions implemented in these studies did not contain human waste and did not adequately reduce exposure to enteropathogens in the environment.FundingBill and Melinda Gates Foundation and the UK Foreign and Commonwealth Development Office.

OBJECTIVE: To understand which anthropometric diagnostic criteria best discriminate higher from lower risk of death in children and explore programme implications. DESIGN: A multiple cohort individual data meta-analysis of mortality risk (within 6 months of measurement) by anthropometric case definitions. Sensitivity, specificity, informedness and inclusivity in predicting mortality, face validity and compatibility with current standards and practice were assessed and operational consequences were modelled. SETTING: Community-based cohort studies in twelve low-income countries between 1977 and 2013 in settings where treatment of wasting was not widespread. PARTICIPANTS: Children aged 6 to 59 months. RESULTS: Of the twelve anthropometric case definitions examined, four (weight-for-age Z-score (WAZ)

BACKGROUND: Real-world data, such as administrative claims and electronic health records, are increasingly used for safety monitoring and to help guide regulatory decision-making. In these settings, it is important to document analytic decisions transparently and objectively to assess and ensure that analyses meet their intended goals. METHODS: The Causal Roadmap is an established framework that can guide and document analytic decisions through each step of the analytic pipeline, which will help investigators generate high-quality real-world evidence. RESULTS: In this paper, we illustrate the utility of the Causal Roadmap using two case studies previously led by workgroups sponsored by the Sentinel Initiative - a program for actively monitoring the safety of regulated medical products. Each case example focuses on different aspects of the analytic pipeline for drug safety monitoring. The first case study shows how the Causal Roadmap encourages transparency, reproducibility, and objective decision-making for causal analyses. The second case study highlights how this framework can guide analytic decisions beyond inference on causal parameters, improving outcome ascertainment in clinical phenotyping. CONCLUSION: These examples provide a structured framework for implementing the Causal Roadmap in safety surveillance and guide transparent, reproducible, and objective analysis.

Risk of death from undernutrition is thought to be higher in younger than in older children, but evidence is mixed. Research also demonstrates sex differences whereby boys have a higher prevalence of undernutrition than girls. This analysis described mortality risk associated with anthropometric deficits (wasting, underweight and stunting) in children 6-59 months by age and sex. We categorised children into younger (6-23 months) and older (24-59 months) age groups. Age and sex variations in near-term (within 6 months) mortality risk, associated with individual anthropometric deficits were assessed in a secondary analysis of multi-country cohort data. A random effects meta-analysis was performed. Data from seven low-or-middle-income-countries collected between 1977 and 2013 were analysed. One thousand twenty deaths were recorded for children with anthropometric deficits. Pooled meta-analysis estimates showed no differences by age in absolute mortality risk for wasting (RR 1.08, p = 0.826 for MUAC

Childhood wasting and stunting affect large numbers of children globally. Both are important risk factors for illness and death yet, despite the fact that these conditions can share common risk factors and are often seen in the same child, they are commonly portrayed as relatively distinct manifestations of undernutrition. In 2014, the Wasting and Stunting project was launched by the Emergency Nutrition Network. Its aim was to better understand the complex relationship and associations between wasting and stunting and examine whether current separations that were apparent in approaches to policy, financing, and programs were justified or useful. Based on the project's work, this article aims to bring a wasting and stunting lens to how research is designed and financed in order for the nutrition community to better understand, prevent, and treat child undernutrition. Discussion of lessons learnt focuses on the synergy and temporal relationships between children's weight loss and linear growth faltering, the proximal and distal factors that drive diverse forms of undernutrition, and identifying and targeting people most at risk. Supporting progress in all these areas requires research collaborations across interest groups that highlight the value of research that moves beyond a focus on single forms of undernutrition, and ensures that there is equal attention given to wasting as to other forms of malnutrition, wherever it is present.

BackgroundHousehold-level sanitation interventions have had limited effects on child health or environmental contamination, potentially due to low community coverage. Higher community-level coverage with safely managed sanitation can reduce opportunities for disease transmission.MethodsWe estimated associations between community sanitation coverage, environmental fecal contamination, and child health among 360 compounds in the control arm of the WASH Benefits trial in rural Bangladesh (NCT01590095). In each compound, we enumerated E. coli in environmental samples and recorded the 7-day prevalence of caregiver-reported diarrheal disease and acute respiratory infections (ARI) in children under five. We observed indicators of latrine access and quality among all neighboring compounds within 100 m of study compounds. We defined community coverage as the proportion of neighboring compounds with (1) at least one latrine, and (2) exclusively hygienic latrines (improved facility observed to safely contain feces), within both 50 m and 100 m of study compounds. We assessed effect modification by population density and season.ResultsAdjusted for confounders, study compounds surrounded by 100% coverage of at least one latrine per compound within 50 m had slightly lower log10E. coli counts in stored water (Δlog = -0.13, 95% CI -0.26, -0.01), child hand rinses (Δlog = -0.13, 95% CI -0.24, -0.02), and caregiver hand rinses (Δlog = -0.16, 95% CI -0.29, -0.03) and marginally lower prevalence of diarrheal disease (prevalence ratio [PR] = 0.82, 95% CI 0.64, 1.04) and ARI (PR = 0.84, 95% CI 0.69, 1.03) compared to compounds surrounded by

BackgroundEstimates of the effectiveness of water, sanitation, and hygiene (WASH) interventions that provide high levels of service on childhood diarrhoea are scarce. We aimed to provide up-to-date estimates on the burden of disease attributable to WASH and on the effects of different types of WASH interventions on childhood diarrhoea in low-income and middle-income countries (LMICs).MethodsIn this systematic review and meta-analysis, we updated previous reviews following their search strategy by searching MEDLINE, Embase, Scopus, Cochrane Library, and BIOSIS Citation Index for studies of basic WASH interventions and of WASH interventions providing a high level of service, published between Jan 1, 2016, and May 25, 2021. We included randomised and non-randomised controlled trials conducted at household or community level that matched exposure categories of the so-called service ladder approach of the Sustainable Development Goal (SDG) for WASH. Two reviewers independently extracted study-level data and assessed risk of bias using a modified Newcastle-Ottawa Scale and certainty of evidence using a modified Grading of Recommendations, Assessment, Development, and Evaluation approach. We analysed extracted relative risks (RRs) and 95% CIs using random-effects meta-analyses and meta-regression models. This study is registered with PROSPERO, CRD42016043164.Findings19 837 records were identified from the search, of which 124 studies were included, providing 83 water (62 616 children), 20 sanitation (40 799 children), and 41 hygiene (98 416 children) comparisons. Compared with untreated water from an unimproved source, risk of diarrhoea was reduced by up to 50% with water treated at point of use (POU): filtration (n=23 studies; RR 0·50 [95% CI 0·41-0·60]), solar treatment (n=13; 0·63 [0·50-0·80]), and chlorination (n=25; 0·66 [0·56-0·77]). Compared with an unimproved source, provision of an improved drinking water supply on premises with higher water quality reduced diarrhoea risk by 52% (n=2; 0·48 [0·26-0·87]). Overall, sanitation interventions reduced diarrhoea risk by 24% (0·76 [0·61-0·94]). Compared with unimproved sanitation, providing sewer connection reduced diarrhoea risk by 47% (n=5; 0·53 [0·30-0·93]). Promotion of handwashing with soap reduced diarrhoea risk by 30% (0·70 [0·64-0·76]).InterpretationWASH interventions reduced risk of diarrhoea in children in LMICs. Interventions supplying either water filtered at POU, higher water quality from an improved source on premises, or basic sanitation services with sewer connection were associated with increased reductions. Our results support higher service levels called for under SDG 6. Notably, no studies evaluated interventions that delivered access to safely managed WASH services, the level of service to which universal coverage by 2030 is committed under the SDG.FundingWHO, Foreign, Commonwealth & Development Office, and National Institute of Environmental Health Sciences.

Several recently developed methods have the potential to harness machine learning in the pursuit of target quantities inspired by causal inference, including inverse weighting, doubly robust estimating equations and substitution estimators like targeted maximum likelihood estimation. There are even more recent augmentations of these procedures that can increase robustness, by adding a layer of cross-validation (cross-validated targeted maximum likelihood estimation and double machine learning, as applied to substitution and estimating equation approaches, respectively). While these methods have been evaluated individually on simulated and experimental data sets, a comprehensive analysis of their performance across real data based simulations have yet to be conducted. In this work, we benchmark multiple widely used methods for estimation of the average treatment effect using ten different nutrition intervention studies data. A nonparametric regression method, undersmoothed highly adaptive lasso, is used to generate the simulated distribution which preserves important features from the observed data and reproduces a set of true target parameters. For each simulated data, we apply the methods above to estimate the average treatment effects as well as their standard errors and resulting confidence intervals. Based on the analytic results, a general recommendation is put forth for use of the cross-validated variants of both substitution and estimating equation estimators. We conclude that the additional layer of cross-validation helps in avoiding unintentional over-fitting of nuisance parameter functionals and leads to more robust inferences.

Complementing a recent systematic review and meta-analysis which showed that boys are more likely to be wasted, stunted, and underweight than girls, we conducted a narrative review to explore which early life mechanisms might underlie these sex differences. We addressed different themes, including maternal and newborn characteristics, immunology and endocrinology, evolutionary biology, care practices, and anthropometric indices to explore potential sources of sex differences in child undernutrition. Our review found that the evidence on why sex differences occur is limited but that a complex interaction of social, environmental, and genetic factors likely underlies these differences throughout the life cycle. Despite their bigger size at birth and during infancy, in conditions of food deprivation, boys experience more undernutrition from as early as the foetal period. Differences appear to be more pronounced in more severe presentations of undernutrition and in more socioeconomically deprived contexts. Boys are more vulnerable to infectious disease, and differing immune and endocrine systems appear to explain some of this disadvantage. Limited evidence also suggests that different sociological factors and care practices might exert influence and have the potential to exacerbate or reverse observed differences. Further research is needed to better understand sex differences in undernutrition and the implications of these for child outcomes and prevention and treatment programming.

BackgroundDiarrhea and acute respiratory infection (ARI) are leading causes of death in children. The WASH Benefits Bangladesh trial implemented a multicomponent sanitation intervention that led to a 39% reduction in the prevalence of diarrhea among children and a 25% reduction for ARI, measured 1 to 2 years after intervention implementation. We measured longer-term intervention effects on these outcomes between 1 to 3.5 years after intervention implementation, including periods with differing intensity of behavioral promotion.Methods and findingsWASH Benefits Bangladesh was a cluster-randomized controlled trial of water, sanitation, hygiene, and nutrition interventions (NCT01590095). The sanitation intervention included provision of or upgrades to improved latrines, sani-scoops for feces removal, children's potties, and in-person behavioral promotion. Promotion was intensive up to 2 years after intervention initiation, decreased in intensity between years 2 to 3, and stopped after 3 years. Access to and reported use of latrines was high in both arms, and latrine quality was significantly improved by the intervention, while use of child feces management tools was low. We enrolled a random subset of households from the sanitation and control arms into a longitudinal substudy, which measured child health with quarterly visits between 1 to 3.5 years after intervention implementation. The study period therefore included approximately 1 year of high-intensity promotion, 1 year of low-intensity promotion, and 6 months with no promotion. We assessed intervention effects on diarrhea and ARI prevalence among children

Shifting the public towards plant-based diets is critical for achieving environmental and public health outcomes. Increasingly news articles and organizations have begun using the saliency of the COVID-19 crisis to highlight the link between animal agriculture, pandemic risks, and other widespread public health threats. Yet, little is known about the effectiveness of this messaging strategy for motivating dietary change. We conducted a randomized trial with an online sample to examine the impact of: (1) a message that uses the saliency of the COVID-19 pandemic to highlight the risk of disease transmission from factory farms, and (2) a message that uses the saliency of the COVID-19 pandemic to highlight the threat to worker's health created by factory farms. We examine whether these messages are more effective at changing beliefs about and behavioral intentions towards plant-based eating, as compared to more traditional messages that highlight the environmental, personal health, or animal welfare implications of factory farmed meat consumption. We find that all messages differentially influenced beliefs about the various negative consequences of meat consumption. However, these altered beliefs did not differentially motivate changes in respondents' intentions to reduce meat consumption and choose plant-based alternatives. This was possibly due to the numerous other barriers to behavior change identified in qualitative survey responses, such as cost, taste, and social factors. We did find that messages that highlight the personal health benefits of reduced meat consumption were more effective at increasing public trust in the message deliverer. Our results suggest that highlighting personal health benefits in messaging and addressing the additional identified barriers to behavior change may be critical for building trust and shifting the public towards plant-based diets.

BackgroundPreviously, we demonstrated that a water, sanitation, handwashing, and nutritional intervention improved linear growth and was unexpectedly associated with shortened childhood telomere length (TL) (Lin et al., 2017). Here, we assessed the association between TL and growth.MethodsWe measured relative TL in whole blood from 713 children. We reported differences between the 10th percentile and 90th percentile of TL or change in TL distribution using generalized additive models, adjusted for potential confounders.ResultsIn cross-sectional analyses, long TL was associated with a higher length-for-age Z score at age 1 year (0.23 SD adjusted difference in length-for-age Z score [95% CI 0.05, 0.42; FDR-corrected p-value = 0.01]). TL was not associated with other outcomes.ConclusionsConsistent with the metabolic telomere attrition hypothesis, our previous trial findings support an adaptive role for telomere attrition, whereby active TL regulation is employed as a strategy to address 'emergency states' with increased energy requirements such as rapid growth during the first year of life. Although short periods of active telomere attrition may be essential to promote growth, this study suggests that a longer overall initial TL setting in the first 2 years of life could signal increased resilience against future telomere erosion events and healthy growth trajectories.FundingFunded by the Bill and Melinda Gates Foundation.Clinical trial numberNCT01590095.

Household latrine access generally is not associated with reduced fecal contamination in the environment, but its long-term effectiveness has not been measured. We conducted an environmental assessment nested within the WASH Benefits Bangladesh randomized controlled trial (NCT01590095). We quantified E. coli and fecal coliforms in samples of stored drinking water, child hands, mother hands, soil, and food among a random sample of households from the sanitation and control arms of the trial. Samples were collected during eight quarterly visits approximately 1-3.5 years after intervention initiation. Overall, there were no substantial differences in environmental fecal contamination between households enrolled in the sanitation and control arms. Statistically significant reductions were found in stored water and child hands after pooling across sampling rounds, but the effects were small and not consistent across rounds. In addition, we assessed potential effect modification of intervention effects by follow-up time, season, wealth, community-level latrine density and coverage, population density, and domestic animal ownership. While the intervention had statistically significant effects within some subgroups, there were no consistent patterns of effect modification. Our findings support a growing consensus that on-site latrines are insufficient to prevent fecal contamination in the rural household environment.

BackgroundSoil-transmitted helminths and Giardia duodenalis are responsible for a large burden of disease globally. In low-resource settings, household finished floors (eg, concrete floors) might reduce transmission of soil-transmitted helminths and G duodenalis.MethodsIn a prospective cohort of children nested within two randomised trials in rural Bangladesh and Kenya, we estimated associations between household finished flooring and soil-transmitted helminths and G duodenalis prevalence. In 2015-16, we collected stool samples from children aged 2-16 years in rural Bangladesh and Kenya. We detected soil-transmitted helminth infection using quantitative PCR (qPCR; Bangladesh n=2800; Kenya n=3094), and G duodenalis using qPCR in Bangladesh (n=6894) and ELISA in Kenya (n=8899). We estimated adjusted prevalence ratios (aPRs) using log-linear models adjusted for potential confounders.Findings7187 (92·2%) of 7795 children in Bangladesh and 9077 (93·7%) of 9686 children in Kenya provided stool specimens that were analysed by qPCR. At enrolment, 691 (10%) households in Bangladesh and 471 (5%) households in Kenya had finished floors. In both countries, household finished flooring was associated with lower Ascaris lumbricoides prevalence (Bangladesh aPR 0·33, 95% CI 0·14-0·78; Kenya 0·62, 0·39-0·98) and any soil-transmitted helminths (Bangladesh 0·73, 0·52-1·01; Kenya 0·57, 0·37-0·88). Household finished floors were also associated with lower Necator americanus prevalence in Bangladesh (0·52, 0·29-0·94) and G duodenalis prevalence in both countries (Bangladesh 0·78, 0·64-0·95; Kenya 0·82, 0·70-0·97).InterpretationIn low-resource settings, living in households with finished floors over a 2-year period was associated with lower prevalence of G duodenalis and some soil-transmitted helminths in children.FundingBill & Melinda Gates Foundation and Task Force for Global Health.

Accurate estimates of the burden of SARS-CoV-2 infection are critical to informing pandemic response. Confirmed COVID-19 case counts in the U.S. do not capture the total burden of the pandemic because testing has been primarily restricted to individuals with moderate to severe symptoms due to limited test availability. Here, we use a semi-Bayesian probabilistic bias analysis to account for incomplete testing and imperfect diagnostic accuracy. We estimate 6,454,951 cumulative infections compared to 721,245 confirmed cases (1.9% vs. 0.2% of the population) in the United States as of April 18, 2020. Accounting for uncertainty, the number of infections during this period was 3 to 20 times higher than the number of confirmed cases. 86% (simulation interval: 64-99%) of this difference is due to incomplete testing, while 14% (0.3-36%) is due to imperfect test accuracy. The approach can readily be applied in future studies in other locations or at finer spatial scale to correct for biased testing and imperfect diagnostic accuracy to provide a more realistic assessment of COVID-19 burden.

We propose a method for summarizing the strength of association between a set of variables and a multivariate outcome. Classical summary measures are appropriate when linear relationships exist between covariates and outcomes, while our approach provides an alternative that is useful in situations where complex relationships may be present. We utilize machine learning to detect nonlinear relationships and covariate interactions and propose a measure of association that captures these relationships. A hypothesis test about the proposed associative measure can be used to test the strong null hypothesis of no association between a set of variables and a multivariate outcome. Simulations demonstrate that this hypothesis test has greater power than existing methods against alternatives where covariates have nonlinear relationships with outcomes. We additionally propose measures of variable importance for groups of variables, which summarize each groups' association with the outcome. We demonstrate our methodology using data from a birth cohort study on childhood health and nutrition in the Philippines.

AbstractBackgroundSoil-transmitted helminths (STH) and Giardia duodenalis are responsible for a large burden of disease globally. In low-resource settings, household finished floors (e.g., concrete floors) may reduce transmission of STH and G. duodenalis.MethodsIn a prospective cohort of children nested within two randomised trials in rural Bangladesh and Kenya, we estimated associations between household finished flooring and STH and G. duodenalis prevalence. In 2015-2016, we collected stool samples from children aged 2-16 years in rural Bangladesh and Kenya. We detected STH infection using qPCR (Bangladesh N=2,800; Kenya N=3,094) and detected G. duodenalis using qPCR in Bangladesh (N=6,894) and ELISA in Kenya (N=8,899). We estimated adjusted prevalence ratios (aPRs) using log-linear models adjusted for potential confounders.FindingsAt enrolment, 10% of households in Bangladesh and 5% in Kenya had finished floors. In both countries, household finished flooring was associated with lower Ascaris lumbricoides prevalence (Bangladesh aPR: 0.33, 95% CI 0.14, 0.78; Kenya aPR: 0.62, 95% CI 0.39, 0.98) and any STH (Bangladesh aPR: 0.73, 95% CI 0.52, 1.01; Kenya aPR: 0.57, 95% CI 0.37, 0.88). Household finished floors were also associated with lower Necator americanus prevalence in Bangladesh (aPR: 0.52, 95% CI 0.29, 0.94) and G. duodenalis prevalence in both countries (Bangladesh aPR: 0.78, 95% CI 0.64, 0.95; Kenya: aPR: 0.82, 95% CI 0.70, 0.97).InterpretationIn low-resource settings, living in households with finished floors over a two-year period was associated with lower prevalence of G. duodenalis and certain STH in children.FundingBill & Melinda Gates Foundation grant OPPGD759

Failures to reproduce research findings across scientific disciplines from psychology to physics have garnered increasing attention in recent years. External replication of published findings by outside investigators has emerged as a method to detect errors and bias in the published literature. However, some studies influence policy and practice before external replication efforts can confirm or challenge the original contributions. Uncovering and resolving errors before publication would increase the efficiency of the scientific process by increasing the accuracy of published evidence. Here we summarize the rationale and best practices for internal replication, a process in which multiple independent data analysts replicate an analysis and correct errors prior to publication. We explain how internal replication should reduce errors and bias that arise during data analyses and argue that it will be most effective when coupled with pre-specified hypotheses and analysis plans and performed with data analysts masked to experimental group assignments. By improving the reproducibility of published evidence, internal replication should contribute to more rapid scientific advances.

Globally 149 million children under five are estimated to be stunted (length more than 2 standard deviations below international growth standards). Stunting, a form of linear growth faltering, increases risk of illness, impaired cognitive development, and mortality. Global stunting estimates rely on cross-sectional surveys, which cannot provide direct information about the timing of onset or persistence of growth faltering- a key consideration for defining critical windows to deliver preventive interventions. We performed the largest pooled analysis of longitudinal studies in low- and middle-income countries to date (n=32 cohorts, 52,640 children, ages 0-24 months), allowing us to identify the typical age of linear growth faltering onset and to investigate recurrent faltering in early life. The highest incidence of stunting onset occurred from birth to age 3 months. From 0 to 15 months, less than 5% of children per month reversed their stunting status, and among those who did, stunting relapse was common. Early timing and low reversal rates emphasize the importance of preventive intervention delivery within the prenatal and early postnatal phases coupled with continued delivery of postnatal interventions through the first 1000 days of life.

SummarySustainable Development Goal 2.2.2, to end malnutrition by 2030, measures progress through elimination of child wasting, defined as weight-for-length more than 2 standard deviations below international standards. Prevailing methods to measure wasting rely on cross-sectional surveys that cannot measure onset, recovery, and persistence — key features of wasting epidemiology that could inform preventive interventions and disease burden estimates. Here, we show through an analysis of 21 longitudinal cohorts that wasting is a highly dynamic process of onset and recovery, and incidence peaks between birth and 3 months — far earlier than peak prevalence at 12-15 months. By age 24 months 29.2% of children had experienced at least one wasting episode, more than 5-fold higher than point prevalence (5.6%), demonstrating that wasting incidence is far higher than cross-sectional surveys suggest. Children wasted before 6 months were more likely to experience concurrent wasting and stunting (low height-for-age) later, increasing their risk of mortality. In diverse populations with seasonal rainfall, population average weight-for-length varied substantially (>0.5 z in some cohorts), with the lowest mean Z-scores during the rainiest months, creating potential for seasonally targeted interventions. Our results motivate a new focus on extending preventive interventions for wasting to pregnant and lactating mothers, and for preventive and therapeutic interventions to include children below age 6 months in addition to current targets of ages 6-59 months.

SummaryGrowth faltering (low length-for-age or weight-for length) in the first 1000 days — from conception to two years of age — influences both short and long-term health and survival. Evidence for interventions to prevent growth faltering such as nutritional supplementation during pregnancy and the postnatal period has increasingly accumulated, but programmatic action has been insufficient to eliminate the high burden of stunting and wasting in low- and middle-income countries. In addition, there is need to better understand age-windows and population subgroups in which to focus future preventive efforts. Here, we show using a population intervention effects analysis of 33 longitudinal cohorts (83,671 children) and 30 separate exposures that improving maternal anthropometry and child condition at birth, in particular child length-at-birth, accounted for population increases by age 24 months in length-for-age Z of 0.04 to 0.40 and weight-for-length Z by 0.02 to 0.15. Boys had consistently higher risk of all forms of growth faltering than girls, and early growth faltering predisposed children to subsequent and persistent growth faltering. Children with multiple growth deficits had higher mortality rates from birth to two years than those without deficits (hazard ratios 1.9 to 8.7). The importance of prenatal causes, and severe consequences for children who experienced early growth faltering, support a focus on pre-conception and pregnancy as key opportunities for new preventive interventions.

Accurate estimates of the burden of SARS-CoV-2 infection are critical to informing pandemic response. Current confirmed COVID-19 case counts in the U.S. do not capture the total burden of the pandemic because testing has been primarily restricted to individuals with moderate to severe symptoms due to limited test availability. Using a semi-Bayesian probabilistic bias analysis to account for incomplete testing and imperfect diagnostic accuracy, we estimated 6,275,072 cumulative infections compared to 721,245 confirmed cases (1.9% vs. 0.2% of the population) as of April 18, 2020. Accounting for uncertainty, the number of infections was 3 to 20 times higher than the number of confirmed cases. 86% (simulation interval: 64-99%) of this difference was due to incomplete testing, while 14% (0.3-36%) was due to imperfect test accuracy. Estimates of SARS-CoV-2 infections that transparently account for testing practices and diagnostic accuracy reveal that the pandemic is larger than confirmed case counts suggest.

BackgroundWe hypothesized that drinking water, sanitation, handwashing (WSH), and nutritional interventions would improve environmental enteric dysfunction (EED), a potential contributor to stunting.MethodsWithin a subsample of a cluster-randomized, controlled trial in rural Bangladesh, we enrolled pregnant women in 4 arms: control, WSH, child nutrition counseling plus lipid-based nutrient supplements (N), and nutrition plus WSH (N+WSH). Among the birth cohort, we measured biomarkers of gut inflammation (myeloperoxidase, neopterin), permeability (alpha-1-antitrypsin, lactulose, mannitol), and repair (regenerating gene 1β) at median ages 3, 14, and 28 months. Analysis was intention-to-treat.ResultsWe assessed 1512 children. At age 3 months, compared to controls, neopterin was reduced by nutrition (-0.21 log nmol/L; 95% confidence interval [CI], -.37, -.05) and N+WSH (-0.20 log nmol/L; 95% CI, -.34, -.06) interventions; similar reductions were observed at 14 months. At 3 months, all interventions reduced lactulose and mannitol (-0.60 to -0.69 log mmol/L). At 28 months, myeloperoxidase was elevated in the WSH and nutrition arms (0.23-0.27 log ng/mL) and lactulose was higher in the WSH arm (0.30 log mmol/L; 95% CI, .07, .53).ConclusionsReductions in permeability and inflammation at ages 3 and 14 months suggest that the interventions promoted healthy intestinal maturation; however, by 28 months, the WSH and nutrition arms showed elevated EED biomarkers. These results underscore the importance of developing a better understanding of EED pathophysiology and targeting interventions early in childhood, when they are likely to have the largest benefit to intestinal health.Clinical trials registrationNCT01590095.

Summary Growth faltering (low length-for-age or weight-for-length) in the first 1000 days — from conception to two years of age — influences short and long-term health and survival. Interventions such as nutritional supplementation during pregnancy and the postnatal period could help prevent growth faltering, but programmatic action has been insufficient to eliminate the high burden of stunting and wasting in low- and middle-income countries. Future preventive efforts will benefit from understanding age-windows and population subgroups in which to focus. Here, we use a population intervention effects analysis of 33 longitudinal cohorts (83,671 children, 662,763 measurements) and 30 separate exposures to show that improving maternal anthropometry and child condition at birth accounted for population increases in length-for-age Z of up to 0.40 and weight-for-length Z of up to 0.15 by age 24 months. Boys had consistently higher risk of all forms of growth faltering than girls. Early post-natal growth faltering predisposed children to subsequent and persistent growth faltering. Children with multiple growth deficits had higher mortality rates from birth to two years than those without deficits (hazard ratios 1.9 to 8.7). The importance of prenatal causes, and severe consequences for children who experienced early growth faltering, support a focus on pre-conception and pregnancy as key opportunities for new preventive interventions.