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The Ganges-Brahmaputra-Meghna river basin, running through Tibet, Nepal, Bhutan, Bangladesh, and northern India, is home to more than 618 million people. Annual monsoons bring extensive flooding to the basin, with floods predicted to be more frequent and extreme due to climate change. Yet, evidence regarding the long-term impacts of floods on children's health is lacking. In this analysis, we used high-resolution maps of recent large floods in Bangladesh to identify flood-prone areas over the country. We then used propensity score techniques to identify, among 58,945 mothers interviewed in six demographic population-based surveys throughout Bangladesh, matched cohorts of exposed and unexposed mothers and leverage data on 150,081 births to estimate that living in flood-prone areas was associated with an excess risk in infant mortality of 5.3 (95% CI 2.2 to 8.4) additional deaths per 1,000 births compared to living in non-flood-prone areas over the 30-y period between 1988 and 2017, with higher risk for children born during rainy (7.9, 95% CI: 3.3 to 12.5) vs. dry months (3.1, 95% CI: -1.1 to 7.2). Finally, drawing on national-scale, high-resolution estimates of flood risk and population distribution, we estimated an excess of 152,753 (64,120 to 241,386) infant deaths were attributable to living in flood-prone areas in Bangladesh over the past 30 y, with marked heterogeneity in attributable burden by subdistrict. Our approach demonstrates the importance of measuring longer-term health impacts from floods and provides a generalizable example for how to study climate-related exposures and long-term health effects. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

• We used a matched cohort design to study the differential impacts of SLIV by race and ethnicity. • Racial disparities in vaccine coverage and hospitalizations persisted in the presence of SLIV. • Vaccine hesitance remained a common reason for non-vaccination in school-aged children. 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. 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. 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. 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. [ABSTRACT FROM AUTHOR]

We measured the effectiveness of a city-wide school-located influenza vaccination (SLIV) program implemented in over 102 elementary schools in Oakland, California. 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. 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. 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. [ABSTRACT FROM AUTHOR]

Purpose: To compare the accuracy of Barrett Universal II formula with other formulas (Holladay 2, Hoffer Q, and SRK/T formulas) in the prediction of postoperative refraction for pediatric intraocular lens implantation. Setting: Academic medical center/children's hospital, San Francisco, California. Design: Retrospective case series. Methods: Children aged 16 years or younger who underwent cataract extraction and IOL implantation (2012 to 2019) and had refraction assessed at 3 to 16 weeks postoperatively were included. Prediction error (PE) was calculated as postoperative mean spherical equivalent minus the target refraction. Mean, median, and standard deviation was calculated for PE and absolute PE. Performance across covariables (axial length, age, biometry type, keratometry, etc.) was studied, and a multivariate regression analysis was performed using a single prediction model for each formula. Results: Sixty-four eyes of 64 patients, aged 1.5 to 15.5 years, were included. Barrett Universal II formula had the lowest mean PE (-0.22 diopters [D]), SD (1.18 D), median PE (-0.26 D), and median absolute PE (0.71) compared with those of the other formulas. Holladay 2 formula performed similarly to Barrett Universal II formula, and SRK/T formula had the greatest mean PE (-0.50 D) and SD (1.22 D). Barrett Universal II formula predictions were stable across all variables. Conclusions: Barrett Universal II formula demonstrated similar or superior performance when compared with other formulas in this pediatric study. Holladay 2 formula performed similarly to Barrett Universal II formula, and SRK/T formula had the least reliable performance, across several key biometric characteristics. Although PEs can be highly variable in pediatric populations, this study supports Barrett Universal II formula as a reasonable and reliable option for lens power calculation in children, including those with extreme biometric measurements. [ABSTRACT FROM AUTHOR]

Schistosomiasis is among the most common parasitic diseases in the world, with over 142 million people infected in low- and middle-income countries. Measuring population-level transmission is centrally important in guiding schistosomiasis control programs. Traditionally, human Schistosoma mansoni infections have been detected using stool microscopy, which is logistically difficult at program scale and has low sensitivity when people have low infection burdens. We compared serological measures of transmission based on antibody response to S. mansoni soluble egg antigen (SEA) with stool-based measures of infection among 3,663 preschool-age children in an area endemic for S. mansoni in western Kenya. We estimated force of infection among children using the seroconversion rate and examined how it varied geographically and by age. At the community level, serological measures of transmission aligned with stool-based measures of infection (ρ = 0.94), and serologicalmeasures provided more resolution for between-community differences at lower levels of infection. Force of infection showed a clear gradient of transmission with distance from Lake Victoria, with 94% of infections and 93% of seropositive children in communities <1.5 km from the lake. Force of infection increased through age 3 y, by which time 65% (95% CI: 53%, 75%) of children were SEA positive in hightransmission communities'2 y before they would be reached by school-based deworming programs. Our results show that serologic surveillance platforms represent an important opportunity to guide and monitor schistosomiasis control programs, and that in hightransmission settings preschool-age children represent a key population missed by school-based deworming programs. [ABSTRACT FROM AUTHOR]

Background: It is estimated that vaccinating 50%-70% of school-aged children for influenza can produce population-wide indirect effects. We evaluated a city-wide school-located influenza vaccination (SLIV) intervention that aimed to increase influenza vaccination coverage. The intervention was implemented in ≥95 preschools and elementary schools in northern California from 2014 to 2018. Using a matched cohort design, we estimated intervention impacts on student influenza vaccination coverage, school absenteeism, and community-wide indirect effects on laboratory-confirmed influenza hospitalizations.Methods and Findings: We used a multivariate matching algorithm to identify a nearby comparison school district with pre-intervention characteristics similar to those of the intervention school district and matched schools in each district. To measure student influenza vaccination, we conducted cross-sectional surveys of student caregivers in 22 school pairs (2017 survey, N = 6,070; 2018 survey, N = 6,507). We estimated the incidence of laboratory-confirmed influenza hospitalization from 2011 to 2018 using surveillance data from school district zip codes. We analyzed student absenteeism data from 2011 to 2018 from each district (N = 42,487,816 student-days). To account for pre-intervention differences between districts, we estimated difference-in-differences (DID) in influenza hospitalization incidence and absenteeism rates using generalized linear and log-linear models with a population offset for incidence outcomes. Prior to the SLIV intervention, the median household income was $51,849 in the intervention site and $61,596 in the comparison site. The population in each site was predominately white (41% in the intervention site, 48% in the comparison site) and/or of Hispanic or Latino ethnicity (26% in the intervention site, 33% in the comparison site). The number of students vaccinated by the SLIV intervention ranged from 7,502 to 10,106 (22%-28% of eligible students) each year. During the intervention, influenza vaccination coverage among elementary students was 53%-66% in the comparison district. Coverage was similar between the intervention and comparison districts in influenza seasons 2014-2015 and 2015-2016 and was significantly higher in the intervention site in seasons 2016-2017 (7%; 95% CI 4, 11; p < 0.001) and 2017-2018 (11%; 95% CI 7, 15; p < 0.001). During seasons when vaccination coverage was higher among intervention schools and the vaccine was moderately effective, there was evidence of statistically significant indirect effects: The DID in the incidence of influenza hospitalization per 100,000 in the intervention versus comparison site was -17 (95% CI -30, -4; p = 0.008) in 2016-2017 and -37 (95% CI -54, -19; p < 0.001) in 2017-2018 among non-elementary-school-aged individuals and -73 (95% CI -147, 1; p = 0.054) in 2016-2017 and -160 (95% CI -267, -53; p = 0.004) in 2017-2018 among adults 65 years or older. The DID in illness-related school absences per 100 school days during the influenza season was -0.63 (95% CI -1.14, -0.13; p = 0.014) in 2016-2017 and -0.80 (95% CI -1.28, -0.31; p = 0.001) in 2017-2018. Limitations of this study include the use of an observational design, which may be subject to unmeasured confounding, and caregiver-reported vaccination status, which is subject to poor recall and low response rates.Conclusions: A city-wide SLIV intervention in a large, diverse urban population was associated with a decrease in the incidence of laboratory-confirmed influenza hospitalization in all age groups and a decrease in illness-specific school absence rate among students in 2016-2017 and 2017-2018, seasons when the vaccine was moderately effective, suggesting that the intervention produced indirect effects. Our findings suggest that in populations with moderately high background levels of influenza vaccination coverage, SLIV programs are associated with further increases in coverage and reduced influenza across the community. [ABSTRACT FROM AUTHOR]

Antibodies are unique among biomarkers in their ability to identify persons with protective immunity to vaccine-preventable diseases and to measure past exposure to diverse pathogens. Most infectious disease surveillance maintains a single-disease focus, but broader testing of existing serologic surveys with multiplex antibody assays would create new opportunities for integrated surveillance. In this perspective, we highlight multiple areas for potential synergy where integrated surveillance could add more value to public health efforts than the current trend of independent disease monitoring through vertical programs. We describe innovations in laboratory and data science that should accelerate integration and identify remaining challenges with respect to specimen collection, testing, and analysis. Throughout, we illustrate how information generated through integrated surveillance platforms can create new opportunities to more quickly and precisely identify global health program gaps that range from undervaccination to emerging pathogens to multilayered health disparities that span diverse communicable diseases. [ABSTRACT FROM AUTHOR]

Many public health interventions provide benefits that extend beyond their direct recipients and impact people in close physical or social proximity who did not directly receive the intervention themselves. A classic example of this phenomenon is the herd protection provided by many vaccines. If these 'spillover effects' (i.e. 'herd effects') are present in the same direction as the effects on the intended recipients, studies that only estimate direct effects on recipients will likely underestimate the full public health benefits of the intervention. Causal inference assumptions for spillover parameters have been articulated in the vaccine literature, but many studies measuring spillovers of other types of public health interventions have not drawn upon that literature. In conjunction with a systematic review we conducted of spillovers of public health interventions delivered in low- and middle-income countries, we classified the most widely used spillover parameters reported in the empirical literature into a standard notation. General classes of spillover parameters include: cluster-level spillovers; spillovers conditional on treatment or outcome density, distance or the number of treated social network links; and vaccine efficacy parameters related to spillovers. We draw on high quality empirical examples to illustrate each of these parameters. We describe study designs to estimate spillovers and assumptions required to make causal inferences about spillovers. We aim to advance and encourage methods for spillover estimation and reporting by standardizing spillover parameter nomenclature and articulating the causal inference assumptions required to estimate spillovers. [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]

Rainstorms increase levels of fecal indicator bacteria in urban coastal waters, but it is unknown whether exposure to seawater after rainstorms increases rates of acute illness. Our objective was to provide the first estimates of rates of acute illness after seawater exposure during both dry- and wet-weather periods and to determine the relationship between levels of indicator bacteria and illness among surfers, a population with a high potential for exposure after rain. We enrolled 654 surfers in San Diego, California, and followed them longitudinally during the 2013--2014 and 2014--2015 winters (33,377 days of observation, 10,081 surf sessions). We measured daily surf activities and illness symptoms (gastrointestinal illness, sinus infections, ear infections, infected wounds). Compared with no exposure, exposure to seawater during dry weather increased incidence rates of all outcomes (e.g., for earache or infection, adjusted incidence rate ratio (IRR) = 1.86, 95% confidence interval (CI): 1.27, 2.71; for infected wounds, IRR = 3.04, 95% CI: 1.54, 5.98); exposure during wet weather further increased rates (e.g., for earache or infection, IRR = 3.28, 95% CI: 1.95, 5.51; for infected wounds, IRR = 4.96, 95% CI: 2.18, 11.29). Fecal indicator bacteria measured in seawater (Enterococcus species, fecal coliforms, total coliforms) were strongly associated with incident illness only during wet weather. Urban coastal seawater exposure increases the incidence rates of many acute illnesses among surfers, with higher incidence rates after rainstorms. [ABSTRACT FROM AUTHOR]

Background: Serological antibody levels are a sensitive marker of pathogen exposure, and advances in multiplex assays have created enormous potential for large-scale, integrated infectious disease surveillance. Most methods to analyze antibody measurements reduce quantitative antibody levels to seropositive and seronegative groups, but this can be difficult for many pathogens and may provide lower resolution information than quantitative levels. Analysis methods have predominantly maintained a single disease focus, yet integrated surveillance platforms would benefit from methodologies that work across diverse pathogens included in multiplex assays. Methods/Principal findings: We developed an approach to measure changes in transmission from quantitative antibody levels that can be applied to diverse pathogens of global importance. We compared age-dependent immunoglobulin G curves in repeated cross-sectional surveys between populations with differences in transmission for multiple pathogens, including: lymphatic filariasis (Wuchereria bancrofti) measured before and after mass drug administration on Mauke, Cook Islands, malaria (Plasmodium falciparum) before and after a combined insecticide and mass drug administration intervention in the Garki project, Nigeria, and enteric protozoans (Cryptosporidium parvum, Giardia intestinalis, Entamoeba histolytica), bacteria (enterotoxigenic Escherichia coli, Salmonella spp.), and viruses (norovirus groups I and II) in children living in Haiti and the USA. Age-dependent antibody curves fit with ensemble machine learning followed a characteristic shape across pathogens that aligned with predictions from basic mechanisms of humoral immunity. Differences in pathogen transmission led to shifts in fitted antibody curves that were remarkably consistent across pathogens, assays, and populations. Mean antibody levels correlated strongly with traditional measures of transmission intensity, such as the entomological inoculation rate for P. falciparum (Spearman’s rho = 0.75). In both high- and low transmission settings, mean antibody curves revealed changes in population mean antibody levels that were masked by seroprevalence measures because changes took place above or below the seropositivity cutoff. Conclusions/Significance: Age-dependent antibody curves and summary means provided a robust and sensitive measure of changes in transmission, with greatest sensitivity among young children. The method generalizes to pathogens that can be measured in high-throughput, multiplex serological assays, and scales to surveillance activities that require high spatiotemporal resolution. Our results suggest quantitative antibody levels will be particularly useful to measure differences in exposure for pathogens that elicit a transient antibody response or for monitoring populations with very high- or very low transmission, when seroprevalence is less informative. The approach represents a new opportunity to conduct integrated serological surveillance for neglected tropical diseases, malaria, and other infectious diseases with well-defined antigen targets. [ABSTRACT FROM AUTHOR]

BACKGROUND: The recent global climate agreement in Paris aims to mitigate greenhouse gas emissions while fostering sustainable development and establishes an international trading mechanism to meet this goal. Currently, carbon offset program implementers are allowed to collect their own monitoring data to determine the number of carbon credits to be awarded. OBJECTIVES: We summarize reasons for mandating independent monitoring of greenhouse gas emission reduction projects. In support of our policy recommendations, we describe a case study of a program designed to earn carbon credits by distributing almost one million drinking water filters in rural Kenya to avert the use of fuel for boiling water. We compare results from an assessment conducted by our research team in the program area among households with pregnant women or caregivers in rural villages with low piped water access with the reported program monitoring data and discuss the implications. DISCUSSION: Our assessment in Kenya found lower levels of household water filter usage than the internal program monitoring reported estimates used to determine carbon credits; we found 19% (n = 4,041) of households reported filter usage 2 -- 3 years after filter distribution compared to the program stated usage rate of 81% (n = 14,988) 2.7 years after filter distribution. Although carbon financing could be a financially sustainable approach to scale up water treatment and improve health in low-income settings, these results suggest program effectiveness will remain uncertain in the absence of requiring monitoring data be collected by third-party organizations. CONCLUSION: Independent monitoring should be a key requirement for carbon credit verification in future international carbon trading mechanisms to ensure programs achieve benefits in line with sustainable development goals. CITATION: Pickering AJ, Arnold BF, Dentz HN, Colford JM Jr., Null C. 2017. Climate and health co-benefits in low-income countries: a case study of carbon financed water filters in Kenya and a call for independent monitoring. Environ Health Perspect 125:278 -- 283; http://dx.doi. org/10.1289/EHP342 [ABSTRACT FROM AUTHOR]

Objectives: Escherichia coli is the standard water quality indicator for diarrhoea risk. Yet, the association between E. coli and diarrhoea is inconsistent across studies without a systematic assessment of methodological differences behind this variation. Most studies measure water quality cross-sectionally with diarrhoea, risking exposure misclassification and reverse causation. Studies use different recall windows for self-reported diarrhoea; longer periods increase potential outcome misclassification through misrecall. Control of confounding is inconsistent across studies. Additionally, diarrhoea measured in unblinded intervention trials can present courtesy bias. We utilised measurements from a randomised trial of water interventions in Bangladesh to assess how these factors affect the E. coli-diarrhoea association.Methods: We compared cross-sectional versus prospective measurements of water quality and diarrhoea, 2-versus 7-day symptom recall periods, estimates with and without controlling for confounding and using measurements from control versus intervention arms of the trial.Results: In the control arm, 2-day diarrhoea prevalence, measured prospectively 1 month after water quality, significantly increased with log10 E. coli (PR = 1.50, 1.02-2.20). This association weakened when we used 7-day recall (PR = 1.18, 0.88-1.57), cross-sectional measurements of E. coli and diarrhoea (PR = 1.11, 0.79-1.56) or did not control for confounding (PR = 1.20, 0.88-1.62). Including data from intervention arms led to less interpretable associations, potentially due to courtesy bias, effect modification and/or reverse causation.Conclusions: By systematically addressing potential sources of bias, our analysis demonstrates a clear relationship between E. coli in drinking water and diarrhoea, suggesting that the continued use of E. coli as an indicator of waterborne diarrhoea risk is justified. [ABSTRACT FROM AUTHOR]

Objectives. To provide summary estimates of gastroenteritis risks and illness burden associated with recreational water exposure and determine whether children have higher risks and burden. Methods. We combined individual participant data from 13 prospective cohorts at marine and freshwater beaches throughout the United States (n = 84 411). We measured incident outcomes within 10 days of exposure: diarrhea, gastrointestinal illness, missed daily activity (work, school, vacation), and medical visits. We estimated the relationship between outcomes and 2 exposures: body immersion swimming and Enterococcus spp. fecal indicator bacteria levels in the water. We also estimated the population-attributable risk associated with these exposures. Results. Water exposure accounted for 21% of diarrhea episodes and 9% of missed daily activities but was unassociated with gastroenteritis leading to medical consultation. Children aged 0 to 4 and 5 to 10 years had the most water exposure, exhibited stronger associations between levels of water quality and illness, and accounted for the largest attributable illness burden. Conclusions. The higher gastroenteritis risk and associated burden in young children presents important new information to inform future recreational water quality guidelines designed to protect public health. [ABSTRACT FROM AUTHOR]

Background: Intermittent delivery of piped water can lead to waterborne illness through contamination in the pipelines or during household storage, use of unsafe water sources during intermittencies, and limited water availability for hygiene. We assessed the association between continuous versus intermittent water supply and waterborne diseases, child mortality, and weight for age in Hubli-Dharwad, India.Methods and Findings: We conducted a matched cohort study with multivariate matching to identify intermittent and continuous supply areas with comparable characteristics in Hubli-Dharwad. We followed 3,922 households in 16 neighborhoods with children <5 y old, with four longitudinal visits over 15 mo (Nov 2010-Feb 2012) to record caregiver-reported health outcomes (diarrhea, highly credible gastrointestinal illness, bloody diarrhea, typhoid fever, cholera, hepatitis, and deaths of children <2 y old) and, at the final visit, to measure weight for age for children <5 y old. We also collected caregiver-reported data on negative control outcomes (cough/cold and scrapes/bruises) to assess potential bias from residual confounding or differential measurement error. Continuous supply had no significant overall association with diarrhea (prevalence ratio [PR] = 0.93, 95% confidence interval [CI]: 0.83-1.04, p = 0.19), bloody diarrhea (PR = 0.78, 95% CI: 0.60-1.01, p = 0.06), or weight-for-age z-scores (Δz = 0.01, 95% CI: -0.07-0.09, p = 0.79) in children <5 y old. In prespecified subgroup analyses by socioeconomic status, children <5 y old in lower-income continuous supply households had 37% lower prevalence of bloody diarrhea (PR = 0.63, 95% CI: 0.46-0.87, p-value for interaction = 0.03) than lower-income intermittent supply households; in higher-income households, there was no significant association between continuous versus intermittent supply and child diarrheal illnesses. Continuous supply areas also had 42% fewer households with ≥1 reported case of typhoid fever (cumulative incidence ratio [CIR] = 0.58, 95% CI: 0.41-0.78, p = 0.001) than intermittent supply areas. There was no significant association with hepatitis, cholera, or mortality of children <2 y old; however, our results were indicative of lower mortality of children <2 y old (CIR = 0.51, 95% CI: 0.22-1.07, p = 0.10) in continuous supply areas. The major limitations of our study were the potential for unmeasured confounding given the observational design and measurement bias from differential reporting of health symptoms given the nonblinded treatment. However, there was no significant difference in the prevalence of the negative control outcomes between study groups that would suggest undetected confounding or measurement bias.Conclusions: Continuous water supply had no significant overall association with diarrheal disease or ponderal growth in children <5 y old in Hubli-Dharwad; this might be due to point-of-use water contamination from continuing household storage and exposure to diarrheagenic pathogens through nonwaterborne routes. Continuous supply was associated with lower prevalence of dysentery in children in low-income households and lower typhoid fever incidence, suggesting that intermittently operated piped water systems are a significant transmission mechanism for Salmonella typhi and dysentery-causing pathogens in this urban population, despite centralized water treatment. Continuous supply was associated with reduced transmission, especially in the poorer higher-risk segments of the population. [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]

Complier average causal effects (CACE) estimate the impact of an intervention among treatment compliers in randomized trials. Methods used to estimate CACE have been outlined for parallel-arm trials (e.g., using an instrumental variables (IV) estimator) but not for other randomized study designs. Here, we propose a method for estimating CACE in randomized stepped wedge trials, where experimental units cross over from control conditions to intervention conditions in a randomized sequence. We illustrate the approach with a cluster-randomized drinking water trial conducted in rural Mexico from 2009 to 2011. Additionally, we evaluated the plausibility of assumptions required to estimate CACE using the IV approach, which are testable in stepped wedge trials but not in parallel-arm trials. We observed small increases in the magnitude of CACE risk differences compared with intention-to-treat estimates for drinking water contamination (risk difference (RD) = −22% (95% confidence interval (CI): −33, −11) vs. RD = −19% (95% CI: −26, −12)) and diarrhea (RD = −0.8% (95% CI: −2.1, 0.4) vs. RD = −0.1% (95% CI: −1.1, 0.9)). Assumptions required for IV analysis were probably violated. Stepped wedge trials allow investigators to estimate CACE with an approach that avoids the stronger assumptions required for CACE estimation in parallel-arm trials. Inclusion of CACE estimates in stepped wedge trials with imperfect compliance could enhance reporting and interpretation of the results of such trials. [ABSTRACT FROM PUBLISHER]

Background: Efforts to monitor malaria transmission increasingly use cross-sectional surveys to estimate transmission intensity from seroprevalence data using malarial antibodies. To date, seroconversion rates estimated from cross-sectional surveys have not been compared to rates estimated in prospective cohorts. Our objective was to compare seroconversion rates estimated in a prospective cohort with those from a cross-sectional survey in a low-transmission population. Methods and Findings: The analysis included two studies from Haiti: a prospective cohort of 142 children ages ≤11 years followed for up to 9 years, and a concurrent cross-sectional survey of 383 individuals ages 0–90 years old. From all individuals, we analyzed 1,154 blood spot specimens for the malaria antibody MSP-119 using a multiplex bead antigen assay. We classified individuals as positive for malaria using a cutoff derived from the mean plus 3 standard deviations in antibody responses from a negative control set of unexposed individuals. We estimated prospective seroconversion rates from the longitudinal cohort based on 13 incident seroconversions among 646 person-years at risk. We also estimated seroconversion rates from the cross-sectional survey using a reversible catalytic model fit with maximum likelihood. We found the two approaches provided consistent results: the seroconversion rate for ages ≤11 years was 0.020 (0.010, 0.032) estimated prospectively versus 0.023 (0.001, 0.052) in the cross-sectional survey. Conclusions: The estimation of seroconversion rates using cross-sectional data is a widespread and generalizable problem for many infectious diseases that can be measured using antibody titers. The consistency between these two estimates lends credibility to model-based estimates of malaria seroconversion rates using cross-sectional surveys. This study also demonstrates the utility of including malaria antibody measures in multiplex assays alongside targets for vaccine coverage and other neglected tropical diseases, which together could comprise an integrated, large-scale serological surveillance platform. [ABSTRACT FROM AUTHOR]

Many community-based studies of acute child illness rely on cases reported by caregivers. In prior investigations, researchers noted a reporting bias when longer illness recall periods were used. The use of recall periods longer than 2–3 days has been discouraged to minimize this reporting bias. In the present study, we sought to determine the optimal recall period for illness measurement when accounting for both bias and variance. Using data from 12,191 children less than 24 months of age collected in 2008–2009 from Himachal Pradesh in India, Madhya Pradesh in India, Indonesia, Peru, and Senegal, we calculated bias, variance, and mean squared error for estimates of the prevalence ratio between groups defined by anemia, stunting, and underweight status to identify optimal recall periods for caregiver-reported diarrhea, cough, and fever. There was little bias in the prevalence ratio when a 7-day recall period was used (<10% in 35 of 45 scenarios), and the mean squared error was usually minimized with recall periods of 6 or more days. Shortening the recall period from 7 days to 2 days required sample-size increases of 52%–92% for diarrhea, 47%–61% for cough, and 102%–206% for fever. In contrast to the current practice of using 2-day recall periods, this work suggests that studies should measure caregiver-reported illness with a 7-day recall period. [ABSTRACT FROM PUBLISHER]

Background Diarrhoea remains a leading cause of morbidity and mortality but is difficult to measure in epidemiological studies. Challenges include the diagnosis based on self-reported symptoms, the logistical burden of intensive surveillance and the variability of diarrhoea in space, time and person.Methods We review current practices in sampling procedures to measure diarrhoea, and provide guidance for diarrhoea measurement across a range of study goals. Using 14 available data sets, we estimated typical design effects for clustering at household and village/neighbourhood level, and measured the impact of adjusting for baseline variables on the precision of intervention effect estimates.Results Incidence is the preferred outcome measure in aetiological studies, health services research and vaccine trials. Repeated prevalence measurements (longitudinal prevalence) are appropriate in high-mortality settings where malnutrition is common, although many repeat measures are rarely useful. Period prevalence is an inadequate outcome if an intervention affects illness duration. Adjusting point estimates for age or diarrhoea at baseline in randomized trials has little effect on the precision of estimates. Design effects in trials randomized at household level are usually <2 (range 1.0–3.2). Design effects for larger clusters (e.g. villages or neighbourhoods) vary greatly among different settings and study designs (range 0.1–25.8).Conclusions Using appropriate sampling strategies and outcome measures can improve the efficiency, validity and comparability of diarrhoea studies. Allocating large clusters in cluster randomized trials is compromized by unpredictable design effects and should be carried out only if the research question requires it. [ABSTRACT FROM PUBLISHER]

Background: Estimating the required sample size and statistical power for a study is an integral part of study design. For standard designs, power equations provide an efficient solution to the problem, but they are unavailable for many complex study designs that arise in practice. For such complex study designs, computer simulation is a useful alternative for estimating study power. Although this approach is well known among statisticians, in our experience many epidemiologists and social scientists are unfamiliar with the technique. This article aims to address this knowledge gap. Methods: We review an approach to estimate study power for individual- or cluster-randomized designs using computer simulation. This flexible approach arises naturally from the model used to derive conventional power equations, but extends those methods to accommodate arbitrarily complex designs. The method is universally applicable to a broad range of designs and outcomes, and we present the material in a way that is approachable for quantitative, applied researchers. We illustrate the method using two examples (one simple, one complex) based on sanitation and nutritional interventions to improve child growth. Results: We first show how simulation reproduces conventional power estimates for simple randomized designs over a broad range of sample scenarios to familiarize the reader with the approach. We then demonstrate how to extend the simulation approach to more complex designs. Finally, we discuss extensions to the examples in the article, and provide computer code to efficiently run the example simulations in both R and Stata. Conclusions: Simulation methods offer a flexible option to estimate statistical power for standard and nontraditional study designs and parameters of interest. The approach we have described is universally applicable for evaluating study designs used in epidemiologic and social science research. [ABSTRACT FROM AUTHOR]

Empirical measurement of interventions to address significant global health and development problems is necessary to ensure that resources are applied appropriately. Such intervention programs are often deployed at the group or community level. The gold standard design to measure the effectiveness of community-level interventions is the community-randomized trial, but the conditions of these trials often make it difficult to assess their external validity and sustainability. The sheer number of community interventions, relative to randomized studies, speaks to a need for rigorous observational methods to measure their impact. In this article, we use the potential outcomes model for causal inference to motivate a matched cohort design to study the impact and sustainability of nonrandomized, preexisting interventions. We illustrate the method using a sanitation mobilization, water supply, and hygiene intervention in rural India. In a matched sample of 25 villages, we enrolled 1,284 children <5 y old and measured outcomes over 12 mo. Although we found a 33 percentage point difference in new toilet construction [95% confidence interval (Cl) = 28%, 39%), we found no impacts on height-for-age Z scores (adjusted difference = 0.01. 95% Cl= -0.15,0.19) or diarrhea (adjusted longitudinal prevalence difference = 0.003, 95% Cl = -0.001, 0.008) among children <5 y old. This study demonstrates that matched cohort designs can estimate impacts from nonrandomized, preexistirig interventions that are used widely in development efforts. Interpreting the impacts as causal, however, requires stronger assumptions than prospective, randomized studies. [ABSTRACT FROM AUTHOR]

Author summary: The use of biomarkers to measure immune responses in serum is crucial for understanding population-level exposure and susceptibility to human pathogens. Advances in sample collection, multiplex testing, and computational modeling are transforming serosurveillance into a powerful tool for public health program design and response to infectious threats. In July 2018, 70 scientists from 16 countries met to perform a landscape analysis of approaches that support an integrated serosurveillance platform, including the consideration of issues for successful implementation. Here, we summarize the group's insights and proposed roadmap for implementation, including objectives, technical requirements, ethical issues, logistical considerations, and monitoring and evaluation. [ABSTRACT FROM AUTHOR]

Purpose: The purpose of this study was to assess the association between antifungal susceptibility as measured by minimum inhibitory concentration (MIC) and clinical outcomes in fungal keratitis. Methods: This pre-specified secondary analysis of the Mycotic Ulcer Treatment Trial II (MUTT II) involved patients with filamentous fungal keratitis presenting to Aravind Eye Hospitals in South India. Antifungal susceptibility testing for natamycin and voriconazole was performed on all samples with positive fungal culture results according to Clinical and Laboratory Standards Institute Guidelines. The relationship between MIC and clinical outcomes of best-corrected visual acuity, infiltrate or scar size, corneal perforation, need for therapeutic penetrating keratoplasty, and time to re-epithelialization were assessed. Results: We obtained MIC values from 141 patients with fungal keratitis. The most commonly cultured organisms were Aspergillus (46.81%, n = 66) and Fusarium (44.68%, n = 63) species. Overall, there was no association between antifungal MICs and clinical outcomes. Subgroup analysis revealed that among Fusarium-positive cases, higher voriconazole MIC was correlated with worse three-month best-corrected visual acuity (p = 0.03), increased need for therapeutic penetrating keratoplasty (p = 0.04), and time to re-epithelialization (p = 0.03). No significant correlations were found among Aspergillus-positive cases. There were no significant correlations found between natamycin MIC and clinical outcomes among organism subgroups. Conclusions: Decreased susceptibility to voriconazole was associated with increased odds of requiring a therapeutic penetrating keratoplasty in Fusarium-positive cases. Susceptibility to natamycin was not associated with any of the measured outcomes. [ABSTRACT FROM AUTHOR]

Monitoring trachoma transmission with antibody data requires characterization of decay in IgG to Chlamydia trachomatis antigens. In a 3-year longitudinal cohort in a high-transmission setting, we estimated a median IgG half-life of 3 years and a seroreversion rate of 2.5 per 100 person-years (95% confidence interval, 1.6–3.5). Clinical Trials Registration NCT02754583. [ABSTRACT FROM AUTHOR]

BACKGROUND: Diarrheal disease is a leading cause of childhood morbidity and mortality globally. Household water, sanitation, and handwashing (WASH) interventions can reduce exposure to diarrhea-causing pathogens, but meteorological factors may impact their effectiveness. Information about effect heterogeneity under different weather conditions is critical to refining these targeted interventions. OBJECTIVES: We aimed to determine whether temperature and precipitation modified the effect of low-cost, point-of-use WASH interventions on child diarrhea. METHODS: We analyzed data from a trial in rural Bangladesh that compared child diarrhea prevalence between clusters (푁 = 720) that were randomized to different WASH interventions between 2012 and 2016 (NCT01590095). We matched temperature and precipitation measurements to diarrhea outcomes (푁 = 12,440 measurements, 6,921 children) by geographic coordinates and date. We estimated prevalence ratios (PRs) using generative additive models and targeted maximum likelihood estimation to assess the effectiveness of each WASH intervention under different weather conditions. RESULTS: Generally, WASH interventions most effectively prevented diarrhea during monsoon season, particularly following weeks with heavy rain or high temperatures. The PR for diarrhea in the WASH interventions group compared with the control group was 0.49 (95% CI: 0.35, 0.68) after 1 d of heavy rainfall, with a less-protective effect [PR = 0:87 (95% CI: 0.60, 1.25)] when there were no days with heavy rainfall. Similarly, the PR for diarrhea in the WASH intervention group compared with the control group was 0.60 (95% CI: 0.48, 0.75) following above-median temperatures vs. 0.91 (95% CI: 0.61, 1.35) following below-median temperatures. The influence of precipitation and temperature varied by intervention type; for precipitation, the largest differences in effectiveness were for the sanitation and combined WASH interventions. DISCUSSION: WASH intervention effectiveness was strongly influenced by precipitation and temperature, and nearly all protective effects were observed during the rainy season. Future implementation of these interventions should consider local environmental conditions to maximize effectiveness, including targeted efforts to maintain latrines and promote community adoption ahead of monsoon seasons. [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]

A response from the authors of the article "Acute gastroenteritis and recreational water: Highest burden among young U.S. children" which was published in a previous article is presented.

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.

Background: Three large new trials of unprecedented scale and cost, which included novel factorial designs, have found no effect of basic water, sanitation and hygiene (WASH) interventions on childhood stunting, and only mixed effects on childhood diarrhea. Arriving at the inception of the United Nations' Sustainable Development Goals, and the bold new target of safely managed water, sanitation and hygiene for all by 2030, these results warrant the attention of researchers, policy-makers and practitioners.Main Body: Here we report the conclusions of an expert meeting convened by the World Health Organization and the Bill and Melinda Gates Foundation to discuss these findings, and present five key consensus messages as a basis for wider discussion and debate in the WASH and nutrition sectors. We judge these trials to have high internal validity, constituting good evidence that these specific interventions had no effect on childhood linear growth, and mixed effects on childhood diarrhea. These results suggest that, in settings such as these, more comprehensive or ambitious WASH interventions may be needed to achieve a major impact on child health.Conclusion: These results are important because such basic interventions are often deployed in low-income rural settings with the expectation of improving child health, although this is rarely the sole justification. Our view is that these three new trials do not show that WASH in general cannot influence child linear growth, but they do demonstrate that these specific interventions had no influence in settings where stunting remains an important public health challenge. We support a call for transformative WASH, in so much as it encapsulates the guiding principle that - in any context - a comprehensive package of WASH interventions is needed that is tailored to address the local exposure landscape and enteric disease burden. [ABSTRACT FROM AUTHOR]

Key Points: Question: Does twice-annual mass azithromycin distribution prevent all-cause childhood mortality among children in Burkina Faso aged 1 to 59 months in the setting of seasonal malaria chemoprevention distribution? Findings: In this randomized trial of twice-yearly mass azithromycin distribution, 498 deaths were recorded over 60 592 person-years (8.2 deaths/1000 person-years) in the azithromycin group compared with 588 deaths over 58 547 person-years (10.0 deaths/1000 person-years) in the placebo group. The difference was not statistically significant. Meaning: Communities with mass azithromycin distribution had lower child mortality than controls, although the difference was not statistically significant. The study may have been underpowered to detect a clinically relevant difference. Importance: Repeated mass distribution of azithromycin has been shown to reduce childhood mortality by 14% in sub-Saharan Africa. However, the estimated effect varied by location, suggesting that the intervention may not be effective in different geographical areas, time periods, or conditions. Objective: To evaluate the efficacy of twice-yearly azithromycin to reduce mortality in children in the presence of seasonal malaria chemoprevention. Design, Setting, and Participants: This cluster randomized placebo-controlled trial evaluating the efficacy of single-dose azithromycin for prevention of all-cause childhood mortality included 341 communities in the Nouna district in rural northwestern Burkina Faso. Participants were children aged 1 to 59 months living in the study communities. Interventions: Communities were randomized in a 1:1 ratio to receive oral azithromycin or placebo distribution. Children aged 1 to 59 months were offered single-dose treatment twice yearly for 3 years (6 distributions) from August 2019 to February 2023. Main Outcomes and Measures: The primary outcome was all-cause childhood mortality, measured during a twice-yearly enumerative census. Results: A total of 34 399 children (mean [SD] age, 25.2 [18] months) in the azithromycin group and 33 847 children (mean [SD] age, 25.6 [18] months) in the placebo group were included. A mean (SD) of 90.1% (16.0%) of the censused children received the scheduled study drug in the azithromycin group and 89.8% (17.1%) received the scheduled study drug in the placebo group. In the azithromycin group, 498 deaths were recorded over 60 592 person-years (8.2 deaths/1000 person-years). In the placebo group, 588 deaths were recorded over 58 547 person-years (10.0 deaths/1000 person-years). The incidence rate ratio for mortality was 0.82 (95% CI, 0.67-1.02; P =.07) in the azithromycin group compared with the placebo group. The incidence rate ratio was 0.99 (95% CI, 0.72-1.36) in those aged 1 to 11 months, 0.92 (95% CI, 0.67-1.27) in those aged 12 to 23 months, and 0.73 (95% CI, 0.57-0.94) in those aged 24 to 59 months. Conclusions and Relevance: Mortality in children (aged 1-59 months) was lower with biannual mass azithromycin distribution in a setting in which seasonal malaria chemoprevention was also being distributed, but the difference was not statistically significant. The study may have been underpowered to detect a clinically relevant difference. Trial Registration: ClinicalTrials.gov Identifier: NCT03676764 This cluster randomized placebo-controlled trial examines the efficacy of single-dose azithromycin for prevention of all-cause childhood mortality in rural Burkina Faso. [ABSTRACT FROM AUTHOR]

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 Mass distribution of azithromycin to children 1 to 59 months of age has been shown to reduce childhood all-cause mortality in some sub-Saharan African regions, with the largest reduction seen among infants younger than 12 months of age. Whether the administration of azithromycin at routine health care visits for infants would be effective in preventing death is unclear. METHODS We conducted a randomized, placebo-controlled trial of a single dose of azithromycin (20 mg per kilogram of body weight) as compared with placebo, administered during infancy (5 to 12 weeks of age). The primary end point was death before 6 months of age. Infants were recruited at routine vaccination or other well-child visits in clinics and through community outreach in three regions of Burkina Faso. Vital status was assessed at 6 months of age. RESULTS Of the 32,877 infants enrolled from September 2019 through October 2022, a total of 16,416 infants were randomly assigned to azithromycin and 16,461 to placebo. Eighty-two infants in the azithromycin group and 75 infants in the placebo group died before 6 months of age (hazard ratio, 1.09; 95% confidence interval [CI], 0.80 to 1.49; P=0.58); the absolute difference in mortality was 0.04 percentage points (95% CI, -0.10 to 0.21). There was no evidence of an effect of azithromycin on mortality in any of the prespecified subgroups, including subgroups defined according to age, sex, and baseline weight, and no evidence of a difference between the two trial groups in the incidence of adverse events. CONCLUSIONS In this trial conducted in Burkina Faso, we found that administration of azithromycin to infants through the existing health care system did not prevent death. [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]

To assess noninfectious uveitis (NIU) risk after coronavirus disease 2019 (COVID-19) vaccination in patients without a history of uveitis. A retrospective matched cohort study and self-controlled case series (SCCS) analysis using a longitudinal data asset with claims data from the OptumLabs Data Warehouse from December 11, 2020, through November 30, 2021. The matched cohort analysis included patients continuously enrolled for 730 days before December 11, 2020, who received a COVID-19 vaccination during the study period. This COVID-19–vaccinated group was matched to a COVID-19–unvaccinated historical cohort enrolled in 2018 and 2019. The SCCS design included individuals from the vaccinated cohort who experienced an NIU event during the study period. Enrollees with a history of uveitis were excluded. Hazard ratios (HRs) were calculated using Cox proportional hazards models in the matched cohort design. Incidence rate ratios (IRRs) comparing NIU incidence in exposed risk periods after vaccination and unexposed control periods within individuals were calculated using conditional Poisson regression models in the SCCS design. Models were adjusted for age, recent receipt of non–COVID-19 vaccinations, corticosteroid or immunosuppressive use, and smoking history. Subgroup analyses were conducted by vaccination type and age group. Rates of NIU identified with International Classification of Diseases, Tenth Revision, codes. The matched cohort analysis included 4 611 378 patients, with 2 305 689 per cohort. The adjusted HR comparing NIU incidence in the COVID-19–vaccinated and unvaccinated cohort was 0.91 (95% confidence interval [CI], 0.75–1.10; P = 0.33). The SCCS analysis included 686 patients. The IRR comparing NIU risk after vaccination with risk during control intervals was 1.05 (95% CI, 0.89–1.23; P = 0.57). An increased risk was found in the subgroup aged 5 to 44 years (IRR, 1.40; 95% CI, 1.04–1.87; P = 0.024). The matched cohort and SCCS analyses did not detect increased NIU risk after COVID-19 vaccination overall in individuals without history of uveitis, providing reassurance about the vaccine's safety. The finding of increased risk in the youngest subgroup suggests heightened immune responses in younger individuals, warranting further investigation. Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article. [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]

A letter to the editor is presented in response to the article "Randomized Intervention Study of Solar Disinfection of Drinking Water in the Prevention of Dysentery in Kenyan Children Aged under 5 Years" by M. du Preez and colleagues in a 2011 issue.

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. 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. 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. 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. WHO and Foreign, Commonwealth & Development Office. [ABSTRACT FROM AUTHOR]

Recombinant zoster vaccine (RZV) is recommended for individuals ≥ 50 years of age for protection against herpes zoster (HZ). This study quantifies RZV coverage and assesses predictors for RZV vaccination using a U.S. claims database. Univariate linear regression provided annual prevalence of RZV vaccination and multivariable logistic regression provided ORs and 95% CIs for associations between predictors and RZV vaccination. A total of 4,124,315 individuals (19,080,914 person-years) were included in this study. Since receiving FDA approval for the prevention of HZ, RZV coverage (of at least one dose) has reached approximately 17% within the eligible U.S. population by January 2021, although significant disparities between demographic groups were noted. Our findings suggest that HZ vaccine coverage may be reduced below goal in the U.S. and highlights the importance of continuing to monitor RZV vaccination. Additionally, as our study found disparities in vaccine coverage, attention towards marginalized and medically underserved populations is needed. [ABSTRACT FROM AUTHOR]

Background Maternal age is increasingly recognized as a predictor of birth outcomes. Given the importance of birth and growth outcomes for children's development, wellbeing and survival, this study examined the effect of maternal age on infant birth and growth outcomes at 6 months and mortality. Additionally, we conducted quantitative bias analysis (QBA) to estimate the role of selection bias and unmeasured confounding on the effect of maternal age on infant mortality. Methods We used data from randomized–controlled trials (RCTs) of 21 555 neonates in Burkina Faso conducted in 2019–2020. Newborns of mothers aged 13–19 years (adolescents) and 20–40 years (adults) were enrolled in the study 8–27 days after birth and followed for 6 months. Measurements of child's anthropometric measures were collected at baseline and 6 months. We used multivariable linear regression to compare child anthropometric measures at birth and 6 months, and logistic regression models to obtain the odds ratio (OR) of all-cause mortality. Using multidimensional deterministic analysis, we assessed scenarios in which the difference in selection probability of adolescent and adult mothers with infant mortality at 6 months increased from 0% to 5%, 10%, 15% and 20% if babies born to adolescent mothers more often died during the first week or were of lower weight and hence were not eligible to be included in the original RCT. Using probabilistic bias analysis, we assessed the role of unmeasured confounding by socio-economic status (SES). Results Babies born to adolescent mothers on average had lower weight at birth, lower anthropometric measures at baseline, similar growth outcomes from enrolment to 6 months and higher odds of all-cause mortality by 6 months (adjusted OR = 2.17, 95% CI 1.35 to 3.47) compared with those born to adult mothers. In QBA, we found that differential selection of adolescent and adult mothers could bias the observed effect (OR = 2.24, 95% CI 1.41 to 3.57) towards the null [bias-corrected OR range: 2.37 (95% CI 1.49 to 3.77) to 2.84 (95% CI 1.79 to 4.52)], whereas unmeasured confounding by SES could bias the observed effect away from the null (bias-corrected OR: 2.06, 95% CI 1.31 to 2.64). Conclusions Our findings suggest that delaying the first birth from adolescence to adulthood may improve birth outcomes and reduce mortality of neonates. Babies born to younger mothers, who are smaller at birth, may experience catch-up growth, reducing some of the anthropometric disparities by 6 months of age. [ABSTRACT FROM AUTHOR]

Background: Poor sanitation is thought to be a major cause of enteric infections among young children. However, there are no previously published randomized trials to measure the health impacts of large-scale sanitation programs. India's Total Sanitation Campaign (TSC) is one such program that seeks to end the practice of open defecation by changing social norms and behaviors, and providing technical support and financial subsidies. The objective of this study was to measure the effect of the TSC implemented with capacity building support from the World Bank's Water and Sanitation Program in Madhya Pradesh on availability of individual household latrines (IHLs), defecation behaviors, and child health (diarrhea, highly credible gastrointestinal illness [HCGI], parasitic infections, anemia, growth).Methods and Findings: We conducted a cluster-randomized, controlled trial in 80 rural villages. Field staff collected baseline measures of sanitation conditions, behaviors, and child health (May-July 2009), and revisited households 21 months later (February-April 2011) after the program was delivered. The study enrolled a random sample of 5,209 children <5 years old from 3,039 households that had at least one child <24 months at the beginning of the study. A random subsample of 1,150 children <24 months at enrollment were tested for soil transmitted helminth and protozoan infections in stool. The randomization successfully balanced intervention and control groups, and we estimated differences between groups in an intention to treat analysis. The intervention increased percentage of households in a village with improved sanitation facilities as defined by the WHO/UNICEF Joint Monitoring Programme by an average of 19% (95% CI for difference: 12%-26%; group means: 22% control versus 41% intervention), decreased open defecation among adults by an average of 10% (95% CI for difference: 4%-15%; group means: 73% intervention versus 84% control). However, the intervention did not improve child health measured in terms of multiple health outcomes (diarrhea, HCGI, helminth infections, anemia, growth). Limitations of the study included a relatively short follow-up period following implementation, evidence for contamination in ten of the 40 control villages, and bias possible in self-reported outcomes for diarrhea, HCGI, and open defecation behaviors.Conclusions: The intervention led to modest increases in availability of IHLs and even more modest reductions in open defecation. These improvements were insufficient to improve child health outcomes (diarrhea, HCGI, parasite infection, anemia, growth). The results underscore the difficulty of achieving adequately large improvements in sanitation levels to deliver expected health benefits within large-scale rural sanitation programs.Trial Registration: ClinicalTrials.gov NCT01465204. Please see later in the article for the Editors' Summary. [ABSTRACT FROM AUTHOR]

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]

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]

To identify initial, preintervention magnetic resonance imaging (MRI) findings that are predictive of visual and mortality outcomes in acute invasive fungal rhinosinusitis (AIFRS). Retrospective cohort study. Patients with histopathologically or microbiologically confirmed AIFRS cared for at a single, tertiary academic institution between January 2000 and February 2020. A retrospective review of MRI scans and clinical records of patients with confirmed diagnosis of AIFRS was performed. For each radiologic characteristic, a modified Poisson regression with robust standard errors was used to estimate the risk ratio for blindness. A multivariate Cox proportional hazards model was used to study AIFRS-specific risk factors associated with mortality. Identification of initial, preintervention MRI findings associated with visual and mortality outcomes. The study comprised 78 patients (93 orbits, 63 with unilateral disease and 15 with bilateral disease) with AIFRS. The leading causes of immunosuppression were hematologic malignancy (38%) and diabetes mellitus (36%). Mucormycota constituted 56% of infections, and Ascomycota constituted 37%. The overall death rate resulting from infection was 38%. Risk factors for poor visual acuity outcomes on initial MRI included involvement of the orbital apex (relative risk [RR], 2.0; 95% confidence interval [CI], 1.1–3.8; P = 0.026) and cerebral arteries (RR, 1.8; 95% CI, 1.3–2.5; P < 0.001). Increased mortality was associated with involvement of the facial soft tissues (hazard ratio [HR], 4.9; 95% CI, 1.3–18.2; P = 0.017), nasolacrimal drainage apparatus (HR, 5.0; 95% CI, 1.5–16.1; P = 0.008), and intracranial space (HR, 3.5; 95% CI, 1.4–8.6; P = 0.006). Orbital soft tissue involvement was associated with decreased mortality (HR, 0.3; 95% CI, 0.1–0.6; P = 0.001). Extrasinonasal involvement in AIFRS typically signals advanced infection with the facial soft tissues most commonly affected. The initial, preintervention MRI is prognostic for a poor visual acuity outcome when orbital apex or cerebral arterial involvement, or both, are present. Facial soft tissues, nasolacrimal drainage apparatus, intracranial involvement, or a combination thereof is associated with increased mortality risk, whereas orbital soft tissue involvement is correlated with a reduced risk of mortality. [ABSTRACT FROM AUTHOR]

To determine the dose-dependent risk of systemic corticosteroids (SCs) and the risk of other immunosuppressive therapies on coronavirus disease 2019 (COVID-19) infection, hospitalization, and death in patients with noninfectious uveitis (NIU). A retrospective cohort study from January 20, 2020, to December 31, 2020 (an era before widespread COVID-19 vaccination), using the Optum Labs Data Warehouse, a US national de-identified claims database. Patients who had at least 1 NIU diagnosis from January 1, 2017. Unadjusted and adjusted hazard ratios (HRs) were estimated for each variable and COVID-19 outcome using Cox proportional hazards models, with time-updated dichotomous indicators for outpatient immunosuppressive medication exposure. To assess the dose-dependent effect of SC exposure, the average daily dose of prednisone over the exposed interval was included in the adjusted models as a continuous variable, in addition to the dichotomous variable. Incidence rates of COVID-19 infection, COVID-19–related hospitalization, and COVID-19–related in-hospital death. This study included 52 286 NIU patients of whom 12 000 (23.0%) were exposed to immunosuppressive medications during the risk period. In adjusted models, exposure to SCs was associated with increased risk of COVID-19 infection (HR, 2.66; 95% confidence interval [CI], 2.19–3.24; P < 0.001), hospitalization (HR, 3.26; 95% CI, 2.46–4.33; P < 0.001), and in-hospital death (HR, 1.99; 95% CI, 0.93–4.27; P = 0.08). Furthermore, incremental increases in the dosage of SCs were associated with a greater risk for these outcomes. Although tumor necrosis factor-α (TNF-α) inhibitors were associated with an increased risk of infection (HR, 1.48; 95% CI, 1.08–2.04; P = 0.02), other immunosuppressive treatments did not increase the risk of COVID-19 infection, hospitalization, or death. This study from an era before widespread COVID-19 vaccination demonstrates that outpatient SC exposure is associated with greater risk of COVID-19 infection and severe outcomes in patients with NIU. Future studies should evaluate the impact of immunosuppression in vaccinated NIU patients. Limiting exposure to SCs and use of alternative therapies may be warranted. [ABSTRACT FROM AUTHOR]

Introduction Advances in molecular methods provide new opportunities for directly measuring pathogens or host-associated markers of fecal pollution instead of relying on fecal indicator bacteria (FIB) alone for beach water quality monitoring. Adoption of new indicators depends on identifying relationships between either the presence or concentration of the indicators and illness among swimmers. Here we present results from three epidemiologic studies in which a broad range of bacterial and viral indicators of fecal contamination were measured simultaneously by either culture or molecular methods along with Enterococcus to assess whether they provide better health risk prediction than current microbial indicators of recreational water quality. Methods We conducted prospective cohort studies at three California beaches -- Avalon Bay (Avalon), Doheny State Beach (Doheny), Surfrider State Beach (Malibu) -- during the summers of 2007, 2008 and 2009. The studies enrolled 10,785 swimmers across the beaches and recorded each swimmer's water exposure. Water and sand samples were collected several times per day at multiple locations at each beach and analyzed for up to 41 target indicators using 67 different methodologies. Interviewers contacted participants by phone 10–14 days later and recorded symptoms of gastrointestinal illness occurring after their beach visit. Regression models were used to evaluate the association between water quality indicators and gastrointestinal illness among swimmers at each beach. Results F+ coliphage (measured using EPA Method 1602) exhibited a stronger association with GI illness than did EPA Method 1600 at the two beaches where it was measured, while a molecular method, F+ RNA Coliphage Genotype II, was the only indicator significantly associated with GI illness at Malibu. MRSA, a known pathogen, had the strongest association with GI illness of any microbe measured at Avalon. There were two methods targeting human-associated fecal anaerobic bacteria that were more strongly associated with GI illness than EPA Method 1600, but only at Avalon. No indicator combinations consistently had a higher odds ratio than EPA Method 1600, but one composite indicator, based on the number of pathogens detected at a beach, was significantly associated with gastrointestinal illness at both Avalon and Doheny when freshwater flow was high. Discussion While EPA Method1600 performed adequately at two beaches based on its consistency of association with gastrointestinal illness and the precision of its estimated associations, F+ coliphage measured by EPA Method 1602 had a stronger association with GI illness under high risk conditions at the two beaches where it was measured. One indicator, F+ Coliphage Genotype II was the only indicator significantly associated with GI illness at Malibu. Several indicators, particularly those targeting human associated bacteria, exhibited relationships with GI illness that were equal to or greater than that of EPA Method 1600 at Avalon, which has a focused human fecal source. Our results suggest that site-specific conditions at each beach determine which indicator or indicators best predict GI illness. [ABSTRACT FROM AUTHOR]