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Background: Antibiotic use during early infancy has been linked to childhood obesity in high-income countries. We evaluated whether a single oral dose of azithromycin administered during infant-well visits led to changes in infant growth outcomes at 6 months of age in a setting with a high prevalence of undernutrition in rural Burkina Faso. Methods and findings: Infants were enrolled from September 25, 2019, until October 22, 2022, in a randomized controlled trial designed to evaluate the efficacy of a single oral dose of azithromycin (20 mg/kg) compared to placebo when administered during well-child visits for prevention of infant mortality. The trial found no evidence of a difference in the primary endpoint. This paper presents prespecified secondary anthropometric endpoints including weight gain (g/day), height change (mm/day), weight-for-age Z-score (WAZ), weight-for-length Z-score (WLZ), length-for-age Z-score (LAZ), and mid-upper arm circumference (MUAC). Infants were eligible for the trial if they were between 5 and 12 weeks of age, able to orally feed, and their families were planning to remain in the study area for the duration of the study. Anthropometric measurements were collected at enrollment (5 to 12 weeks of age) and 6 months of age. Among 32,877 infants enrolled in the trial, 27,298 (83%) were followed and had valid anthropometric measurements at 6 months of age. We found no evidence of a difference in weight gain (mean difference 0.03 g/day, 95% confidence interval (CI) −0.12 to 0.18), height change (mean difference 0.004 mm/day, 95% CI −0.05 to 0.06), WAZ (mean difference −0.004 SD, 95% CI −0.03 to 0.02), WLZ (mean difference 0.001 SD, 95% CI −0.03 to 0.03), LAZ (mean difference −0.005 SD, 95% CI −0.03 to 0.02), or MUAC (mean difference 0.01 cm, 95% CI −0.01 to 0.04). The primary limitation of the trial was that measurements were only collected at enrollment and 6 months of age, precluding assessment of shorter-term or long-term changes in growth. Conclusions: Single-dose azithromycin does not appear to affect weight and height outcomes when administered during early infancy. Trial registration: ClinicalTrials.govNCT03676764 Ali Sié and colleagues present pre-specified anthropometric outcomes from a randomized controlled trial that assessed the impact of a single-dose of oral azithromycin on infant mortality in Burkina Faso. Author summary: Why was this study done?: Antibiotics have been linked to obesity in children in nonrandomized studies in high-income settings. In low-income settings, malnutrition is a strong risk factor for child mortality, and interventions that increase weight gain may be beneficial. Single-dose azithromycin has previously been shown to reduce child mortality in sub-Saharan Africa, and it is possible that some of this effect is via weight gain. Why did the researchers do and find?: We conducted a randomized controlled trial in which infants aged 5 to 12 weeks were randomly assigned to a single dose of azithromycin or a matching placebo. The primary outcome of the parent trial was all-cause mortality, and the trial found no evidence of a benefit of azithromycin for prevention of mortality. Infants were followed until 6 months of age and had anthropometric measurements, including height, weight, and mid-upper arm circumference, collected. We found no evidence of a difference in any anthropometric endpoint in infants randomized to azithromycin compared to placebo. What do these findings mean?: Single-dose azithromycin does not appear to affect growth when administered to healthy infants who are 5 to 12 weeks of age. Growth outcomes were only measured at 6 months of age, and thus, any shorter or longer-term effects of azithromycin would not be detected by this study. This study only considered a single dose of azithromycin, as is used for prevention of child mortality and trachoma, and thus, it is possible that higher doses or longer duration of antibiotics could have a different effects on child growth. [ABSTRACT FROM AUTHOR]

Background Biannual azithromycin distribution to children 1–59 months old reduced all-cause mortality by 18% [incidence rate ratio (IRR) 0.82, 95% confidence interval (CI): 0.74, 0.90] in an intention-to-treat analysis of a randomized controlled trial in Niger. Estimation of the effect in compliance-related subgroups can support decision making around implementation of this intervention in programmatic settings. Methods The cluster-randomized, placebo-controlled design of the original trial enabled unbiased estimation of the effect of azithromycin on mortality rates in two subgroups: (i) treated children (complier average causal effect analysis); and (ii) untreated children (spillover effect analysis), using negative binomial regression. Results In Niger, 594 eligible communities were randomized to biannual azithromycin or placebo distribution and were followed from December 2014 to August 2017, with a mean treatment coverage of 90% [standard deviation (SD) 10%] in both arms. Subgroup analyses included 2581 deaths among treated children and 245 deaths among untreated children. Among treated children, the incidence rate ratio comparing mortality in azithromycin communities to placebo communities was 0.80 (95% CI: 0.72, 0.88), with mortality rates (deaths per 1000 person-years at risk) of 16.6 in azithromycin communities and 20.9 in placebo communities. Among untreated children, the incidence rate ratio was 0.91 (95% CI: 0.69, 1.21), with rates of 33.6 in azithromycin communities and 34.4 in placebo communities. Conclusions As expected, this analysis suggested similar efficacy among treated children compared with the intention-to-treat analysis. Though the results were consistent with a small spillover benefit to untreated children, this trial was underpowered to detect spillovers. [ABSTRACT FROM AUTHOR]

Background: Azithromycin is a broad-spectrum antibiotic that has moderate antimalarial activity and has been shown to reduce all-cause mortality when biannually administered to children under five in high mortality settings in sub-Saharan Africa. One potential mechanism for this observed reduction in mortality is via a reduction in malaria transmission.Methods: We evaluated whether a single oral dose of azithromycin reduces malaria positivity by rapid diagnostic test (RDT). We conducted an individually randomized placebo-controlled trial in Burkina Faso during the high malaria transmission season in August 2020. Children aged 8 days to 59 months old were randomized to a single oral dose of azithromycin (20 mg/kg) or matching placebo. At baseline and 14 days following treatment, we administered a rapid diagnostic test (RDT) to detect Plasmodium falciparum and measured tympanic temperature for all children. Caregiver-reported adverse events and clinic visits were recorded at the day 14 visit.Results: We enrolled 449 children with 221 randomized to azithromycin and 228 to placebo. The median age was 32 months and 48% were female. A total of 8% of children had a positive RDT for malaria at baseline and 11% had a fever (tympanic temperature ≥ 37.5 °C). In the azithromycin arm, 8% of children had a positive RDT for malaria at 14 days compared to 7% in the placebo arm (P = 0.65). Fifteen percent of children in the azithromycin arm had a fever ≥ 37.5 °C compared to 21% in the placebo arm (P = 0.12). Caregivers of children in the azithromycin group had lower odds of reporting fever as an adverse event compared to children in the placebo group (OR 0.41, 95% CI 0.18-0.96, P = 0.04). Caregiver-reported clinic visits were uncommon, and there were no observed differences between arms (P = 0.32).Conclusions: We did not find evidence that a single oral dose of azithromycin reduced malaria positivity during the high transmission season. Caregiver-reported fever occurred less often in children receiving azithromycin compared to placebo, indicating that azithromycin may have some effect on non-malarial infections. Trial registration Clinicaltrials.gov NCT04315272, registered 19/03/2020. [ABSTRACT FROM AUTHOR]

We evaluated the gut resistome of children from communities treated with 10 twice-yearly azithromycin distributions. Although the macrolide resistance remained higher in the azithromycin arm, the selection of non-macrolide resistance observed at earlier time points did not persist. Longitudinal resistance monitoring should be a critical component of mass distribution programs. Clinical trials registration NCT02047981 [ABSTRACT FROM AUTHOR]

Background Current guidelines recommend community-wide mass azithromycin for trachoma, but a targeted treatment strategy could reduce the volume of antibiotics required. Methods In total, 48 Ethiopian communities were randomized to mass, targeted, or delayed azithromycin distributions. In the targeted arm, only children aged 6 months to 5 years with evidence of ocular chlamydia received azithromycin, distributed thrice over the following year. The primary outcome was ocular chlamydia at months 12 and 24, comparing the targeted and delayed arms (0–5 year-olds, superiority analysis) and the targeted and mass azithromycin arms (8–12 year-olds, noninferiority analysis, 10% noninferiority margin). Results At baseline, the mean prevalence of ocular chlamydia in the 3 arms ranged from 7% to 9% among 0–5 year-olds and from 3% to 9% among 8–12 year-olds. Averaged across months 12–24, the mean prevalence of ocular chlamydia among 0–5 year-olds was 16.7% (95% confidence interval [CI]: 9.0%–24.4%) in the targeted arm and 22.3% (95% CI: 11.1%–33.6%) in the delayed arm (P  = .61). The final mean prevalence of ocular chlamydia among 8–12 year-olds was 13.5% (95% CI: 7.9%–19.1%) in the targeted arm and 5.5% (95% CI: 0.3%–10.7%) in the mass treatment arm (adjusted risk difference 8.5 percentage points [pp] higher in the targeted arm, 95% CI: 0.9 pp–16.1 pp higher). Conclusions Antibiotic treatments targeted to infected preschool children did not result in significantly less ocular chlamydia infections compared with untreated communities and did not meet noninferiority criteria relative to mass azithromycin distributions. Targeted approaches may require treatment of a broader segment of the population in areas with hyperendemic trachoma. [ABSTRACT FROM AUTHOR]

Importance: Azithromycin has been hypothesized to have activity against SARS-CoV-2.Objective: To determine whether oral azithromycin in outpatients with SARS-CoV-2 infection leads to absence of self-reported COVID-19 symptoms at day 14.Design, Setting, and Participants: Randomized clinical trial of azithromycin vs matching placebo conducted from May 2020 through March 2021. Outpatients from the US were enrolled remotely via internet-based surveys and followed up for 21 days. Eligible participants had a positive SARS-CoV-2 diagnostic test result (nucleic acid amplification or antigen) within 7 days prior to enrollment, were aged 18 years or older, and were not hospitalized at the time of enrollment. Among 604 individuals screened, 297 were ineligible, 44 refused participation, and 263 were enrolled. Participants, investigators, and study staff were masked to treatment randomization.Interventions: Participants were randomized in a 2:1 fashion to a single oral 1.2-g dose of azithromycin (n = 171) or matching placebo (n = 92).Main Outcomes and Measures: The primary outcome was absence of self-reported COVID-19 symptoms at day 14. There were 23 secondary clinical end points, including all-cause hospitalization at day 21.Results: Among 263 participants who were randomized (median age, 43 years; 174 [66%] women; 57% non-Hispanic White and 29% Latinx/Hispanic), 76% completed the trial. The trial was terminated by the data and safety monitoring committee for futility after the interim analysis. At day 14, there was no significant difference in proportion of participants who were symptom free (azithromycin: 50%; placebo: 50%; prevalence difference, 0%; 95% CI, -14% to 15%; P > .99). Of 23 prespecified secondary clinical end points, 18 showed no significant difference. By day 21, 5 participants in the azithromycin group had been hospitalized compared with 0 in the placebo group (prevalence difference, 4%; 95% CI, -1% to 9%; P = .16).Conclusions and Relevance: Among outpatients with SARS-CoV-2 infection, treatment with a single dose of azithromycin compared with placebo did not result in greater likelihood of being symptom free at day 14. These findings do not support the routine use of azithromycin for outpatient SARS-CoV-2 infection.Trial Registration: ClinicalTrials.gov Identifier: NCT04332107. [ABSTRACT FROM AUTHOR]

Background: Biannual distribution of azithromycin to children 1-59 months old reduced mortality by 14% in a cluster-randomized trial. The World Health Organization has proposed targeting this intervention to the subgroup of children 1-11 months old to reduce selection for antimicrobial resistance. Here, we describe a trial designed to determine the impact of age-based targeting of biannual azithromycin on mortality and antimicrobial resistance.Methods: AVENIR is a cluster-randomized, placebo-controlled, double-masked, response-adaptive large simple trial in Niger. During the 2.5-year study period, 3350 communities are targeted for enrollment. In the first year, communities in the Dosso region will be randomized 1:1:1 to 1) azithromycin 1-11: biannual azithromycin to children 1-11 months old with placebo to children 12-59 months old, 2) azithromycin 1-59: biannual azithromycin to children 1-59 months old, or 3) placebo: biannual placebo to children 1-59 months old. Regions enrolled after the first year will be randomized with an updated allocation based on the probability of mortality in children 1-59 months in each arm during the preceding study period. A biannual door-to-door census will be conducted to enumerate the population, distribute azithromycin and placebo, and monitor vital status. Primary mortality outcomes are defined as all-cause mortality rate (deaths per 1000 person-years) after 2.5 years from the first enrollment in 1) children 1-59 months old comparing the azithromycin 1-59 and placebo arms, 2) children 1-11 months old comparing the azithromycin 1-11 and placebo arm, and 3) children 12-59 months in the azithromycin 1-11 and azithromycin 1-59 arms. In the Dosso region, 50 communities from each arm will be followed to monitor antimicrobial resistance. Primary resistance outcomes will be assessed after 2 years of distributions and include 1) prevalence of genetic determinants of macrolide resistance in nasopharyngeal samples from children 1-59 months old, and 2) load of genetic determinants of macrolide resistance in rectal samples from children 1-59 months old.Discussion: As high-mortality settings consider this intervention, the results of this trial will provide evidence to support programmatic and policy decision-making on age-based strategies for azithromycin distribution to promote child survival.Trial Registration: This trial was registered on January 13, 2020 (clinicaltrials.gov: NCT04224987 ). [ABSTRACT FROM AUTHOR]

Background: Given the high risk of infectious mortality among children with severe acute malnutrition (SAM), the World Health Organization recommends routine administration of a broad-spectrum antibiotic like amoxicillin as part of the management of uncomplicated SAM. However, evidence for the efficacy of amoxicillin to improve nutritional recovery or reduce mortality has been mixed. With a long half-life and evidence of efficacy to reduce mortality in high-risk populations, azithromycin is a potential alternative to amoxicillin in the management of SAM. In this pilot study, we aim to compare the efficacy of azithromycin to amoxicillin to improve nutritional outcomes in children with uncomplicated SAM. Methods: This pilot randomized controlled trial will enroll 300 children with uncomplicated SAM from 6 Centre de Santé et de Promotion Sociale in the Boromo health district in Burkina Faso. Eligible children are randomized to receive a single directly observed dose of oral azithromycin or a 7-day course of oral amoxicillin in addition to the standard package of care for uncomplicated SAM. Enrolled children are followed weekly until nutritional recovery, and all children return for a final study visit at 8 weeks after enrollment. Anthropometric indicators, vital status, and clinical outcomes are monitored at each visit and compared by arm. Primary feasibility outcomes include enrollment potential, refusals, loss to follow-up, and completeness of data collection. The primary clinical outcome is weight gain (g/kg/day) over the 8-week study period. Discussion: This pilot trial will establish the feasibility of conducting a full-scale randomized controlled trial to evaluate alternative antibiotics in this setting and provide preliminary evidence for the efficacy of azithromycin compared to amoxicillin to improve outcomes for children with SAM. Trial registration: This trial was first registered on clinicaltrials.gov on 26 June 2018 (NCT03568643). [ABSTRACT FROM AUTHOR]

Background: In lower resource settings, previous randomized controlled trials have demonstrated evidence of increased weight gain following antibiotic administration in children with acute illness. We conducted an individually randomized trial to assess whether single dose azithromycin treatment causes weight gain in a general population sample of children in Burkina Faso.Methods: Children aged 8 days to 59 months were enrolled in November 2019 and followed through June 2020 in Nouna Town, Burkina Faso. Participants were randomly assigned to a single oral dose of azithromycin (20 mg/kg) or matching placebo. Anthropometric measurements were collected at baseline and 14 days and 6 months after enrollment. The primary anthropometric outcome was weight gain velocity in g/kg/day from baseline to 14 days and 6 months in separate linear regression models.Results: Of 450 enrolled children, 230 were randomly assigned to azithromycin and 220 to placebo. Median age was 26 months (IQR 16 to 38 months) and 51% were female. At 14 days, children in the azithromycin arm gained a mean difference of 0.9 g/kg/day (95% CI 0.2 to 1.6 g/kg/day, P = 0.01) more than children in the placebo arm. There was no difference in weight gain velocity in children receiving azithromycin compared to placebo at 6 months (mean difference 0.04 g/kg/day, 95% CI - 0.05 to 0.13 g/kg/day, P = 0.46). There were no significant differences in other anthropometric outcomes.Conclusions: Transient increases in weight gain were observed after oral azithromycin treatment, which may provide short-term benefits.Clinical Trials Registration: ClinicalTrials.gov NCT03676751 . Registered 19/09/2018. [ABSTRACT FROM AUTHOR]

Background: The World Health Organization (WHO) recommends annual mass azithromycin distribution until districts drop below 5% prevalence of trachomatous inflammation-follicular (TF). Districts with very low TF prevalence may have little or no transmission of the ocular strains of Chlamydia trachomatis that cause trachoma, and additional rounds of mass azithromycin distribution may not be useful. Here, we describe the protocol for a randomized controlled trial designed to evaluate whether mass azithromycin distribution can be stopped prior to the current WHO guidelines.Methods: The Azithromycin Reduction to Reach Elimination of Trachoma (ARRET) study is a 1:1 community randomized non-inferiority trial designed to evaluate whether mass azithromycin distribution can be stopped in districts with baseline prevalence of TF under 20%. Communities in Maradi, Niger are randomized after baseline assessment either to continued annual mass azithromycin distribution or stopping annual azithromycin distribution over a 3-year period. We will compare the prevalence of ocular C. trachomatis (primary outcome), TF and other clinical signs of trachoma, and serologic markers of trachoma after 3 years. We hypothesize that stopping annual azithromycin distribution will be non-inferior to continued annual azithromycin distributions for all markers of trachoma prevalence and transmission.Discussion: The results of this trial are anticipated to provide potentially guideline-changing evidence for when mass azithromycin distributions can be stopped in low TF prevalence areas. TRIAL REGISTRATION NUMBER: This study is registered at clinicaltrials.gov ( NCT04185402 ). Registered December 4, 2019; prospectively registered pre-results. [ABSTRACT FROM AUTHOR]

Background: Juvenile idiopathic arthritis (JIA)-associated uveitis is a chronic paediatric ocular inflammatory condition that can result in visual impairment. Adalimumab, a tumour necrosis factor (TNF)-alpha inhibitor, effectively controls joint and eye inflammation; however, its long-term use may increase the risk of adverse health outcomes and place an undue financial burden on the patient and healthcare system given its high cost. There is great interest for patients to stop adalimumab following remission due to these reasons but there is a lack of information on the ability to maintain control after discontinuing adalimumab.Methods: The Adalimumab in Juvenile Idiopathic Arthritis-associated Uveitis Trial (ADJUST) is a multicentred, international trial that will randomise 118 participants aged 2 years and older with controlled JIA-associated uveitis to either continue adalimumab or discontinue adalimumab and receive a placebo. The trial will compare the time to uveitis recurrence between the two groups over 12 months. All participants will receive the standard weight-based dose of adalimumab or placebo: 20 mg biweekly (if < 30 kg) or 40 mg biweekly (if ≥ 30 kg).Discussion: This is the first randomised controlled trial to assess the efficacy of discontinuing adalimumab after demonstrating control of JIA-associated uveitis for at least 12 months. The results of ADJUST will provide information on clinical outcomes to guide clinicians in their decision-making regarding discontinuation of adalimumab.Trial Registration: ClinicalTrials.gov NCT03816397. Registered on 25 January 2019. EudraCT 2019-000412-29. Registered on 17 January 2019. [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: Soil transmitted helminths (STH) infect >1.5 billion people. Mass drug administration (MDA) effectively reduces infection; however, there is evidence for rapid reinfection and risk of potential drug resistance. We conducted a randomized controlled trial in Bangladesh (WASH Benefits, NCT01590095) to assess whether water, sanitation, hygiene and nutrition interventions, alone and combined, reduce STH in a setting with ongoing MDA. Methodology/Principal findings: In 2012–2013, we randomized 720 clusters of 5551 pregnant women into water treatment, sanitation, handwashing, combined water+sanitation+handwashing (WSH), nutrition, nutrition+WSH (N+WSH) or control arms. In 2015–2016, we enrolled 7795 children, aged 2–12 years, of 4102 available women for STH follow-up and collected stool from 7187. We enumerated STH infections with Kato-Katz. We estimated intention-to-treat intervention effects on infection prevalence and intensity. Participants and field staff were not blinded; laboratory technicians and data analysts were blinded. Prevalence among controls was 36.8% for A. lumbricoides, 9.2% for hookworm and 7.5% for T. trichiura. Most infections were low-intensity. Compared to controls, the water intervention reduced hookworm by 31% (prevalence ratio [PR] = 0.69 (0.50,0.95), prevalence difference [PD] = -2.83 (-5.16,-0.50)) but did not affect other STH. Sanitation improvements reduced T. trichiura by 29% (PR = 0.71 (0.52,0.98), PD = -2.17 (-4.03,-0.38)), had a similar borderline effect on hookworm and no effect on A. lumbricoides. Handwashing and nutrition interventions did not reduce any STH. WSH and N+WSH reduced hookworm prevalence by 29–33% (WSH: PR = 0.71 (0.52,0.99), PD = -2.63 (-4.95,-0.31); N+WSH: PR = 0.67 (0.50,0.91), PD = -3.00 (-5.14,-0.85)) and marginally reduced A. lumbricoides. Effects on infection intensity were similar. Conclusions/Significance: In a low-intensity infection setting with MDA, we found modest but sustained hookworm reduction from water treatment and combined WSH interventions. Impacts were more pronounced on STH species with short vs. long-term environmental survival. Our findings suggest possible waterborne transmission for hookworm. Water treatment and sanitation improvements can augment MDA to interrupt STH transmission. Trial registration: . [ABSTRACT FROM AUTHOR]

Background: Anemia in young children is a global health problem. Risk factors include poor nutrient intake and poor water quality, sanitation, or hygiene. Objective: We evaluated the effects of water quality, sanitation, handwashing, and nutrition interventions on micronutrient status and anemia among children in rural Kenya and Bangladesh. Design: We nested substudies within 2 cluster-randomized controlled trials enrolling pregnant women and following their children for 2 y. These substudies included 4 groups: water, sanitation, and handwashing (WSH); nutrition (N), including lipid-based nutrient supplements (LNSs; ages 6–24 mo) and infant and young child feeding (IYCF) counseling; WSH+N; and control. Hemoglobin and micronutrient biomarkers were measured after 2 y of intervention and compared between groups using generalized linear models with robust SEs. Results: In Kenya, 699 children were assessed at a mean ± SD age of 22.1 ± 1.8 mo, and in Bangladesh 1470 participants were measured at a mean ± SD age of 28.0 ± 1.9 mo. The control group anemia prevalences were 48.8% in Kenya and 17.4% in Bangladesh. There was a lower prevalence of anemia in the 2 N intervention groups in both Kenya [N: 36.2%; prevalence ratio (PR): 0.74; 95% CI: 0.58, 0.94; WSH+N: 27.3%; PR: 0.56; 95% CI: 0.42, 0.75] and Bangladesh (N: 8.7%; PR: 0.50; 95% CI: 0.32, 0.78; WSH+N: 7.9%, PR: 0.46; 95% CI: 0.29, 0.73). In both trials, the 2 N groups also had significantly lower prevalences of iron deficiency, iron deficiency anemia, and low vitamin B-12 and, in Kenya, a lower prevalence of folate and vitamin A deficiencies. In Bangladesh, the WSH group had a lower prevalence of anemia (12.8%; PR: 0.74; 95% CI: 0.54, 1.00) than the control group, whereas in Kenya, the WSH+N group had a lower prevalence of anemia than did the N group (PR: 0.75; 95% CI: 0.53, 1.07), but this was not significant (P = 0.102). Conclusions: IYCF counseling with LNSs reduced the risks of anemia, iron deficiency, and low vitamin B-12. Effects on folate and vitamin A varied between studies. Improvements in WSH also reduced the risk of anemia in Bangladesh but did not provide added benefit over the nutrition-specific intervention [ABSTRACT FROM AUTHOR]

Background We evaluated effects of individual and combined water, sanitation, handwashing (WSH), and nutritional interventions on protozoan infections in children. Methods We randomized geographical clusters of pregnant women in rural Bangladesh into chlorinated drinking water, hygienic sanitation, handwashing, nutrition, combined WSH, nutrition plus WSH (N+WSH), or control arms. Participants were not masked. After approximately 2.5 years of intervention, we measured Giardia, Cryptosporidium, and Entamoeba histolytica prevalence and infection intensity by multiplex real-time polymerase chain reaction of child stool. Analysis was intention-to-treat. Results Between May 2012 and July 2013, we randomized 5551 pregnant women. At follow-up, among 4102 available women, we enrolled 6694 children into the protozoan assessment. We analyzed stool from 5933 children (aged ~31 months) for protozoan infections. Compared with 35.5% prevalence among controls, Giardia infection prevalence was lower in the sanitation (26.5%; prevalence ratio [PR], 0.75 [95% confidence interval {CI},.64–.88]), handwashing (28.2%; PR, 0.80 [95% CI,.66–.96]), WSH (29.7%; PR, 0.83 [95% CI,.72–.96]), and N+WSH (26.7%; PR, 0.75 [95% CI,.64–.88]) arms. Water and nutrition interventions had no effect. Low prevalence of E. histolytica and Cryptosporidium (<2%) resulted in imprecise effect estimates. Conclusions Individual handwashing and hygienic sanitation interventions significantly reduced childhood Giardia infections, and there were no effects of chlorinated drinking water and nutrition improvements in this context. Combined WSH interventions provided no additional benefit. To reduce Giardia infection, individual WSH interventions may be more feasible and cost-effective than combined interventions in similar rural, low-income settings. Clinical Trials Registration NCT01590095. [ABSTRACT FROM AUTHOR]

Water, sanitation, and handwashing interventions may confer spillover effects on intervention recipients’ neighbors by interrupting pathogen transmission. We measured geographically local spillovers in the Water Quality, Sanitation, and Handwashing (WASH) Benefits Study, a cluster-randomized trial in rural Bangladesh, by comparing outcomes among neighbors of intervention versus those of control participants. Geographically defined clusters were randomly allocated to a compound-level intervention (i.e., chlorinated drinking water, upgraded sanitation, and handwashing promotion) or control arm. From January 2015 to August 2015, in 180 clusters, we enrolled 1,799 neighboring children who were age matched to trial participants who would have been eligible for the study had they been conceived slightly earlier or later. After 28 months of intervention, we quantified fecal indicator bacteria in toy rinse and drinking water samples and measured soil-transmitted helminth infections and caregiver-reported diarrhea and respiratory illness. Neighbors’ characteristics were balanced across arms. Detectable Escherichia coli prevalence in tubewell samples was lower for intervention participants’ neighbors than control participants’ (prevalence ratio = 0.83; 95% confidence interval: 0.73, 0.95). Fecal indicator bacteria prevalence did not differ between arms for other environmental samples. Prevalence was similar in neighbors of intervention participants versus those of control participants for soil-transmitted helminth infection, diarrhea, and respiratory illness. A compound-level water, sanitation, and handwashing intervention reduced neighbors’ tubewell water contamination but did not affect neighboring children’s health. [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]

Background: Breast milk vitamin B-12 concentration may be inadequate in regions in which animal-source food consumption is low or infrequent. Vitamin B-12 deficiency causes megaloblastic anemia and impairs growth and development in children.Objective: We measured vitamin B-12 in breast milk and examined its associations with household hunger, recent animal-source food consumption, and vitamin B-12 intake.Methods: In a cross-sectional substudy nested within a cluster-randomized trial assessing water, sanitation, hygiene, and nutrition interventions in Kenya, we sampled 286 women 1-6 mo postpartum. Mothers hand-expressed breast milk 1 min into a feeding after 90 min observed nonbreastfeeding. The Household Hunger Scale was used to measure hunger, food intake in the previous week was measured with the use of a food-frequency questionnaire (FFQ), and vitamin B-12 intake was estimated by using 24-h dietary recall. An animal-source food score was based on 10 items from the FFQ (range: 0-70). Breast milk vitamin B-12 concentration was measured with the use of a solid-phase competitive chemiluminescent enzyme immunoassay and was modeled with linear regression. Generalized estimating equations were used to account for correlated observations at the cluster level.Results: Median (IQR) vitamin B-12 intake was 1.5 μg/d (0.3, 9.7 μg/d), and 60% of women consumed <2.4 μg/d, the estimated average requirement during lactation. Median (IQR) breast milk vitamin B-12 concentration was 113 pmol/L (61, 199 pmol/L); 89% had concentrations <310 pmol/L, the estimated adequate concentration. Moderate or severe hunger prevalence was 27%; the animal-source food score ranged from 0 to 30 item-d/wk. Hunger and recent animal-source food and vitamin B-12 intake were not associated with breast milk vitamin B-12 concentrations. Maternal age was negatively associated with breast milk vitamin B-12 concentrations.Conclusion: Most lactating Kenyan women consumed less than the estimated average requirement of vitamin B-12 and had low breast milk vitamin B-12 concentrations. We recommend interventions that improve vitamin B-12 intake in lactating Kenyan women to foster maternal health and child development. The main trial was registered at clinicaltrials.gov as NCT01704105. [ABSTRACT FROM AUTHOR]

Background: Shallow tubewells are the primary drinking water source for most rural Bangladeshis. Fecal contamination has been detected in tubewells, at low concentrations at the source and at higher levels at the point of use. We conducted a randomized controlled trial to assess whether improving the microbiological quality of tubewell drinking water by household water treatment and safe storage would reduce diarrhea in children <2 years in rural Bangladesh. Methods: We randomly assigned 1800 households with a child aged 6-18 months (index child) into one of three arms: chlorine plus safe storage, safe storage and control. We followed households with monthly visits for one year to promote the interventions, track their uptake, test participants’ source and stored water for fecal contamination, and record caregiver-reported child diarrhea prevalence (primary outcome). To assess reporting bias, we also collected data on health outcomes that are not expected to be impacted by our interventions. Findings: Both interventions had high uptake. Safe storage, alone or combined with chlorination, reduced heavy contamination of stored water. Compared to controls, diarrhea in index children was reduced by 36% in the chlorine plus safe storage arm (prevalence ratio, PR = 0.64, 0.55-0.73) and 31% in the safe storage arm (PR = 0.69, 0.60-0.80), with no difference between the two intervention arms. One limitation of the study was the non-blinded design with self-reported outcomes. However, the prevalence of health outcomes not expected to be impacted by water interventions did not differ between study arms, suggesting minimal reporting bias. Conclusions: Safe storage significantly improved drinking water quality at the point of use and reduced child diarrhea in rural Bangladesh. There was no added benefit from combining safe storage with chlorination. Efforts should be undertaken to implement and evaluate long-term efforts for safe water storage in Bangladesh. Trial Registration: ClinicalTrials.gov [ABSTRACT FROM AUTHOR]

: Sumeet Patil and colleagues conduct a cluster randomized controlled trial to measure the effect of India's Total Sanitation Campaign in Madhya Pradesh on the availability of individual household latrines, defecation behaviors, and child health. Please see later in the article for the Editors' Summary [ABSTRACT FROM AUTHOR]

The authors present their thoughts on how negative control outcomes can be used to identify bias in randomized trials and epidemiological studies. They discuss how negative control outcomes compare to exposures in a randomized trial, noting that negative control outcomes are not controlled by investigators. Other topic covered include confounding, selection bias, and measurement bias.

Poor infant and young child feeding (IYCF) practices are associated with linear growth faltering. Our objective was to evaluate the impact of a nutrition and water and sanitation for health intervention on three IYCF indicators—minimum dietary diversity (MDD), minimum meal frequency (MMF), and minimum acceptable diet (MAD) in Kenyan children. Households were randomized into one of eight groups: (a) active control; (b) passive control; (c) water quality (W); (d) sanitation (S); (e) handwashing (H); (f) combined Water, Sanitation, and Handwashing; (g) nutrition (N); and (h) combined WSH + N. In the N and WSH + N arms, community‐based promoters counselled households on optimal IYCF practices, and small‐quantity lipid‐based nutrient supplements (SQ‐LNS) were provided to children 6–24 months of age. Twelve months (Year 1) and 24 months (Year 2) after interventions began, enumerators surveyed mothers to ascertain IYCF practices. We made pairwise comparisons of each intervention arm versus the active control arm using log binomial models. In total, 3,652 caretakers were surveyed at Year 1 and 4,987 caretakers at Year 2. Compared with the active control, there were no differences in any of the arms in MDD, MMF, or MAD, aside from an increase in MDD at Year 1 in the nutrition only arm but not in the combined WSH + N arm (N: 68%; WSH + N: 61%; C: 61%; N arm prevalence ratio: 1.13 95% CI [1.01, 1.25]). In this setting, a nutrition behaviour change communication intervention had little impact on IYCF indicators. The provision of SQ‐LNS was not detrimental to current IYCF indicators in the community. [ABSTRACT FROM AUTHOR]

Objective To determine whether a water, sanitation and hygiene intervention could change hygiene behaviours thought to be important for trachoma control. Methods We conducted a cluster-randomized trial in rural Ethiopia from 9 November 2015 to 5 March 2019. We randomized 20 clusters to an intervention consisting of water and sanitation infrastructure and hygiene promotion and 20 clusters to no intervention. All intervention clusters received a primary-school hygiene curriculum, community water point, household wash station, household soap and home visits from hygiene promotion workers. We assessed intervention fidelity through annual household surveys. Findings Over the 3 years, more wash stations, soap and latrines were seen at households in the intervention clusters than the control clusters: risk difference 47 percentage points (95% confidence interval, CI: 41--53) for wash stations, 18 percentage points (95% CI: 12--24) for soap and 12 percentage points (95% CI: 5--19) for latrines. A greater proportion of people in intervention clusters reported washing their faces with soap (e.g. risk difference 21 percentage points; 95% CI: 15--27 for 0--5 year-old children) and using a latrine (e.g. risk difference 9 percentage points; 95% CI: 2--15 for 6--9 year-old children). Differences between the intervention and control arms were not statistically significant for many indicators until the programme had been implemented for at least a year; they did not decline during later study visits. Conclusion The community- and school-based intervention was associated with improved hygiene access and behaviours, although changes in behaviour were slow and required several years of the intervention. [ABSTRACT FROM AUTHOR]