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Diarrhoea is the second leading cause of mortality in children worldwide, but establishing the cause can be complicated by diverse diagnostic approaches and varying test characteristics. We used quantitative molecular diagnostic methods to reassess causes of diarrhoea in the Global Enteric Multicenter Study (GEMS). GEMS was a study of moderate to severe diarrhoea in children younger than 5 years in Africa and Asia. We used quantitative real-time PCR (qPCR) to test for 32 enteropathogens in stool samples from cases and matched asymptomatic controls from GEMS, and compared pathogen-specific attributable incidences with those found with the original GEMS microbiological methods, including culture, EIA, and reverse-transcriptase PCR. We calculated revised pathogen-specific burdens of disease and assessed causes in individual children. We analysed 5304 sample pairs. For most pathogens, incidence was greater with qPCR than with the original methods, particularly for adenovirus 40/41 (around five times), Shigella spp or enteroinvasive Escherichia coli (EIEC) and Campylobactor jejuni o C coli (around two times), and heat-stable enterotoxin-producing E coli ([ST-ETEC] around 1·5 times). The six most attributable pathogens became, in descending order, Shigella spp, rotavirus, adenovirus 40/41, ST-ETEC, Cryptosporidium spp, and Campylobacter spp. Pathogen-attributable diarrhoeal burden was 89·3% (95% CI 83·2–96·0) at the population level, compared with 51·5% (48·0–55·0) in the original GEMS analysis. The top six pathogens accounted for 77·8% (74·6–80·9) of all attributable diarrhoea. With use of model-derived quantitative cutoffs to assess individual diarrhoeal cases, 2254 (42·5%) of 5304 cases had one diarrhoea-associated pathogen detected and 2063 (38·9%) had two or more, with Shigella spp and rotavirus being the pathogens most strongly associated with diarrhoea in children with mixed infections. A quantitative molecular diagnostic approach improved population-level and case-level characterisation of the causes of diarrhoea and indicated a high burden of disease associated with six pathogens, for which targeted treatment should be prioritised. Bill & Melinda Gates Foundation.

We estimated the prevalence of extended-spectrum cephalosporin-resistant Enterobacterales (ESCrE), carbapenem-resistant Enterobacterales (CRE), and methicillin-resistant Staphylococcus aureus (MRSA) in communities and hospitals in Kenya to identify human colonization with multidrug-resistant bacteria. Nasal and fecal specimen were collected from inpatients and community residents in Nairobi (urban) and Siaya (rural) counties. Swabs were plated on chromogenic agar to presumptively identify ESCrE, CRE and MRSA isolates. Confirmatory identification and antibiotic susceptibility testing were done using the VITEK®2 instrument. A total of 1999 community residents and 1023 inpatients were enrolled between January 2019 and March 2020. ESCrE colonization was higher in urban than rural communities (52 vs. 45%; P  = 0.013) and in urban than rural hospitals (70 vs. 63%; P  = 0.032). Overall, ESCrE colonization was ~ 18% higher in hospitals than in corresponding communities. CRE colonization was higher in hospital than community settings (rural: 7 vs. 1%; urban: 17 vs. 1%; with non-overlapping 95% confidence intervals), while MRSA was rarely detected (≤ 3% overall). Human colonization with ESCrE and CRE was common, particularly in hospitals and urban settings. MRSA colonization was uncommon. Evaluation of risk factors and genetic mechanisms of resistance can guide prevention and control efforts tailored to different environments.

Background Adolescent girls in sub-Saharan Africa are disproportionally vulnerable to sexual and reproductive health (SRH) harms. In western Kenya, where unprotected transactional sex is common, young females face higher rates of school dropout, often due to pregnancy, and sexually transmitted infections (STIs), including HIV. Staying in school has shown to protect girls against early marriage, teen pregnancy, and HIV infection. This study evaluates the impact of menstrual cups and cash transfer interventions on a composite of deleterious outcomes (HIV, HSV-2, and school dropout) when given to secondary schoolgirls in western Kenya, with the aim to inform evidence-based policy to improve girls’ health, school equity, and life-chances. Methods Single site, 4-arm, cluster randomised controlled superiority trial. Secondary schools are the unit of randomisation, with schoolgirls as the unit of measurement. Schools will be randomised into one of four intervention arms using a 1:1:1:1 ratio and block randomisation: (1) menstrual cup arm; (2) cash transfer arm, (3) cups and cash combined intervention arm, or (4) control arm. National and county agreement, and school level consent will be obtained prior to recruitment of schools, with parent consent and girls’ assent obtained for participant enrolment. Participants will be trained on safe use of interventions, with all arms receiving puberty and hygiene education. Annually, the state of latrines, water availability, water treatment, handwashing units and soap in schools will be measured. The primary endpoint is a composite of incident HIV, HSV-2, and all-cause school dropout, after 3 years follow-up. School dropout will be monitored each term via school registers and confirmed through home visits. HIV and HSV-2 incident infections and risk factors will be measured at baseline, mid-line and end-line. Intention to treat analysis will be conducted among all enrolled participants. Focus group discussions will provide contextual information on uptake of interventions. Monitoring for safety will occur throughout. Discussion If proved safe and effective, the interventions offer a potential contribution toward girls’ schooling, health, and equity in low- and middle-income countries. Trial registration ClinicalTrials.gov NCT03051789 , 15th February 2017.

Little is known about enteropathogen seroepidemiology among children in low-resource settings. We measured serological IgG responses to eight enteropathogens (Giardia intestinalis, Cryptosporidium parvum, Entamoeba histolytica, Salmonella enterica, enterotoxigenic Escherichia coli, Vibrio cholerae, Campylobacter jejuni, norovirus) in cohorts from Haiti, Kenya, and Tanzania. We studied antibody dynamics and force of infection across pathogens and cohorts. Enteropathogens shared common seroepidemiologic features that enabled between-pathogen comparisons of transmission. Overall, exposure was intense: for most pathogens the window of primary infection was <3 years old; for highest transmission pathogens primary infection occurred within the first year. Longitudinal profiles demonstrated significant IgG boosting and waning above seropositivity cutoffs, underscoring the value of longitudinal designs to estimate force of infection. Seroprevalence and force of infection were rank-preserving across pathogens, illustrating the measures provide similar information about transmission heterogeneity. Our findings suggest antibody response can be used to measure population-level transmission of diverse enteropathogens in serologic surveillance. Diarrhea, which is caused by bacteria such as Salmonella or by viruses like norovirus, is the fourth leading cause of death among children worldwide, with children in low-resource settings being at highest risk. The pathogens that cause diarrhea spread when stool from infected people comes into contact with new hosts, for example, through inadequate sanitation or by drinking contaminated water. Currently, the best way to track these infections is to collect stool samples from people and test them for the presence of the pathogens. Unfortunately, this is costly and difficult to do on a large scale outside of clinical settings, making it hard to track the spread of diarrhea-causing pathogens. The body produces antibodies – small proteins that can detect specific pathogens – in response to an infection. These antibodies help ward off future infections by the same pathogen, so if they are present in the blood, this indicates a current or previous infection. Scientists already collect blood samples to track malaria, HIV and vaccine-preventable diseases in low-resource settings. These samples could be tested more broadly to measure the levels of antibodies against diarrhea-causing pathogens. Now, Arnold et al. have used blood samples collected from children in Haiti, Kenya, and Tanzania to measure antibody responses to 8 diarrhea-causing pathogens. The results showed that many children in these settings had been infected with all 8 pathogens before age three, and that all of the pathogens shared similar age-dependent patterns of antibody response. This finding enabled Arnold et al. to combine antibody measurements with statistical models to estimate each pathogen’s force of infection, that is, the rate at which susceptible individuals in the population become infected. This is a key step for epidemiologists to understand which pathogens cause the most infections in a population. The experiments show that testing blood samples for antibodies could provide scientists with a new tool to track the transmission of diarrhea-causing pathogens in low-resource settings. This information could help public health officials design and test efforts to prevent diarrhea, for example, by improving water treatment or developing vaccines.

Non-typhoidal Salmonella (NTS) is a leading cause of bloodstream infections in Africa, but the various contributions of host susceptibility versus unique pathogen virulence factors are unclear. We used data from a population-based surveillance platform (population ~25,000) between 2007-2014 and NTS genome-sequencing to compare host and pathogen-specific factors between individuals presenting with NTS bacteremia and those presenting with NTS diarrhea. Salmonella Typhimurium ST313 and Salmonella Enteritidis ST11 were the most common isolates. Multi-drug resistant strains of NTS were more commonly isolated from patients presenting with NTS bacteremia compared to NTS diarrhea. This relationship was observed in patients under age five [aOR = 15.16, 95% CI (2.84-81.05), P = 0.001], in patients five years and older, [aOR = 6.70 95% CI (2.25-19.89), P = 0.001], in HIV-uninfected patients, [aOR = 21.61, 95% CI (2.53-185.0), P = 0.005], and in patients infected with Salmonella serogroup B [aOR = 5.96, 95% CI (2.28-15.56), P < 0.001] and serogroup D [aOR = 14.15, 95% CI (1.10-182.7), P = 0.042]. Thus, multi-drug-resistant NTS was strongly associated with bacteremia compared to diarrhea among children and adults. This association was seen in HIV-uninfected individuals infected with either S. Typhimurium or S. Enteritidis. Risk of developing bacteremia from NTS infection may be driven by virulence properties of the Salmonella pathogen.

Shigellosis is an ongoing global public health crisis with >270 million annual episodes among all age groups; however, the greatest disease burden is among children in low- and middle-income countries (LMIC). The lack of a licensed Shigella vaccine and the observed rise in antimicrobial-resistant Shigella spp. highlights the urgency for effective preventative and interventional strategies. The inclusion of S. flexneri serotype 6 ( Sf 6) is a necessary component of a multivalent vaccine strategies based on its clinical and epidemiological importance. Given the genomic diversity of Sf 6 compared with other S. flexneri serotypes and Sf 6 unique O-antigen core structure, serotype-specific characterization of Sf 6 is a critical step to inform Shigella -directed vaccine and alternative therapeutic designs. Herein, we identified conserved genomic content among a large collection of temporally and geographically diverse Sf 6 clinical isolates and characterized genotypic and phenotypic properties that separate Sf 6 from non- Sf 6 S. flexneri serotypes.

Background Kenya introduced the monovalent G1P [8] Rotarix® vaccine into the infant immunization schedule in July 2014. We examined trends in rotavirus group A (RVA) genotype distribution pre- (January 2010–June 2014) and post- (July 2014–December 2018) RVA vaccine introduction. Methods Stool samples were collected from children aged < 13 years from four surveillance sites across Kenya: Kilifi County Hospital, Tabitha Clinic Nairobi, Lwak Mission Hospital, and Siaya County Referral Hospital (children aged < 5 years only). Samples were screened for RVA using enzyme linked immunosorbent assay (ELISA) and VP7 and VP4 genes sequenced to infer genotypes. Results We genotyped 614 samples in pre-vaccine and 261 in post-vaccine introduction periods. During the pre-vaccine introduction period, the most frequent RVA genotypes were G1P [8] (45.8%), G8P [4] (15.8%), G9P [8] (13.2%), G2P [4] (7.0%) and G3P [6] (3.1%). In the post-vaccine introduction period, the most frequent genotypes were G1P [8] (52.1%), G2P [4] (20.7%) and G3P [8] (16.1%). Predominant genotypes varied by year and site in both pre and post-vaccine periods. Temporal genotype patterns showed an increase in prevalence of vaccine heterotypic genotypes, such as the commonly DS-1-like G2P [4] (7.0 to 20.7%, P  < .001) and G3P [8] (1.3 to 16.1%, P  < .001) genotypes in the post-vaccine introduction period. Additionally, we observed a decline in prevalence of genotypes G8P [4] (15.8 to 0.4%, P  < .001) and G9P [8] (13.2 to 5.4%, P  < .001) in the post-vaccine introduction period. Phylogenetic analysis of genotype G1P [8], revealed circulation of strains of lineages G1-I, G1-II and P [8]-1, P [8]-III and P [8]-IV. Considerable genetic diversity was observed between the pre and post-vaccine strains, evidenced by distinct clusters. Conclusion Genotype prevalence varied from before to after vaccine introduction. Such observations emphasize the need for long-term surveillance to monitor vaccine impact. These changes may represent natural secular variation or possible immuno-epidemiological changes arising from the introduction of the vaccine. Full genome sequencing could provide insights into post-vaccine evolutionary pressures and antigenic diversity.

ObjectivesTo evaluate how postmortem anthropometric malnutrition (PAM) measures align with expert panel attribution of malnutrition as a causal or significant condition in under-5 mortality (U5M).DesignCohort study using data from the Child Health and Mortality Prevention Surveillance network, incorporating clinical records, postmortem anthropometrics, minimally invasive tissue sampling, clinical abstraction and verbal autopsy to determine multiple causes of death.Setting/participants1405 deaths of children aged 1–59 months from six African countries between 2016 and 2023.Primary and secondary outcome measuresPAM was determined using z-scores from the WHO Child Growth Standards: underweight (weight-for-age<(−2)), wasting (arm circumference-for-age or weight-for-length<(−2)) and stunting (length-for-age <(−2)). Performance metrics (sensitivity (SE), specificity (SP) and positive predictive values (PPV)) were calculated to determine the alignment between PAM and expert panel attribution of malnutrition as a causal or significant condition to death.ResultsNearly 75% of cases demonstrated moderate-to-severe malnutrition by PAM, while expert panels attributed malnutrition in 41% of cases. Performance metrics varied across anthropometric indices: underweight exhibited the highest SE (89.7%), while wasting based on arm circumference had the highest SP (81.9%) and PPV (76.8%). Discrepancies between PAM classification and expert panel attribution differed significantly by site, age, location of death and preventability of death (p<0.05). Adjusted multivariate regression showed that expert panel attribution was more likely with increasing severity of PAM.ConclusionsThe proportion of U5M attributable to malnutrition ranged between 41% (expert panel attribution) and 74% (PAM). Variability in classification underscores the need for monitoring and quality improvement measures to address discrepancies. Improved alignment between PAM and panel assessments is essential for accurately identifying malnutrition-related deaths and designing effective interventions to reduce U5M.

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. 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. 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 Rotavirus vaccine was introduced in Kenya immunization program in July 2014. Pre-vaccine disease burden estimates are important for assessing vaccine impact. Methods Children with acute gastroenteritis (AGE) (≥3 loose stools and/or ≥ 1 episode of unexplained vomiting followed by loose stool within a 24-h period), hospitalized in Siaya County Referral Hospital (SCRH) from January 2010 through December 2013 were enrolled. Stool specimens were tested for rotavirus (RV) using an enzyme immunoassay (EIA). Hospitalization rates were calculated using person-years of observation (PYO) from the Health Demographic Surveillance System (HDSS) as a denominator, while adjusting for healthcare utilization at household level and proportion of stool specimen collected from patients who met the case definition at the surveillance hospital. Mortality rates were calculated using PYO as the denominator and number of deaths estimated using total deaths in the HDSS, proportion of deaths attributed to diarrhoea by verbal autopsy (VA) and percent positive for rotavirus AGE (RVAGE) hospitalizations. Results Of 7760 all-cause hospitalizations among children < 5 years of age, 3793 (49%) were included in the analysis. Of these, 21% (805) had AGE; RV was detected in 143 (26%) of 541 stools tested. Among children < 5 years, the estimated hospitalization rates per 100,000 PYO for AGE and RVAGE were 2413 and 429, respectively. Mortality rate associated with AGE and RVAGE were 176 and 45 per 100,000 PYO, respectively. Conclusion AGE and RVAGE caused substantial health care burden (hospitalizations and deaths) before rotavirus vaccine introduction in Kenya.