The Global Enteric Multicenter Study (GEMS) demonstrated that Shigella and enterotoxigenic Escherichia coli (ETEC) producing heat stable toxin (ST) (either alone or in combination with heat labile toxin) are among the most important pathogens associated with moderate-to-severe diarrhea (MSD) in children younger than 5years of age living in developing countries. To inform the design of vaccines and other interventions, we reviewed published data and new results from GEMS characterizing the burden of Shigella and ST-ETEC infections. Clinical parameters were assessed to examine the value of various case definitions as indicators of MSD associated with Shigella and ST-ETEC for use in clinical trials. We discussed advantages and disadvantages of culture-based and culture-independent molecular diagnostics for detecting clinically and epidemiologically relevant disease. Shigella serotyping data from GEMS were examined to identify desirable components of Shigella and ETEC vaccines likely to confer broad protection. These findings can inform the development and implementation of vaccines to prevent these important infections among infants and children in developing countries.

BackgroundRotavirus is a leading cause of diarrhoeal mortality in children but there is considerable disagreement about how many deaths occur each year.Methods and findingsWe compared CHERG, GBD and WHO/CDC estimates of age under 5 years (U5) rotavirus deaths at the global, regional and national level using a standard year (2013) and standard list of 186 countries. The global estimates were 157,398 (CHERG), 122,322 (GBD) and 215,757 (WHO/CDC). The three groups used different methods: (i) to select data points for rotavirus-positive proportions; (ii) to extrapolate data points to individual countries; (iii) to account for rotavirus vaccine coverage; (iv) to convert rotavirus-positive proportions to rotavirus attributable fractions; and (v) to calculate uncertainty ranges. We conducted new analyses to inform future estimates. We found that acute watery diarrhoea was associated with 87% (95% CI 83–90%) of U5 diarrhoea hospitalisations based on data from 84 hospital sites in 9 countries, and 65% (95% CI 57–74%) of U5 diarrhoea deaths based on verbal autopsy reports from 9 country sites. We reanalysed data from the Global Enteric Multicenter Study (GEMS) and found 44% (55% in Asia, and 32% in Africa) rotavirus-positivity among U5 acute watery diarrhoea hospitalisations, and 28% rotavirus-positivity among U5 acute watery diarrhoea deaths. 97% (95% CI 95–98%) of the U5 diarrhoea hospitalisations that tested positive for rotavirus were entirely attributable to rotavirus. For all clinical syndromes combined the rotavirus attributable fraction was 34% (95% CI 31–36%). This increased by a factor of 1.08 (95% CI 1.02–1.14) when the GEMS results were reanalysed using a more sensitive molecular test.ConclusionsWe developed consensus on seven proposals for improving the quality and transparency of future rotavirus mortality estimates.

Background Pediatric diarrhea can be caused by a wide variety of pathogens, from bacteria to viruses to protozoa. Pathogen prevalence is often described as seasonal, peaking annually and associated with specific weather conditions. Although many studies have described the seasonality of diarrheal disease, these studies have occurred predominantly in temperate regions. In tropical and resource-constrained settings, where nearly all diarrhea-associated mortality occurs, the seasonality of many diarrheal pathogens has not been well characterized. As a retrospective study, we analyze the seasonal prevalence of diarrheal pathogens among children with moderate-to-severe diarrhea (MSD) over three years from the seven sites of the Global Enteric Multicenter Study (GEMS), a case–control study. Using data from this expansive study on diarrheal disease, we characterize the seasonality of different pathogens, their association with site-specific weather patterns, and consistency across study sites. Methodology/Principal findings Using traditional methodologies from signal processing, we found that certain pathogens peaked at the same time every year, but not at all sites. We also found associations between pathogen prevalence and weather or “seasons,” which are defined by applying modern machine-learning methodologies to site-specific weather data. In general, rotavirus was most prevalent during the drier “winter” months and out of phase with bacterial pathogens, which peaked during hotter and rainier times of year corresponding to “monsoon,” “rainy,” or “summer” seasons. Conclusions/Significance Identifying the seasonally-dependent prevalence for diarrheal pathogens helps characterize the local epidemiology and inform the clinical diagnosis of symptomatic children. Our multi-site, multi-continent study indicates a complex epidemiology of pathogens that does not reveal an easy generalization that is consistent across all sites. Instead, our study indicates the necessity of local data to characterizing the epidemiology of diarrheal disease. Recognition of the local associations between weather conditions and pathogen prevalence suggests transmission pathways and could inform control strategies in these settings.

Background The association between childhood diarrheal disease and linear growth faltering in developing countries is well-described. However, the impact attributed to specific pathogens has not been elucidated, nor has the impact of recommended antibiotic treatment. Methods The Global Enteric Multicenter Study (GEMS) enrolled children seeking healthcare with moderate-to-severe diarrhea (MSD) at seven sites in sub-Saharan Africa and South Asia. At enrollment, we collected stool samples to identify enteropathogens. Length/height was measured at enrollment and follow-up, ~60 days later, to calculate change in length/height for age Z scores (ΔHAZ). The association of pathogens with ΔHAZ was tested by linear mixed effects regression models. Results Among 8,077 MSD cases analyzed, the proportion with stunting (HAZ<-1) increased from 59% at enrollment to 65% at follow-up (p<.0001). Pathogens significantly associated with linear growth decline were Cryptosporidium (p<0.001), typical enteropathogenic Escherichia coli (p=0.013), and untreated Shigella (p=0.009) among infants (0-11 months), and enterotoxigenic E. coli encoding heat stable toxin (p<0.001) and Cryptosporidium (p=0.03) among toddlers (12-23 months). Shigella-infected toddlers given antibiotics had improved linear growth (p=0.02). Conclusion Linear growth faltering among children aged 0-23 months with MSD is associated with specific pathogens and can be mitigated with targeted treatment strategies, as demonstrated for Shigella.

Methcathinone abusers develop a distinctive hypokinetic syndrome. Though the biomarkers of Mn exposure are characteristic only of recent abuse, the syndrome is not reversible.

Diarrheal disease is one of the leading causes of death among young children in the developing world. It is difficult to determine which of a wide variety of pathogens are most responsible for disease, since this differs by location and time of year. Here, we study the seasonal prevalence of several pathogens among children with moderate-to-severe diarrhea across study sites in Africa and South Asia. We found that several pathogens, including rotavirus, had regular annual peaks. Some pathogens were associated with weather conditions, such as heat or rain, or with general seasons of the year, such as summer or winter. We believe that describing the seasonal epidemiology of these pathogens could enable better diagnoses of symptomatic children based on the time of the year. Additionally, weather is a major driver of diarrheal pathogen transmission, and identifying the conditions associated with each pathogen could help us infer pathogen transmission pathways, predict large outbreaks, and develop intervention strategies. January 31, 2019 2/21 Pediatric diarrheal disease is caused by a wide variety of pathogens [1-3]. Various 2 studies have found that some pathogens are seasonal, peaking at different times of the 3 year [4-6]. Frequently, the seasonal periodicity of diarrheal disease is attributed to 4 weather, which could drive incidence by diverse mechanisms. For example, weather 5 conditions can favor the survival and replication of pathogens on fomites [7], the 6 transmission between human hosts through flooding and contamination of drinking 7 water [8], and the prevalence of vectors that transmit disease between hosts [9, 10]. 8 Weather has broadly been shown to be mathematically correlated with diarrhea 9 incidence [11, 12], with some computational studies claiming a causal link [13] despite 10 potential limitations to their methodology [14-16]. 11 However, most studies of disease seasonality have been conducted in temperate 12 climates, and substantially less is known about the seasonality of diseases in tropical 13 countries [17, 18], where diarrheal disease is one of the leading causes of morbidity and 14 mortality among children [19]. The wide variety of climates and populations in the 15 tropics make it challenging to uncover general patterns in the epidemiology of diarrheal 16 disease. Compounding these challenges, most studies are limited to sites within a single 17 country focused on a specific disease. Characterizing the seasonal epidemiology of these 18 pathogens could enable clinicians to better diagnose children based on the time of the 19 year. Additionally, identifying the weather conditions associated with each pathogen 20 could help us infer pathogen transmission pathways, predict large outbreaks, and 21 develop intervention strategies. 22 hydration; dysentery identified by blood in stool; or admission to the hospital for 49 diarrhea or dysentery [2]. To limit the number of enrollments and ensure balanced 50 enrollment by age, 8-9 children in each age strata (0-11 months, 12-23 months, 24-59 51 m...

Diarrheal disease remains a major cause of childhood mortality and morbidity causing poor health and economic outcomes. In low-resource settings, young children are exposed to numerous risk factors for enteric pathogen transmission within their dwellings, though the relative importance of different transmission pathways varies by pathogen species. The objective of this analysis was to model associations between five household-level risk factors—water, sanitation, flooring, caregiver education, and crowding—and infection status for endemic enteric pathogens in children in five surveillance studies. Data were combined from 22 sites in which a total of 58,000 stool samples were tested for 16 specific enteropathogens using qPCR. Risk ratios for pathogen- and taxon-specific infection status were modeled using generalized linear models along with hazard ratios for all-cause diarrhea in proportional hazard models, with the five household-level variables as primary exposures adjusting for covariates. Improved drinking water sources conferred a 17% reduction in diarrhea risk; however, the direction of its association with particular pathogens was inconsistent. Improved sanitation was associated with a 9% reduction in diarrhea risk with protective effects across pathogen species and taxa of around 10–20% risk reduction. A 9% reduction in diarrhea risk was observed in subjects with covered floors, which were also associated with decreases in risk for zoonotic enteropathogens. Caregiver education and household crowding showed more modest, inconclusive results. Combining data from diverse sites, this analysis quantified associations between five household-level exposures on risk of specific enteric infections, effects which differed by pathogen species but were broadly consistent with hypothesized transmission mechanisms. Such estimates may be used within expanded water, sanitation, and hygiene (WASH) programs to target interventions to the particular pathogen profiles of individual communities and prioritize resources.

Background Cryptosporidium is a major pathogen associated with diarrheal disease in young children. We studied Cryptosporidium diarrhea in children enrolled in the Global Enteric Multicenter Study (GEMS) in rural Gambia. Methods We recruited children <5 years of age with moderate-to-severe diarrhea (MSD) for 3 years (2008–2010), and children with either MSD or less severe diarrhea (LSD) for one year (November 2011-November 2012) at sentinel health centers. One or more randomly selected controls were matched to each case. Stool samples were tested to identify Cryptosporidium by immunoassay. A subset of randomly selected case-controls pairs were tested for Cryptosporidium species. We investigated the epidemiology of, and evaluated possible risk factors for, Cryptosporidium- positive diarrhea. Results We enrolled 1938 cases (1381 MSD, 557 LSD) and 2969 matched controls; 231/1929 (12.0%) of diarrhea cases and 141/2962 (4.8%) of controls were positive for Cryptosporidium . Most Cryptosporidium diarrhea cases (85.7%, 198/231) were aged 6–23 months, and most (81.4%, 188/231) occurred during the rainy season. Cryptosporidium hominis (C . hominis) was the predominant (82.6%) species. We found associations between increased risk of Cryptosporidium -positive MSD or LSD, or both, with consumption of stored drinking water and certain animals living in the compound—cow, cat (MSD only) and rodents (LSD only). Larger households, fowl living in the compound, and the presence of Giardia infection were associated with decreased risk of Cryptosporidium MSD and LSD. Conclusion Cryptosporidium -positive diarrhea is prevalent in this setting, especially at 6–23 months of age. The preponderance of Cryptosporidium infection in the rainy season and increased risk of Cryptosporidium -positive diarrhea with consumption of stored drinking water suggest water-borne transmission. Further investigation is needed to clarify the role of animals and contamination of stored drinking water in Cryptosporidium transmission.