Frequency of bystander exposure to antibiotics for enteropathogenic bacteria among young children in low-resource settings.

Children in low-resource settings carry enteric pathogens asymptomatically and are frequently treated with antibiotics, resulting in opportunities for pathogens to be exposed to antibiotics when not the target of treatment (i.e., bystander exposure). We quantified the frequency of bystander antibiotic exposures for enteric pathogens and estimated associations with resistance among children in eight low-resource settings. We analyzed 15,697 antibiotic courses from 1,715 children aged 0 to 2 y from the MAL-ED birth cohort. We calculated the incidence of bystander exposures and attributed exposures to respiratory and diarrheal illnesses. We associated bystander exposure with phenotypic susceptibility of E. coli isolates in the 30 d following exposure and at the level of the study site. There were 744.1 subclinical pathogen exposures to antibiotics per 100 child-years. Enteroaggregative Escherichia coli was the most frequently exposed pathogen, with 229.6 exposures per 100 child-years. Almost all antibiotic exposures for Campylobacter (98.8%), enterotoxigenic E. coli (95.6%), and typical enteropathogenic E. coli (99.4%), and the majority for Shigella (77.6%), occurred when the pathogens were not the target of treatment. Respiratory infections accounted for half (49.9%) and diarrheal illnesses accounted for one-fourth (24.6%) of subclinical enteric bacteria exposures to antibiotics. Bystander exposure of E. coli to class-specific antibiotics was associated with the prevalence of phenotypic resistance at the community level. Antimicrobial stewardship and illness-prevention interventions among children in low-resource settings would have a large ancillary benefit of reducing bystander selection that may contribute to antimicrobial resistance.

Azithromycin for Bacterial Watery Diarrhea: A Reanalysis of the AntiBiotics for Children With Severe Diarrhea (ABCD) Trial Incorporating Molecular Diagnostics.

BACKGROUND: Bacterial pathogens cause substantial diarrhea morbidity and mortality among children living in endemic settings, yet antimicrobial treatment is only recommended for dysentery or suspected cholera. METHODS: AntiBiotics for Children with severe Diarrhea was a 7-country, placebo-controlled, double-blind efficacy trial of azithromycin in children 2-23 months of age with watery diarrhea accompanied by dehydration or malnutrition. We tested fecal samples for enteric pathogens utilizing quantitative polymerase chain reaction to identify likely and possible bacterial etiologies and employed pathogen-specific cutoffs based on genomic target quantity in previous case-control diarrhea etiology studies to identify likely and possible bacterial etiologies. RESULTS: Among 6692 children, the leading likely etiologies were rotavirus (21.1%), enterotoxigenic Escherichia coli encoding heat-stable toxin (13.3%), Shigella (12.6%), and Cryptosporidium (9.6%). More than one-quarter (1894 [28.3%]) had a likely and 1153 (17.3%) a possible bacterial etiology. Day 3 diarrhea was less common in those randomized to azithromycin versus placebo among children with a likely bacterial etiology (risk difference [RD]likely, -11.6 [95% confidence interval {CI}, -15.6 to -7.6]) and possible bacterial etiology (RDpossible, -8.7 [95% CI, -13.0 to -4.4]) but not in other children (RDunlikely, -0.3% [95% CI, -2.9% to 2.3%]). A similar association was observed for 90-day hospitalization or death (RDlikely, -3.1 [95% CI, -5.3 to -1.0]; RDpossible, -2.3 [95% CI, -4.5 to -.01]; RDunlikely, -0.6 [95% CI, -1.9 to .6]). The magnitude of risk differences was similar among specific likely bacterial etiologies, including Shigella. CONCLUSIONS: Acute watery diarrhea confirmed or presumed to be of bacterial etiology may benefit from azithromycin treatment. CLINICAL TRIALS REGISTRATION: NCT03130114.

HIV Risk Behaviors and the Use of Geosocial Networking Dating Apps among Men Who have Sex with Men and Transgender Women in Lima, Peru: a Cross-Sectional Study.

Geosocial networking dating apps (GSN apps) are an increasingly widespread technology used by populations throughout the world to facilitate sexual encounters. Studies from a variety of settings suggest a possible association between GSN app use and HIV risk behaviors, including among sexual and gender minority populations such as men who have sex with men (MSM) and transgender women (TW). However, it remains unclear to what extent GSN apps play a causal role. We explored the relationship between GSN app use and sexual risk behaviors among MSM and TW in Lima, Peru by analyzing data from a multi-site cross-sectional survey assessing both general and partner-specific sexual behaviors. We performed bivariate analysis to estimate the association of GSN app use with different individual and partner-specific factors, then fit multivariable regression models adjusting for age and education. Among 741 total participants (698 MSM, 43 TW), 64% met at least one sex partner in the prior three months using a GSN app. GSN app users were significantly more likely to report engaging in HIV risk behaviors in general, including condomless receptive anal sex, group sex, transactional sex, and sex under the influence of alcohol or drugs. Having condomless anal sex with a given partner was not associated with meeting that partner via GSN app. These findings highlight GSN app users as a particularly vulnerable subpopulation among MSM and TW in Lima. GSN apps could provide a useful vehicle for targeted HIV prevention efforts for priority populations in Peru.

RESUMEN: Las aplicaciones de citas de redes geosociales (aplicaciones GSN) son una tecnología con creciente alcance en todo el mundo usadas para facilitar encuentros sexuales. Diferentes estudios sugieren una posible relación entre uso de aplicaciones GSN y comportamientos de riesgo para VIH entre hombres que tienen sexo con hombres (HSH) y mujeres transgénero (MT). No es claro hasta qué punto aplicaciones GSN tendrían un papel causal directo. Exploramos la relación entre uso de aplicaciones GSN y comportamientos sexuales de riesgo entre HSH y MT en Lima, Perú, analizando datos de una encuesta transversal que evaluó comportamientos sexuales en general y en parejas específicas. Realizamos análisis bivariable para estimar la asociación del uso de aplicaciones GSN con diferentes factores individuales y específicos de la pareja. También aplicamos modelos de regresión multivariables ajustados por edad y educación. Entre 741 participantes totales (698 HSH, 43 MT), 64% conoció al menos a una pareja sexual en los últimos tres meses mediante una aplicación GSN. Los usuarios de aplicaciones GSN fueron significativamente más propensos a reportar comportamientos de riesgo de VIH en general, incluyendo sexo anal receptivo sin condón, y sexo grupal, transaccional y bajo influencia de alcohol o drogas. Tener sexo anal sin condón con una pareja determinada no se asoció con conocer a esa pareja mediante aplicación GSN. Estos hallazgos muestran a usuarios de aplicaciones GSN como una subpoblación particularmente vulnerable entre HSH y MT en Lima. Aplicaciones GSN podrían ser útiles para iniciativas de prevención del VIH en poblaciones prioritarias en Perú.

Differences in Rotavirus Shedding and Duration by Infant Oral Rotavirus Vaccination Status in Dhaka, Bangladesh 2011 - 2014.

To evaluate how breakthrough rotavirus disease contributes to transmission, we examined the impact of rotavirus vaccination on fecal shedding and duration of illness. We used multivariable linear regression to analyze rotavirus quantity by RT-qPCR and duration among 184 episodes of rotavirus diarrhea positive by ELISA in the PROVIDE study. Vaccinated children had less fecal viral shedding compared to unvaccinated children (mean difference = -0.59 log copies per gram of stool, 95% CI: -0.99, -0.19). Duration of illness was on average 0.47 days (95% CI: -0.23, 1.17) shorter among vaccinated children. Rotarix vaccination reduces shedding burden among breakthrough cases of RVGE.

We estimated the effect of rotavirus vaccination on duration and quantity of rotavirus shed during rotavirus gastroenteritis in Bangladesh. Virus quantity was lower in symptomatic vaccinated children compared to symptomatic unvaccinated children, but differences in episode duration were small.

Burden of diarrhea and antibiotic use among children in low-resource settings preventable by Shigella vaccination: A simulation study.

BACKGROUND: Shigella is a leading cause of diarrhea and dysentery in children in low-resource settings, which is frequently treated with antibiotics. The primary goal of a Shigella vaccine would be to reduce mortality and morbidity associated with Shigella diarrhea. However, ancillary benefits could include reducing antibiotic use and antibiotic exposures for bystander pathogens carried at the time of treatment, specifically for fluoroquinolones and macrolides (F/M), which are the recommended drug classes to treat dysentery. The aim of the study was to quantify the reduction in Shigella attributable diarrhea, all diarrhea, and antibiotic use in the first 2 years of life that could be prevented by a Shigella vaccine. METHODS AND FINDINGS: We used data from the Etiology, Risk Factors, and Interactions of Enteric Infections and Malnutrition and the Consequences for Child Health and Development (MAL-ED) study, a birth cohort study that followed 1,715 children with twice weekly surveillance for enteric infections, illnesses, and antibiotic use for the first 2 years of life from November 2009 to February 2014 at 8 sites. We estimated the impact of 2 one-dose (6 or 9 months) and 3 two-dose (6 and 9 months, 9 and 12 months, and 12 and 15 months) Shigella vaccines on diarrheal episodes, overall antibiotic use, and F/M use. Further, we considered additional protection through indirect and boosting effects. We used Monte Carlo simulations to estimate the absolute and relative reductions in the incidence of diarrhea and antibiotic use comparing each vaccination scenario to no vaccination. We analyzed 9,392 diarrhea episodes and 15,697 antibiotic courses among 1,715 children in the MAL-ED birth cohort study. There were 273.8 diarrhea episodes, 30.6 shigellosis episodes, and 457.6 antibiotic courses per 100 child-years. A Shigella vaccine with a mean vaccine efficacy of 60% against severe disease given at 9 and 12 months prevented 10.6 (95% CI [9.5, 11.5]) Shigella diarrhea episodes of any severity per 100 child-years (relative 34.5% reduction), 3.0 (95% CI [2.5, 3.5]) F/M courses for Shigella treatment per 100 child-years (relative 35.8% reduction), and 5.6 (95% CI [5.0, 6.3]) antibiotic courses of any drug class for Shigella treatment per 100 child-years (relative 34.5% reduction). This translated to a relative 3.8% reduction in all diarrhea, a relative 2.8% reduction in all F/M courses, a relative 3.1% reduction in F/M exposures to bystander pathogens, and a relative 0.9% reduction in all antibiotic courses. These results reflect Shigella incidence and antibiotic use patterns at the 8 MAL-ED sites and may not be generalizable to all low-resource settings. CONCLUSIONS: Our simulation results suggest that a Shigella vaccine meeting WHO targets for efficacy could prevent about a third of Shigella diarrhea episodes, antibiotic use to treat shigellosis, and bystander exposures due to shigellosis treatment. However, the reductions in overall diarrhea episodes and antibiotic use are expected to be modest (<5%).

Association of Circulating Biomarkers with Growth and Cognitive Development in Rural Tanzania: A Secondary Analysis of the Early Life Interventions in Childhood Growth and Development In Tanzania (ELICIT) Study.

BACKGROUND: Children in low-resource areas experience nutritional and infection challenges delaying growth and cognitive development. OBJECTIVES: Our goal was to assess for associations of circulating biomarkers related to nutrition and inflammation, with growth and developmental outcomes among children in a birth cohort in a resource-poor area in rural Tanzania. METHODS: We assessed data from 1,120 children participating in the Early Life Interventions for Childhood Growth and Development in Tanzania (ELICIT) study. At age 12 and 18 mo, participants had blood tests performed for hemoglobin, collagen-X, insulin-like growth factor-1 (IGF-1), fibroblast growth factor-21 (FGF21), thyroglobulin, ferritin, soluble transferrin receptor (sTFR), retinol binding protein-4 (RBP4), C-reactive protein (CRP), α1-acid glycoprotein (AGP), and CD14. At 18 mo, participants had anthropometry measured and converted to z-scores for length-for-age (LAZ), weight-for-age (WAZ) and head-circumference-for-age (HCZ) and had the Malawi Developmental Assessment Tool (MDAT) performed to evaluate cognitive development. We performed linear regression assessing biomarkers (predictor variable) on anthropometry and MDAT scores (dependent variables), adjusted for sex, socioeconomic status, and baseline values. RESULTS: There was a high degree of intrafactor correlation between 12 and 18 mo and interfactor correlation between biomarkers. IGF-1 and sTFR were positively and FGF21 and ferritin negatively associated with LAZ at 18 mo, whereas collagen-X and CD14 were additionally associated with recent linear growth. Only markers predominantly related to nutrition were consistently linked with WAZ at 18 mo, while RBP4 and AGP were additionally associated with recent change in WAZ. IGF-1 was positively and thyroglobulin, RBP4, and CD14 negatively linked to MDAT scores. IGF-1 was the only factor linked to both 18-mo LAZ and MDAT. CONCLUSIONS: Individual biomarkers were consistently linked to growth and cognitive outcomes, providing support for relationships between nutrition and inflammation in early child development. Further research is needed to assess overlaps in how biomarker-related processes interact with both growth and learning. REGISTERED AT CLINICALTRIALS.GOV: NCT03268902.

Transporting monovalent rotavirus vaccine efficacy estimates to an external target population: a secondary analysis of data from a randomised controlled trial in Malawi.

Oral rotavirus vaccine efficacy estimates from randomised controlled trials are highly variable across settings. Although the randomised study design increases the likelihood of internal validity of findings, results from trials may not always apply outside the context of the study due to differences between trial participants and the target population. Here, we used a weight-based method to transport results from a monovalent rotavirus vaccine clinical trial conducted in Malawi between 2005 and 2008 to a target population of all trial-eligible children in Malawi, represented by data from the 2015-2016 Malawi Demographic and Health Survey (DHS). We reweighted trial participants to reflect the population characteristics described by the Malawi DHS. Vaccine efficacy was estimated for 1008 trial participants after applying these weights such that they represented trial-eligible children in Malawi. We also conducted subgroup analyses to examine the heterogeneous treatment effects by stunting and tuberculosis vaccination status at enrolment. In the original trial, the estimates of one-year vaccine efficacy against severe rotavirus gastroenteritis and any-severity rotavirus gastroenteritis in Malawi were 49.2% (95% CI 15.6%-70.3%) and 32.1% (95% CI 2.5%-53.1%), respectively. After weighting trial participants to represent all trial-eligible children in Malawi, vaccine efficacy increased to 62.2% (95% CI 35.5%-79.0%) against severe rotavirus gastroenteritis and 38.9% (95% CI 11.4%-58.5%) against any-severity rotavirus gastroenteritis. Rotavirus vaccine efficacy may differ between trial participants and target populations when these two populations differ. Differences in tuberculosis vaccination status between the trial sample and DHS population contributed to varying trial and target population vaccine efficacy estimates.

Risk factors and titers of COVID-19 infection in a longitudinal statewide seroepidemiology cohort.

BACKGROUND: Virginia is a large state in the USA, yet it remains unclear what percentage of the population has had natural COVID-19 infection and whether risk factors for infection have changed over time. METHODS: Using a longitudinal cohort, from December 2021-July 2022 we performed follow up serology and a questionnaire on 784 individuals from across Virginia who had previously participated in a statewide COVID-19 seroepidemiology study in 2020. Children were also invited to participate and an additional 62 children also completed the study. Serology was performed using Roche nucleocapsid and spike serological assays. RESULTS: The majority of participants were white (78.6%), over 50 years old (60.9%), and reported having received COVID-19 vaccine (93.4%). 28.6% had evidence of prior COVID-19 infection (nucleocapsid positive). Reweighted by region, age, and sex to match the Virginia census data, the seroprevalence of nucleocapsid antibodies was estimated to be 30.6% (95% CI: 24.7, 36.6). We estimated that 25-53% of COVID-19 infections were asymptomatic. Infection rates were lower in individuals > 60 years old and were higher in Blacks and Hispanics. Infection rates were also higher in those without health insurance, in those with greater numbers of household children, and in those that reported a close contact or having undergone quarantine for COVID-19. Participants from Southwest Virginia had lower seropositivity (16.2%, 95% CI 6.5, 26.0) than other geographic regions. Boosted vaccinees had lower infection rates than non-boosted vaccinees. Frequenting indoor bars was a risk factor for infection, while frequently wearing an N95 mask was protective, though the estimates of association were imprecise. Infection rates were higher in children than adults (56.5% vs. 28.6%). Infection in the parent was a risk factor for child infection. Spike antibody levels declined with time since last vaccination, particularly in those that were vaccinated but not previously infected. Neutralizing antibody positivity was high (97-99%) for wild type, alpha, beta, gamma, delta, and omicron variants. Neutralizing antibody levels were higher in the follow-up survey compared to the first survey in 2020 and among individuals with evidence of natural infection compared to those without. CONCLUSIONS: In this longitudinal statewide cohort we observed a lower-than-expected COVID-19 infection rate as of August 2022. Boosted vaccinees had lower infection rates. Children had higher infection rates and infections tracked within households. Previously identified demographic risk factors for infection tended to persist. Even after the omicron peak, a large number of Virginians remain uninfected with COVID-19, underscoring the need for ongoing vaccination strategies.

Minimizing error in estimates of the effect of interventions by accounting for baseline measurements: A simulation study analyzing effects on child growth.

Interventions to reduce childhood stunting burden require clinical trials with a primary outcome of linear growth. When growth is measured longitudinally, there are several options for including baseline measurements in the analysis. This study compares the performance of several methods. Randomized controlled trials evaluating a hypothetical intervention to improve length-for-age z-score (LAZ) from birth through 24 months of age were simulated. The intervention effect was evaluated using linear regression and five methods for handling baseline measurements: comparing final measurements only (FINAL), comparing final measurement adjusted for baseline (ADJUST), comparing the change in the measurement over time (DELTA), adjusting for baseline when comparing the changes over time (DELTA+ADJUST) and adjusting for baseline in two-step residuals approach (RESIDUALS). We calculated bias, precision and power of each method for scenarios with and without a baseline imbalance in LAZ. Using a 0.15 effect size at 18 months, FINAL and DELTA required 1200 and 1500 enroled participants, respectively, to reach 80% power, whereas ADJUST, DELTA+ADJUST and RESIDUALS only required 900 participants. The adjusted models also produced unbiased estimates when there was a baseline imbalance, whereas the FINAL and DELTA methods produced biased estimates, as large as 0.07 lower and higher, respectively, than the true effect. Adjusted methods required smaller sample size and produced more precise results than both DELTA and FINAL methods in all test scenarios. If randomization fails, and there is an imbalance in LAZ at baseline, DELTA and FINAL methods can produce biased estimates, but adjusted models remain unbiased. These results warn against using the FINAL or DELTA methods.

Impact of Biannual Mass Azithromycin Treatment on Enteropathogen Carriage in Children <5 Years Old in Niger.

We analyzed samples obtained at baseline and 24 months in a mass azithromycin administration trial in Niger using quantitative polymerase chain reaction. In villages randomized to azithromycin, Shigella was the only pathogen reduced at 24 months (prevalence ratio, 0.36 [95% confidence interval: .17-.79]; difference in log quantity, -.42 [-.75 to -.10]).

Sex Differences in Early Childhood Growth in a Resource-Limited Setting: A Secondary Analysis of the Early Life Interventions in Childhood Growth and Development in Tanzania (ELICIT) Study.

BACKGROUND: In population-based growth surveys in sub-Saharan Africa, boys have higher rates of growth failure than girls. OBJECTIVES: Our goal was to assess for the presence, timing, and potential etiology of sex-based differences in length-for-age z score (LAZ), weight-for-age z score (WAZ), and head circumference-for-age z score (HCZ) in a birth cohort in rural Tanzania. METHODS: We performed a secondary analysis of randomized controlled trial data on 1084 children followed from age <2 wk to 18 mo, assessing anthropometry (measured every 3 mo), illness (hospitalization and monthly maternal report of symptoms), and feeding [monthly maternal report of exclusive breastfeeding (EBF) and complementary solids and liquids (CSLs)]. We used linear regression to assess sex differences in LAZ, WAZ, and HCZ over time. RESULTS: Although male and female infants had similar anthropometry measures at study entry, males exhibited poorer growth through 6 mo (e.g., 3-mo mean LAZ: males -0.94, females -0.74, P < 0.01; 3-mo mean WAZ: males -0.63, females -0.48, P < 0.05), without significant worsening from 6 to 18 mo. Males had lower HCZ only at 9 mo. In evaluating possible etiologies, mediation analysis failed to identify illness or hospitalization as mediators of poorer growth among males, although at age 3 mo, males with recently reported illness exhibited greater decline in WAZ than females with illness (ΔWAZ: males -0.24, females 0.03, heterogeneity test P = 0.01). Differences in EBF and introduction of CSL did not explain the sex-based growth outcomes. CONCLUSIONS: In longitudinal analysis, males exhibited more severe growth failure by 3 mo than girls and did not exhibit catchup growth between 6 and 18 mo. Reported symptoms of illness and early introduction of CSL did not appear to be mediators of these sex-based differences, although likely not all sickness was captured by monthly maternal report. Given the early nature of these deficits, LAZ and WAZ measures at 6 mo may be good outcomes for intervention studies targeting improvements in early childhood growth and thriving.

Duration of Postdiarrheal Enteric Pathogen Carriage in Young Children in Low-resource Settings.

BACKGROUND: Prolonged enteropathogen shedding after diarrhea complicates the identification of etiology in subsequent episodes and is an important driver of pathogen transmission. A standardized approach has not been applied to estimate the duration of shedding for a wide range of pathogens. METHODS: We used a multisite birth cohort of children 0-24 months of age from whom diarrheal and monthly nondiarrheal stools were previously tested by quantitative polymerase chain reaction for 29 enteropathogens. We modeled the probability of detection of the etiologic pathogen before and after diarrhea using a log-normal accelerated failure time survival model and estimated the median duration of pathogen carriage as well as differences in subclinical pathogen carriage 60 days after diarrhea onset in comparison to a prediarrhea baseline. RESULTS: We analyzed 3247 etiologic episodes of diarrhea for the 9 pathogens with the highest attributable burdens of diarrhea. The median duration of postdiarrheal carriage varied widely by pathogen, from about 1 week for rotavirus (median, 8.1 days [95% confidence interval {CI}, 6.2-9.6]) to >1 month for Cryptosporidium (39.5 days [95% CI, 30.6-49.0]). The largest increases in subclinical pathogen carriage before and after diarrhea were seen for Cryptosporidium (prevalence difference between 30 days prior and 60 days after diarrhea onset, 0.30 [95% CI, .23-.39]) and Shigella (prevalence difference, 0.21 [95% CI, .16-.27]). CONCLUSIONS: Postdiarrheal shedding was widely variable between pathogens, with strikingly prolonged shedding seen for Cryptosporidium and Shigella. Targeted antimicrobial therapy and vaccination for these pathogens may have a relatively large impact on transmission.

Effect of scheduled antimicrobial and nicotinamide treatment on linear growth in children in rural Tanzania: A factorial randomized, double-blind, placebo-controlled trial.

BACKGROUND: Stunting among children in low-resource settings is associated with enteric pathogen carriage and micronutrient deficiencies. Our goal was to test whether administration of scheduled antimicrobials and daily nicotinamide improved linear growth in a region with a high prevalence of stunting and enteric pathogen carriage. METHODS AND FINDINGS: We performed a randomized, 2 × 2 factorial, double-blind, placebo-controlled trial in the area around Haydom, Tanzania. Mother-child dyads were enrolled by age 14 days and followed with monthly home visits and every 3-month anthropometry assessments through 18 months. Those randomized to the antimicrobial arm received 2 medications (versus corresponding placebos): azithromycin (single dose of 20 mg/kg) at months 6, 9, 12, and 15 and nitazoxanide (3-day course of 100 mg twice daily) at months 12 and 15. Those randomized to nicotinamide arm received daily nicotinamide to the mother (250 mg pills months 0 to 6) and to the child (100 mg sachets months 6 to 18). Primary outcome was length-for-age z-score (LAZ) at 18 months in the modified intention-to-treat group. Between September 5, 2017 and August 31, 2018, 1,188 children were randomized, of whom 1,084 (n = 277 placebo/placebo, 273 antimicrobial/placebo, 274 placebo/nicotinamide, and 260 antimicrobial/nicotinamide) were included in the modified intention-to-treat analysis. The study was suspended for a 3-month period by the Tanzanian National Institute for Medical Research (NIMR) because of concerns related to the timing of laboratory testing and the total number of serious adverse events (SAEs); this resulted in some participants receiving their final study assessment late. There was a high prevalence of stunting overall (533/1,084, 49.2%). Mean 18-month LAZ did not differ between groups for either intervention (mean LAZ with 95% confidence interval [CI]: antimicrobial: -2.05 CI -2.13, -1.96, placebo: -2.05 CI -2.14, -1.97; mean difference: 0.01 CI -0.13, 0.11, p = 0.91; nicotinamide: -2.06 CI -2.13, -1.95, placebo: -2.04 CI -2.14, -1.98, mean difference 0.03 CI -0.15, 0.09, p = 0.66). There was no difference in LAZ for either intervention after adjusting for possible confounders (baseline LAZ, age in days at 18-month measurement, ward, hospital birth, birth month, years of maternal education, socioeconomic status (SES) quartile category, sex, whether the mother was a member of the Datoga tribe, and mother's height). Adverse events (AEs) and SAEs were overall similar between treatment groups for both the nicotinamide and antimicrobial interventions. Key limitations include the absence of laboratory measures of pathogen carriage and nicotinamide metabolism to provide context for the negative findings. CONCLUSIONS: In this study, we observed that neither scheduled administration of azithromycin and nitazoxanide nor daily provision of nicotinamide was associated with improved growth in this resource-poor setting with a high force of enteric infections. Further research remains critical to identify interventions toward improved early childhood growth in challenging conditions. TRIAL REGISTRATION: ClinicalTrials.gov NCT03268902.

Shigellosis in young children in low-income and middle-income countries: insights from molecular diagnostics.

PURPOSE OF REVIEW: To describe the impact of molecular diagnostics on our understanding of the burden and epidemiology of shigellosis in children in low-income and middle-income countries. RECENT FINDINGS: The incorporation of molecular diagnostics has led to a substantial increase in estimates of the burden of shigellosis and have allowed for further resolution of other aspects of Shigella epidemiology, including the clinical characteristics of shigellosis, the association between clinical and subclinical Shigella infection and linear growth shortfalls, protection after natural infection, duration of convalescent shedding, and host determinants of susceptibility. SUMMARY: The increased sensitivity and precision afforded by molecular approaches has represented a major advance in our understanding of the epidemiology and burden of shigellosis in the settings of highest importance.

Higher Energy and Zinc Intakes from Complementary Feeding Are Associated with Decreased Risk of Undernutrition in Children from South America, Africa, and Asia.

BACKGROUND: Few studies have focused on quantitatively analyzing nutrients from infant diets, compromising complementary feeding evaluation and health promotion worldwide. OBJECTIVES: This study aimed to describe dietary intake in infants from 9 to 24 mo of age, determining nutrient intakes associated with the risk of underweight, wasting, and stunting. METHODS: Usual nutrient intakes from complementary feeding were determined by 24-h recalls collected when infants were 9-24 mo of age in communities from 7 low- and middle-income countries: Brazil (n = 169), Peru (n = 199), South Africa (n = 221), Tanzania (n = 210), Bangladesh (n = 208), India (n = 227), and Nepal (n = 229), totaling 1463 children and 22,282 food recalls. Intakes were corrected for within- and between-person variance and energy intake. Multivariable regression models were constructed to determine nutrient intakes associated with the development of underweight, wasting, and stunting at 12, 18, and 24 mo of age. RESULTS: Children with malnutrition presented significantly lower intakes of energy and zinc at 12, 18, and 24 mo of age, ranging from -16.4% to -25.9% for energy and -2.3% to -48.8% for zinc. Higher energy intakes decreased the risk of underweight at 12 [adjusted odds ratio (AOR): 0.90; 95% CI: 0.84, 0.96] and 24 mo (AOR: 0.91; 95% CI: 0.86, 0.96), and wasting at 18 (AOR: 0.91; 95% CI: 0.83, 0.99) and 24 mo (AOR: 0.83; 95% CI: 0.74, 0.92). Higher zinc intakes decreased the risk of underweight (AOR: 0.12; 95% CI: 0.03, 0.55) and wasting (AOR: 0.19; 95% CI: 0.04, 0.92) at 12 mo, and wasting (AOR: 0.05; 95% CI: 0.00, 0.76) at 24 mo. CONCLUSIONS: Higher intakes of energy and zinc in complementary feeding were associated with decreased risk of undernutrition in the studied children. Data suggest these are characteristics to be improved in children's complementary feeding across countries.

Community knowledge, attitudes and practices towards malaria in Ha-Lambani, Limpopo Province, South Africa: a cross-sectional household survey.

BACKGROUND: Malaria remains a global health concern and is endemic in Limpopo, Mpumalanga and KwaZulu Natal Provinces of South Africa, which aims to eliminate malaria by 2025. Community engagement plays a significant role in improving the acceptability and effectiveness of programmes aimed at reducing malaria transmission. The success of such intervention efforts depends on the knowledge, attitudes and practices (KAP) of the community, and understanding the KAP of community residents may support malaria control efforts in the locality. In this context, a cross-sectional household survey to assess community KAP on malaria transmission and prevention in the Ha-Lambani village, Vhembe District, Limpopo Province was conducted. METHODS: Data were collected between November 2018 and May 2019 by questionnaire of 261 consenting adults (213 females and 48 males, aged between 18 and 95 years) selected from different households. Also, a focus group discussion among 13 randomly selected participants was conducted. Pearson's Chi Square test was used to determine statistical differences by village. RESULTS: Study participants (100%, 261/261) were aware of the presence of malaria in their community and 95% associated it with mosquito bites. The local health clinic was the most prominent source of malaria information (85%). Only 22% correctly identified headache, chills and fever as the three most common symptoms of malaria. The majority of participants (98%) knew that effective medication for malaria is available and had a positive treatment-seeking behaviour. Knowledge of malaria prevention measures was high (82%); contrarily, 97% of respondents did not sleep under a bed net the previous night. The focus group data concurred with these results and also revealed that poor bed net use resulted from lack of access to bed nets because community residents could not afford them. CONCLUSIONS: The study demonstrates that participants have appropriate knowledge about malaria transmission and a positive treatment-seeking behaviour. However, economic barriers are responsible for the inadequate use of bed nets. Therefore, distribution of bed nets to the community should be considered to improve practice of malaria prevention measures. Furthermore, knowledge of signs and symptoms and appropriate malaria treatment was limited, and initiatives to improve awareness on these topics should be continued.

Embedding Usage Sensors in Point-of-Use Water Treatment Devices: Sensor Design and Application in Limpopo, South Africa.

Health benefits from point-of-use (POU) water treatment devices come only with consistent use. Embedded sensors can measure the consistency of POU-device use and can provide insights about improving it. We demonstrate both potentials with data from SmartSpouts: accelerometer-based sensors embedded in spigot handles that record the duration and timing of use. In the laboratory, most sensor readings correlated well (>0.98) with manually timed water withdrawals. In the field, SmartSpouts measured >60,000 water withdrawals across 232 households in Limpopo, South Africa. Sensors proved critical to understanding consistent use; surveys overestimated it by 53 percentage points. Sensor data showed when households use POU devices (evening peaks and delayed weekend routines) and user preferences (safe storage over filters). We demonstrate analytically and with data that (i) consistent use (e.g., 7 continuous days) is extremely sensitive to single-day use prevalence and (ii) use prevalence affects the performance of contact-time-based POU devices, exemplified with silver tablets. Deployed SmartSpouts had limitations, including memory overflows and confounding device relocation with water withdrawal. Nevertheless, SmartSpouts provided useful and objective data on the prevalence of single-day and consistent use. Considerably less expensive than alternatives, SmartSpouts enable an order of magnitude increase in how many POU-device sensors can be deployed.

Protection From Natural Immunity Against Enteric Infections and Etiology-Specific Diarrhea in a Longitudinal Birth Cohort.

BACKGROUND: The degree of protection conferred by natural immunity is unknown for many enteropathogens, but it is important to support the development of enteric vaccines. METHODS: We used the Andersen-Gill extension of the Cox model to estimate the effects of previous infections on the incidence of subsequent subclinical infections and diarrhea in children under 2 using quantitative molecular diagnostics in the MAL-ED cohort. We used cross-pathogen negative control associations to correct bias due to confounding by unmeasured heterogeneity of exposure and susceptibility. RESULTS: Prior rotavirus infection was associated with a 50% lower hazard (calibrated hazard ratio [cHR], 0.50; 95% confidence interval [CI], 0.41-0.62) of subsequent rotavirus diarrhea. Strong protection was evident against Cryptosporidium diarrhea (cHR, 0.32; 95% CI, 0.20-0.51). There was also protection due to prior infections for norovirus GII (cHR against diarrhea, 0.67; 95% CI, 0.49-0.91), astrovirus (cHR, 0.62; 95% CI, 0.48-0.81), and Shigella (cHR, 0.79; 95% CI, 0.65-0.95). Minimal protection was observed for other bacteria, adenovirus 40/41, and sapovirus. CONCLUSIONS: Natural immunity was generally stronger for the enteric viruses than bacteria, potentially due to less antigenic diversity. Vaccines against major causes of diarrhea may be feasible but likely need to be more immunogenic than natural infection.

Impact of Water Quality, Sanitation, Handwashing, and Nutritional Interventions on Enteric Infections in Rural Zimbabwe: The Sanitation Hygiene Infant Nutrition Efficacy (SHINE) Trial.

BACKGROUND: We assessed the impact of water, sanitation, and hygiene (WASH) and infant and young child feeding (IYCF) interventions on enteric infections in the Sanitation Hygiene Infant Nutrition Efficacy (SHINE) trial in rural Zimbabwe. METHODS: We tested stool samples collected at 1, 3, 6, and 12 months of age and during diarrhea using quantitative molecular diagnostics for 29 pathogens. We estimated the effects of the WASH, IYCF, and combined WASH + IYCF interventions on individual enteropathogen prevalence and quantity, total numbers of pathogens detected, and incidence of pathogen-attributable diarrhea. RESULTS: WASH interventions decreased the number of parasites detected (difference in number compared to non-WASH arms, -0.07 [95% confidence interval, -.14 to -.02]), but had no statistically significant effects on bacteria, viruses, or the prevalence and quantity of individual enteropathogens after accounting for multiple comparisons. IYCF interventions had no significant effects on individual or total enteropathogens. Neither intervention had significant effects on pathogen-attributable diarrhea. CONCLUSIONS: The WASH interventions implemented in SHINE (improved pit latrine, hand-washing stations, liquid soap, point-of-use water chlorination, and clean play space) did not prevent enteric infections. Transformative WASH interventions are needed that are more efficacious in interrupting fecal-oral microbial transmission in children living in highly contaminated environments.

Effect of water, sanitation, handwashing and nutrition interventions on enteropathogens in children 14 months old: a cluster-randomized controlled trial in rural Bangladesh.

BACKGROUND: We evaluated the impact of low-cost water, sanitation, 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 PCR. Outcomes included the number of co-occurring pathogens; cumulative quantity of four stunting-associated pathogens; and prevalence and quantity of individual pathogens. Masked analysis was by intention-to-treat. RESULTS: 326 (99.1%) control children had one 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.