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Abstract In this paper we reflect on the contribution, style and legacy of Professor Val Curtis, an important, and sometimes controversial, figure in the water, sanitation and hygiene (WASH) sector who sadly passed away on October 19, 2020. Across numerous scientific articles, and several books, and operational programmes, she established herself as a world-renowned scientific expert in the field of hygiene and behaviour change, as well as a major thought-leader in the WASH sector. We identify four major scientific contributions which she made over three decades of research that spanned multiple fields, including engineering, epidemiology, and psychology. Beyond her research, she tirelessly championed hygiene as a public health priority, using her talents as a communicator to secure concrete changes in relevant policy and practice. We are confident that her example, as both a public health researcher, and as a hygiene champion, will inspire future generations of WASH researchers and practitioners to be bold and ambitious.

The COVID-19 pandemic placed hygiene at the centre of disease prevention. Yet, access to the levels of water supply that support good hand hygiene and institutional cleaning, our understanding of hygiene behaviours, and access to soap are deficient in low-, middle-and high-income countries. This paper reviews the role of water, sanitation and hygiene (WaSH) in disease emergence, previous outbreaks, combatting COVID-19 and in preparing for future pandemics. We consider settings where these factors are particularly important and identify key preventive contributions to disease control and gaps in the evidence base. Urgent substantial action is required to remedy deficiencies in WaSH, particularly the provision of reliable, continuous piped water on-premises for all households and settings. Hygiene promotion programmes, underpinned by behavioural science, must be adapted to high-risk populations (such as the elderly and marginalised) and settings (such as healthcare facilities, transport hubs and workplaces). WaSH must be better integrated into preparation plans and with other sectors in prevention efforts. More finance and better use of financing instruments would extend and improve WaSH services. The lessons outlined justify no-regrets investment by government in response to and recovery from the current pandemic; to improve day-to-day lives and as preparedness for future pandemics.

Employingamatchedcohortresearchdesign,eight wardswithintermittentwatersupply arecomparedto eightwardsupgradedtocontinuous(24x7)supplyina demonstrationprojectinHubli–Dharwad,Karnataka, withrespecttotapwaterquality,childhealth, waterstoragepractices,andcopingcostsacross socio-economicstrata.Waterconsumptionandwastein theintermittentzones,andthepotentialforscale-upof continuoussupplytotheentirecity,areestimated.Itwas foundthatthe24x7projectimprovedwaterquality,did notimproveoverallchildhealth,butdidreduceserious waterborneillnessesinthelowest-incomestrata, reducedthecostsofwaiting,increasedmonthlywater bills,andpotentiallyreducedwatersecurityforsomeof thepooresthouseholds.

Advances in serologic assays for Cryptosporidium parvum have made serology an attractive surveillance tool. The sensitivity, specificity, and predictive value of these new assays for surveillance of immunocompromised populations, however, have not been reported. Using stored serum specimens collected for the San Francisco Men's Health Study, we conducted a case-control study with 11 clinically confirmed cases of cryptosporidiosis. Based on assays using a 27-kDa antigen (CP23), the serum specimens from cases had a median response immunoglobulin (Ig) G level following clinical diagnosis (1,334) and a net response (433, change in IgG level from baseline) that were significantly higher than their respective control values (329 and -32, Wilcoxon p value = 0.01). Receiver operator curves estimated a cutoff of 625 U as the optimal sensitivity (0.86 [0.37, 1.0]) and specificity (0.86 [0.37, 1.0]) for predicting Cryptosporidium infection. These data suggest that the enzyme-linked immunosorbent assay technique can be an effective epidemiologic tool to monitor Cryptosporidium infection in immunocompromised populations.

Rationale: Although interferon-gamma (IFN-gamma) assays are promising alternatives to the tuberculin skin test (TST), their serial testing performance is unknown.Objective: To compare TST and IFN-gamma conversions and reversions in healthcare workers.Methods: We prospectively followed-up 216 medical and nursing students in India who underwent baseline and repeat testing (after 18 mo) with TST and QuantiFERON-TB Gold In-Tube (QFT). TST conversions were defined as reactions greater than or equal to 10 mm, with increments of 6 or 10 mm over baseline. QFT conversions were defined as baseline IFN-gamma less than 0.35 and follow-up IFN-gamma greater than or equal to 0.35 or 0.70 IU/ml. QFT reversions were defined as baseline IFN-gamma greater than or equal to 0.35 and follow-up IFN-gamma less than 0.35 IU/ml.Results: Of the 216 participants, 48 (22%) were TST-positive, and 38 (18%) were QFT-positive at baseline. Among 147 participants with concordant baseline negative results, TST conversions occurred in 14 (9.5%; 95% confidence interval [CI] = 5.3-15.5) using the 6 mm increment definition, and 6 (4.1%; 95% CI = 1.5-8.7) using the 10 mm increment definition. QFT conversions occurred in 17/147 participants (11.6%; 95% CI = 6.9-17.9) using the definition of IFN-gamma greater than or equal to 0.35 IU/ml, and 11/147 participants (7.5%; 95% CI = 3.8-13.0) using IFN-gamma greater than or equal to 0.70 IU/ml. Agreement between TST (10 mm increment) and QFT conversions (>or= 0.70 IU/ml) was 96% (kappa = 0.70). QFT reversions occurred in 2/28 participants (7%) with baseline concordant positive results, as compared with 7/10 participants (70%) with baseline discordant results (p < 0.001).Conclusions: IFN-gamma assay shows promise for serial testing, but repeat results need to be interpreted carefully. To meaningfully interpret serial results, the optimal thresholds to distinguish new infections from nonspecific variations must be determined. [ABSTRACT FROM AUTHOR]

Context: Mycobacterium tuberculosis infection in health care workers has not been adequately studied in developing countries using newer diagnostic tests.Objectives: To estimate latent tuberculosis infection prevalence in health care workers using the tuberculin skin test (TST) and a whole-blood interferon gamma (IFN-gamma) assay; to determine agreement between the tests; and to compare their correlation with risk factors.Design, Setting, and Participants: A cross-sectional comparison study of 726 health care workers aged 18 to 61 years (median age, 22 years) with no history of active tuberculosis conducted from January to May 2004, at a rural medical school in India. A total of 493 (68%) of the health care workers had direct contact with patients with tuberculosis and 514 (71%) had BCG vaccine scars.Interventions: Tuberculin skin testing was performed using 1-TU dose of purified protein derivative RT23, and the IFN-gamma assay was performed by measuring IFN-gamma response to early secreted antigenic target 6, culture filtrate protein 10, and a portion of tuberculosis antigen TB7.7.Main Outcome Measures: Agreement between TST and the IFN-gamma assay, and comparison of the tests with respect to their association with risk factors.Results: A large proportion of the health care workers were latently infected; 360 (50%) were positive by either TST or IFN-gamma assay, and 226 (31%) were positive by both tests. The prevalence estimates of TST and IFN-gamma assay positivity were comparable (41%; 95% confidence interval [CI], 38%-45% and 40%; 95% CI, 37%-43%, respectively). Agreement between the tests was high (81.4%; kappa = 0.61; 95% CI, 0.56-0.67). Increasing age and years in the health profession were significant risk factors for both IFN-gamma assay and TST positivity. BCG vaccination had little impact on TST and IFN-gamma assay results.Conclusions: Our study showed high latent tuberculosis infection prevalence in Indian health care workers, high agreement between TST and IFN-gamma assay, and similar association between positive test results and risk factors. Although TST and IFN-gamma assay appear comparable in this population, they have different performance and operational characteristics; therefore, the decision to select one test over the other will depend on the population, purpose of testing, and resource availability. [ABSTRACT FROM AUTHOR]

Despite numerous studies, uncertainty remains about how water quality indicators can best be used in the regulation of recreational water. We conducted a systematic review of this topic with the goal of quantifying the association between microbial indicators of recreational water quality and gastrointestinal (GI) illness. A secondary goal was to evaluate the potential for GI illness below current guidelines. We screened 976 potentially relevant studies and from these identified 27 studies. From the latter, we determined summary relative risks for GI illness in relation to water quality indicator density. Our results support the use of enterococci in marine water at U.S. Environmental Protection Agency guideline levels. In fresh water, Escherichia coli was a more consistent predictor of GI illness than are enterococci and other bacterial indicators. A log (base 10) unit increase in enterococci was associated with a 1.34 [95% confidence intervals (CI), 1.00-1.75] increase in relative risk in marine waters, and a log (base 10) unit increase in E. coli was associated with a 2.12 (95% CI, 0.925-4.85) increase in relative risk in fresh water. Indicators of viral contamination were strong predictors of GI illness in both fresh and marine environments. Significant heterogeneity was noted among the studies. In our analysis of heterogeneity, studies that used a nonswimming control group, studies that focused on children, and studies of athletic or other recreational events found elevated relative risks. Future studies should focus on the ability of new, more rapid and specific microbial methods to predict health effects, and estimating the risks of recreational water exposure among susceptible persons. [ABSTRACT FROM AUTHOR]

Background: Solar drinking water disinfection (SODIS) is a low-cost, point-of-use water purification method that has been disseminated globally. Laboratory studies suggest that SODIS is highly efficacious in inactivating waterborne pathogens. Previous field studies provided limited evidence for its effectiveness in reducing diarrhoea.Methods and Findings: We conducted a cluster-randomized controlled trial in 22 rural communities in Bolivia to evaluate the effect of SODIS in reducing diarrhoea among children under the age of 5 y. A local nongovernmental organisation conducted a standardised interactive SODIS-promotion campaign in 11 communities targeting households, communities, and primary schools. Mothers completed a daily child health diary for 1 y. Within the intervention arm 225 households (376 children) were trained to expose water-filled polyethyleneteraphtalate bottles to sunlight. Eleven communities (200 households, 349 children) served as a control. We recorded 166,971 person-days of observation during the trial representing 79.9% and 78.9% of the total possible person-days of child observation in intervention and control arms, respectively. Mean compliance with SODIS was 32.1%. The reported incidence rate of gastrointestinal illness in children in the intervention arm was 3.6 compared to 4.3 episodes/year at risk in the control arm. The relative rate of diarrhoea adjusted for intracluster correlation was 0.81 (95% confidence interval 0.59-1.12). The median length of diarrhoea was 3 d in both groups.Conclusions: Despite an extensive SODIS promotion campaign we found only moderate compliance with the intervention and no strong evidence for a substantive reduction in diarrhoea among children. These results suggest that there is a need for better evidence of how the well-established laboratory efficacy of this home-based water treatment method translates into field effectiveness under various cultural settings and intervention intensities. Further global promotion of SODIS for general use should be undertaken with care until such evidence is available.Trial Registration: www.ClinicalTrials.govNCT00731497 Please see later in the article for Editors' Summary. [ABSTRACT FROM AUTHOR]

Field studies often use caregiver-reported diarrhoea and related symptoms to measure child morbidity. There are various vernacular terms to define diarrhoea that vary across the local cultural contexts. The relationship between vernacular definitions of diarrhoea and symptoms-based definitions is not well-documented. This paper describes the association of the vernacular Quechua term k'echalera with the symptoms-based standard definition of diarrhoea in rural Bolivian settings. During a cluster randomized trial in rural Bolivia, both signs and symptoms of diarrhoea and reports of k'echalera were collected for children aged less than five years. Reported k'echalera were found to be associated with important changes in stool frequency, consistency, and presence of blood and mucus. Reported k'echalera were highly related to three of four recorded categories of watery stool. The intermediate (milk-rice) stool consistency, which fits into the definition of watery stool, was not strongly related to k'echalera. Mucus in the stool was also associated with k'echalera; however, its presence in k'echalera-free days accounted for at least 50% of the possible false negatives. The sensitivity and specificity of the term k'echalera were estimated by Bayesian methods, allowing for both symptoms of diarrhoea and reports of k'echalera to be subject to diagnosis error. An average specificity of at least 97% and the sensitivity of at least 50% were obtained. The findings suggest that the use of k'echalera would identify fewer cases of diarrhoea than a symptom-based definition in rural Bolivia. [ABSTRACT FROM AUTHOR]

Background: Postacute sequelae of COVID-19 (PASC), also known as long COVID, is a broad grouping of a range of long-term symptoms following acute COVID-19. These symptoms can occur across a range of biological systems, leading to challenges in determining risk factors for PASC and the causal etiology of this disorder. An understanding of characteristics that are predictive of future PASC is valuable, as this can inform the identification of high-risk individuals and future preventative efforts. However, current knowledge regarding PASC risk factors is limited., Objective: Using a sample of 55,257 patients (at a ratio of 1 patient with PASC to 4 matched controls) from the National COVID Cohort Collaborative, as part of the National Institutes of Health Long COVID Computational Challenge, we sought to predict individual risk of PASC diagnosis from a curated set of clinically informed covariates. The National COVID Cohort Collaborative includes electronic health records for more than 22 million patients from 84 sites across the United States., Methods: We predicted individual PASC status, given covariate information, using Super Learner (an ensemble machine learning algorithm also known as stacking) to learn the optimal combination of gradient boosting and random forest algorithms to maximize the area under the receiver operator curve. We evaluated variable importance (Shapley values) based on 3 levels: individual features, temporal windows, and clinical domains. We externally validated these findings using a holdout set of randomly selected study sites., Results: We were able to predict individual PASC diagnoses accurately (area under the curve 0.874). The individual features of the length of observation period, number of health care interactions during acute COVID-19, and viral lower respiratory infection were the most predictive of subsequent PASC diagnosis. Temporally, we found that baseline characteristics were the most predictive of future PASC diagnosis, compared with characteristics immediately before, during, or after acute COVID-19. We found that the clinical domains of health care use, demographics or anthropometry, and respiratory factors were the most predictive of PASC diagnosis., Conclusions: The methods outlined here provide an open-source, applied example of using Super Learner to predict PASC status using electronic health record data, which can be replicated across a variety of settings. Across individual predictors and clinical domains, we consistently found that factors related to health care use were the strongest predictors of PASC diagnosis. This indicates that any observational studies using PASC diagnosis as a primary outcome must rigorously account for heterogeneous health care use. Our temporal findings support the hypothesis that clinicians may be able to accurately assess the risk of PASC in patients before acute COVID-19 diagnosis, which could improve early interventions and preventive care. Our findings also highlight the importance of respiratory characteristics in PASC risk assessment., International Registered Report Identifier (irrid): RR2-10.1101/2023.07.27.23293272., (©Zachary Butzin-Dozier, Yunwen Ji, Haodong Li, Jeremy Coyle, Junming Shi, Rachael V Phillips, Andrew N Mertens, Romain Pirracchio, Mark J van der Laan, Rena C Patel, John M Colford, Alan E Hubbard, The National COVID Cohort Collaborative (N3C) Consortium. Originally published in JMIR Public Health and Surveillance (https://publichealth.jmir.org), 15.08.2024.)

Combined water, sanitation, and handwashing (WSH) interventions could reduce fecal contamination along more transmission pathways than single interventions alone. We measured Escherichia coli levels in 3909 drinking water samples, 2691 child hand rinses, and 2422 toy ball rinses collected from households enrolled in a 2-year cluster-randomized controlled trial evaluating single and combined WSH interventions. Water treatment with chlorine reduced E. coli in drinking water. A combined WSH intervention improved water quality by the same magnitude but did not affect E. coli levels on hands or toys. One potential explanation for the limited impact of the sanitation intervention (upgraded latrines) is failure to address dog and livestock fecal contamination. Small ruminant (goat or sheep) ownership was associated with increased E. coli levels in stored water and on child hands. Cattle and poultry ownership was protective against child stunting, and domesticated animal ownership was not associated with child diarrhea. Our findings do not support restricting household animal ownership to prevent child diarrheal disease or stunting but do support calls for WSH infrastructure that can more effectively reduce household fecal contamination.

Background: Hundreds of millions of children in low- and middle-income countries are exposed to chronic stressors, such as poverty, poor sanitation and hygiene, and sub-optimal nutrition. These stressors can have physiological consequences for children and may ultimately have detrimental effects on child development. This study explores associations between biological measures of chronic stress in early life and developmental outcomes in a large cohort of young children living in rural Bangladesh., Methods: We assessed physiologic measures of stress in the first two years of life using measures of the hypothalamic-pituitary-adrenal (HPA) axis (salivary cortisol and glucocorticoid receptor gene methylation), the sympathetic-adrenal-medullary (SAM) system (salivary alpha-amylase, heart rate, and blood pressure), and oxidative status (F2-isoprostanes). We assessed child development in the first two years of life with the MacArthur-Bates Communicative Development Inventories (CDI), the WHO gross motor milestones, and the Extended Ages and Stages Questionnaire (EASQ). We compared development outcomes of children at the 75th and 25th percentiles of stress biomarker distributions while adjusting for potential confounders using generalized additive models, which are statistical models where the outcome is predicted by a potentially non-linear function of predictor variables., Results: We analyzed data from 684 children (49% female) at both 14 and 28 months of age; we included an additional 765 children at 28 months of age. We detected a significant relationship between HPA axis activity and child development, where increased HPA axis activity was associated with poor development outcomes. Specifically, we found that cortisol reactivity (coefficient -0.15, 95% CI (-0.29, -0.01)) and post-stressor levels (coefficient -0.12, 95% CI (-0.24, -0.01)) were associated with CDI comprehension score, post-stressor cortisol was associated with combined EASQ score (coefficient -0.22, 95% CI (-0.41, -0.04), and overall glucocorticoid receptor methylation was associated with CDI expression score (coefficient -0.09, 95% CI (-0.17, -0.01)). We did not detect a significant relationship between SAM activity or oxidative status and child development., Conclusions: Our observations reveal associations between the physiological evidence of stress in the HPA axis with developmental status in early childhood. These findings add to the existing evidence exploring the developmental consequences of early life stress., Competing Interests: Declaration of Competing Interest This work was supported by Global Development grants [OPPGD759 and OPP1165144] from the Bill & Melinda Gates Foundation to the University of California, Berkeley and by the National Institute of Allergy and Infectious Diseases of the National Institutes of Health [grant number K01AI136885 to AL]. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. In the interest of full disclosure and transparency, we would like to disclose the roles of co-authors. Douglas Granger is the founder and chief scientific and strategy advisor at Salimetrics LLC and SalivaBio LLC, and these relationships are managed by the policies of the committees on conflict of interest at the Johns Hopkins University School of Medicine and the University of California at Irvine. Liying Yan is the president of EpigenDx, Inc. Ann Meyer is the Associate Director of Operations at EpigenDx, Inc., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

A regulated stress response is essential for healthy child growth and development trajectories. We conducted a cluster-randomized trial in rural Bangladesh (funded by the Bill & Melinda Gates Foundation, ClinicalTrials.gov NCT01590095) to assess the effects of an integrated nutritional, water, sanitation, and handwashing intervention on child health. We previously reported on the primary outcomes of the trial, linear growth and caregiver-reported diarrhea. Here, we assessed additional prespecified outcomes: physiological stress response, oxidative stress, and DNA methylation (N = 759, ages 1-2 years). Eight neighboring pregnant women were grouped into a study cluster. Eight geographically adjacent clusters were block-randomized into the control or the combined nutrition, water, sanitation, and handwashing (N + WSH) intervention group (receiving nutritional counseling and lipid-based nutrient supplements, chlorinated drinking water, upgraded sanitation, and handwashing with soap). Participants and data collectors were not masked, but analyses were masked. There were 358 children (68 clusters) in the control group and 401 children (63 clusters) in the intervention group. We measured four F2-isoprostanes isomers (iPF(2α)-III; 2,3-dinor-iPF(2α)-III; iPF(2α)-VI; 8,12-iso-iPF(2α)-VI), salivary alpha-amylase and cortisol, and methylation of the glucocorticoid receptor (NR3C1) exon 1F promoter including the NGFI-A binding site. Compared with control, the N + WSH group had lower concentrations of F2-isoprostanes isomers (differences ranging from -0.16 to -0.19 log ng/mg of creatinine, P < 0.01), elevated post-stressor cortisol (0.24 log µg/dl; P < 0.01), higher cortisol residualized gain scores (0.06 µg/dl; P = 0.023), and decreased methylation of the NGFI-A binding site (-0.04; P = 0.037). The N + WSH intervention enhanced adaptive responses of the physiological stress system in early childhood., (© 2024. The Author(s).)

Background: The WASH benefits Bangladesh trial multi-component sanitation intervention reduced diarrheal disease among children < 5 years. Intervention components included latrine upgrades, child feces management tools, and behavioral promotion. It remains unclear which components most impacted diarrhea., Methods: We conducted mediation analysis within a subset of households (n = 720) from the sanitation and control arms. Potential mediators were categorized into indicators of latrine quality, latrine use practices, and feces management practices. We estimated average causal mediation effects (ACME) as prevalence differences (PD), defined as the intervention's effect on diarrhea through its effect on the mediator., Results: The intervention improved all indicators compared to controls. We found significant mediation through multiple latrine use and feces management practice indicators. The strongest mediators during monsoon seasons were reduced open defecation among children aged < 3 and 3-8 years, and increased disposal of child feces into latrines. The strongest mediators during dry seasons were access to a flush/pour-flush latrine, reduced open defecation among children aged 3-8 years, and increased disposal of child feces into latrines. Individual mediation effects were small (PD = 0.5-2 percentage points) compared to the overall intervention effect but collectively describe significant mediation pathways., Discussion: The effect of the WASH Benefits Bangladesh sanitation intervention on diarrheal disease was mediated through improved child feces management and reduced child open defecation. Although the intervention significantly improved latrine quality, relatively high latrine quality at baseline may have limited benefits from additional improvements. Targeting safe child feces management may increase the health benefits of rural sanitation interventions., (© 2024. The Author(s).)

Background: Quantifying contributions of environmental faecal contamination to child diarrhoea and growth faltering can illuminate causal mechanisms behind modest health benefits in recent water, sanitation, and hygiene (WASH) trials. We aimed to assess associations between environmental detection of enteropathogens and human or animal microbial source tracking markers (MSTM) and subsequent child health outcomes., Methods: In this individual participant data meta-analysis we searched we searched PubMed, Embase, CAB Direct Global Health, Agricultural and Environmental Science Database, Web of Science, and Scopus for WASH intervention studies with a prospective design and concurrent control that measured enteropathogens or MSTM in environmental samples, or both, and subsequently measured enteric infections, diarrhoea, or height-for-age Z-scores (HAZ) in children younger than 5 years. We excluded studies that only measured faecal indicator bacteria. The initial search was done on Jan 19, 2021, and updated on March 22, 2023. One reviewer (AM) screened abstracts, and two independent reviewers (AM and RT) examined the full texts of short-listed articles. All included studies include at least one author that also contributed as an author to the present Article. Our primary outcomes were the 7-day prevalence of caregiver-reported diarrhoea and HAZ in children. For specific enteropathogens in the environment, primary outcomes also included subsequent child infection with the same pathogen ascertained by stool testing. We estimated associations using covariate-adjusted regressions and pooled estimates across studies., Findings: Data from nine published reports from five interventions studies, which included 8603 children (4302 girls and 4301 boys), were included in the meta-analysis. Environmental pathogen detection was associated with increased infection prevalence with the same pathogen and lower HAZ (ΔHAZ -0·09 [95% CI -0·17 to -0·01]) but not diarrhoea (prevalence ratio 1·22 [95% CI 0·95 to 1·58]), except during wet seasons. Detection of MSTM was not associated with diarrhoea (no pooled estimate) or HAZ (ΔHAZ -0·01 [-0·13 to 0·11] for human markers and ΔHAZ -0·02 [-0·24 to 0·21] for animal markers). Soil, children's hands, and stored drinking water were major transmission pathways., Interpretation: Our findings support a causal chain from pathogens in the environment to infection to growth faltering, indicating that the lack of WASH intervention effects on child growth might stem from insufficient reductions in environmental pathogen prevalence. Studies measuring enteropathogens in the environment should subsequently measure the same pathogens in stool to further examine theories of change between WASH, faecal contamination, and health. Given that environmental pathogen detection was predictive of infection, programmes targeting specific pathogens (eg, vaccinations and elimination efforts) can environmentally monitor the pathogens of interest for population-level surveillance instead of collecting individual biospecimens., Funding: The Bill & Melinda Gates Foundation and the UK Foreign and Commonwealth Development Office., Competing Interests: Declaration of interests A portion of JK's salary is supported by an unrestricted donation to the London School of Hygiene & Tropical Medicine from Reckitt; this salary support is wholly unrelated to her role in the preparation of this manuscript. All other authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

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., (© 2024. The Author(s).)

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 growth 1 . 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., (© 2023. The Author(s).)

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 survival 1,2 . 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., (© 2023. The Author(s).)

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., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: Poor immune function increases children's 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 child's immune status., (© 2023 The Authors.)

Background: Assessments of disease burden are important to inform national, regional, and global strategies and to guide investment. We aimed to estimate the drinking water, sanitation, and hygiene (WASH)-attributable burden of disease for diarrhoea, acute respiratory infections, undernutrition, and soil-transmitted helminthiasis, using the WASH service levels used to monitor the UN Sustainable Development Goals (SDGs) as counterfactual minimum risk-exposure levels., Methods: We assessed the WASH-attributable disease burden of the four health outcomes overall and disaggregated by region, age, and sex for the year 2019. We calculated WASH-attributable fractions of diarrhoea and acute respiratory infections by country using modelled WASH exposures and exposure-response relationships from two updated meta-analyses. We used the WHO and UNICEF Joint Monitoring Programme for Water Supply, Sanitation and Hygiene public database to estimate population exposure to different WASH service levels. WASH-attributable undernutrition was estimated by combining the population attributable fractions (PAF) of diarrhoea caused by unsafe WASH and the PAF of undernutrition caused by diarrhoea. Soil-transmitted helminthiasis was fully attributed to unsafe WASH., Findings: We estimate that 1·4 (95% CI 1·3-1·5) million deaths and 74 (68-80) million disability-adjusted life-years (DALYs) could have been prevented by safe WASH in 2019 across the four designated outcomes, representing 2·5% of global deaths and 2·9% of global DALYs from all causes. The proportion of diarrhoea that is attributable to unsafe WASH is 0·69 (0·65-0·72), 0·14 (0·13-0·17) for acute respiratory infections, and 0·10 (0·09-0·10) for undernutrition, and we assume that the entire disease burden from soil-transmitted helminthiasis was attributable to unsafe WASH., Interpretation: WASH-attributable burden of disease estimates based on the levels of service established under the SDG framework show that progress towards the internationally agreed goal of safely managed WASH services for all would yield major public-health returns., Funding: WHO and Foreign, Commonwealth & Development Office., Competing Interests: Declaration of interests JW reports grants from UK Foreign, Commonwealth & Development Office (FCDO), during this study. MB reports grants from Bill & Melinda Gates Foundation during this study. CFL reports non-financial support from WHO COVID-19 Vaccine Effectiveness Working Group, grants from CureVac AG, grants from PATH, grants from HilleVax, and personal fees from Valneva outside the submitted work. JB reports grants from Bill & Melinda Gates Foundation, grants from US Centers for Disease Control & Prevention, and grants from Columbia World Projects during this study. MCF reports Consulting for Rickett's Global Scientific Advisory Committee. RBJ reports grants from UK FCDO during this study, grants from Agence française de développement, grants from Australian Government Department of Foreign Affairs and Trade, grants from Austrian Development Agency, grants from Bill & Melinda Gates Foundation, grants from German Federal Ministry for Economic Development and Cooperation, grants from The Netherlands Directorate-General for International Cooperation, grants from Swiss Agency for Development and Cooperation, and grants from United States Agency for International Development outside the submitted work. All other authors declare no competing interests., (Copyright © 2023 World Health Organization. Published by Elsevier Ltd. All rights reserved. This is an Open Access article published under the CC BY 3·0 IGO license which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. In any use of this article, there should be no suggestion that WHO endorses any specific organisation, products or services. The use of the WHO logo is not permitted. This notice should be preserved along with the article's original URL.)

Background: Sanitation 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., Methods: We 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., Results: The intervention increased hygienic latrine access from 37% among controls to 94% in the sanitation arm (p < 0.001). Access among intervention recipients remained high 3.5 years after intervention initiation, including periods with no active promotion. Gains in access were higher among households with less education, less wealth and larger number of residents. The intervention increased availability of child potties from 29% among controls to 98% in the sanitation arm (p < 0.001). However, fewer than 25% of intervention households reported exclusive child defecation in a potty or had observed indicators of potty and sani-scoop use, and gains in potty use declined over the follow-up period, even with ongoing promotion., Conclusion: Our findings from an intervention that provided free products and intensive initial behavior change promotion suggest a sustained increase in hygienic latrine access up to 3.5 years after intervention initiation but infrequent use of child feces management tools. Studies should investigate strategies to ensure sustained adoption of safe child feces management practices., Competing Interests: Declaration of competing interest We declare no conflicts of interest., (Copyright © 2023 The Authors. Published by Elsevier GmbH.. All rights reserved.)

Background: Water, 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., Methods: We 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., Findings: Few 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])., Interpretation: The 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., Funding: Bill and Melinda Gates Foundation and the UK Foreign and Commonwealth Development Office., Competing Interests: Declaration of interests JER reports that a portion of her salary is supported by an unrestricted donation to The London School of Hygiene & Tropical Medicine from Reckitt; the salary support is wholly unrelated to her role in the preparation of this manuscript. TC has interest in publicly traded companies. All other authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background: Meta-analyses show that small-quantity lipid-based nutrient supplements (SQ-LNSs) reduce child wasting and stunting. There is little information regarding effects on severe wasting or stunting., Objectives: We aimed to identify the effect of SQ-LNSs on prevalence of severe wasting (weight-for-length z score < -3) and severe stunting (length-for-age z score < -3)., Methods: We conducted a 2-stage meta-analysis of individual participant data from 14 randomized controlled trials of SQ-LNSs provided to children 6-24 mo of age. We generated study-specific and subgroup estimates of SQ-LNS compared with control and pooled the estimates using fixed-effects models. We used random-effects meta-regression to examine study-level effect modifiers. In sensitivity analyses, we examined whether results differed depending on study arm inclusion criteria and types of comparisons., Results: SQ-LNS provision led to a relative reduction of 31% in severe wasting [prevalence ratio (PR): 0.69; 95% CI: 0.55, 0.86; n = 34,373] and 17% in severe stunting (PR: 0.83; 95% CI: 0.78, 0.90; n = 36,795) at endline. Results were similar in most of the sensitivity analyses but somewhat attenuated when comparisons using passive control arms were excluded (PR: 0.74; 95% CI: 0.57, 0.96; n = 26,327 for severe wasting and PR: 0.88; 95% CI: 0.81, 0.95; n = 28,742 for severe stunting). Study-level characteristics generally did not significantly modify the effects of SQ-LNSs, but results suggested greater effects of SQ-LNSs in sites with greater burdens of wasting or stunting, or with poorer water quality or sanitation., Conclusions: Including SQ-LNSs in preventive interventions to promote healthy child growth and development is likely to reduce rates of severe wasting and stunting. This meta-analysis was registered at www.crd.york.ac.uk/PROSPERO as CRD42019146592., (Copyright © 2022 American Society for Nutrition.)

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 <5 years through intention-to-treat analysis using generalized linear models with robust standard errors. Masking was not possible during data collection, but data analysis was masked. We enrolled 720 households (360 per arm) from the parent trial and made 9,800 child observations between June 2014 and December 2016. Over the entire study period, diarrheal prevalence was lower among children in the sanitation arm (11.9%) compared to the control arm (14.5%) (prevalence ratio [PR] = 0.81, 95% CI 0.66, 1.00, 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., Competing Interests: The authors have declared that no competing interests exist.

Background: Household-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., Methods: We 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., Results: Adjusted for confounders, study compounds surrounded by 100% coverage of at least one latrine per compound within 50 m had slightly lower log 10 E. 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 <100% coverage. Effects were similar but less pronounced at 100 m. At higher population densities, community latrine coverage was associated with larger reductions in E. coli on child and caregiver hands and prevalence of diarrheal disease. Coverage with exclusively hygienic latrines was not associated with any outcome., Conclusion: Higher community sanitation coverage was associated with reduced fecal contamination and improved child health, with stronger effects at highly local scales (50m) and at high population densities. Our findings indicate that the relationship between community sanitation coverage, environmental contamination, and child health varies by definition of coverage, distance, and population density. This work highlights significant uncertainty around how to best measure sanitation coverage and the expected health effects of increasing sanitation coverage using a specific metric. Better understanding of community-level sanitation access is needed to inform policy for implementing sanitation systems that effectively protect community health., (Copyright © 2022 The Authors. Published by Elsevier GmbH.. All rights reserved.)

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., Competing Interests: Declaration of interests JW and BG report grants from the UK Foreign, Commonwealth and Development Office, during the conduct of the study. SH reports grants from the National Institute of Environmental Health Sciences, during the conduct of the study. MB reports grants from Bill & Melinda Gates Foundation during the conduct of the study. BFA reports grants from National Institutes of Health, and grants and non-financial support from Bill & Melinda Gates Foundation, outside the submitted work. MCF reports personal fees from Reckitt, outside the submitted work. AM has received funding as a statistical consultant on The Lancet Commission on water, sanitation and hygiene, and health to analyse the associations between water, sanitation, hygiene, and handwashing and child health using Multiple Indicator Cluster Survey data and to complete an individual-participant data meta-analysis of WASH trials on pathogen contamination in the environment and child health. All other authors declare no competing interests., (Copyright © 2022 World Health Organization; licensee Elsevier. This is an Open Access article published under the CC BY 3.0 IGO license which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. In any use of this article, there should be no suggestion that WHO endorses any specific organisation, products or services. The use of the WHO logo is not permitted. This notice should be preserved along with the article's original URL.)

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., (© 2022 John Wiley & Sons Ltd.)

Background: Children may be at higher risk for swimming-associated illness following exposure to fecally-contaminated recreational waters. We analyzed a pooled data set of over 80,000 beachgoers from 13 beach sites across the United States to compare risks associated with the fecal indicator bacteria Enterococcus spp. (measured by colony forming units, CFU and quantitative polymerase chain reaction cell equivalents, qPCR CE) for different age groups across different exposures, sites and health endpoints., Methods: Sites were categorized according to the predominant type of fecal contamination (human or non-human). Swimming exposures of varying intensity were considered according to degree of contact and time spent in the water. Health endpoints included gastrointestinal and respiratory symptoms and skin rashes. Logistic regression models were used to analyze the risk of illness as a function of fecal contamination in water as measured by Enterococcus spp. among the exposed groups. Non-swimmers (those who did not enter the water) were excluded from the models to reduce bias and facilitate comparison across groups., Results: Gastrointestinal symptoms were the most sensitive health endpoint and strongest associations were observed with Enterococcus qPCR CE at sites impacted by human fecal contamination. Under several exposure scenarios, associations between illness and Enterococcus spp. levels were significantly higher among children compared to adolescents and adults. Respiratory symptoms were also associated with Enterococcus spp. exposures among young children at sites affected by human fecal sources, although small sample sizes resulted in imprecise estimates for these associations., Conclusion: Under many exposure scenarios, children were at higher risk of illness associated with exposure to fecal contamination as measured by the indicator bacteria Enterococcus spp. The source of fecal contamination and the intensity of swimming exposure were also important factors affecting the association between Enterococcus spp. and swimming-associated illness., Competing Interests: The authors have declared that no competing interests exist.

Background: Increasing influenza vaccination coverage in school-aged children may substantially reduce community transmission. School-located influenza vaccinations (SLIV) aim to promote vaccinations by increasing accessibility, which may be especially beneficial to race/ethnicity groups that face high barriers to preventative care. Here, we evaluate the effectiveness of a city-wide SLIV program by race/ethnicity from 2014 to 2018., Methods: We used multivariate matching to pair schools in the intervention district in Oakland, CA with schools in a comparison district in West Contra Costa County, CA. We distributed cross-sectional surveys to measure caregiver-reported student vaccination status and estimated differences in vaccination coverage levels and reasons for non-vaccination between districts stratifying by race/ethnicity. We estimated difference-in-differences (DID) of laboratory confirmed influenza hospitalization incidence between districts stratified by race/ethnicity using surveillance data., Results: Differences in influenza vaccination coverage in the intervention vs. comparison district were larger among White (2017-18: 21.0% difference [95% CI: 9.7%, 32.3%]) and Hispanic/Latino (13.4% [8.8%, 18.0%]) students than Asian/Pacific Islander (API) (8.9% [1.3%, 16.5%]), Black (5.9% [-2.2%, 14.0%]), and multiracial (6.3% [-1.8%, 14.3%)) students. Concerns about vaccine effectiveness or safety were more common among Black and multiracial caregivers. Logistical barriers were less common in the intervention vs. comparison district, with the largest difference among White students. In both districts, hospitalizations in 2017-18 were higher in Blacks (Intervention: 111.5 hospitalizations per 100,00; Comparison: 134.1 per 100,000) vs. other races/ethnicities. All-age influenza hospitalization incidence was lower in the intervention site vs. comparison site among White/API individuals in 2016-17 (DID -25.14 per 100,000 [95% CI: -40.14, -10.14]) and 2017-18 (-36.6 per 100,000 [-52.7, -20.5]) and Black older adults in 2017-18 (-282.2 per 100,000 (-508.4, -56.1]), but not in other groups., Conclusions: SLIV was associated with higher vaccination coverage and lower influenza hospitalization, but associations varied by race/ethnicity. SLIV alone may be insufficient to ensure equitable influenza outcomes., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: EP reports prior grant support from the Shoo the Flu organization during her work at the Alameda County Public Health Department. PDK and TL report grant support from the U.S. Centers for Disease Control and Prevention to the California Emerging Infections Program., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Meta-analyses show that small-quantity lipid-based nutrient supplements (SQ-LNSs) reduce child stunting and wasting. Identification of subgroups who benefit most from SQ-LNSs may facilitate program design., Objectives: We aimed to identify study-level and individual-level modifiers of the effect of SQ-LNSs on child growth outcomes., Methods: We conducted a 2-stage meta-analysis of individual participant data from 14 randomized controlled trials of SQ-LNSs provided to children 6-24 mo of age (n = 37,066). We generated study-specific and subgroup estimates of SQ-LNS compared with control and pooled the estimates using fixed-effects models. We used random-effects meta-regression to examine study-level effect modifiers. In sensitivity analyses, we examined whether results differed depending on study arm inclusion criteria and types of comparisons., Results: SQ-LNS provision decreased stunting (length-for-age z score < -2) by 12% (relative reduction), wasting [weight-for-length (WLZ) z score < -2] by 14%, low midupper arm circumference (MUAC) (<125 mm or MUAC-for-age z score < -2) by 18%, acute malnutrition (WLZ < -2 or MUAC < 125 mm) by 14%, underweight (weight-for-age z score < -2) by 13%, and small head size (head circumference-for-age z score < -2) by 9%. Effects of SQ-LNSs generally did not differ by study-level characteristics including region, stunting burden, malaria prevalence, sanitation, water quality, duration of supplementation, frequency of contact, or average compliance with SQ-LNS. Effects of SQ-LNSs on stunting, wasting, low MUAC, and small head size were greater among girls than among boys; effects on stunting, underweight, and low MUAC were greater among later-born (than among firstborn) children; and effects on wasting and acute malnutrition were greater among children in households with improved (as opposed to unimproved) sanitation., Conclusions: The positive impact of SQ-LNSs on growth is apparent across a variety of study-level contexts. Policy-makers and program planners should consider including SQ-LNSs in packages of interventions to prevent both stunting and wasting.This trial was registered at www.crd.york.ac.uk/PROSPERO as CRD42019146592., (© The Author(s) 2021. Published by Oxford University Press on behalf of the American Society for Nutrition.)

Background: We measured the effectiveness of a city-wide school-located influenza vaccination (SLIV) program implemented in over 102 elementary schools in Oakland, California., Methods: We conducted a retrospective cohort study among Kaiser Permanente Northern California (KPNC) members of all ages residing in either the intervention or a multivariate-matched comparison site from September 2011 - August 2017. Outcomes included medically attended acute respiratory illness (MAARI), influenza hospitalization, and Oseltamivir prescriptions. We estimated difference-in-differences (DIDs) in 2014-15, 2015-16, and 2016-17 using generalized linear models and adjusted for race, ethnicity, age, sex, health plan, and language., Results: Pre-intervention member characteristics were similar between sites. The proportion of KPNC members vaccinated for influenza by KPNC or the SLIV program was 8-11% higher in the intervention site than the comparison site during the intervention period. Among school-aged children, SLIV was associated with lower Oseltamivir prescriptions per 1,000 (DIDs: -3.5 (95% CI -5.5, -1.5) in 2015-16; -4.0 (95% CI -6.5, -1.6) in 2016-17) but not with other outcomes. SLIV was associated with lower MAARI per 1,000 in adults 65 + years (2014-15: -13.2, 95% CI -23.2, -3.2; 2015-16: -21.5, 95% CI -31.1, -11.9; 2016-17: -13.0, 95% CI -23.2, -2.9). There were few significant associations with other outcomes among adults., Conclusions: A city-wide SLIV intervention was associated with higher influenza vaccination coverage, lower Oseltamivir prescriptions in school-aged children, and lower MAARI among people over 65 years, suggesting possible indirect effects of SLIV among older adults., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Art Reingold reports financial support was provided by Flu Lab. Nicola P Klein reports a relationship with Protein Science (Sanofi Pasteur), Sanofi Pasteur, GlaxoSmithKline, Merck & Co, and Pfizer that includes: funding grants., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

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., Competing Interests: AL, CS, AH, SA, JB, AS, MR, SF, PM, SA, MR, LU, RN, KP, FD, PK, SL J.L. is a co-founder of Telomere Diagnostics Inc, a telomere measurement company. Assays and all other activity for the current report are, however, unrelated to this company. All other co-authors have no competing interests to declare. AM, BA, ST, JL, MH, MM, LF, JC No competing interests declared, (© 2021, Lin et al.)