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BACKGROUND: Estimates 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). METHODS: In 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. FINDINGS: 19 837 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]). INTERPRETATION: WASH 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. FUNDING: WHO, Foreign, Commonwealth & Development Office, and National Institute of Environmental Health Sciences.

Custer 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. Pair matched randomization is one strategy with potential to increase trial efficiency, but to our knowledge there have been no empirical evaluations of pair-matching in large-scale, epidemiologic field trials. Location integrates many socio-demographic and environmental characteristics into a single feature. Here, we show that geographic pair-matching 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. We estimate relative efficiencies ≥ 1.1 for all outcomes assessed and relative efficiencies regularly exceed 2.0, meaning an unmatched trial would have needed 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.

BackgroundUnderstanding pathogen-specific relationships with climate is crucial to informing interventions under climate change.MethodsWe matched spatiotemporal temperature, precipitation, surface water, and humidity data to data from a trial in rural Bangladesh that measured diarrhea and enteropathogen prevalence in children 0-2 years from 2012-2016. We fit generalized additive models and estimated percent changes in prevalence using projected precipitation under Shared Socio-Economic pathways describing sustainable development (SSP1), middle of the road (SSP2), and fossil fuel development (SSP5) scenarios.FindingsAn increase from 15°C to 30°C in weekly average temperature was associated with 5.0% higher diarrhea, 6.4% higher Norovirus, and 13.0% higher STEC prevalence. Above-median precipitation was associated with 1.27-fold (95% CI 0.99, 1.61) higher diarrhea; higher Cryptosporidium, tEPEC, ST-ETEC, STEC, Shigella, EAEC, Campylobacter, Aeromonas, and Adenovirus 40/41; and lower aEPEC, Giardia, Sapovirus, and Norovirus prevalence. Other associations were weak or null. Compared to the study period, diarrhea prevalence was similar under SSP1 (7%), 3.4% (2.7%, 4.3%) higher under SSP2, and 5.7% (4.4%, 7.0%) higher under SSP5. Prevalence of pathogens responsible for a large share of moderate-to-severe diarrhea in this setting (Shigella, Aeromonas) were 13-20% higher under SSP2 and SSP5.InterpretationHigher temperatures and precipitation were associated with higher prevalence of diarrhea and multiple enteropathogens; higher precipitation was associated with lower prevalence of some enteric viruses. Under likely climate change scenarios, we projected increased prevalence of diarrhea and enteropathogens responsible for clinical illness. Our findings inform pathogen-specific adaptation and mitigation strategies and priorities for vaccine development.FundingBill & Melinda Gates Foundation, National Institute of Allergy and Infectious Diseases, National Heart, Lung, And Blood Institute, Stanford University School of Medicine, Chan Zuckerberg BiohubResearch in ContextEvidence before this studyWe searched Google Scholar and Scopus for studies published from January 1, 2000 to present using the following three queries: 1) child; and diarrhea OR “enteric infection”; and meteorological OR environmental OR “surface water” OR “standing water”; and risk AND/OR factors; 2) Climate AND change AND project* AND diarrhea OR diarrhoea; 3) climate AND change AND project* OR model AND enter* AND infect* AND E. coli. Studies generally focused on individual risk factors for diarrhea transmission or enteric infection, with an emphasis on temperature and precipitation. Studies found that higher temperatures were associated with higher incidence of bacterial diarrhea and lower incidence of viral diarrhea; few studies have investigated associations between temperature and parasitic diarrhea. Heavy rainfall, particularly after dry periods, was associated with higher diarrhea prevalence, though heavy rainfall during rainy seasons was found to protect against diarrhea incidence. Similarly, flooding of surface water and shallow wells was also associated with higher diarrhea prevalence. Very few studies investigated associations between diarrhea or enteropathogen carriage and surface water presence, or humidity. A recent individual participant meta-analysis of studies in 19 low- and middle-income countries found that higher precipitation was associated with a small decrease in enterotoxigenic E. coli (ETEC) and Campylobacter spp. prevalence and no difference in Shigella, Cryptosporidium, or Giardia, or enteric virus prevalence. Weekly average temperature increases of 10-40° C within the study period were associated with higher risk of Campylobacter, ETEC, Shigella, Cryptosporidium, Giardia, and adenovirus, and lower risk of sapovirus and rotavirus, and generally, associations were stronger. Higher humidity was associated with higher risk of enteric bacterial infections and lower risk of enteric virus infection. A small number of studies have projected diarrhea under climate change in low- and middle-income countries. Studies have estimated a 15-20% increase in global diarrhea risk in 2040-2069 relative to 1961-1990, up to 21% increase in diarrhea incidence in northern India from 2013 to the 2040s, 3-10% increase in diarrhea cases in the Gaza Strip associated with 1.5° to 2°C increases in temperature, and an 8% increase in diarrhea burden by 2050 in Nepal. One study estimated an additional 1,625,073 ETEC diarrhea cases in Bangladesh from 2046-2065 due to climate change. No studies estimated changes in the presence of multiple enteropathogens under possible climate change scenarios.Added value of this studyThis study matched remote sensing data on precipitation, temperature, surface water, and humidity to data on diarrhea and enteropathogen carriage in children under 2 years from a trial in rural Bangladesh. We fit flexible models to investigate potentially non-linear relationships between each climate and environmental risk factor and each health outcome. In addition, we predicted the prevalence of each outcome under three possible climate change scenarios. Our predictions leveraged the spatiotemporal distributions of both climate precipitation projections and diarrhea and enteropathogen carriage in the trial. To our knowledge, this is the first study to predict prevalence under climate change scenarios for both diarrhea and multiple enteropathogens in a rural, low-resource south Asian setting. Our study sheds light on how climate change may impact diarrhea and enteropathogen carriage in Bangladesh, which is highly vulnerable to climate change due to its low altitude and seasonal flooding.Implications of all the available evidenceWe found that both higher temperatures and precipitation were associated with higher diarrhea prevalence, consistent with prior studies. Compared to prior studies, which have primarily found associations between diarrhea and heavy rainfall following a dry period, we found that moderate levels of weekly precipitation were associated with higher diarrhea prevalence. Relationships between climatic and environmental variables and enteropathogen carriage varied by taxa, as other studies have found, but for some pathogens and risk factors, we observed associations in different directions than prior studies. Under middle of the road and fossil fuel-based development climate change scenarios, we projected increased diarrhea prevalence and taxa-specific changes in enteropathogen prevalence. Our findings suggest that climate change may exacerbate diarrhea burden in rural Bangladesh in the absence of sustainable development and inform prioritization of pathogen-specific mitigation and/or adaptation interventions (e.g., vaccines) for young children in rural, South Asian settings under climate change.

BackgroundClimate change may influence the effectiveness of environmental interventions. We investigated if climate and environment modified the effect of low-cost, point-of-use water, sanitation, and handwashing (WASH) interventions on diarrhea and predicted intervention effectiveness under climate change scenarios.MethodsWe analyzed data from a cluster-randomized trial in rural Bangladesh that measured diarrhea prevalence in children 0-2 years from 2012-2016. We matched remote sensing data on temperature, precipitation, humidity, and surface water to households by location and measurement date. We estimated prevalence ratios (PR) for WASH interventions vs. control stratified by environmental factors using generative additive models and targeted maximum likelihood estimation. We estimated intervention effects under predicted precipitation in the study region in 2050 for climate change scenarios from different Shared Socioeconomic Pathways (SSPs).FindingsWASH interventions more effectively prevented diarrhea under higher levels of total precipitation in the previous week and when there was heavy rain in the previous week (heavy rainfall PR = 0.38, 95% CI 0.23-0.62 vs. no heavy rainfall PR = 0.77, 0.60-0.98). We did not detect substantial effect modification by other environmental variables. WASH intervention effectiveness increased under most climate change scenarios; in a fossil-fueled development scenario (SSP5), the PR was 0.46 (0.44-0.48) compared to 0.67 (0.65-0.68) in the study.InterpretationWASH interventions had the strongest effect on diarrhea under higher precipitation, and effectiveness may increase under climate change without sustainable development. WASH interventions may improve population resilience to climate-related health risks.FundingBill & Melinda Gates Foundation, National Institute of Allergy and Infectious Diseases, National Heart, Lung, And Blood InstituteResearch in Context PanelEvidence before this studyWe searched Google Scholar using the search terms “sanitation” OR “hygiene” OR “WASH” OR “water quality”; and “heterogen*” or “effect modif*”; and “climate” OR “environmental”; and “diarrhea” OR “enteric infection”; and “risk” AND/OR “factors”. In general, the effect modification of sanitation and hygiene on diarrhea or enteropathogen infection by climate and environment is not well studied. One study in Ecuador investigated different relationships between rainfall, diarrhea, and unimproved sanitation and water sources. They found that poor sanitation was most strongly associated with elevated diarrhea after precipitation minimums, whereas poor water sources were most strongly associated with elevated diarrhea after precipitation maximums. One study in Rwanda also found that high levels of runoff were protective against diarrhea only in households with unimproved toilets. In Bangladesh, one study found that access to tubewells was most effective at reducing childhood diarrhea in non-flood controlled areas. No prior studies have projected changes in WASH effectiveness under different climate change scenarios.Added value of this studyTo our knowledge, this is the first study to assess differences in WASH intervention effectiveness for multiple environmental variables and the first to predict future intervention effectiveness under different climate change scenarios. We spatiotemporally matched individual-level data from a trial in rural Bangladesh to remote sensing data on temperature, precipitation, humidity, and surface water presence. We compared the effectiveness of WASH interventions to prevent diarrhea under different levels of potential environmental effect modifiers. We then used climate models with high spatiotemporal resolution to predict changes in intervention effectiveness under different climate change scenarios.Implications of all the available evidenceWe found that WASH interventions were more effective under increasing precipitation and following heavy rain (over 80th percentile) events. Prior studies have found that diarrhea tends to increase with rainfall. Several studies have documented that precipitation-associated increases in diarrhea occurred primarily after heavy rain that followed dry periods, but we found that WASH intervention effectiveness in preventing diarrhea was higher even at moderate precipitation levels that were not necessarily preceded by a dry period. Under climate change scenarios with higher precipitation, we projected that WASH interventions may become more effective. In settings similar to rural Bangladesh, our findings suggest that regions that are expected to experience greater rainfall should be prioritized for intervention installation, promotion, and maintenance and that these activities might be most impactful during the rainy season.

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 < 125 mm; RR 1.35, p = 0.272 for WHZ < −2). For underweight and stunting, absolute risk of death was higher in younger (RR 2.57, p < 0.001) compared with older children (RR 2.83, p < 0.001). For all deficits, there were no differences in mortality risk for girls compared with boys. There were no differences in the risk of mortality between younger and older wasted children, supporting continued inclusion of all children under-five in wasting treatment programmes. The risk of mortality associated with underweight and stunting was higher among younger children, suggesting that prevention programmes might be justified in focusing on younger children where resources are limited. There were no sex differences by age in mortality risk for all deficits.

Background Diarrhea 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 findings WASH 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 p = 0.05; prevalence difference [PD] = −0.027, 95% CI −0.053, 0, p = 0.05). ARI prevalence did not differ between sanitation (21.3%) and control (22.7%) arms (PR = 0.93, 95% CI 0.82, 1.05, p = 0.23; PD = −0.016, 95% CI −0.043, 0.010, p = 0.23). There were no significant differences in intervention effects between periods with high-intensity versus low-intensity/no promotion. Study limitations include use of caregiver-reported symptoms to define health outcomes and limited data collected after promotion ceased. Conclusions The observed effect of the WASH Benefits Bangladesh sanitation intervention on diarrhea in children appeared to be sustained for at least 3.5 years after implementation, including 1.5 years after heavy promotion ceased. Existing latrine access was high in the study setting, suggesting that improving on-site latrine quality can deliver health benefits when latrine use practices are in place. Further work is needed to understand how latrine adoption can be achieved and sustained in settings with low existing access and how sanitation programs can adopt transformative approaches of excreta management, including safe disposal of child and animal feces, to generate a hygienic home environment. Trial registration ClinicalTrials.gov; NCT01590095; https://clinicaltrials.gov/ct2/show/NCT01590095.

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., An on-site latrine and child feces management intervention in rural Bangladesh did not reduce fecal indicator bacteria in the household environment, adding to growing literature on the limitations of latrines as a sanitation solution.

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 100m 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 50m and 100m 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 50m 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

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-world'' 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 realistic set of simulations, based on a novel method, highly adaptive lasso, for estimating the data-generating distribution that guarantees a certain level of complexity (undersmoothing) is used to better mimic the complexity of the true data-generating distribution. We have applied this novel method for estimating the data-generating distribution by individual study and to subsequently use these fits to simulate data and estimate treatment effects parameters 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.

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. publishedVersion

ImportanceA regulated stress response is essential for healthy trajectories, but the integrated effects of early childhood environmental and nutritional interventions on stress physiology are unknown.ObjectiveTo assess the effects of a combined nutritional, water, sanitation, and handwashing intervention on physiological stress response, oxidative stress, and DNA methylation.Design, Setting, and ParticipantsIn a trial in rural Bangladesh, we randomized geographical clusters of pregnant women and their in-utero children into either the combined nutritional, water, sanitation, and handwashing intervention or the control group. Physiological stress response, oxidative stress, and methylation levels of 757 children were measured at ages one and two years. Analysis was intention-to-treat.InterventionsThe intervention group received combined nutritional counseling and lipid-based nutrient supplements, chlorinated drinking water, upgraded sanitation, and handwashing with soap (N+WSH). The control group did not receive interventions.Main Outcomes and MeasuresWe measured four isomers of urinary F2-isoprostanes [iPF(2α)-III; 2,3-dinor-iPF(2α)-III; iPF(2α)-VI; 8,12-iso-iPF(2α)-VI] at year one. At year two, we measured pre- and post-stressor concentrations of salivary alpha-amylase and cortisol, overall methylation of the glucocorticoid receptor (NR3C1) exon 1F promoter including methylation levels at the nerve growth factor-inducible protein A (NGFI-A) binding site, mean arterial pressure, and resting heart rate.ResultsChildren in the N+WSH group had lower levels of F2-isoprostanes compared to controls (difference -0.16 to -0.19 log ng/mg of creatinine, PPP=0.023) in the N+WSH group. Children in the N+WSH group exhibited decreased logit-transformed methylation of the NGFI-A transcription factor binding site (−0.04; 95% CI, -0.08 to 0; P=0.037).Conclusions and RelevanceA nutritional, water, sanitation, and handwashing intervention reduced oxidative stress, enhanced hypothalamic-pituitary-adrenocortical axis activity, and reduced methylation levels in a transcription factor binding site of the glucocorticoid receptor gene. A targeted environmental and nutritional intervention affected the set point, reactivity, and regulation of the physiological stress system in early childhood, which may have implications for long-term health and developmental trajectories.Trial RegistrationClinicalTrials.govNCT01590095Key PointsQuestionDo intensive nutritional and environmental interventions alter physiological stress response, oxidative stress levels, and epigenetic programming during the first two years of life?FindingsIn this cluster randomized clinical trial of 757 children, a combined nutritional, drinking water, sanitation, and handwashing intervention significantly reduced oxidative stress, enhanced the cortisol response, and reduced methylation levels in a transcription factor binding site of the glucocorticoid receptor gene.MeaningThe integrated nutritional, drinking water, sanitation, and handwashing intervention enhanced adaptive responses of the physiological stress system in early childhood, which may have implications for long-term health and developmental trajectories.

While studies have speculated that immune function may play a role in how water, sanitation, hygiene, and nutritional (N+WSH) interventions may individually impact child growth and development, the combined effects of these interventions on immune system development are unknown. Here, we report on a trial in rural Bangladesh, where we cluster-randomized pregnant women into control and N+WSH arms. Among the birth cohort, we quantified plasma IL-1β, IL-6, TNF-α, IL-2, IL-12p70, IFN-γ, IL-4, IL-5, IL-13, IL-17A, IL-21, IL-10, and GM-CSF at ages 14 and 28 months. Cytokine ratios were included as prespecified outcomes to examine the net inflammatory environment. We assessed 704 children. After one year, TNF-α/IL-10, IL-12/IL-10, and IL-17A/IL-10 ratios were lower in the intervention group compared to the control group (mean difference: -0.12 to -0.19, p

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.

Background:Previously, 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.Methods:We 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.Results:In 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.Conclusions:Consistent 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.Funding:Funded by the Bill and Melinda Gates Foundation.Clinical trial number:NCT01590095

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., Estimating the extent of SARS-CoV-2 infection in a population is challenging due to the limitations of testing. Here, the authors estimate that the true number of infections in the United States in mid-April was up to 20 times higher than the number of confirmed cases.

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.

Author(s): Benjamin-Chung, Jade; Mertens, Andrew; Colford, John M; Hubbard, Alan E; van der Laan, Mark J; Coyle, Jeremy; Sofrygin, Oleg; Cai, Wilson; Nguyen, Anna; Pokpongkiat, Nolan N; Djajadi, Stephanie; Seth, Anmol; Jilek, Wendy M; Jung, Esther; Chung, Esther O; Dayal, Sonali; Hejazi, Nima; Malenica, Ivana; Li, Haodong; Hafen, Ryan; Subramoney, Vishak; Haggstrom, Jonas; Norman, Thea; Brown, Kenneth H; Christian, Parul; Arnold, Benjamin F | Abstract: 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.

Author(s): Mertens, Andrew; Benjamin-Chung, Jade; Colford, John M; Hubbard, Alan E; van der Laan, Mark J; Coyle, Jeremy; Sofrygin, Oleg; Cai, Wilson; Jilek, Wendy; Dayal, Sonali; Nguyen, Anna; Pokpongkiat, Nolan N; Djajadi, Stephanie; Seth, Anmol; Chung, Esther O; Malenica, Ivana; Hejazi, Nima; Li, Haodong; Hafen, Ryan; Subramoney, Vishak; Haggstrom, Jonas; Norman, Thea; Christian, Parul; Brown, Kenneth H; Arnold, Benjamin F | Abstract: AbstractAcute malnutrition accounts for an immense disease burden and is implicated as a key, underlying cause of child mortality in low resource settings. Child wasting, defined as weight-for-length more than 2 standard deviations below international standards, is a leading indicator to measure the Sustainable Development Goal target to end malnutrition by 2030. Prevailing methods to measure wasting rely on cross-sectional surveys that are unable to 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 18 longitudinal cohorts that child wasting is a highly dynamic process of incident onset and recovery, and that peak incidence is between birth and 3 months — far earlier than peak prevalence at 12-15 months. By age 24 months the proportion of children who had ever experienced a wasting episode (33%) was more than 5-fold higher than prevalence (6%), suggesting that the wasting burden is likely far higher than cross-sectional surveys suggest. Seasonally driven changes in population mean weight-for-length were large (g0.5 z in some cohorts) and were synchronous with rainfall across diverse settings, creating potential for seasonally targeted interventions. Our results motivate a new focus on extending preventive interventions for child 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.

Author(s): Wu, Sean L; Mertens, Andrew; Crider, Yoshika S; Nguyen, Anna; Pokpongkiat, Nolan N; Djajadi, Stephanie; Seth, Anmol; Hsiang, Michelle S; Colford, John M; Reingold, Art; Arnold, Benjamin F; Hubbard, Alan; Benjamin-Chung, Jade | Abstract: 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.

Norms can be powerful motivators of conservation behavior. Research has distinguished between subjective or injunctive norms, descriptive norms, and personal norms. To date, there is no clear consensus on the relative influence of these different norms on intentions to engage in different conservation behaviors. We conducted a meta-analysis of 100 articles (142 evaluation contexts) examining links between subjective/injunctive, descriptive, and/or personal norms and behavioral intentions to identify how correlations vary by the type of norm and type of conservation behavior. Adding personal and descriptive norms to behavioral intention models significantly reduced the effect of subjective/injunctive norms on intentions. Personal and descriptive norms had a larger relative influence on intentions and were more often significantly associated with intentions compared to subjective norms. Our review highlights the importance of including all three types of norms in models of conservation behavior intentions.

BackgroundSoil-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

Author(s): Mertens, Andrew; Benjamin-Chung, Jade; Colford, John M; Coyle, Jeremy; van der Laan, Mark J; Hubbard, Alan E; Rosete, Sonali; Malenica, Ivana; Hejazi, Nima; Sofrygin, Oleg; Cai, Wilson; Li, Haodong; Nguyen, Anna; Pokpongkiat, Nolan N; Djajadi, Stephanie; Seth, Anmol; Jung, Esther; Chung, Esther O; Jilek, Wendy; Subramoney, Vishak; Hafen, Ryan; Haggstrom, Jonas; Norman, Thea; Brown, Kenneth H; Christian, Parul; Arnold, Benjamin F | Abstract: 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.

BackgroundThe effects of weather on diarrhea could influence the health impacts of climate change. Children have the highest diarrhea incidence, especially in India, where many lack safe water and sanitation.ObjectivesIn a prospective cohort of 1,284 children under 5 y of age from 900 households across 25 villages in rural Tamil Nadu, India, we examined whether high temperature and heavy rainfall was associated with increased all-cause diarrhea and water contamination.MethodsSeven-day prevalence of diarrhea was assessed monthly for up to 12 visits from January 2008 to April 2009, and hydrogen sulfide ([Formula: see text]) presence in drinking water, a fecal contamination indicator, was tested in a subset of households. We estimated associations between temperature and rainfall exposures and diarrhea and [Formula: see text] using binomial regressions, adjusting for potential confounders, random effects for village, and autoregressive-1 error terms for study week.ResultsThere were 259 cases of diarrhea. The prevalence of diarrhea during the 7 d before visits was 2.95 times higher (95% CI: 1.99, 4.39) when mean temperature in the week before the 7-d recall was in the hottest versus the coolest quartile of weekly mean temperature during 1 December 2007 to 15 April 2009. Diarrhea prevalence was 1.50 times higher when the 3 weeks before the diarrhea recall period included [Formula: see text] (vs. 0 d) with rainfall of [Formula: see text] (95% CI: 1.12, 2.02), and 2.60 times higher (95% CI: 1.55, 4.36) for heavy rain weeks following a 60-d dry period. The [Formula: see text] prevalence in household water was not associated with heavy rain prior to sample collection.ConclusionsThe results suggest that, in rural Tamil Nadu, heavy rainfall may wash pathogens that accumulate during dry weather into child contact. Higher temperatures were positively associated with diarrhea 1-3 weeks later. Our findings suggest that diarrhea morbidity could worsen under climate change without interventions to reduce enteric pathogen transmission through multiple pathways. https://doi.org/10.1289/EHP3711.

Planning a sentence with concrete concepts whose referents can be mentally imaged has been shown in past work to require the limited resources of visual working memory. By contrast, grammatically encoding such concepts as lexical items in a syntactic structure requires verbal working memory. We report an experiment designed to demonstrate a double dissociation of these two stores of working memory by manipulating the difficulty of (1) planning by comparing related concepts to unrelated concepts and (2) grammatical encoding of an English sentence in active voice versus the more complex structure of the passive voice. College students (N = 46) composed sentences that were to include two noun prompts (related versus unrelated) while concurrently performing either a visual or a verbal distracting task. Instructions to produce either active or passive sentences were manipulated between groups. The results surprisingly indicated that the supposedly easier planning with related concepts made a large demand on verbal working memory, rather than unrelated concepts demanding more visual working memory. The temporal dynamics of the sentence production process appear to best account for the unexpected findings.

Little is known about whether messaging strategies drawing from behavioral science theory may effectively change public attitudes, beliefs, and behavior with regard to biodiversity conservation. We conducted a randomized survey experiment with 1415 Colorado residents to examine how messaging approaches influence beliefs, voting intentions, and collective action intentions related to a proposed ballot initiative mandating wolf reintroduction to the state. We tested 6 different messages that drew from behavioral science literature on extreme versus moderate appeals, anthropomorphism, and perceived social norms. We find that overall, message framing has little impact on Coloradans’ intentions to vote for or against wolf reintroduction. We find preliminary evidence that extreme arguments that do not address ranchers’ concerns may decrease the willingness of individuals with neutral attitudes to share positive information about wolf reintroduction with others. Furthermore, moderate arguments discussing how ranchers’ concerns will be addressed reduce intentions to engage in organized opposition to reintroduction (compared to arguments used by those opposed to wolf reintroduction). We find that providing descriptive normative information changes perceptions of norms regarding wolf reintroduction, but such changed perceptions do not lead to changes in behavioral intentions compared to control messages. Our study suggests that to increase the diffusion of positive information about a conservation program and prevent organized opposition, conservation practitioners should avoid extreme arguments that ignore the concerns of the opposition and utilize more moderate arguments that acknowledge and address those concerns.

Sanitation improvements have had limited effectiveness in reducing the spread of fecal pathogens into the environment. We conducted environmental measurements within a randomized controlled trial in Bangladesh that implemented individual and combined water treatment, sanitation, handwashing (WSH) and nutrition interventions (WASH Benefits, NCT01590095). Following approximately 4 months of intervention, we enrolled households in the trial’s control, sanitation and combined WSH arms to assess whether sanitation improvements, alone and coupled with water treatment and handwashing, reduce fecal contamination in the domestic environment. We quantified fecal indicator bacteria in samples of drinking and ambient waters, child hands, food given to young children, courtyard soil and flies. In the WSH arm, Escherichia coli prevalence in stored drinking water was reduced by 62% (prevalence ratio = 0.38 (0.32, 0.44)) and E. coli concentration by 1-log (Δlog10 = −0.88 (−1.01, −0.75)). The interventions did not reduce E. coli along other sampled pathways. Ambient contamination remained high among intervention households. Potential reasons include noncommunity-level sanitation coverage, child open defecation, animal fecal sources, or naturalized E. coli in the environment. Future studies should explore potential threshold effects of different levels of community sanitation coverage on environmental contamination.

While ecologists primarily focus on the immediate impact of ecological subsidies, understanding the importance of ecological subsidies requires quantifying the long-term temporal dynamics of subsidies on recipient ecosystems. Deciduous leaf litter transferred from terrestrial to aquatic ecosystems exerts both immediate and lasting effects on stream food webs. Recently, deciduous leaf additions have also been shown to be important subsidies for planktonic food webs in ponds during autumn; however, the inter-seasonal effects of autumn leaf subsidies on planktonic food webs have not been studied. We hypothesized that autumn leaf drop will affect the spring dynamics of freshwater pond food webs by altering the availability of resources, water transparency, and the metabolic state of ponds. We created leaf-added and no-leaf-added field mesocosms in autumn 2012, allowed mesocosms to ice-over for the winter, and began sampling the physical, chemical, and biological properties of mesocosms immediately following ice-off in spring 2013. At ice-off, leaf additions reduced dissolved oxygen, elevated total phosphorus concentrations and dissolved materials, and did not alter temperature or total nitrogen. These initial abiotic effects contributed to higher bacterial densities and lower chlorophyll concentrations, but by the end of spring, the abiotic environment, chlorophyll and bacterial densities converged. By contrast, zooplankton densities diverged between treatments during the spring, with leaf additions stimulating copepods but inhibiting cladocerans. We hypothesized that these differences between zooplankton orders resulted from resource shifts following leaf additions. These results suggest that leaf subsidies can alter both the short- and long-term dynamics of planktonic food webs, and highlight the importance of fully understanding how ecological subsidies are integrated into recipient food webs.

The energy and materials that move across ecosystem boundaries influence food web structure and key ecosystem functions. Despite the acknowledged importance of such ecological subsidies, surprisingly little information is available regarding the role of environmental temperature in influencing subsidy quality and the response of the recipient ecosystem. We evaluated the impacts of temperature-mediated changes in leaves from deciduous trees, an important subsidy from terrestrial to freshwater ecosystems, on both the producer-based and detritivore-based components of a pelagic pond food web in a field mesocosm experiment. We hypothesized that variation in leaf chemistry driven by increased soil temperature would alter both the quality of leaf subsidies and the pond response. We collected red maple Acer rubrum leaves from heated and ambient temperature plots from the long-term soil warming experiment at the Harvard Experimental Forest and added them to 167-l field mesocosms containing established plankton communities, creating ‘no leaf’, ‘ambient leaf’ and ‘heated leaf’ treatments during autumn 2012. We then monitored physical, chemical, and biological responses to treatments until the mesocosms froze six weeks later. Experimental soil warming altered the chemical composition of deciduous leaves, the physical and chemical environment of the aquatic ecosystems to which leaves were added, and the pelagic pond food webs as measured by community composition. Compared to leaves from ambient-temperature soils, leaves from warmed soils initially resulted in lower water column phosphorus and dissolved organic carbon, reducing bacterial densities. However, the diminished carbon and phosphorus resulting from soil warming also increased light availability that ultimately stimulated cladoceran zooplankton relative to ambient-temperature leaves. Our results suggest that changes in temperature can alter ecological subsidies in unanticipated ways, and suggest that accurately predicting the potential consequences of climate change will require conducting research across ecosystem boundaries.

Summary 1. Ecological differences among co-occurring taxa are often invoked as an explanation for the maintenance of biodiversity. Whether these differences facilitate coexistence, which allows unequal competitors to remain in systems and thus maintain biodiversity, is still unclear. 2. Here, we used observational and experimental studies to test for ecological partitioning in ways that would promote coexistence among three co-occurring damselfly genera. We evaluated two necessary conditions for coexistence: (i) that the damselfly genera differ in their abilities to engage in interactions with other damselfly genera and environmental conditions such that their relative abundances covary differently along environmental gradients and (ii) that an increase in intrageneric abundance is more detrimental to performance-related demographic features of each genus than increases in intergeneric abundances. 3. Observational studies across 40 lakes showed that relative abundances of each genus covaried differently along an environmental gradient of lake abiotic and biotic features consistent with ecological partitioning. Field experiments in which we manipulated both intra- and intergeneric densities demonstrated that per capita growth rates of each genus are negatively density-dependent and are only limited by increases in intra- not intergeneric densities. 4. Collectively, these results show a clear signature of ecological partitioning among each genus, which should prevent competitive exclusion and maintain each genus in this system. The results do not guarantee local coexistence among the three genera but are consistent with criteria that should promote their coexistence. Our results also suggest that a food web model coupling keystone predation and apparent competition is likely necessary to explain the ecological dynamics of persistence among these genera.