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Background We evaluated the impact of low-cost water, sanitation, and handwashing (WSH) and child nutrition interventions on enteropathogen carriage in the WASH Benefits cluster-randomized controlled trial in rural Bangladesh. Methods We analyzed 1411 routine fecal samples from children 14 ± 2 months old in the WSH (n = 369), nutrition counseling plus lipid-based nutrient supplement (n = 353), nutrition plus WSH (n = 360), and control (n = 329) arms for 34 enteropathogens using quantitative polymerase chain reaction. Outcomes included the number of co-occurring pathogens; cumulative quantity of 4 stunting-associated pathogens; and prevalence and quantity of individual pathogens. Masked analysis was by intention-to-treat. Results Three hundred twenty-six (99.1%) control children had 1 or more enteropathogens detected (mean, 3.8 ± 1.8). Children receiving WSH interventions had lower prevalence and quantity of individual viruses than controls (prevalence difference for norovirus: –11% [95% confidence interval {CI}, –5% to –17%]; sapovirus: –9% [95% CI, –3% to –15%]; and adenovirus 40/41: –9% [95% CI, –2% to –15%]). There was no difference in bacteria, parasites, or cumulative quantity of stunting-associated pathogens between controls and any intervention arm. Conclusions WSH interventions were associated with fewer enteric viruses in children aged 14 months. Different strategies are needed to reduce enteric bacteria and parasites at this critical young age. [ABSTRACT FROM AUTHOR]

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. 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. 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. 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. • We measured stress biomarkers and development in young children in Bangladesh. • We evaluated biomarkers from multiple stress systems. • We used generalized additive models to flexibly assess correlations. • Hypothalamic-pituitary-adrenal axis markers were associated with child development. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background We hypothesized that drinking water, sanitation, handwashing (WSH), and nutritional interventions would improve environmental enteric dysfunction (EED), a potential contributor to stunting. Methods Within a subsample of a cluster-randomized, controlled trial in rural Bangladesh, we enrolled pregnant women in 4 arms: control, WSH, child nutrition counseling plus lipid-based nutrient supplements (N), and nutrition plus WSH (N+WSH). Among the birth cohort, we measured biomarkers of gut inflammation (myeloperoxidase, neopterin), permeability (alpha-1-antitrypsin, lactulose, mannitol), and repair (regenerating gene 1β) at median ages 3, 14, and 28 months. Analysis was intention-to-treat. Results We assessed 1512 children. At age 3 months, compared to controls, neopterin was reduced by nutrition (–0.21 log nmol/L; 95% confidence interval [CI], –.37, –.05) and N+WSH (–0.20 log nmol/L; 95% CI, –.34, –.06) interventions; similar reductions were observed at 14 months. At 3 months, all interventions reduced lactulose and mannitol (–0.60 to –0.69 log mmol/L). At 28 months, myeloperoxidase was elevated in the WSH and nutrition arms (0.23–0.27 log ng/mL) and lactulose was higher in the WSH arm (0.30 log mmol/L; 95% CI,.07,.53). Conclusions Reductions in permeability and inflammation at ages 3 and 14 months suggest that the interventions promoted healthy intestinal maturation; however, by 28 months, the WSH and nutrition arms showed elevated EED biomarkers. These results underscore the importance of developing a better understanding of EED pathophysiology and targeting interventions early in childhood, when they are likely to have the largest benefit to intestinal health. Clinical Trials Registration NCT01590095. [ABSTRACT FROM AUTHOR]

Background: Young children frequently defecate in the living environment in low-income countries. Unsafe child feces disposal has been associated with risk of diarrhea. Additionally, reported practices can underestimate socially undesirable unhygienic behaviors. This analysis aimed to assess (1) the sensitivity of reported child feces disposal practices as an indicator for observed presence of human feces in the domestic environment, (2) household characteristics associated with reported unsafe feces disposal and (3) whether unsafe feces disposal is associated with fly presence and diarrhea among children <3 years. Methods: We recorded caregiver-reported feces disposal practices for children <3 years; unsafe disposal was defined as feces put/rinsed into a drain, ditch, bush or garbage heap or left on the ground and safe disposal as feces put/rinsed into latrine or specific pit or buried. We conducted spot checks for human feces, counted flies in the compound and recorded caregiver-reported child diarrhea prevalence among 803 rural Bangladeshi households. We assessed associations using generalized estimating equations (GEE) and generalized linear models (GLM) with robust standard errors. Results: Unsafe disposal of child feces was reported by 80% of households. Reported disposal practices had high sensitivity (91%) but low positive predictive value (15%) as an indicator of observed feces in the compound. Unsafe disposal was more common among households that reported daily adult open defecation (PR: 1.13, 1.02–1.24) and had children defecating in a nappy or on the ground versus in a potty (PR: 2.92, 1.98–4.32), and less common in households where adults reported always defecating in latrines (PR: 0.91, 0.84–0.98). The presence of observed human feces was similarly associated with these household characteristics. Reported unsafe feces disposal or observed human feces were not associated with fly detection or child diarrhea. Conclusion: Despite access to on-site sanitation, unsafe child feces disposal was reported by the majority of households. However, this practices was not associated with diarrhea; suggesting that child feces may not be the most important fecal exposure. Before resources are invested to improve child feces management practices, studies should explore whether these contribute meaningfully to risk of enteric disease. [ABSTRACT FROM AUTHOR]

Background: Shorter childhood telomere length (TL) and more rapid TL attrition are widely regarded as manifestations of stress. However, the potential effects of health interventions on child TL are unknown. We hypothesized that a water, sanitation, handwashing (WSH), and nutritional intervention would slow TL attrition during the first two years of life. Methods: In a trial in rural Bangladesh (ClinicalTrials.gov, NCT01590095), we randomized geographical clusters of pregnant women into individual water treatment, sanitation, handwashing, nutrition, combined WSH, combined nutrition plus WSH (N + WSH), or control arms. We conducted a substudy enrolling children from the control arm and the N + WSH intervention arm. Participants and outcome assessors were not masked; analyses were masked. Relative TL was measured at 1 and 2 years after intervention, and the change in relative TL was reported. Analysis was intention-to-treat. Findings: Between May 2012 and July 2013, in the overall trial, we randomized 720 geographical clusters of 5551 pregnant women to a control or an intervention arm. In this substudy, after 1 year of intervention, we assessed a total of 662 children (341 intervention and 321 control) and 713 children after 2 years of intervention (383 intervention and 330 control). Children in the intervention arm had significantly shorter relative TL compared with controls after 1 year of intervention (difference -163 base pairs (bp), p=0.001). Between years 1 and 2, TL increased in the intervention arm (+76 bp) and decreased in the controls (-23 bp) (p=0.050). After 2 years, there was no difference between the arms (p=0.305). Interpretation: Our unexpected finding of increased telomere attrition during the first year of life in the intervention group suggests that rapid telomere attrition during this critical period could reflect the improved growth in the intervention group, rather than accumulated stress. Funding: The Bill and Melinda Gates Foundation [ABSTRACT FROM AUTHOR]