IMPORTANCE: Associations between prenatal SARS-CoV-2 exposure and neurodevelopmental outcomes have substantial public health relevance. A previous study found no association between prenatal SARS-CoV-2 infection and parent-reported infant neurodevelopmental outcomes, but standardized observational assessments are needed to confirm this finding. OBJECTIVE: To assess whether mild or asymptomatic maternal SARS-CoV-2 infection vs no infection during pregnancy is associated with infant neurodevelopmental differences at ages 5 to 11 months. DESIGN, SETTING, AND PARTICIPANTS: This cohort study included infants of mothers from a single-site prospective cross-sectional study (COVID-19 Mother Baby Outcomes [COMBO] Initiative) of mother-infant dyads and a multisite prospective cohort study (Epidemiology of Severe Acute Respiratory Syndrome Coronavirus 2 in Pregnancy and Infancy [ESPI]) of pregnant individuals. A subset of ESPI participants was subsequently enrolled in the ESPI COMBO substudy. Participants in the ongoing COMBO study were enrolled beginning on May 26, 2020; participants in the ESPI study were enrolled from May 7 to November 3, 2021; and participants in the ESPI COMBO substudy were enrolled from August 2020 to March 2021. For the current analysis, infant neurodevelopment was assessed between March 2021 and June 2022. A total of 407 infants born to 403 mothers were enrolled (204 from Columbia University Irving Medical Center in New York, New York; 167 from the University of Utah in Salt Lake City; and 36 from the University of Alabama in Birmingham). Mothers of unexposed infants were approached for participation based on similar infant gestational age at birth, date of birth, sex, and mode of delivery to exposed infants. EXPOSURES: Maternal symptomatic or asymptomatic SARS-CoV-2 infection. MAIN OUTCOMES AND MEASURES: Infant neurodevelopment was assessed using the Developmental Assessment of Young Children, second edition (DAYC-2), adapted for telehealth assessment. The primary outcome was age-adjusted standard scores on 5 DAYC-2 subdomains: cognitive, gross motor, fine motor, expressive language, and receptive language. RESULTS: Among 403 mothers, the mean (SD) maternal age at delivery was 32.1 (5.4) years; most mothers were of White race (240 [59.6%]) and non-Hispanic ethnicity (253 [62.8%]). Among 407 infants, 367 (90.2%) were born full term and 212 (52.1%) were male. Overall, 258 infants (63.4%) had no documented prenatal exposure to SARS-CoV-2 infection, 112 (27.5%) had confirmed prenatal exposure, and 37 (9.1%) had exposure before pregnancy or at an indeterminate time. In adjusted models, maternal SARS-CoV-2 infection during pregnancy was not associated with differences in cognitive (β = 0.31; 95% CI, -2.97 to 3.58), gross motor (β = 0.82; 95% CI, -1.34 to 2.99), fine motor (β = 0.36; 95% CI, -0.74 to 1.47), expressive language (β = -1.00; 95% CI, -4.02 to 2.02), or receptive language (β = 0.45; 95% CI, -2.15 to 3.04) DAYC-2 subdomain scores. Trimester of exposure and maternal symptom status were not associated with DAYC-2 subdomain scores. CONCLUSIONS AND RELEVANCE: In this study, results of a novel telehealth-adapted observational neurodevelopmental assessment extended a previous finding of no association between prenatal exposure to maternal SARS-CoV-2 infection and infant neurodevelopment. Given the widespread and continued high prevalence of COVID-19, these data offer information that may be helpful for pregnant individuals who experience asymptomatic or mild SARS-CoV-2 infections.

Understanding the complex interactions between virus and host that drive new strain evolution is key to predicting the emergence potential of variants and informing vaccine development. Under our hypothesis, future dominant human norovirus GII.4 variants with critical antigenic properties that allow them to spread are currently circulating undetected, having diverged years earlier. Through large-scale sequencing of GII.4 surveillance samples, we identified two variants with extensive divergence within domains that mediate neutralizing antibody binding. Subsequent serological characterization of these strains using temporally resolved adult and child sera suggests that neither candidate could spread globally in adults with multiple GII.4 exposures, yet young children with minimal GII.4 exposure appear susceptible. Antigenic cartography of surveillance and outbreak sera indicates that continued population exposure to GII.4 Sydney 2012 and antigenically related variants over a 6-year period resulted in a broadening of immunity to heterogeneous GII.4 variants, including those identified here. We show that the strongest antibody responses in adults exposed to GII.4 Sydney 2012 are directed to previously circulating GII.4 viruses. Our data suggest that the broadening of antibody responses compromises establishment of strong GII.4 Sydney 2012 immunity, thereby allowing the continued persistence of GII.4 Sydney 2012 and modulating the cycle of norovirus GII.4 variant replacement. Our results indicate a cycle of norovirus GII.4 variant replacement dependent upon population immunity. Young children are susceptible to divergent variants; therefore, emergence of these strains worldwide is driven proximally by changes in adult serological immunity and distally by viral evolution that confers fitness in the context of immunity. IMPORTANCE In our model, preepidemic human norovirus variants harbor genetic diversification that translates into novel antigenic features without compromising viral fitness. Through surveillance, we identified two viruses fitting this profile, forming long branches on a phylogenetic tree. Neither evades current adult immunity, yet young children are likely susceptible. By comparing serological responses, we demonstrate that population immunity varies by age/exposure, impacting predicted susceptibility to variants. Repeat exposure to antigenically similar variants broadens antibody responses, providing immunological coverage of diverse variants but compromising response to the infecting variant, allowing continued circulation. These data indicate norovirus GII.4 variant replacement is driven distally by virus evolution and proximally by immunity in adults.

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 enrolled children with moderate to severe diarrhea (MSD) seeking healthcare at 7 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, approximately 60 days later, to calculate change in height-for-age z scores (ΔHAZ). The association of pathogens with ΔHAZ was tested using linear mixed effects regression models. RESULTS: Among 8077 MSD cases analyzed, the proportion with stunting (HAZ below -1) increased from 59% at enrollment to 65% at follow-up (P < .0001). Pathogens significantly associated with linear growth decline included Cryptosporidium (P < .001), typical enteropathogenic Escherichia coli (P = .01), and untreated Shigella (P = .009) among infants (aged 0-11 months) and enterotoxigenic E. coli encoding heat-stable toxin (P < .001) and Cryptosporidium (P = .03) among toddlers (aged 12-23 months). Shigella-infected toddlers given antibiotics had improved linear growth (P = .02). CONCLUSIONS: 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.

BACKGROUND: The Global Enteric Multicenter Study (GEMS) determined the etiologic agents of moderate-to-severe diarrhea (MSD) in children under 5 years old in Africa and Asia. Here, we describe the prevalence and antimicrobial susceptibility of non-typhoidal Salmonella (NTS) serovars in GEMS and examine the phylogenetics of Salmonella Typhimurium ST313 isolates. METHODS: Salmonella isolated from children with MSD or diarrhea-free controls were identified by classical clinical microbiology and serotyped using antisera and/or whole genome sequence data. We evaluated antimicrobial susceptibility using the Kirby-Bauer disk diffusion method. Salmonella Typhimurium sequence types were determined using multi-locus sequence typing and whole genome sequencing was performed to assess the phylogeny of ST313. RESULTS: Out of 370 Salmonella-positive individuals, 190 (51.4%) were MSD cases and 180 (48.6%) were diarrhea-free controls. The most frequent Salmonella serovars identified were Salmonella Typhimurium, serogroup O:8 (C2-C3), serogroup O:6,7 (C1), Salmonella Paratyphi B Java and serogroup O:4 (B). The prevalence of NTS was low but similar across sites, regardless of age, and was similar amongst both cases and controls except in Kenya, where Salmonella Typhimurium was more commonly associated with cases than controls. Phylogenetic analysis showed that these Salmonella Typhimurium isolates, all ST313, were highly genetically related to isolates from controls. Generally, Salmonella isolates from Asia were resistant to ciprofloxacin and ceftriaxone but African isolates were susceptible to these antibiotics. CONCLUSION: Our data confirms that NTS is prevalent, albeit at low levels, in Africa and South Asia. Our findings provide further evidence that multi-drug resistant Salmonella Typhimurium ST313 can be carried asymptomatically by humans in sub-Saharan Africa.

Household water chlorination has been shown to reduce diarrhea incidence among people living with Human Immunodeficiency Virus (PLHIV). Some HIV programs in Ethiopia previously provided a socially marketed chlorination product (brand name WuhaAgar) to prevent diarrhea. To evaluate the program, we compared WuhaAgar use and water treatment practices between 795 clients from 20 antiretroviral therapy (ART) clinics and 795 community members matched by age, sex, and neighborhood. Overall, 19% of study participants reported water treatment with WuhaAgar. Being an ART clinic client was associated with reported treatment of drinking water (matched odds ratios (mOR): 3.8, 95% confidence interval (CI): 2.9-5.0), reported current water treatment with WuhaAgar (mOR: 5.5, 95% CI 3.9-7.7), and bottles of WuhaAgar observed in the home (mOR: 8.8, 95% CI 5.4-14.3). Being an ART clinic client was also associated with reported diarrhea among respondents (mOR: 4.8, 95% CI 2.9-7.9) and household members (mOR:2.8, 95% CI: 1.9-4.2) in the two weeks preceding the survey. Results suggest that promoting and distributing water chlorination products in ART clinics was effective in increasing access to and use of water treatment products among PLHIV. The positive association between ART clinic attendees and diarrhea likely resulted from the immunocompromised status of ART clinic clients.

Typical enteropathogenic Escherichia coli (tEPEC) infection is a major cause of diarrhoea and contributor to mortality in children <5 years old in developing countries. Data were analysed from the Global Enteric Multicenter Study examining children <5 years old seeking care for moderate-to-severe diarrhoea (MSD) in Kenya. Stool specimens were tested for enteric pathogens, including by multiplex polymerase chain reaction for gene targets of tEPEC. Demographic, clinical and anthropometric data were collected at enrolment and ~60-days later; multivariable logistic regressions were constructed. Of 1778 MSD cases enrolled from 2008 to 2012, 135 (7.6%) children tested positive for tEPEC. In a case-to-case comparison among MSD cases, tEPEC was independently associated with presentation at enrolment with a loss of skin turgor (adjusted odds ratio (aOR) 2.08, 95% confidence interval (CI) 1.37-3.17), and convulsions (aOR 2.83, 95% CI 1.12-7.14). At follow-up, infants with tEPEC compared to those without were associated with being underweight (OR 2.2, 95% CI 1.3-3.6) and wasted (OR 2.5, 95% CI 1.3-4.6). Among MSD cases, tEPEC was associated with mortality (aOR 2.85, 95% CI 1.47-5.55). This study suggests that tEPEC contributes to morbidity and mortality in children. Interventions aimed at defining and reducing the burden of tEPEC and its sequelae should be urgently investigated, prioritised and implemented.

While there have been no cases of type-2 wild poliovirus for over 20 years, transmission of type-2 vaccine-derived poliovirus (VDPV2) and associated paralytic cases in several continents represent a threat to eradication. The withdrawal of the type-2 component of oral poliovirus vaccine (OPV2) was implemented in April 2016 to stop VDPV2 emergence and secure eradication of all poliovirus type 2. Globally, children born after this date have limited immunity to prevent transmission. Using a statistical model, we estimate the emergence date and source of VDPV2s detected between May 2016 and November 2019. Outbreak response campaigns with monovalent OPV2 are the only available method to induce immunity to prevent transmission. Yet, our analysis shows that using monovalent OPV2 is generating more paralytic VDPV2 outbreaks with the potential for establishing endemic transmission. The novel OPV2 is urgently required, alongside a contingency strategy if this vaccine does not materialize or perform as anticipated.

Papua New Guinea (PNG) faces a critical shortage of human resources to address pressing public health challenges arising from an increasing burden of communicable and non-communicable diseases. PNG is an independent State in the Pacific and home to 8.2 million people. Resource and infrastructure constraints due to the country's challenging geography have made it difficult and expensive to deliver health services and implement health programmes. The National Department of Health and its partners developed a field epidemiology training programme of Papua New Guinea (FETPNG) to strengthen the country's public health workforce. The training programme covers field epidemiology competencies and includes the design, implementation and evaluation of evidence-based interventions by Fellows. From 2013 to 2018, FETPNG graduated 81 field epidemiologists. Most FETPNG graduates (84%) were from provincial or district health departments or organisations. Many of their intervention projects resulted in successful public health outcomes with tangible local impacts. Health challenges addressed included reducing the burden of multi-drug resistant-tuberculosis (TB), increasing immunisation coverage, screening and treating HIV/TB patients, and improving reproductive health outcomes. FETPNG Fellows and graduates have also evaluated disease surveillance systems and investigated disease outbreaks. Early and unwavering national ownership of FETPNG created a sustainable programme fitting the needs of this low-resource country. A focus on designing and implementing effective public health interventions not only provides useful skills to Fellows but also contributes to real-time, tangible and meaningful improvements in the health of the population. The graduates of FETPNG now provide a critical mass of public health practitioners across the country. Their skills in responding to outbreaks and public health emergencies, in collecting, analysing and interpreting data, and in designing, implementing and evaluating public health interventions continues to advance public health in PNG.

BACKGROUND: The Global Enteric Multicenter Study (GEMS) was a 3-year case-control study that measured the burden, aetiology, and consequences of moderate-to-severe diarrhoea (MSD) in children aged 0-59 months. GEMS-1A, a 12-month follow-on study, comprised two parallel case-control studies, one assessing MSD and the other less-severe diarrhoea (LSD). In this report, we analyse the risk of death with each diarrhoea type and the specific pathogens associated with fatal outcomes. METHODS: GEMS was a prospective, age-stratified, matched case-control study done at seven sites in Africa and Asia. Children aged 0-59 months with MSD seeking care at sentinel health centres were recruited along with one to three randomly selected matched community control children without diarrhoea. In the 12-month GEMS-1A follow-on study, children with LSD and matched controls, in addition to children with MSD and matched controls, were recruited at six of the seven sites; only cases of MSD and controls were enrolled at the seventh site. We compared risk of death during the period between enrolment and one follow-up household visit done about 60 days later (range 50-90 days) in children with MSD and LSD and in their respective controls. Approximately 50 pathogens were detected using, as appropriate, classic bacteriology, immunoassays, gel-based PCR and reverse transcriptase PCR, and quantitative real-time PCR (qPCR). Specimens from a subset of GEMS cases and controls were also tested by a TaqMan Array Card that compartmentalised probe-based qPCR for 32 enteropathogens. FINDINGS: 223 (2.0%) of 11 108 children with MSD and 43 (0.3%) of 16 369 matched controls died between study enrolment and the follow-up visit at about 60 days (hazard ratio [HR] 8.16, 95% CI 5.69-11.68, p<0.0001). 12 (0.4%) of 2962 children with LSD and seven (0.2%) of 4074 matched controls died during the follow-up period (HR 2.78, 95% CI 0.95-8.11, p=0.061). Risk of death was lower in children with dysenteric MSD than in children with non-dysenteric MSD (HR 0.20, 95% CI 0.05-0.87, p=0.032), and lower in children with LSD than in those with non-dysenteric MSD (HR 0.29, 0.14-0.59, p=0.0006). In children younger than 24 months with MSD, infection with typical enteropathogenic Escherichia coli, enterotoxigenic E coli encoding heat-stable toxin, enteroaggregative E coli, Shigella spp (non-dysentery cases), Aeromonas spp, Cryptosporidium spp, and Entamoeba histolytica increased risk of death. Of 61 deaths in children aged 12-59 months with non-dysenteric MSD, 31 occurred among 942 children qPCR-positive for Shigella spp and 30 deaths occurred in 1384 qPCR-negative children (HR 2.2, 95% CI 1.2-3.9, p=0.0090), showing that Shigella was strongly associated with increased risk of death. INTERPRETATION: Risk of death is increased following MSD and, to a lesser extent, LSD. Considering there are approximately three times more cases of LSD than MSD in the population, more deaths are expected among children with LSD than in those with MSD. Because the major attributable LSD-associated and MSD-associated pathogens are the same, implementing vaccines and rapid diagnosis and treatment interventions against these major pathogens are rational investments. FUNDING: Bill & Melinda Gates Foundation.

Diarrheal illness, a common occurrence among people living with human immunodeficiency virus (PLHIV), is largely preventable through access to safe drinking water quality, sanitation, and hygiene (WASH) facilities. We examined WASH characteristics among households with and without HIV-positive residents enrolled in the Global Enteric Multicenter Study (GEMS) in rural Western Kenya. Using univariable logistic regression, we examined differences between HIV-positive and HIV-negative households in regard to WASH practices. Among HIV-positive households, we explored the relationship between the length of time knowing their HIV status and GEMS enrollment. No statistically significant differences were apparent in the WASH characteristics among HIV-positive and HIV-negative households. However, we found differences in the WASH characteristics among HIV-positive households who were aware of their HIV status >/= 30 days before enrollment compared with HIV-positive households who found out their status < 30 days before enrollment or thereafter. Significantly more households aware of their HIV-positive status before enrollment reported treating their drinking water (odds ratio [OR] confidence interval [CI]: 2.34 [1.12, 4.86]) and using effective water treatment methods (OR [CI]: 9.6 [3.09, 29.86]), and had better drinking water storage practices. This suggests that within this region of Kenya, HIV programs are effective in promoting the importance of practicing positive WASH-related behaviors among PLHIV.

Despite the fact that the 15 leading causes of global deaths and disability-adjusted life years are from conditions amenable to emergency care, and that this burden is highest in low-income and middle-income countries (LMICs), there is a paucity of research on LMIC emergency care to guide policy making, resource allocation and service provision. A literature review of the 550 articles on LMIC emergency care published in the 10-year period from 2007 to 2016 yielded 106 articles for LMIC emergency care surveillance and registry research. Few articles were from established longitudinal surveillance or registries and primarily composed of short-term data collection. Using these articles, a working group was convened by the US National Institutes of Health Fogarty International Center to discuss challenges and potential solutions for established systems to better understand global emergency care in LMICs. The working group focused on potential uses for emergency care surveillance and registry data to improve the quality of services provided to patients. Challenges included a lack of dedicated resources for such research in LMIC settings as well as over-reliance on facility-based data collection without known correlation to the overall burden of emergency conditions in the broader community. The group outlined potential solutions including incorporating data from sources beyond traditional health records, use of standard clinical forms that embed data needed for research and policy making and structured population-based research to establish clear linkages between what is seen in emergency units and the wider community. The group then identified current gaps in LMIC emergency care surveillance and registry research to form a research agenda for the future.

Alternative sanitation options are needed for effective waste management in low-income countries where centralized, large-scale waste treatment is not easily achievable. A newly designed solar concentrator technology utilizes solar thermal energy to treat feces contained in drums. This pilot study assessed the efficacy of the new design to inactivate microbes in 13 treatment drums under field conditions in Kenya. Three-quarters of the drums contained <1000E. coli/g of total solids following 6h of solar thermal treatment and inactivation of thermotolerant C. perfringens spores ranged from <1.8 to >5.0log10. Nearly all (94%) samples collected from treatment drums achieved thermophilic temperatures (>50 degrees C) during the treatment period, however this alone did not ensure samples met the WHO E. coli guideline; higher, sustained thermophilic temperatures tended to be more effective in reaching this guideline. The newly designed solar concentrator was capable of inactivating thermotolerant, environmentally-stable microorganisms as, or possibly more, efficiently than a previous design. Additional data are needed to better characterize how temperature, time, and other parameters affect the ability of the solar concentrator to inactivate microbes in feces.

Background: Antibiotics are essential to treat for many childhood bacterial infections; however inappropriate antibiotic use contributes to antimicrobial resistance. For childhood diarrhea, empiric antibiotic use is recommended for dysentery (bloody diarrhea) for which first-line therapy is ciprofloxacin. We assessed inappropriate antibiotic prescription for childhood diarrhea in two primary healthcare facilities in Kenya. Methods: We analyzed data from the Kenya Population Based Infectious Disease Surveillance system in Asembo (rural, malaria-endemic) and Kibera (urban slum, non-malaria-endemic). We examined records of children aged 2-59 months with diarrhea (≥3 loose stools in 24 h) presenting for care from August 21, 2009 to May 3, 2016, excluding visits with non-diarrheal indications for antibiotics. We examined the frequency of antibiotic over-prescription (antibiotic prescription for non-dysentery), under-prescription (no antibiotic prescription for dysentery), and inappropriate antibiotic selection (non-recommended antibiotic). We examined factors associated with over-prescription and under-prescription using multivariate logistic regression with generalized estimating equations. Results: Of 2808 clinic visits with diarrhea in Asembo, 2685 (95.6%) were non-dysentery visits and antibiotic over-prescription occurred in 52.5%. Of 4697 clinic visits with diarrhea in Kibera, 4518 (96.2%) were non-dysentery and antibiotic over-prescription occurred in 20.0%. Antibiotic under-prescription was noted in 26.8 and 73.7% of dysentery cases in Asembo and Kibera, respectively. Ciprofloxacin was used for 11% of dysentery visits in Asembo and 0% in Kibera. Factors associated with over- and under-prescription varied by site. In Asembo a discharge diagnosis of gastroenteritis was associated with over-prescription (adjusted odds ratio [aOR]:8.23, 95% confidence interval [95%CI]: 3.68-18.4), while malaria diagnosis was negatively associated with antibiotic over-prescription (aOR 0.37, 95%CI: 0.25-0.54) but positively associated with antibiotic under-prescription (aOR: 1.82, 95%CI: 1.05-3.13). In Kibera, over-prescription was more common among visits with concurrent signs of respiratory infection (difficulty breathing; aOR: 3.97, 95%CI: 1.28-12.30, cough: aOR: 1.42, 95%CI: 1.06-1.90) and less common among children aged < 1 year (aOR: 0.82, 95%CI: 0.71-0.94). Conclusions: Inappropriate antibiotic prescription was common in childhood diarrhea management and efforts are needed to promote rational antibiotic use. Interventions to improve antibiotic use for diarrhea should consider the influence of malaria diagnosis on clinical decision-making and address both over-prescription, under-prescription, and inappropriate antibiotic selection.

BACKGROUND: Enterotoxigenic Escherichia coli (ETEC) encoding heat-stable enterotoxin (ST) alone or with heat-labile enterotoxin (LT) cause moderate-to-severe diarrhea (MSD) in developing country children. The Global Enteric Multicenter Study (GEMS) identified ETEC encoding ST among the top four enteropathogens. Since the GEMS objective was to provide evidence to guide development and implementation of enteric vaccines and other interventions to diminish diarrheal disease morbidity and mortality, we examined colonization factor (CF) prevalence among ETEC isolates from children age <5 years with MSD and from matched controls in four African and three Asian sites. We also assessed strength of association of specific CFs with MSD. METHODOLOGY/PRINCIPAL FINDINGS: MSD cases enrolled at healthcare facilities over three years and matched controls were tested in a standardized manner for many enteropathogens. To identify ETEC, three E. coli colonies per child were tested by polymerase chain reaction (PCR) to detect genes encoding LT, ST; confirmed ETEC were examined by PCR for major CFs (Colonization Factor Antigen I [CFA/I] or Coli Surface [CS] antigens CS1-CS6) and minor CFs (CS7, CS12, CS13, CS14, CS17, CS18, CS19, CS20, CS21, CS30). ETEC from 806 cases had a single toxin/CF profile in three tested strains per child. Major CFs, components of multiple ETEC vaccine candidates, were detected in 66.0% of LT/ST and ST-only cases and were associated with MSD versus matched controls by conditional logistic regression (p</=0.006); major CFs detected in only 25.0% of LT-only cases weren't associated with MSD. ETEC encoding exclusively CS14, identified among 19.9% of 291 ST-only and 1.5% of 259 LT/ST strains, were associated with MSD (p = 0.0011). No other minor CF exhibited prevalence >/=5% and significant association with MSD. CONCLUSIONS/SIGNIFICANCE: Major CF-based efficacious ETEC vaccines could potentially prevent up to 66% of pediatric MSD cases due to ST-encoding ETEC in developing countries; adding CS14 extends coverage to ~77%.

Given the challenges in accurately identifying unexposed controls in case-control studies of diarrhoea, we examined diarrhoea incidence, subclinical enteric infections and growth stunting within a reference population in the Global Enteric Multicenter Study, Kenya site. Within 'control' children (0-59 months old without diarrhoea in the 7 days before enrolment, n = 2384), we examined surveys at enrolment and 60-day follow-up, stool at enrolment and a 14-day post-enrolment memory aid for diarrhoea incidence. At enrolment, 19% of controls had 1 enteric pathogen associated with moderate-to-severe diarrhoea ('MSD pathogens') in stool; following enrolment, many reported diarrhoea (27% in 7 days, 39% in 14 days). Controls with and without reported diarrhoea had similar carriage of MSD pathogens at enrolment; however, controls reporting diarrhoea were more likely to report visiting a health facility for diarrhoea (27% vs. 7%) or fever (23% vs. 16%) at follow-up than controls without diarrhoea. Odds of stunting differed by both MSD and 'any' (including non-MSD pathogens) enteric pathogen carriage, but not diarrhoea, suggesting control classification may warrant modification when assessing long-term outcomes. High diarrhoea incidence following enrolment and prevalent carriage of enteric pathogens have implications for sequelae associated with subclinical enteric infections and for design and interpretation of case-control studies examining diarrhoea.

BACKGROUND: Cryptosporidium is a leading cause of moderate-to-severe diarrhea (MSD) in young children in Africa. We examined factors associated with Cryptosporidium infection in MSD cases enrolled at the rural western Kenya Global Enteric Multicenter Study (GEMS) site from 2008-2012. METHODOLOGY/PRINCIPAL FINDINGS: At health facility enrollment, stool samples were tested for enteric pathogens and data on clinical, environmental, and behavioral characteristics collected. Each child's health status was recorded at 60-day follow-up. Data were analyzed using logistic regression. Of the 1,778 children with MSD enrolled as cases in the GEMS-Kenya case-control study, 11% had Cryptosporidium detected in stool by enzyme immunoassay; in a genotyped subset, 81% were C. hominis. Among MSD cases, being an infant, having mucus in stool, and having prolonged/persistent duration diarrhea were associated with being Cryptosporidium-positive. Both boiling drinking water and using rainwater as the main drinking water source were protective factors for being Cryptosporidium-positive. At follow-up, Cryptosporidium-positive cases had increased odds of being stunted (adjusted odds ratio [aOR] = 1.65, 95% CI: 1.06-2.57), underweight (aOR = 2.08, 95% CI: 1.34-3.22), or wasted (aOR = 2.04, 95% CI: 1.21-3.43), and had significantly larger negative changes in height- and weight-for-age z-scores from enrollment. CONCLUSIONS/SIGNIFICANCE: Cryptosporidium contributes significantly to diarrheal illness in young children in western Kenya. Advances in point of care detection, prevention/control approaches, effective water treatment technologies, and clinical management options for children with cryptosporidiosis are needed.

BACKGROUND: From December 2014 to September 2016, a cholera outbreak in Kenya, the largest since 2010, caused 16,840 reported cases and 256 deaths. The outbreak affected 30 of Kenya's 47 counties and occurred shortly after the decentralization of many healthcare services to the county level. This mixed-methods study, conducted June-July 2015, assessed cholera preparedness in Homa Bay, Nairobi, and Mombasa counties and explored clinic- and community-based health care workers' (HCW) experiences during outbreak response. METHODS: Counties were selected based on cumulative cholera burden and geographic characteristics. We conducted 44 health facility cholera preparedness checklists (according to national guidelines) and 8 focus group discussions (FGDs). Frequencies from preparedness checklists were generated. To determine key themes from FGDs, inductive and deductive codes were applied; MAX software for qualitative data analysis (MAXQDA) was used to identify patterns. RESULTS: Some facilities lacked key materials for treating cholera patients, diagnosing cases, and maintaining infection control. Overall, 82% (36/44) of health facilities had oral rehydration salts, 65% (28/43) had IV fluids, 27% (12/44) had rectal swabs, 11% (5/44) had Cary-Blair transport media, and 86% (38/44) had gloves. A considerable number of facilities lacked disease reporting forms (34%, 14/41) and cholera treatment guidelines (37%, 16/43). In FDGs, HCWs described confusion regarding roles and reporting during the outbreak, which highlighted issues in coordination and management structures within the health system. Similar to checklist findings, FGD participants described supply challenges affecting laboratory preparedness and infection prevention and control. Perceived successes included community engagement, health education, strong collaboration between clinic and community HCWs, and HCWs' personal passion to help others. CONCLUSIONS: The confusion over roles, reporting, and management found in this evaluation highlights a need to adapt, implement, and communicate health strategies at the county level, in order to inform and train HCWs during health system transformations. International, national, and county stakeholders could strengthen preparedness and response for cholera and other public health emergencies in Kenya, and thereby strengthen global health security, through further investment in the existing Integrated Disease Surveillance and Response structure and national cholera prevention and control plan, and the adoption of county-specific cholera control plans.

Cryptosporidium is a leading cause of diarrhea among Kenyan infants. Ceramic water filters (CWFs) are used for household water treatment. We assessed the impact of CWFs on diarrhea, cryptosporidiosis prevention, and water quality in rural western Kenya. A randomized, controlled intervention trial was conducted in 240 households with infants 4-10 months old. Twenty-six weekly household surveys assessed infant diarrhea and health facility visits. Stool specimens from infants with diarrhea were examined for Cryptosporidium. Source water, filtered water, and filter retentate were tested for Cryptosporidium and/or microbial indicators. To estimate the effect of CWFs on health outcomes, logistic regression models using generalized estimating equations were performed; odds ratios (ORs) and 95% confidence intervals (CIs) are reported. Households reported using surface water (36%), public taps (29%), or rainwater (17%) as their primary drinking water sources, with no differences in treatment groups. Intervention households reported less diarrhea (7.6% versus 8.9%; OR: 0.86 [0.64-1.16]) and significantly fewer health facility visits for diarrhea (1.0% versus 1.9%; OR: 0.50 [0.30-0.83]). In total, 15% of intervention and 12% of control stools yielded Cryptosporidium (P = 0.26). Escherichia coli was detected in 93% of source water samples; 71% of filtered water samples met World Health Organization recommendations of < 1 E. coli/100 mL. Cryptosporidium was not detected in source water and was detected in just 2% of filter rinses following passage of large volumes of source water. Water quality was improved among CWF users; however, the short study duration and small sample size limited our ability to observe reductions in cryptosporidiosis.

In an environment of constrained resources, policymakers must identify solutions for financing and delivering health services that are efficient and sustainable. However, such solutions require that policymakers understand the complex interaction between household utilization patterns, factors influencing household medical decisions, and provider performance. This study examined whether and under what conditions out-of-pocket, transportation, and time costs influenced Kenyan households' choice of medical provider for childhood diarrhoeal illnesses. It compared these decisions with the actual cost and quality of those providers to assess strategies for increasing the utilization of high quality, low-cost primary care. This study analyzed nationally-representative survey data through several multinomial nested logit models. On average, time costs accounted for the greatest share of total costs. Households spent the most time and transportation costs utilizing public care, yet were more likely to incur catastrophic time and out-of-pocket costs seeking private care for their child's diarrhoeal illness. Out-of-pocket, transportation, and time costs influenced households' choice of provider, though demand was cost inelastic and households were most responsive to transportation costs. Poorer households were the most responsive to changes in all cost types and most likely to self-treat or utilize informal care. Many households utilized informal care that, relative to formal care, cost the same but was of worse quality-suggesting that such households were making poor medical decisions for their children. To achieve public policy objectives, such as financial risk protection for childhood illnesses and equitable access to primary care, policymakers could focus on three areas: (1) refine financing strategies for further reducing household out-of-pocket costs; (2) reduce or subsidize time and transportation costs for households seeking public and private care; and (3) increase transparency of costs and quality to improve household decisions.

The second author’s name is spelled incorrectly. The correct name is: Andrew M. Foote. The correct citation is: Nyoka R, Foote AM, Woods E, Lokey H, O’Reilly CE, Magumba F, et al. (2017) Sanitation practices and perceptions in Kakuma refugee camp, Kenya: Comparing the status quo with a novel service-based approach. PLoS ONE 12(7): e0180864.

BACKGROUND: Diarrheal disease remains among the leading causes of global mortality in children younger than 5 years. Exposure to domestic animals may be a risk factor for diarrheal disease. The objectives of this study were to identify animal-related exposures associated with cases of moderate-to-severe diarrhea (MSD) in children in rural western Kenya, and to identify the major zoonotic enteric pathogens present in domestic animals residing in the homesteads of case and control children. METHODOLOGY/PRINCIPAL FINDINGS: We characterized animal-related exposures in a subset of case and control children (n = 73 pairs matched on age, sex and location) with reported animal presence at home enrolled in the Global Enteric Multicenter Study in western Kenya, and analysed these for an association with MSD. We identified potentially zoonotic enteric pathogens in pooled fecal specimens collected from domestic animals resident at children's homesteads. Variables that were associated with decreased risk of MSD were washing hands after animal contact (matched odds ratio [MOR] = 0.2; 95% CI 0.08-0.7), and presence of adult sheep that were not confined in a pen overnight (MOR = 0.1; 0.02-0.5). Variables that were associated with increased risk of MSD were increasing number of sheep owned (MOR = 1.2; 1.0-1.5), frequent observation of fresh rodent excreta (feces/urine) outside the house (MOR = 7.5; 1.5-37.2), and participation of the child in providing water to chickens (MOR = 3.8; 1.2-12.2). Of 691 pooled specimens collected from 2,174 domestic animals, 159 pools (23%) tested positive for one or more potentially zoonotic enteric pathogens (Campylobacter jejuni, C. coli, non-typhoidal Salmonella, diarrheagenic E. coli, Giardia, Cryptosporidium, or rotavirus). We did not find any association between the presence of particular pathogens in household animals, and MSD in children. CONCLUSIONS AND SIGNIFICANCE: Public health agencies should continue to promote frequent hand washing, including after animal contact, to reduce the risk of MSD. Future studies should address specific causal relations of MSD with sheep and chicken husbandry practices, and with the presence of rodents.

Diarrheal disease is a leading cause of death among young children worldwide. As rates of acute diarrhea (AD; 1-6 days duration) have decreased, persistent diarrhea (PD; > 14 days duration) accounts for a greater proportion of the diarrheal disease burden. We describe factors associated with the duration of moderate-to-severe diarrhea in Kenyan children < 5 years old enrolled in the Global Enteric Multicenter Study. We found 587 (58%) children experienced AD, 360 (35%) had prolonged acute diarrhea (ProAD; 7-13 days duration), and 73 (7%) had PD. We constructed a Cox proportional hazards model to identify factors associated with diarrheal duration. Risk factors independently associated with longer diarrheal duration included infection with Cryptosporidium (hazard ratio [HR]: 0.868, P = 0.035), using an unimproved drinking water source (HR: 0.87, P = 0.035), and being stunted at enrollment (HR: 0.026, P < 0.0001). Diarrheal illness of extended duration appears to be multifactorial; given its association with adverse health and development outcomes, effective strategies should be implemented to reduce the duration and severity of diarrheal illness. Effective treatments for Cryptosporidium should be identified, interventions to improve drinking water are imperative, and nutrition should be improved through exclusive breastfeeding in infants ≤ 6 months and appropriate continued feeding practices for ill children.

Globally, an estimated 2.5 billion people lack access to improved sanitation. Unimproved sanitation increases the risk of morbidity and mortality, especially in protracted refugee situations where sanitation is based on pit latrine use. Once the pit is full, waste remains in the pit, necessitating the construction of a new latrine, straining available land and funding resources. A viable, sustainable solution is needed. This study used qualitative and quantitative methods to design, implement, and pilot a novel sanitation system in Kakuma refugee camp, Kenya. An initial round of 12 pre-implementation focus group discussions (FGDs) were conducted with Dinka and Somali residents to understand sanitation practices, perceptions, and needs. FGDs and a supplementary pre-implementation survey informed the development of an innovative sanitation management system that incorporated the provision of urine and liquid-diverting toilets, which separate urine and fecal waste, and a service-based sanitation system that included weekly waste collection. The new system was implemented on a pilot scale for 6 weeks. During the implementation, bi-weekly surveys were administered in each study household to monitor user perceptions and challenges. At the end of the pilot, the sanitation system was assessed using a second round of four post-implementation FGDs. Those who piloted the new sanitation system reported high levels of user satisfaction. Reported benefits included odor reduction, insect/pest reduction, the sitting design, the appropriateness for special populations, and waste collection. However, urine and liquid diversion presented a challenge for users who perform anal washing and for women who had experienced female genital mutilation. Refugee populations are often culturally and ethnically diverse. Using residents' input to inform the development of sanitation solutions can increase user acceptability and provide opportunities to improve sanitation system designs based on specific needs.

OBJECTIVE: To evaluate factors associated with rotavirus diarrhea and to describe severity of illness among children <5 years old with non-dysenteric, moderate-to-severe diarrhea (MSD) in rural western Kenya. METHODS: We analyzed data from children <5 years old with non-dysenteric MSD enrolled as cases in the Global Enteric Multicenter Study (GEMS) in Kenya. A non-dysenteric MSD case was defined as a child with ≥3 loose stools in 24 hrs. and one or more of the following: sunken eyes, skin tenting, intravenous rehydration, or hospitalization, who sought care at a sentinel health center within 7 days of illness onset. Rotavirus antigens in stool samples were detected by ELISA. Demographic and clinical information was collected at enrollment and during a single follow-up home visit at approximately 60 days. We analyzed diarrhea severity using a GEMS 17 point numerical scoring system adapted from the Vesikari score. We used logistic regression to evaluate factors associated with rotavirus infection. RESULTS: From January 31, 2008 to September 30, 2012, among 1,637 (92%) non-dysenteric MSD cases, rotavirus was detected in stools of 245 (15.0%). Rotavirus-positive compared with negative cases were: younger (median age, 8 vs. 13 months; p<0.0001), had more severe illness (median severity score, 9 vs 8; p<0.0001) and had to be hospitalized more frequently (37/245 [15.1%] vs. 134/1,392 [9.6%]), p <0.013). Independent factors associated with rotavirus infection included age 0-11 months old (aOR = 5.29, 95% CI 3.14-8.89) and presenting with vomiting ≥3 times/24hrs (aOR = 2.58, 95% CI [1.91-3.48]). Rotavirus was detected more commonly in warm and dry months than in the cool and rainy months (142/691 [20%] vs 70/673 [10%]) p<0.0001). CONCLUSIONS: Diarrhea caused by rotavirus is associated with severe symptoms leading to hospitalization. Consistent with other settings, infants had the greatest burden of disease.

BACKGROUND: The importance of Cryptosporidium as a pediatric enteropathogen in developing countries is recognized. METHODS: Data from the Global Enteric Multicenter Study (GEMS), a 3-year, 7-site, case-control study of moderate-to-severe diarrhea (MSD) and GEMS-1A (1-year study of MSD and less-severe diarrhea [LSD]) were analyzed. Stools from 12,110 MSD and 3,174 LSD cases among children aged <60 months and from 21,527 randomly-selected controls matched by age, sex and community were immunoassay-tested for Cryptosporidium. Species of a subset of Cryptosporidium-positive specimens were identified by PCR; GP60 sequencing identified anthroponotic C. parvum. Combined annual Cryptosporidium-attributable diarrhea incidences among children aged <24 months for African and Asian GEMS sites were extrapolated to sub-Saharan Africa and South Asian regions to estimate region-wide MSD and LSD burdens. Attributable and excess mortality due to Cryptosporidium diarrhea were estimated. FINDINGS: Cryptosporidium was significantly associated with MSD and LSD below age 24 months. Among Cryptosporidium-positive MSD cases, C. hominis was detected in 77.8% (95% CI, 73.0%-81.9%) and C. parvum in 9.9% (95% CI, 7.1%-13.6%); 92% of C. parvum tested were anthroponotic genotypes. Annual Cryptosporidium-attributable MSD incidence was 3.48 (95% CI, 2.27-4.67) and 3.18 (95% CI, 1.85-4.52) per 100 child-years in African and Asian infants, respectively, and 1.41 (95% CI, 0.73-2.08) and 1.36 (95% CI, 0.66-2.05) per 100 child-years in toddlers. Corresponding Cryptosporidium-attributable LSD incidences per 100 child-years were 2.52 (95% CI, 0.33-5.01) and 4.88 (95% CI, 0.82-8.92) in infants and 4.04 (95% CI, 0.56-7.51) and 4.71 (95% CI, 0.24-9.18) in toddlers. We estimate 2.9 and 4.7 million Cryptosporidium-attributable cases annually in children aged <24 months in the sub-Saharan Africa and India/Pakistan/Bangladesh/Nepal/Afghanistan regions, respectively, and ~202,000 Cryptosporidium-attributable deaths (regions combined). ~59,000 excess deaths occurred among Cryptosporidium-attributable diarrhea cases over expected if cases had been Cryptosporidium-negative. CONCLUSIONS: The enormous African/Asian Cryptosporidium disease burden warrants investments to develop vaccines, diagnostics and therapies.

BACKGROUND: Diarrheal disease is the second leading cause of disease in children less than 5 y of age. Poor water, sanitation, and hygiene conditions are the primary routes of exposure and infection. Sanitation and hygiene interventions are estimated to generate a 36% and 48% reduction in diarrheal risk in young children, respectively. Little is known about whether the number of households sharing a sanitation facility affects a child's risk of diarrhea. The objective of this study was to describe sanitation and hygiene access across the Global Enteric Multicenter Study (GEMS) sites in Africa and South Asia and to assess sanitation and hygiene exposures, including shared sanitation access, as risk factors for moderate-to-severe diarrhea (MSD) in children less than 5 y of age. METHODS/FINDINGS: The GEMS matched case-control study was conducted between December 1, 2007, and March 3, 2011, at seven sites in Basse, The Gambia; Nyanza Province, Kenya; Bamako, Mali; Manhica, Mozambique; Mirzapur, Bangladesh; Kolkata, India; and Karachi, Pakistan. Data was collected for 8,592 case children aged <5 y old experiencing MSD and for 12,390 asymptomatic age, gender, and neighborhood-matched controls. An MSD case was defined as a child with a diarrheal illness <7 d duration comprising ≥3 loose stools in 24 h and ≥1 of the following: sunken eyes, skin tenting, dysentery, intravenous (IV) rehydration, or hospitalization. Site-specific conditional logistic regression models were used to explore the association between sanitation and hygiene exposures and MSD. Most households at six sites (>93%) had access to a sanitation facility, while 70% of households in rural Kenya had access to a facility. Practicing open defecation was a risk factor for MSD in children <5 y old in Kenya. Sharing sanitation facilities with 1-2 or ≥3 other households was a statistically significant risk factor for MSD in Kenya, Mali, Mozambique, and Pakistan. Among those with a designated handwashing area near the home, soap or ash were more frequently observed at control households and were significantly protective against MSD in Mozambique and India. CONCLUSIONS: This study suggests that sharing a sanitation facility with just one to two other households can increase the risk of MSD in young children, compared to using a private facility. Interventions aimed at increasing access to private household sanitation facilities may reduce the burden of MSD in children. These findings support the current World Health Organization/ United Nations Children's Emergency Fund (UNICEF) system that categorizes shared sanitation as unimproved.

In the developing world, fetching water for drinking and other household uses is a substantial burden that affects water quantity and quality in the household. We used logistic regression to examine whether reported household water fetching times were a risk factor for moderate-to-severe diarrhea (MSD) using case-control data of 3,359 households from the Global Enterics Multi-Center Study in Kenya in 2009-2011. We collected additional global positioning system (GPS) data for a subset of 254 randomly selected households and compared GPS-based straight line and actual travel path distances to fetching times reported by respondents. GPS-based data were highly correlated with respondent-provided times (Spearman correlation coefficient = 0.81, P < 0.0001). The median estimated one-way distance to water source was 200 m for cases and 171 for controls (Wilcoxon rank sums/Mann-Whitney P = 0.21). A round-trip fetching time of > 30 minutes was reported by 25% of cases versus 15% of controls and was significantly associated with MSD where rainwater was not used in the last 2 weeks (odds ratio = 1.97, 95% confidence interval = 1.56-2.49). These data support the United Nations definition of access to an improved water source being within 30 minutes total round-trip travel time.

On January 6, 2015, a man aged 40 years was admitted to Kenyatta National Hospital in Nairobi, Kenya, with acute watery diarrhea. The patient was found to be infected with toxigenic Vibrio cholerae serogroup O1, serotype Inaba. A subsequent review of surveillance reports identified four patients in Nairobi County during the preceding month who met either of the Kenya Ministry of Health suspected cholera case definitions: 1) severe dehydration or death from acute watery diarrhea (more than four episodes in 12 hours) in a patient aged ≥5 years, or 2) acute watery diarrhea in a patient aged ≥2 years in an area where there was an outbreak of cholera. An outbreak investigation was immediately initiated. A confirmed cholera case was defined as isolation of V. cholerae O1 or O139 from the stool of a patient with suspected cholera or a suspected cholera case that was epidemiologically linked to a confirmed case. By January 15, 2016, a total of 11,033 suspected or confirmed cases had been reported from 22 of Kenya's 47 counties. The outbreak is ongoing.

Populations living in informal settlements with inadequate water and sanitation infrastructure are at risk of epidemic disease. In 2010, we conducted 398 household surveys in two informal settlements in Nairobi, Kenya with isolated cholera cases. We tested source and household water for free chlorine residual (FCR) and Escherichia coli in approximately 200 households. International guidelines are ≥0.5 mg/L FCR at source, ≥0.2 mg/L at household, and <1 E. coli/100 mL. In these two settlements, 82% and 38% of water sources met FCR guidelines; and 7% and 8% were contaminated with E. coli, respectively. In household stored water, 82% and 35% met FCR guidelines and 11% and 32% were contaminated with E. coli, respectively. Source water FCR ≥0.5 mg/L (p = 0.003) and reported purchase of a household water treatment product (p = 0.002) were associated with increases in likelihood that household stored water had ≥0.2 mg/L FCR, which was associated with a lower likelihood of E. coli contamination (p < 0.001). These results challenge the assumption that water quality in informal settlements is universally poor and the route of disease transmission, and highlight that providing centralized water with ≥0.5 mg/L FCR or (if not feasible) household water treatment technologies reduces the risk of waterborne cholera transmission in informal settlements.

In 2009, basic care packages (BCP) containing health products were distributed to HIV-infected persons in Ethiopia who were clients of antiretroviral therapy clinics. To measure health impact, we enrolled clients from an intervention hospital and comparison hospital, and then conducted a baseline survey, and 7 bi-weekly home visits. We enrolled 405 intervention group clients and 344 comparison clients. Intervention clients were more likely than comparison clients to have detectable chlorine in stored water (40% vs. 1%, p<0.001), soap (51% vs. 36%, p<0.001), and a BCP water container (65% vs. 0%, p<0.001) at every home visit. Intervention clients were less likely than comparison clients to report illness (44% vs. 67%, p<0.001) or health facility visits for illness (74% vs. 95%, p<0.001), and had lower median illness scores (1.0 vs. 3.0, p<0.05). Participation in the BCP program appeared to improve reported health outcomes.