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Background: \ud The emergence of increasingly antimicrobial-resistant Salmonella enterica serovar Typhi (S Typhi) threatens to undermine effective treatment and control. Understanding where antimicrobial resistance in S Typhi is emerging and spreading is crucial towards formulating effective control strategies.\ud \ud Methods: \ud In this genomic epidemiology study, we sequenced the genomes of 3489 S Typhi strains isolated from prospective enteric fever surveillance studies in Nepal, Bangladesh, Pakistan, and India (between 2014 and 2019), and combined these with a global collection of 4169 S Typhi genome sequences isolated between 1905 and 2018 to investigate the temporal and geographical patterns of emergence and spread of antimicrobial-resistant S Typhi. We performed non-parametric phylodynamic analyses to characterise changes in the effective population size of fluoroquinolone-resistant, extensively drug-resistant (XDR), and azithromycin-resistant S Typhi over time. We inferred timed phylogenies for the major S Typhi sublineages and used ancestral state reconstruction methods to estimate the frequency and timing of international and intercontinental transfers.\ud \ud Findings: \ud Our analysis revealed a declining trend of multidrug resistant typhoid in south Asia, except for Pakistan, where XDR S Typhi emerged in 2016 and rapidly replaced less-resistant strains. Mutations in the quinolone-resistance determining region (QRDR) of S Typhi have independently arisen and propagated on at least 94 occasions, nearly all occurring in south Asia. Strains with multiple QRDR mutations, including triple mutants with high-level fluoroquinolone resistance, have been increasing in frequency and displacing strains with fewer mutations. Strains containing acrB mutations, conferring azithromycin resistance, emerged in Bangladesh around 2013 and effective population size of these strains has been steadily increasing. We found evidence of frequent international (n=138) and intercontinental transfers (n=59) of antimicrobial-resistant S Typhi, followed by local expansion and replacement of drug-susceptible clades.\ud \ud Interpretation: \ud Independent acquisition of plasmids and homoplastic mutations conferring antimicrobial resistance have occurred repeatedly in multiple lineages of S Typhi, predominantly arising in south Asia before spreading to other regions.\ud \ud Funding: \ud Bill & Melinda Gates Foundation.

The incidence of enteric fever, an invasive bacterial infection caused by typhoidal Salmonellae (Salmonella enterica serovars Typhi and Paratyphi), is largely unknown in regions without blood culture surveillance. The aim of this study was to evaluate whether new diagnostic serological markers for typhoidal Salmonella can reliably estimate population-level incidence.We collected longitudinal blood samples from patients with blood culture-confirmed enteric fever enrolled from surveillance studies in Bangladesh, Nepal, Pakistan, and Ghana between 2016 and 2021 and conducted cross-sectional serosurveys in the catchment areas of each surveillance site. We used ELISAs to measure quantitative IgA and IgG antibody responses to hemolysin E and S Typhi lipopolysaccharide. We used Bayesian hierarchical models to fit two-phase power-function decay models to the longitudinal antibody responses among enteric fever cases and used the joint distributions of the peak antibody titres and decay rate to estimate population-level incidence rates from cross-sectional serosurveys.The longitudinal antibody kinetics for all antigen-isotypes were similar across countries and did not vary by clinical severity. The seroincidence of typhoidal Salmonella infection among children younger than 5 years ranged between 58·5 per 100 person-years (95% CI 42·1-81·4) in Dhaka, Bangladesh, to 6·6 per 100 person-years (4·3-9·9) in Kavrepalanchok, Nepal, and followed the same rank order as clinical incidence estimates.The approach described here has the potential to expand the geographical scope of typhoidal Salmonella surveillance and generate incidence estimates that are comparable across geographical regions and time.BillMelinda Gates Foundation.For the Nepali, Bengali and Urdu translations of the abstract see Supplementary Materials section.

BackgroundThe incidence of enteric fever, an invasive bacterial infection caused by typhoidal Salmonellae, is largely unknown in regions lacking blood culture surveillance. New serologic markers have proven accurate in diagnosing enteric fever, but whether they could be used to reliably estimate population-level incidence is unknown.MethodsWe collected longitudinal blood samples from blood culture-confirmed enteric fever cases enrolled from surveillance studies in Bangladesh, Nepal, Pakistan, and Ghana and conducted cross-sectional serosurveys in the catchment areas of each surveillance site. We used ELISAs to measure quantitative IgA and IgG antibody responses to Hemolysin E (HlyE) and S. Typhi lipopolysaccharide (LPS). We used Bayesian hierarchical models to fit two-phase power-function decay models to the longitudinal antibody responses among enteric fever cases and used the joint distributions of the peak antibody titers and decay rate to estimate population-level incidence rates from cross-sectional serosurveys.FindingsThe longitudinal antibody kinetics for all antigen-isotypes were similar across countries and did not vary by clinical severity. The seroincidence of typhoidal Salmonella infection among children InterpretationThe approach described here has the potential to expand the geographic scope of typhoidal Salmonella surveillance and generate incidence estimates that are comparable across geographic regions and time.FundingThis work was supported by the Bill and Melinda Gates Foundation (INV-000572).Research in contextEvidence before this studyPrevious studies have identified serologic responses to two antigens (Hemolysin E [HlyE] and Salmonella lipopolysaccharide [LPS]) as promising diagnostic markers of acute typhoidal Salmonella infection. We reviewed the evidence for seroepidemiology tools for enteric fever available as of November 01, 2021, by searching the National Library of Medicine article database and medRxiv for preprint publications, published in English, using the terms “enteric fever”, “typhoid fever”, “Salmonella Typhi”, “Salmonella Paratyphi”, “typhoidal Salmonella”, “Hemolysin E”, “Salmonella lipopolysaccharide”, “seroconversion”, “serosurveillance”, “seroepidemiology”, “seroprevalence” and “seropositivity.” We found no studies using HlyE or LPS as markers to measure the incidence or prevalence of enteric fever in a population. Anti-Vi IgG responses were used as a marker of population seroprevalence in cross-sectional studies conducted in South Africa, Fiji, and Nepal, but were not used to calculate population-based incidence estimates.Added value of this studyWe developed and validated a method to estimate typhoidal Salmonella incidence in cross-sectional population samples using antibody responses measured from dried blood spots. First, using longitudinal dried blood spots collected from over 1400 blood culture-confirmed cases in four countries, we modeled the longitudinal dynamics of antibody responses for up to two years following infection, accounting for heterogeneity in antibody responses and age-dependence. We found that longitudinal antibody responses were highly consistent across four countries on two continents and did not differ by clinical severity. We then used these antibody kinetic parameters to estimate incidence in population-based samples in six communities across the four countries, where concomitant population-based incidence was measured using blood cultures. Seroincidence estimates were much higher than blood-culture-based case estimates across all six sites, suggestive of a high incidence of asymptomatic or unrecognized infections. Still, the rank order of seroincidence and culture-based incidence rates were the same, with the highest rates in Bangladesh and lowest in Ghana.Implications of all the available evidenceMany at-risk low- and middle-income countries lack data on typhoid incidence needed to inform and evaluate vaccine introduction. Even in countries where incidence estimates are available, data are typically geographically and temporally sparse due to the resources necessary to initiate and sustain blood culture surveillance. We found that typhoidal Salmonella infection incidence can be estimated from community-based serosurveys using dried blood spots, representing an efficient and scalable approach for generating the typhoid burden data needed to inform typhoid control programs in resource-constrained settings.

The emergence of increasingly antimicrobial-resistant (AMR) Salmonella enterica serovar Typhi (S. Typhi) threatens to undermine effective treatment and control. Here, aiming to investigate the temporal and geographic patterns of emergence and spread of AMR S. Typhi, we sequenced 3,489 S. Typhi isolated from prospective surveillance in South Asia and combined these with a global collection of 4,169 S. Typhi genomes. Our analysis revealed that independent acquisition of plasmids and homoplastic mutations conferring AMR have occurred repeatedly in multiple lineages of S. Typhi, predominantly arising in South Asia. We found evidence of frequent international and intercontinental transfers of AMR S. Typhi, followed by rapid expansion and replacement of antimicrobial-susceptible clades.

Precise enteric fever disease burden data are needed to inform prevention and control measures, including the use of newly available typhoid vaccines. We established the Surveillance for Enteric Fever in Asia Project (SEAP) to inform these strategies.From September, 2016, to September, 2019, we conducted prospective clinical surveillance for Salmonella enterica serotype Typhi (S Typhi) and Paratyphi (S Paratyphi) A, B, and C at health facilities in predetermined catchment areas in Dhaka, Bangladesh; Kathmandu and Kavrepalanchok, Nepal; and Karachi, Pakistan. Patients eligible for inclusion were outpatients with 3 or more consecutive days of fever in the last 7 days; inpatients with suspected or confirmed enteric fever; patients with blood culture-confirmed enteric fever from the hospital laboratories not captured by inpatient or outpatient enrolment and cases from the laboratory network; and patients with non-traumatic ileal perforation under surgical care. We used a hybrid surveillance model, pairing facility-based blood culture surveillance with community surveys of health-care use. Blood cultures were performed for enrolled patients. We calculated overall and age-specific typhoid and paratyphoid incidence estimates for each study site. Adjusted estimates accounted for the sensitivity of blood culture, the proportion of eligible individuals who consented and provided blood, the probability of care-seeking at a study facility, and the influence of wealth and education on care-seeking. We additionally calculated incidence of hospitalisation due to typhoid and paratyphoid.A total of 34 747 patients were enrolled across 23 facilitates (six tertiary hospitals, surgical wards of two additional hospitals, and 15 laboratory network sites) during the study period. Of the 34 303 blood cultures performed on enrolled patients, 8705 (26%) were positive for typhoidal Salmonella. Adjusted incidence rates of enteric fever considered patients in the six tertiary hospitals. Adjusted incidence of S Typhi, expressed per 100 000 person-years, was 913 (95% CI 765-1095) in Dhaka. In Nepal, the adjusted typhoid incidence rates were 330 (230-480) in Kathmandu and 268 (202-362) in Kavrepalanchok. In Pakistan, the adjusted incidence rates per hospital site were 176 (144-216) and 103 (85-126). The adjusted incidence rates of paratyphoid (of which all included cases were due to S Paratyphi A) were 128 (107-154) in Bangladesh, 46 (34-62) and 81 (56-118) in the Nepal sites, and 23 (19-29) and 1 (1-1) in the Pakistan sites. Adjusted incidence of hospitalisation was high across sites, and overall, 2804 (32%) of 8705 patients with blood culture-confirmed enteric fever were hospitalised.Across diverse communities in three south Asian countries, adjusted incidence exceeded the threshold for "high burden" of enteric fever (100 per 100 000 person-years). Incidence was highest among children, although age patterns differed across sites. The substantial disease burden identified highlights the need for control measures, including improvements to water and sanitation infrastructure and the implementation of typhoid vaccines.BillMelinda Gates Foundation.

Background Environmental enteric dysfunction (EED) is thought to increase the risk of micronutrient deficiencies, but few studies adjust for dietary intakes and systemic inflammation. Objective We tested whether EED is associated with micronutrient deficiency risk independent of diet and systemic inflammation, and whether it mediates the relation between intake and micronutrient status. Methods Using data from 1283 children in the MAL-ED (Etiology, Risk Factors, and Interactions of Enteric Infections and Malnutrition and the Consequences for Child Health) birth cohort we evaluated the risk of anemia, low retinol, zinc, and ferritin, and high transferrin receptor (TfR) at 15 mo. We characterized gut inflammation and permeability by myeloperoxidase (MPO), neopterin (NEO), and α-1-antitrypsin (AAT) concentrations from asymptomatic fecal samples averaged from 9 to 15 mo, and averaged the lactulose:mannitol ratio z-score (LMZ) at 9 and 15 mo. Nutrient intakes from complementary foods were quantified monthly from 9 to 15 mo and densities were averaged for analyses. α-1-Acid glycoprotein at 15 mo characterized systemic inflammation. Relations between variables were modeled using a Bayesian network. Results A greater risk of anemia was associated with LMZ [1.15 (95% CI: 1.01, 1.31)] and MPO [1.16 (1.01, 1.34)]. A greater risk of low ferritin was associated with AAT [1.19 (1.03, 1.37)] and NEO [1.22 (1.04, 1.44)]. A greater risk of low retinol was associated with LMZ [1.24 (1.08, 1.45)]. However, MPO was associated with a lower risk of high transferrin receptor [0.86 (0.74, 0.98)], NEO with a lower risk of low retinol [0.75 (0.62, 0.89)], and AAT with a lower risk of low plasma zinc [0.83 (0.70, 0.99)]. Greater nutrient intake densities (vitamins A and B6, calcium, protein, and zinc) were negatively associated with EED. Inverse associations between nutrient densities and micronutrient deficiency largely disappeared after adjustment for EED, suggesting that EED mediates these associations. Conclusions EED is independently associated with an increased risk of low ferritin, low retinol, and anemia. Greater nutrient density from complementary foods may reduce EED, and the control of micronutrient deficiencies may require control of EED.

An adapted version of the Wechsler Preschool and Primary Scale of Intelligence—Third Edition (WPPSI-III) was administered to assess cognitive functioning among 1,253 5-year-old children from the Malnutrition and Enteric Disease (MAL-ED) study—an international, multisite study investigating multiple aspects of child development. In this study, the factor structure and invariance of the WPPSI-III were examined across seven international research sites located in Bangladesh, Brazil, India, Nepal, Pakistan, South Africa, and Tanzania. Using a multiple indicator multiple cause (MIMIC) modeling approach, the findings supported the validity of a fluid reasoning dimension (comprised of block design, matrix reasoning, and picture completion subscales) across each of the seven sites, although the scores were noninvariant. Accordingly, these scores are recommended for research purposes and understanding relationships between variables but not for mean comparisons or clinical purposes.

Background: Precise enteric fever disease burden data are needed to inform prevention and control measures, including the use of newly available typhoid vaccines. To inform these strategies, the Surveillance for Enteric Fever in Asia Project (SEAP) conducted prospective, facility-based surveillance for Salmonella Typhi and S . Paratyphi A from 2016-2019. Methods: To generate population-based incidence estimates of enteric fever, we conducted prospective clinical surveillance at five hospitals in pre-determined catchment areas in Dhaka, Bangladesh, Kathmandu and Kavrepalanchok, Nepal, and Karachi, Pakistan. We employed a hybrid surveillance model, pairing facility-based blood culture surveillance with community surveys of healthcare utilization. Blood cultures were performed for enrolled patients. We calculated overall and age-specific typhoid and paratyphoid incidence estimates for each study site. Adjusted estimates accounted for the sensitivity of blood culture, the proportion of eligible individuals who consented and provided blood, the probability of care-seeking at a study facility, and the influence of wealth and education on care-seeking. Findings: Of the 33,136 blood cultures performed on enrolled patients, 8,705 (26%) were positive for typhoidal Salmonella . Adjusted incidence of S . Typhi, expressed per 100,000 person-years, was 1,110 (95% CI: 949-1,305) in Dhaka. In Nepal, the adjusted typhoid incidence rates were 330 (95% CI: 232-476) in Kathmandu and 271 (95% CI:205-365) in Kavrepalanchok. In Pakistan, the adjusted incidence rates per hospital site were 195 (95% CI:163-236) and 126 (95% CI:106-151). Although lower than the rates of typhoid, the adjusted incidence rates of paratyphoid were 150 ( 95% CI: 127-177) in Bangladesh, 49 (95% CI: 38-65) and 82 (95% CI: 57-116) in the Nepal sites, and 25 (95% CI: 21-31) and 1 (95% CI: 1-1) in the Pakistan sites. Adjusted incidence of hospitalization was high across sites, and overall 32% of case patients were hospitalized. Interpretation: Across diverse communities in three South Asian countries, adjusted incidence exceeded the threshold for “high burden” of enteric fever (100 per 100,000 person-years). Incidence was highest among children, although age patterns differed across sites. The substantial disease burden identified highlights the need for control measures, including improvements to water and sanitation infrastructure and the implementation of typhoid vaccines. Funding: This work was supported by a grant from the Bill and Melinda Gates Foundation (grant number INV-008335). Declaration of Interest: None to declare. Ethical Approval: We obtained written informed consent from all eligible participants and the parents/guardians of participants aged

BACKGROUND:Multiple factors constrain the trajectories of child cognitive development, but the drivers that differentiate the trajectories are unknown. We examine how multiple early life experiences differentiate patterns of cognitive development over the first 5 years of life in low-and middle-income settings.METHODS:Cognitive development of 835 children from the Etiology, Risk Factors, and Interactions of Enteric Infections and Malnutrition and the Consequences for Child Health and Development (MAL-ED) multisite observational cohort study was assessed at 6, 15, 24 (Bayley Scales of Infant and Toddler Development), and 60 months (Wechsler Preschool and Primary Scale of Intelligence). Markers of socioeconomic status, infection, illness, dietary intake and status, anthropometry, and maternal factors were also assessed. Trajectories of development were determined by latent class-mixed models, and factors associated with class membership were examined by discriminant analysis.RESULTS:Five trajectory groups of cognitive development are described. The variables that best discriminated between trajectories included presence of stimulating and learning resources in the home, emotional or verbal responsivity of caregiver and the safety of the home environment (especially at 24 and 60 months), proportion of days (0–24 months) for which the child had diarrhea, acute lower respiratory infection, fever or vomiting, maternal reasoning ability, mean nutrient densities of zinc and phytate, and total energy from complementary foods (9–24 months).CONCLUSIONS:A supporting and nurturing environment was the variable most strongly differentiating the most and least preferable trajectories of cognitive development. In addition, a higher quality diet promoted cognitive development while prolonged illness was indicative of less favorable patterns of development.

Antimicrobial resistance is an ongoing issue in the treatment of typhoid fever. Resistance to first-line antimicrobials and extensively drug resistant (XDR) Salmonella Typhi isolates in Pakistan have left azithromycin as the only remaining effective oral treatment. Here, we report the emergence of organisms with a single point mutation in acrB gene, implicated in azithromycin resistance, in a S. Typhi isolate from Pakistan. The isolation of this organism is worrisome and highlights the significance of the introduction of typhoid conjugate vaccine in South Asia. IMPORTANCE The emergence of XDR Salmonella Typhi in Pakistan has left azithromycin as the only viable oral treatment option. Here, we report the detection of an azithromycin resistance-associated mutation in one S. Typhi isolate. This finding is important because any possible spread of azithromycin resistance in S. Typhi isolates would make it nearly impossible to treat in outpatient settings due to the need of injectable antibiotics. Our findings also signify the importance of introduction of typhoid conjugate vaccine in regions of endemicity such as Pakistan.

Children in low-income countries experience multiple illness symptoms in early childhood. Breastfeeding is protective against diarrhea and respiratory infections, and these illnesses are thought to be risk factors of one another, but these relationships have not been explored simultaneously. In the eight-site MAL-ED study, 1,731 infants were enrolled near birth and followed for 2 years. We collected symptoms and diet information through twice-weekly household visits. Poisson regression was used to determine if recent illness history was associated with incidence of diarrhea or acute lower respiratory infections (ALRI), accounting for exclusive breastfeeding. Recent diarrhea was associated with higher risk of incident diarrhea after the first 6 months of life (relative risk [RR] 1.10, 95% confidence interval [CI] 1.04, 1.16) and with higher risk of incident ALRI in the 3- to 5-month period (RR 1.23, 95% CI 1.03, 1.47). Fever was a consistent risk factor for both diarrhea and ALRI. Exclusive breastfeeding 0–6 months was protective against diarrhea (0–2 months: RR 0.39, 95% CI 0.32, 0.49; 3–5 months: RR 0.83, 95% CI 0.75, 0.93) and ALRI (3–5 months: RR 0.81, 95% CI 0.68, 0.98). Children with recent illness who were exclusively breastfed were half as likely as those not exclusively breastfed to experience diarrhea in the first 3 months of life. Recent illness was associated with greater risk of new illness, causing illnesses to cluster within children, indicating that specific illness-prevention programs may have benefits for preventing other childhood illnesses. The results also underscore the importance of exclusive breastfeeding in the first 6 months of life for disease prevention.

Characteristics of temperament have been shown to predict aspects of personality and psychopathology. Approach temperament (i.e., sensitivity, reactivity, and behavioral disposition toward reward stimuli) may be a particularly salient predictor of developmental outcomes (e.g., Nigg, 2006; Shiner & Caspi, 2003). However, there is little research on approach temperament among children from low- and middle-income nations. This study examined the validity of an adapted version of the Infant Temperament Scale across eight international sites with a focus on approach temperament. Our sample included 1,933 infants from eight study sites in low- and middle-income nations: Bangladesh, Brazil, India, Nepal, Peru, Pakistan, South Africa, and Tanzania. The Infant Temperament Scale was translated and administered as a structured interview to caregivers at each site. Exploratory and confirmatory factor analyses were used to examine the factor structure of the scale, and multiple indicator multiple cause (MIMIC)...

Background In a multicountry birth cohort study, we describe rotavirus infection in the first 2 years of life in sites with and without rotavirus vaccination programs. Methods Children were recruited by 17 days of age and followed to 24 months with collection of monthly surveillance and diarrheal stools. Data on sociodemographics, feeding, and illness were collected at defined intervals. Stools were tested for rotavirus and sera for antirotavirus immunoglobulins by enzyme immunoassays. Results A total of 1737 children contributed 22646 surveillance and 7440 diarrheal specimens. Overall, rotavirus was detected in 5.5% (408/7440) of diarrheal stools, and 344 (19.8%) children ever had rotavirus gastroenteritis. Household overcrowding and a high pathogen load were consistent risk factors for infection and disease. Three prior infections conferred 74% (P < .001) protection against subsequent infection in sites not using vaccine. In Peru, incidence of rotavirus disease was relatively higher during the second year of life despite high vaccination coverage. Conclusions Rotavirus infection and disease were common, but with significant heterogeneity by site. Protection by vaccination may not be sustained in the second year of life in settings with high burdens of transmission and poor response to oral vaccines.

This study increases the number of resident Escherichia coli genome sequences, and explores E. coli diversity through longitudinal sampling. We investigate the genomes of E. coli isolated from human gastrointestinal tracts as part of an antibiotic treatment program among rural Tanzanian children. Phylogenomics demonstrates that resident E. coli are diverse, even within a single host. Though the E. coli isolates of the gastrointestinal community tend to be phylogenomically similar at a given time, they differed across the interrogated time points, demonstrating the variability of the members of the E. coli community in these subjects. Exposure to antibiotic treatment did not have an apparent impact on the E. coli community or the presence of resistance and virulence genes within E. coli genomes. The findings of this study highlight the variable nature of specific bacterial members of the human gastrointestinal tract., The stability of the Escherichia coli populations in the human gastrointestinal tract is not fully appreciated, and represents a significant knowledge gap regarding gastrointestinal community structure, as well as resistance to incoming pathogenic bacterial species and antibiotic treatment. The current study examines the genomic content of 240 Escherichia coli isolates from 30 children, aged 2 to 35 months old, in Tanzania. The E. coli strains were isolated from three time points spanning a six-month time period, with and without antibiotic treatment. The resulting isolates were sequenced, and the genomes compared. The findings in this study highlight the transient nature of E. coli strains in the gastrointestinal tract of these children, as during a six-month interval, no one individual contained phylogenomically related isolates at all three time points. While the majority of the isolates at any one time point were phylogenomically similar, most individuals did not contain phylogenomically similar isolates at more than two time points. Examination of global genome content, canonical E. coli virulence factors, multilocus sequence type, serotype, and antimicrobial resistance genes identified diversity even among phylogenomically similar strains. There was no apparent increase in the antimicrobial resistance gene content after antibiotic treatment. The examination of the E. coli from longitudinal samples from multiple children in Tanzania provides insight into the genomic diversity and population variability of resident E. coli within the rapidly changing environment of the gastrointestinal tract of these children. IMPORTANCE This study increases the number of resident Escherichia coli genome sequences, and explores E. coli diversity through longitudinal sampling. We investigate the genomes of E. coli isolated from human gastrointestinal tracts as part of an antibiotic treatment program among rural Tanzanian children. Phylogenomics demonstrates that resident E. coli are diverse, even within a single host. Though the E. coli isolates of the gastrointestinal community tend to be phylogenomically similar at a given time, they differed across the interrogated time points, demonstrating the variability of the members of the E. coli community in these subjects. Exposure to antibiotic treatment did not have an apparent impact on the E. coli community or the presence of resistance and virulence genes within E. coli genomes. The findings of this study highlight the variable nature of specific bacterial members of the human gastrointestinal tract.

Background Mathematical transmission models are increasingly used to guide public health interventions for infectious diseases, particularly in the context of emerging pathogens; however, the contribution of modeling to the growing issue of antimicrobial resistance (AMR) remains unclear. Here, we systematically evaluate publications on population-level transmission models of AMR over a recent period (2006–2016) to gauge the state of research and identify gaps warranting further work. Methods We performed a systematic literature search of relevant databases to identify transmission studies of AMR in viral, bacterial, and parasitic disease systems. We analyzed the temporal, geographic, and subject matter trends, described the predominant medical and behavioral interventions studied, and identified central findings relating to key pathogens. Results We identified 273 modeling studies; the majority of which (> 70%) focused on 5 infectious diseases (human immunodeficiency virus (HIV), influenza virus, Plasmodium falciparum (malaria), Mycobacterium tuberculosis (TB), and methicillin-resistant Staphylococcus aureus (MRSA)). AMR studies of influenza and nosocomial pathogens were mainly set in industrialized nations, while HIV, TB, and malaria studies were heavily skewed towards developing countries. The majority of articles focused on AMR exclusively in humans (89%), either in community (58%) or healthcare (27%) settings. Model systems were largely compartmental (76%) and deterministic (66%). Only 43% of models were calibrated against epidemiological data, and few were validated against out-of-sample datasets (14%). The interventions considered were primarily the impact of different drug regimens, hygiene and infection control measures, screening, and diagnostics, while few studies addressed de novo resistance, vaccination strategies, economic, or behavioral changes to reduce antibiotic use in humans and animals. Conclusions The AMR modeling literature concentrates on disease systems where resistance has been long-established, while few studies pro-actively address recent rise in resistance in new pathogens or explore upstream strategies to reduce overall antibiotic consumption. Notable gaps include research on emerging resistance in Enterobacteriaceae and Neisseria gonorrhoeae; AMR transmission at the animal-human interface, particularly in agricultural and veterinary settings; transmission between hospitals and the community; the role of environmental factors in AMR transmission; and the potential of vaccines to combat AMR. Electronic supplementary material The online version of this article (10.1186/s12916-019-1314-9) contains supplementary material, which is available to authorized users.

Child cognitive development is influenced by early-life insults and protective factors. To what extent these factors have a long-term legacy on child development and hence fulfillment of cognitive potential is unknown.The aim of this study was to examine the relation between early-life factors (birth to 2 y) and cognitive development at 5 y.Observational follow-up visits were made of children at 5 y, previously enrolled in the community-based MAL-ED longitudinal cohort. The burden of enteropathogens, prevalence of illness, complementary diet intake, micronutrient status, and household and maternal factors from birth to 2 y were extensively measured and their relation with the Wechsler Preschool Primary Scales of Intelligence at 5 y was examined through use of linear regression.Cognitive T-scores from 813 of 1198 (68%) children were examined and 5 variables had significant associations in multivariable models: mean child plasma transferrin receptor concentration (β: -1.81, 95% CI: -2.75, -0.86), number of years of maternal education (β: 0.27, 95% CI: 0.08, 0.45), maternal cognitive reasoning score (β: 0.09, 95% CI: 0.03, 0.15), household assets score (β: 0.64, 95% CI: 0.24, 1.04), and HOME child cleanliness factor (β: 0.60, 95% CI: 0.05, 1.15). In multivariable models, the mean rate of enteropathogen detections, burden of illness, and complementary food intakes between birth and 2 y were not significantly related to 5-y cognition.A nurturing home context in terms of a healthy/clean environment and household wealth, provision of adequate micronutrients, maternal education, and cognitive reasoning have a strong and persistent influence on child cognitive development. Efforts addressing aspects of poverty around micronutrient status, nurturing caregiving, and enabling home environments are likely to have lasting positive impacts on child cognitive development.

The Bayley's Scales of Infant and Toddler Development-Third Edition (Bayley-III) were used to measure the development of 24-month-old children (N = 1,452) in the Interactions of Malnutrition and Enteric Infections: Consequences for Child Health and Development (MAL-ED) study (an international, multisite study on many aspects of child development). This study examined the factor structure and measurement equivalence/invariance of Bayley-III scores across 7 international research sites located in Bangladesh, Brazil, India, Nepal, Pakistan, Peru, and South Africa. Exploratory and confirmatory factor analyses were used to identify the factor structure of Bayley-III scores. Subsequently, reliability analyses and item response theory analyses were applied, and invariance was examined using multiple-indicator, multiple-cause modeling. The findings supported the validity, but not invariance, of Bayley-III language scores at all seven sites and of the cognitive and motor scores at six sites. These findings provide support for the use of scores for research purposes, but mean comparison between sites is not recommended. (PsycINFO Database Record (c) 2018 APA, all rights reserved).

Summary: Background: Optimum management of childhood diarrhoea in low-resource settings has been hampered by insufficient data on aetiology, burden, and associated clinical characteristics. We used quantitative diagnostic methods to reassess and refine estimates of diarrhoea aetiology from the Etiology, Risk Factors, and Interactions of Enteric Infections and Malnutrition and the Consequences for Child Health and Development (MAL-ED) cohort study. Methods: We re-analysed stool specimens from the multisite MAL-ED cohort study of children aged 0–2 years done at eight locations (Dhaka, Bangladesh; Vellore, India; Bhaktapur, Nepal; Naushero Feroze, Pakistan; Venda, South Africa; Haydom, Tanzania; Fortaleza, Brazil; and Loreto, Peru), which included active surveillance for diarrhoea and routine non-diarrhoeal stool collection. We used quantitative PCR to test for 29 enteropathogens, calculated population-level pathogen-specific attributable burdens, derived stringent quantitative cutoffs to identify aetiology for individual episodes, and created aetiology prediction scores using clinical characteristics. Findings: We analysed 6625 diarrhoeal and 30 968 non-diarrhoeal surveillance stools from 1715 children. Overall, 64·9% of diarrhoea episodes (95% CI 62·6–71·2) could be attributed to an aetiology by quantitative PCR compared with 32·8% (30·8–38·7) using the original study microbiology. Viral diarrhoea (36·4% of overall incidence, 95% CI 33·6–39·5) was more common than bacterial (25·0%, 23·4–28·4) and parasitic diarrhoea (3·5%, 3·0–5·2). Ten pathogens accounted for 95·7% of attributable diarrhoea: Shigella (26·1 attributable episodes per 100 child-years, 95% CI 23·8–29·9), sapovirus (22·8, 18·9–27·5), rotavirus (20·7, 18·8–23·0), adenovirus 40/41 (19·0, 16·8–23·0), enterotoxigenic Escherichia coli (18·8, 16·5–23·8), norovirus (15·4, 13·5–20·1), astrovirus (15·0, 12·0–19·5), Campylobacter jejuni or C coli (12·1, 8·5–17·2), Cryptosporidium (5·8, 4·3–8·3), and typical enteropathogenic E coli (5·4, 2·8–9·3). 86·2% of the attributable incidence for Shigella was non-dysenteric. A prediction score for shigellosis was more accurate (sensitivity 50·4% [95% CI 46·7–54·1], specificity 84·0% [83·0–84·9]) than current guidelines, which recommend treatment only of bloody diarrhoea to cover Shigella (sensitivity 14·5% [95% CI 12·1–17·3], specificity 96·5% [96·0–97·0]). Interpretation: Quantitative molecular diagnostics improved estimates of pathogen-specific burdens of childhood diarrhoea in the community setting. Viral causes predominated, including a substantial burden of sapovirus; however, Shigella had the highest overall burden with a high incidence in the second year of life. These data could improve the management of diarrhoea in these low-resource settings. Funding: Bill & Melinda Gates Foundation.

Summary: Background: Enteropathogen infections in early childhood not only cause diarrhoea but contribute to poor growth. We used molecular diagnostics to assess whether particular enteropathogens were associated with linear growth across seven low-resource settings. Methods: We used quantitative PCR to detect 29 enteropathogens in diarrhoeal and non-diarrhoeal stools collected from children in the first 2 years of life obtained during the Etiology, Risk Factors, and Interactions of Enteric Infections and Malnutrition and the Consequences for Child Health and Development (MAL-ED) multisite cohort study. Length was measured monthly. We estimated associations between aetiology-specific diarrhoea and subclinical enteropathogen infection and quantity and attained length in 3 month intervals, at age 2 and 5 years, and used a longitudinal model to account for temporality and time-dependent confounding. Findings: Among 1469 children who completed 2 year follow-up, 35 622 stool samples were tested and yielded valid results. Diarrhoeal episodes attributed to bacteria and parasites, but not viruses, were associated with small decreases in length after 3 months and at age 2 years. Substantial decrements in length at 2 years were associated with subclinical, non-diarrhoeal, infection with Shigella (length-for-age Z score [LAZ] reduction −0·14, 95% CI −0·27 to −0·01), enteroaggregative Escherichia coli (−0·21, −0·37 to −0·05), Campylobacter (−0·17, −0·32 to −0·01), and Giardia (−0·17, −0·30 to −0·05). Norovirus, Cryptosporidium, typical enteropathogenic E coli, and Enterocytozoon bieneusi were also associated with small decrements in LAZ. Shigella and E bieneusi were associated with the largest decreases in LAZ per log increase in quantity per g of stool (−0·13 LAZ, 95% CI −0·22 to −0·03 for Shigella; −0·14, −0·26 to −0·02 for E bieneusi). Based on these models, interventions that successfully decrease exposure to Shigella, enteroaggregative E coli, Campylobacter, and Giardia could increase mean length of children by 0·12–0·37 LAZ (0·4–1·2 cm) at the MAL-ED sites. Interpretation: Subclinical infection and quantity of pathogens, particularly Shigella, enteroaggregative E coli, Campylobacter, and Giardia, had a substantial negative association with linear growth, which was sustained during the first 2 years of life, and in some cases, to 5 years. Successfully reducing exposure to certain pathogens might reduce global stunting. Funding: Bill & Melinda Gates Foundation.

Supplemental Digital Content is available in the text, Objectives: There is a lack of consensus on how to measure diarrheal severity. Within the context of a multisite, prospective cohort study, we evaluated the performance of a modified Vesikari score (MAL-ED), 2 previously published scores (Clark and CODA [a diarrheal severity score (Community DiarrheA) published by Lee et al]), and a modified definition of moderate-to-severe diarrhea (MSD) based on dysentery and health care worker diagnosed dehydration. Methods: Scores were built using maternally reported symptoms or fieldworker-reported clinical signs obtained during the first 7 days of a diarrheal episode. The association between these and the risk of hospitalization were tested using receiver operating characteristic analysis. Severity scores were also related to illness etiology, and the likelihood of the episode subsequently becoming prolonged or persistent. Results: Of 10,159 episodes from 1681 children, 143 (4.0%) resulted in hospitalization. The area under the curve of each score as a predictor of hospitalization was 0.84 (95% confidence interval: 0.81, 0.87) (Clark), 0.85 (0.82, 0.88) (MAL-ED), and 0.87 (0.84, 0.89) (CODA). Severity was also associated with etiology and episode duration. Although families were more likely to seek care for severe diarrhea, approximately half of severe cases never reached the health system. Conclusions: Community-based diarrheal severity scores are predictive of relevant child health outcomes. Because they require no assumptions about health care access or utilization, they are useful in refining estimates of the burden of diarrheal disease, in estimating the effect of disease control interventions, and in triaging children for referral in low- and middle-income countries in which the rates of morbidity and mortality after diarrhea remain high.

Globally more than 150 million children under age 5 years were stunted in 2018, primarily in low- and middle-income countries (LMICs), and the impact of early-onset, persistent stunting has not been well explored. To explore the association between early-onset persistent stunting in children and cognitive development at 5 years of age, and to identify the factors associated with early-onset stunting.Children from the MAL-ED cohort study were followed from birth to 5 years of age in six LMICs. The Wechsler Preschool Primary Scales of Intelligence (WPPSI) was used to assess cognitive abilities (fluid reasoning) at 5 years and was adapted for each culture. Stunting was categorized as early-onset persistent (first stunted at 1-6 months and persisting at 60 months), early-onset recovered (first stunted at 1-6 months and not stunted at 60 months), late-onset persistent (first stunted at 7-24 months and persisting at 60 months), late-onset recovered (first stunted at 7-24 months and not stunted at 60 months), and never (never stunted). Mixed effects linear models were used to estimate the relationship between stunting status and cognitive development. Children with early-onset persistent stunting had significantly lower cognitive scores (-2.10 (95% CI: -3.85, -0.35)) compared with those who were never stunted. Transferrin receptor (TfR) was also negatively associated with cognitive development (-0.31 (95% CI: -0.49, -0.13)), while the HOME inventory, an index of quality of the home environment (0.46 (95% CI: 0.21, 0.72)) and socio-economic status (1.50 (95% CI: 1.03, 1.98)) were positively associated with cognitive development.Early-onset persistent stunting was associated with lower cognitive development in children at 5 years of age in this cohort of children.

Background Globally more than 150 million children under age 5 years were stunted in 2018, primarily in low- and middle-income countries (LMICs), and the impact of early-onset, persistent stunting has not been well explored. To explore the association between early-onset persistent stunting in children and cognitive development at 5 years of age, and to identify the factors associated with early-onset stunting. Methods and findings Children from the MAL-ED cohort study were followed from birth to 5 years of age in six LMICs. The Wechsler Preschool Primary Scales of Intelligence (WPPSI) was used to assess cognitive abilities (fluid reasoning) at 5 years and was adapted for each culture. Stunting was categorized as early-onset persistent (first stunted at 1–6 months and persisting at 60 months), early-onset recovered (first stunted at 1–6 months and not stunted at 60 months), late-onset persistent (first stunted at 7–24 months and persisting at 60 months), late-onset recovered (first stunted at 7–24 months and not stunted at 60 months), and never (never stunted). Mixed effects linear models were used to estimate the relationship between stunting status and cognitive development. Children with early-onset persistent stunting had significantly lower cognitive scores (-2.10 (95% CI: -3.85, -0.35)) compared with those who were never stunted. Transferrin receptor (TfR) was also negatively associated with cognitive development (-0.31 (95% CI: -0.49, -0.13)), while the HOME inventory, an index of quality of the home environment (0.46 (95% CI: 0.21, 0.72)) and socio-economic status (1.50 (95% CI: 1.03, 1.98)) were positively associated with cognitive development. Conclusions Early-onset persistent stunting was associated with lower cognitive development in children at 5 years of age in this cohort of children.

Information on the association between stunting and child development is limited from low‐income settings including Bangladesh where 36% of children under‐ 5 are stunted. This study aimed to explore differences in early childhood development (ECD) between stunted (length‐for‐age z‐score [LAZ]

Noroviruses are a leading cause of diarrhea in children aged

The stability of the Escherichia coli populations in the human gastrointestinal tract are not fully appreciated, and represent a significant knowledge gap regarding gastrointestinal community structure, as well as resistance to incoming pathogenic bacterial species and antibiotic treatment. The current study examines the genomic content of 240 Escherichia coli isolates from children 2 to 35 months old in Tanzania. The E. coli strains were isolated from three time points spanning a six month time period, with or without antibiotic treatment. The resulting isolates were sequenced, and the genomes compared. The findings in this study highlight the transient nature of E. coli strains in the gastrointestinal tract of children, as during a six-month interval, no one individual contained phylogenomically related isolates at all three time points. While the majority of the isolates at any one time point were phylogenomically similar, most individuals did not contain phylogenomically similar isolates at more than two time points. Examination of global genome content, canonical E. coli virulence factors, multilocus sequence type, serotype, and antimicrobial resistance genes identified diversity even among phylogenomically similar strains. There was no apparent increase in the antimicrobial resistance gene content after antibiotic treatment. The examination of the E. coli from longitudinal samples from multiple children in Tanzania provides insight into the genomic diversity and population variability of resident E. coli within the rapidly changing environment of the gastrointestinal tract.ImportanceThis study increases the number of resident Escherichia coli genome sequences, and explores E. coli diversity through longitudinal sampling. We investigate the genomes of E. coli isolated from human gastrointestinal tracts as part of an antibiotic treatment program among rural Tanzanian children. Phylogenomics demonstrates that resident E. coli are diverse, even within a single host. Though the E. coli isolates of the gastrointestinal community tend to be phylogenomically similar at a given time, they differed across the interrogated time points, demonstrating the variability of the members of the E. coli community. Exposure to antibiotic treatment did not have an apparent impact on the E. coli community or the presence of resistance and virulence genes within E. coli genomes. The findings of this study highlight the variable nature of bacterial members of the human gastrointestinal tract.

Immunization programs have leveraged decades of research to maximize oral polio vaccine (OPV) response. Moving toward global poliovirus eradication, the WHO recommended phased OPV-to-IPV replacement on schedules in 2012. Using the MAL-ED prospective birth cohort data, we evaluated the influence of early life exposures impacting OPV immunization by measuring OPV response for serotypes 1 and 3.Polio neutralizing antibody assays were conducted at 7 and 15 months of age for serotypes 1 and 3. Analyses were conducted on children receiving ≥3 OPV doses (n = 1449). History of vaccination, feeding patterns, physical growth, home environment, diarrhea, enteropathogen detection, and gut inflammation were examined as risk factors for non-response [LogSerotype 1 seroconversion was significantly higher than serotype 3 (96.6% vs. 89.6%, 15 months). Model results indicate serotypes 1 and 3 failure was minimized following four and six OPV doses, respectively; however, enteropathogen detection and poor socioeconomic conditions attenuated response in both serotypes. At three months of age, bacterial detection in stool reduced serotype 1 and 3 LogUnder real-world conditions, improved vaccination coverage and socio-environmental conditions, and reducing early life bacterial exposures are key to improving OPV response and should inform polio eradication strategies.

The lactulose mannitol (LM) dual sugar permeability test is the most commonly used test of environmental enteropathy in developing countries. However, there is a large but conflicting literature on its association with enteric infection and host nutritional status. We conducted a longitudinal cohort using a single field protocol and comparable laboratory procedures to examine intestinal permeability in multiple, geographically diverse pediatric populations. Using a previously published systematic review to guide the selection of factors potentially associated with LM test results, we examined the relationships between these factors and mucosal breach, represented by percent lactulose excretion; absorptive area, represented by percent mannitol excretion; and gut barrier function, represented by the L/M ratio. A total of 6,602 LM tests were conducted in 1,980 children at 3, 6, 9, and 15 months old; percent lactulose excretion, percent mannitol excretion, and the L/M ratio were expressed as age- and sex-specific normalized values using the Brazil cohort as the reference population. Among the factors considered, recent severe diarrhea, lower socioeconomic status, and recent asymptomatic enteropathogen infections were associated with decreased percent mannitol excretion and higher L/M ratios. Poorer concurrent weight-for-age, infection, and recent breastfeeding were associated with increased percent lactulose excretion and increased L/M ratios. Our results support previously reported associations between the L/M ratio and factors related to child nutritional status and enteropathogen exposure. These results were remarkably consistent across sites and support the hypothesis that the frequency of these exposures in communities living in poverty leads to alterations in gut barrier function.

Background Campylobacter continues to be an important cause of diarrheal disease worldwide and a leading cause in Southeast Asia. Studies of US soldiers and marines deployed to Thailand for a 2 to 3 week field exercise provide a unique population in which to study traveler’s diarrhea. Methods A case–control study of 217 deployed military personnel was conducted from 2002 through 2004. Of these, 155 subjects who presented to a field medical unit with acute diarrhea were enrolled as cases. These subjects referred an additional 62 diarrhea-free colleagues who served as controls. Frequencies of isolation of Campylobacter spp. and other enteric pathogens were compared in cases and controls, and antibiotic resistance of isolates was described. Results Of the 155 subjects with diarrhea, Campylobacter spp. was the most commonly identified pathogen, found in 54 (35%) of the subjects, followed by non-typhoidal Salmonella species found in 36 (23%) subjects. Of the 57 separate C. jejuni and C. coli isolates from these individuals, 51 (89%) were resistant to ciprofloxacin by the disc diffusion method. Nearly one-third of the Campylobacter species were resistant to ampicillin and trimethoprim-sulfamethoxazole. Resistance to azithromycin remained low at 2% (n = 1). Conclusions The significant morbidity and marked fluoroquinolone resistance associated with Campylobacter infections in Thailand are important considerations for clinicians providing counseling on appropriate antibacterial regimens for civilian and military travelers.

BACKGROUND:Enteroaggregative E. coli (EAEC) have been associated with mildly inflammatory diarrhea in outbreaks and in travelers and have been increasingly recognized as enteric pathogens in young children with and without overt diarrhea. We examined the risk factors for EAEC infections and their associations with environmental enteropathy biomarkers and growth outcomes over the first two years of life in eight low-resource settings of the MAL-ED study. METHODS:EAEC infections were detected by PCR gene probes for aatA and aaiC virulence traits in 27,094 non-diarrheal surveillance stools and 7,692 diarrheal stools from 2,092 children in the MAL-ED birth cohort. We identified risk factors for EAEC and estimated the associations of EAEC with diarrhea, enteropathy biomarker concentrations, and both short-term (one to three months) and long-term (to two years of age) growth. RESULTS:Overall, 9,581 samples (27.5%) were positive for EAEC, and almost all children had at least one detection (94.8%) by two years of age. Exclusive breastfeeding, higher enrollment weight, and macrolide use within the preceding 15 days were protective. Although not associated with diarrhea, EAEC infections were weakly associated with biomarkers of intestinal inflammation and more strongly with reduced length at two years of age (LAZ difference associated with high frequency of EAEC detections: -0.30, 95% CI: -0.44, -0.16). CONCLUSIONS:Asymptomatic EAEC infections were common early in life and were associated with linear growth shortfalls. Associations with intestinal inflammation were small in magnitude, but suggest a pathway for the growth impact. Increasing the duration of exclusive breastfeeding may help prevent these potentially inflammatory infections and reduce the long-term impact of early exposure to EAEC.

The aim of the study was to describe changes in intestinal permeability in early childhood in diverse epidemiologic settings.In a birth cohort study, the lactulose:mannitol (L:M) test was administered to 1980 children at 4 time points in the first 24 months of life in 8 countries. Data from the Brazil site with an incidence of diarrhea similar to that seen in the United States and no growth faltering was used as an internal study reference to derive age- and sex-specific z scores for mannitol and lactulose recoveries and the L:M ratio.A total of 6602 tests demonstrated mannitol recovery, lactulose recovery, and the L:M ratio were associated with country, sex, and age. There was heterogeneity in the recovery of both probes between sites with mean mannitol recovery ranging for 1.34% to 5.88%, lactulose recovery of 0.19% to 0.58%, and L:M ratios 0.10 to 0.17 in boys of 3 months of age across different sites. We observed strong sex-specific differences in both mannitol and lactulose recovery, with boys having higher recovery of both probes. Alterations in intestinal barrier function increased in most sites from 3 to 9 months of age and plateaued or diminished from 9 to 15 months of age.Alterations in recovery of the probes differ markedly in different epidemiologic contexts in children living in the developing world. The rate of change in the L:M-z ratio was most rapid and consistently disparate from the reference standard in the period between 6 and 9 months of age, suggesting that this is a critical period of physiologic impact of enteropathy in these populations.

Objectives: The potential growth-promoting effects of antibiotics are not well understood among undernourished children in environments with high pathogen exposure. We aimed to assess whether early antibiotic exposure duration and class were associated with growth to 2 years of age across 8 low-resource sites in the MAL-ED birth cohort study. Methods: We followed 1954 children twice per week from birth to 2 years to record maternally reported antibiotic exposures and measure anthropometry monthly. We estimated the associations between antibiotic exposure before 6 months of age and weight-for-age and length-for-age (LAZ) z scores to 2 years. We assessed the impact of class-specific exposures and duration, and compared these results to effects of antibiotic exposures after 6 months of age. Results: Antibiotic use before 6 months of age was associated with increased weight from 6 months to 2 years, whereas associations with length were less consistent across sites and antibiotic classes. Compared to unexposed children, 2 or more courses of metronidazole, macrolides, and cephalosporins were associated with adjusted increases in weight-for-age of 0.24 (95% confidence interval (CI): 0.04, 0.43), 0.23 (95% CI: 0.05, 0.42), and 0.19 (95% CI: 0.04, 0.35) from 6 months to 2 years, respectively. Conclusions: Antibiotic use in low-resource settings was most associated with the ponderal growth of children who had multiple exposures to antibiotics with broad spectrum and anaerobic activity in early infancy. Opportunities for rational and targeted antibiotic therapy in low resource settings may also promote short-term weight gain in children, although longer-term physical growth and metabolic impacts are unknown.

Summary In a multisite birth-cohort study, Giardia spp were detected by enzyme immunoassay at least once in two-thirds of the children. Early persistent infection with Giardia, independent of diarrhea, was associated with deficits in both weight and length at 2 years of age., Background. Giardia are among the most common enteropathogens detected in children in low-resource settings. We describe here the epidemiology of infection with Giardia in the first 2 years of life in the Etiology, Risk Factors, and Interactions of Enteric Infections and Malnutrition and the Consequences for Child Health and Development Project (MAL-ED), a multisite birth-cohort study. Methods. From 2089 children, 34916 stool samples collected during monthly surveillance and episodes of diarrhea were tested for Giardia using an enzyme immunoassay. We quantified the risk of Giardia detection, identified risk factors, and assessed the associations with micronutrients, markers of gut inflammation and permeability, diarrhea, and growth using multivariable linear regression. Results. The incidence of at least 1 Giardia detection varied according to site (range, 37.7%–96.4%) and was higher in the second year of life. Exclusive breastfeeding (HR for first Giardia detection in a monthly surveillance stool sample, 0.46 [95% confidence interval (CI), 0.28–0.75]), higher socioeconomic status (HR, 0.74 [95% CI, 0.56–0.97]), and recent metronidazole treatment (risk ratio for any surveillance stool detection, 0.69 [95% CI, 0.56–0.84]) were protective. Persistence of Giardia (consecutive detections) in the first 6 months of life was associated with reduced subsequent diarrheal rates in Naushahro Feroze, Pakistan but not at any other site. Giardia detection was also associated with an increased lactulose/mannitol ratio. Persistence of Giardia before 6 months of age was associated with a −0.29 (95% CI, −0.53 to −0.05) deficit in weight-for-age z score and −0.29 (95% CI, −0.64 to 0.07) deficit in length-for-age z score at 2 years. Conclusions. Infection with Giardia occurred across epidemiological contexts, and repeated detections in 40% of the children suggest that persistent infections were common. Early persistent infection with Giardia, independent of diarrhea, might contribute to intestinal permeability and stunted growth.

To describe the frequency and factors associated with antibiotic use in early childhood, and estimate the proportion of diarrhoea and respiratory illnesses episodes treated with antibiotics.Between 2009 and 2014, we followed 2134 children from eight sites in Bangladesh, Brazil, India, Nepal, Pakistan, Peru, South Africa and the United Republic of Tanzania, enrolled in the MAL-ED birth cohort study. We documented all antibiotic use from mothers' reports at twice-weekly visits over the children's first two years of life. We estimated the incidence of antibiotic use and the associations of antibiotic use with child and household characteristics. We described treatment patterns for diarrhoea and respiratory illnesses, and identified factors associated with treatment and antibiotic class.Over 1 346 388 total days of observation, 16 913 courses of antibiotics were recorded (an incidence of 4.9 courses per child per year), with the highest use in South Asia. Antibiotic treatment was given for 375/499 (75.2%) episodes of bloody diarrhoea and for 4274/9661 (44.2%) episodes of diarrhoea without bloody stools. Antibiotics were used in 2384/3943 (60.5%) episodes of fieldworker-confirmed acute lower respiratory tract illness as well as in 6608/16742 (39.5%) episodes of upper respiratory illness. Penicillins were used most frequently for respiratory illness, while antibiotic classes for diarrhoea treatment varied within and between sites.Repeated antibiotic exposure was common early in life, and treatment of non-bloody diarrhoea and non-specific respiratory illnesses was not consistent with international recommendations. Rational antibiotic use programmes may have the most impact in South Asia, where antibiotic use was highest.Décrire la fréquence et les facteurs associés à l'utilisation d'antibiotiques chez les jeunes enfants et estimer la proportion d'épisodes de diarrhée et de maladies respiratoires traités avec des antibiotiques.De 2009 à 2014, nous avons suivi 2134 enfants qui participaient à l'étude de cohorte de naissance MAL-ED sur huit sites en Afrique du Sud, au Bangladesh, au Brésil, en Inde, au Népal, au Pakistan, au Pérou et en République-Unie de Tanzanie. Nous avons noté l'utilisation de tous les antibiotiques déclarés par les mères lors de consultations bi-hebdomadaires pendant les deux premières années de vie des enfants. Nous avons estimé l'incidence du recours aux antibiotiques ainsi que les associations entre utilisation d'antibiotiques et caractéristiques des enfants et des foyers. Nous avons décrit les habitudes de traitement de la diarrhée et des maladies respiratoires et avons identifié les facteurs associés aux traitements et aux classes d'antibiotiques.Sur 1 346 388 jours d'observation au total, 16 913 traitements aux antibiotiques ont été enregistrés (incidence de 4,9 traitements par enfant et par an), la plus forte utilisation ayant été observée en Asie du Sud. Un traitement antibiotique a été administré pour 375/499 (75,2%) épisodes de diarrhée sanglante et pour 4274/9661 (44,2%) épisodes de diarrhée sans présence de sang dans les selles. Des antibiotiques ont été utilisés pour 2384/3943 (60,5%) épisodes de maladie aiguë des voies respiratoires inférieures confirmée par un professionnel sur le terrain ainsi que pour 6608/16 742 (39,5%) épisodes de maladie des voies respiratoires supérieures. Les pénicillines étaient les plus fréquemment utilisées pour combattre les maladies respiratoires, tandis que les classes d'antibiotiques utilisées pour traiter la diarrhée variaient selon les sites et au sein d'un même site.L'exposition répétée aux antibiotiques à un jeune âge était courante et le traitement de la diarrhée sans présence de sang dans les selles et de maladies respiratoires non spécifiques ne respectait pas les recommandations internationales. C'est en Asie du Sud, où l'usage des antibiotiques était le plus important, que les programmes d'utilisation rationnelle des antibiotiques pourraient avoir le plus fort impact.Describir la frecuencia y los factores relacionados con el uso de antibióticos en la primera infancia y estimar la proporción de los episodios de diarrea y enfermedades respiratorias tratados con antibióticos.Entre 2009 y 2014, se realizó el seguimiento de 2 134 niños de ocho lugares en Bangladesh, Brasil, India, Nepal, Pakistán, Perú, la República Unida de Tanzania y Sudáfrica inscritos en el estudio de cohortes en el nacimiento MAL-ED. Se documentó el uso de todos los antibióticos de los informes de las madres en las visitas dos veces por semana a lo largo de los dos primeros años de vida de los niños. Se estimó la incidencia del uso de antibióticos y las asociaciones del uso de antibióticos con características familiares y con niños. Se describieron los patrones de tratamiento para la diarrea y las enfermedades respiratorias, y se identificaron los factores relacionados con las clases de tratamientos y de antibióticos.De un total de 1 346 388 días de observación, se registraron 16 913 tratamientos con antibióticos (una incidencia de 4,9 tratamientos por niño al año), siendo el mayor uso en el sur de Asia. Se empleó tratamiento con antibióticos en 375/499 (75,2%) episodios de diarrea hemorrágica y en 4 274/9 661 (44,2%) episodios de diarrea sin deposiciones hemorrágicas. Se usaron antibióticos en 2 384/3 943 (60,5%) episodios de enfermedad respiratoria aguda de las vías bajas confirmadas por los investigadores, así como en 6 608/16 742 (39,5%) episodios de enfermedad respiratoria de las vías altas. Las penicilinas se usaron más frecuentemente para las enfermedades respiratorias, mientras que los antibióticos para el tratamiento de la diarrea variaron entre los distintos lugares.La exposición repetida a antibióticos fue común en los primeros años de vida, y el tratamiento de diarrea no hemorrágica y de enfermedades respiratorias no específicas no fue coherente con las recomendaciones internacionales. Los programas de uso racional de antibióticos pueden tener el mayor efecto en el sur de Asia, donde el uso de antibióticos fue el más alto.وصف وتيرة إعطاء المضادات الحيوية للأطفال في مراحلهم العمرية المبكرة والعوامل المرتبطة بذلك، وتقدير نسبة حالات الإصابة بالإسهال وأمراض الجهاز التنفسي التي عولجت بالمضادات الحيوية.قمنا في الفترة ما بين عامي 2009 و 2014 بمتابعة 2134 طفلاً من ثماني مواقع في بنغلاديش والبرازيل والهند ونيبال وباكستان وبيرو وجنوب أفريقيا وجمهورية تنزانيا المتحدة، الذين تم تسجيلهم في دراسة الأترابية الخاصة بالمواليد MAL-ED. وقمنا بتوثيق جميع حالات تناول المضادات الحيوية من بلاغات الأمهات في الزيارات الأسبوعية التي تحدث مرتين طوال العامين الأولين للطفل. كما قمنا بتقدير عدد حالات تناول المضادات الحيوية والروابط بين تناول المضادات الحيوية مع خصائص الطفل والأسرة. وبذلك قدمنا وصفًا لأنماط العلاج للحالات المصابة بالإسهال وأمراض الجهاز التنفسي، وحددنا العوامل المرتبطة بفئة العلاج والمضاد الحيوي.على مدار 1346388 من إجمالي أيام الرصد والملاحظة، تم تسجيل إعداد 16913 خطة علاجية بالمضادات الحيوية (بمعدل إعداد 4.9 خطة علاجية لكل طفل في العام الواحد)، مع ملاحظة أن معدل تناول المضادات الحيوية هو الأعلى في جنوب آسيا. تم إعطاء العلاج بالمضادات الحيوية بمعدل 375/499 (75.2‏%) للحالات المصابة بالإسهال الدموي وبمعدل 4274/9661 (44.2‏%) للحالات المصابة بالإسهال من دون نزول براز دموي. وتم تناول المضادات الحيوية في 2348/3943 (60.5‏%) من حالات الإصابة المؤكدة بعدوى القناة التنفسية السفلية الحاد وكذلك في 6608/16742 (39.5‏%) من حالات الإصابة المؤكدة بعدوى القناة التنفسية العلوية لدى العاملين الميدانيين. تم إعطاء أدوية البنسلين في معظم الأحيان لعلاج أمراض الجهاز التنفسي، بينما تباينت فئات المضادات الحيوية لعلاج الإسهال داخل وبين المواقع المختلفة.لقد كان التعرض المتكرر للمضادات الحيوية شائعًا في مرحلة عمرية مبكرة، ولم يكن علاج الإسهال غير الدموي وأمراض الجهاز التنفسي غير المحددة متناسقًا مع التوصيات الدولية. ولعل برامج تناول المضادات الحيوية المنطقية هي ما حقق أكبر الأكبر في جنوب آسيا، حيث كان معدل تناول المضادات الحيوية هو الأعلى.旨在描述幼儿期抗生素使用频率及相关因素，并评估使用抗生素进行治疗的腹泻和呼吸道疾病病例的比例。.在 2009 年至 2014 年期间，我们对巴基斯坦、巴西、秘鲁、孟加拉国、南非、尼泊尔、坦桑尼亚联合共和国以及印度八个地区报名参加营养不良和肠道疾病联盟 (MAL-ED) 出生群组研究的 2134 名儿童进行了跟踪调查。 我们在儿童出生后两年内对其进行每周两次的访问，通过其母亲的叙述记录了全部抗生素使用情况。 我们对抗生素使用率以及抗生素使用与儿童和家庭特征之间的关联进行了评估。 我们描述了腹泻和呼吸道疾病的治疗模式，并确定了与治疗和抗生素种类有关的因素。.经过共 1 346 388 天的观察，我们记录了 16 913 个抗生素使用案例（每名儿童每年平均使用 4.9 次），其中抗生素在南亚的使用率最高。 出血性腹泻的抗生素治疗比例为 375/499 (75.2%)，无血便性腹泻的抗生素治疗比例为 4274/9661 (44.2%)。 在经实地调查员确认的急性下呼吸道疾病案例中，抗生素使用比例为 2384/3943 (60.5%)，上呼吸道疾病案例中，抗生素使用比例为 6608/16742 (39.5%)。盘尼西林最常用于呼吸道疾病治疗，腹泻治疗用抗生素的种类在同一地区内以及不同地区间均有所不同。.反复接触抗生素在童年时期很常见，并且非出血性腹泻和非特异性呼吸道疾病的疗法与国际建议不一致。 合理使用抗生素项目或许在南非会产生最大影响，在该地区，抗生素的使用率最高。.Описать частоту употребления антибиотиков в раннем детстве и факторы, связанные с этим, и определить долю случаев диареи и заболеваний дыхательных путей, для лечения которых использовались антибиотики.В период между 2009 и 2014 годами авторы осуществляли наблюдение за 2134 детьми из восьми локаций в Бангладеш, Бразилии, Индии, Непале, Объединенной Республике Танзания, Пакистане, Перу и Южной Африке, участвующих в исследовании возрастной группы MAL-ED. Все случаи приема антибиотиков были задокументированы со слов матерей работниками местного центра, совершавшими визит два раза в неделю в течение первых двух лет жизни ребенка. Авторы определили частотность приема антибиотиков и связи между приемом антибиотиков детьми и особенностями домашнего хозяйства. Были описаны модели лечения диареи и заболеваний дыхательных путей, а также определены факторы, связанные с лечением и классом антибиотиков.За 1 346 388 суммарных дней наблюдения было зарегистрировано 16 913 курсов лечения антибиотиками (частотность составила 4,9 курса на ребенка в год), большая доля которых пришлась на Южную Азию. Лечение антибиотиками было прописано в 375 из 499 случаев диареи с кровью (75,2%) и в 4274 из 9661 случая диареи без кровавых примесей (44,2%). Антибиотики применялись в 2384 из 3943 случаев острого заболевания нижних дыхательных путей (60,5%), подтвержденного работниками местного центра, а также в 6608 из 16 742 случаев заболевания верхних дыхательных путей (39,5%). Чаще других для лечения заболеваний дыхательных путей использовались пенициллины, в то время как класс антибиотиков для лечения диареи различался как в пределах одной локации, так и между локациями.В раннем возрасте было распространено неоднократное воздействие антибиотиков, а лечение диареи без следов крови и неспецифических заболеваний дыхательных путей проводилось не в соответствии с международными рекомендациями. Программы рационального использования антибиотиков, возможно, оказывают наибольшее влияние в Южной Азии, где процент применения антибиотиков был наиболее высок.

Individuals in the developing world live in conditions of intense exposure to enteric pathogens due to suboptimal water and sanitation. These environmental conditions lead to alterations in intestinal structure, function, and local and systemic immune activation that are collectively referred to as environmental enteropathy (EE). This condition, although poorly defined, is likely to be exacerbated by undernutrition as well as being responsible for permanent growth deficits acquired in early childhood, vaccine failure, and loss of human potential. This article addresses the underlying theoretical and analytical frameworks informing the methodology proposed by the Etiology, Risk Factors and Interactions of Enteric Infections and Malnutrition and the Consequences for Child Health and Development (MAL-ED) cohort study to define and quantify the burden of disease caused by EE within a multisite cohort. Additionally, we will discuss efforts to improve, standardize, and harmonize laboratory practices within the MAL-ED Network. These efforts will address current limitations in the understanding of EE and its burden on children in the developing world.

Background: Mass drug treatment with azithromycin (MDA) is part of the WHO-endorsed ‘SAFE’ strategy for trachoma control in endemic communities. MDA has been associated with reduced trachoma prevalence and short-term reductions in other bacterial infections, but can also lead to increased circulation of macrolide-resistant bacteria. Methods: We prospectively monitored macrolide resistance in fecal E. coli collected from young children participating in the PRET+ Study in rural Tanzania. MDA was administered in four villages with >10% trachoma prevalence. Four nearby communities with lower trachoma prevalence served as controls. Rectal swabs were collected during cross-sectional surveys performed at baseline, 1, 3 and 6 months after MDA. Fecal E. coli isolates were screened for macrolide susceptibility using disc diffusion and minimum inhibitory concentration methods. Cross-sectional and longitudinal differences in resistance prevalence by MDA exposure were compared using t-tests and logistic regression. Results: There was no difference in the proportion of individuals carrying azithromycin-resistant E. coli at baseline (0.21 vs 0.16, P > 0.05). Azithromycin resistance carriage prevalence remained stable over follow-up in non-MDA villages but increased sharply in MDA villages (0.61 at 1 month, 0.42 at 3 months and 0.31 at 6 months). MDA exposure was highly associated with azithromycin resistance carriage at 1 month post-MDA (OR 15.27, P < 0.001) and subsequent surveys. Younger age and recent diarrhoea were also associated with increased odds of resistance (P < 0.01). Conclusions: MDA resulted in significantly increased prevalence of macrolide resistance in E. coli. Although MDA is effective for trachoma elimination, it has costs; it is essential to monitor antimicrobial resistance following MDA.

BACKGROUND: Emerging evidence suggests that the mass distribution of azithromycin for trachoma control (MDA) may increase circulation of macrolide resistance in bacteria associated with severe pediatric infections in treated communities. METHODS: We examined the effect of MDA on nasopharyngeal carriage of antibiotic-resistant Streptococcus pneumoniae among 1015 young children living in rural Tanzania. MDA with a single dose of oral azithromycin was provided in 4 of 8 communities where trachoma prevalence was ≥10%. Isolates were tested for susceptibility to azithromycin (AZM) and commonly used antibiotics by disk diffusion and Etest. We calculated the proportion of antibiotic-resistant S. pneumoniae carriage at baseline and again 1, 3, and 6 months after treatment, and at comparable intervals in the untreated villages. RESULTS: The proportion of AZM-resistant isolates was similar between groups at baseline (MDA: 35.8% vs non-MDA: 35.4%), however, this proportion was greater in the MDA group in all subsequent surveys. At 6 months, the percentage of AZM-resistant isolates was significantly higher in the MDA group (81.9% vs 46.9%, P < .001). The odds of AZM-resistant carriage was 5-fold greater in the MDA group (odds ratio, 4.95 [95% confidence interval, 3.23-7.61]). The proportion of isolates clinically resistant to AZM (minimum inhibitory concentration ≥16 µg/mL) was also significantly greater in the MDA group at 6 months (35.3% vs 12.4%, P < .006). CONCLUSIONS: Mass distribution of a single dose of oral azithromycin for trachoma was associated with increased circulation of macrolide-resistant S. pneumoniae carriage among young children in the 6 months following treatment. It is crucial that changes in antibiotic resistance patterns and their clinical significance in the treatment of severe pediatric infections be assessed in future MDA trials.

Enteric infections are associated with linear growth failure in children. To quantify the association between intestinal inflammation and linear growth failure three commercially available enzyme-linked immunosorbent assays (neopterin [NEO], alpha-anti-trypsin [AAT], and myeloperoxidase [MPO]) were performed in a structured sampling of asymptomatic stool from children under longitudinal surveillance for diarrheal illness in eight countries. Samples from 537 children contributed 1,169 AAT, 916 MPO, and 954 NEO test results that were significantly associated with linear growth. When combined to form a disease activity score, children with the highest score grew 1.08 cm less than children with the lowest score over the 6-month period following the tests after controlling for the incidence of diarrheal disease. This set of affordable non-invasive tests delineates those at risk of linear growth failure and may be used for the improved assessments of interventions to optimize growth during a critical period of early childhood.

Enteroaggregative, enteropathogenic, and enterotoxigenic E. coli contribute significantly to the burden of diarrheal infections particularly in developing countries. Antibiotic resistance is increasingly common among bacterial pathogens including pathogenic E. coli. We assessed the relationship between pathogenic E. coli carriage and resistance to 6 antibiotics in E. coli isolated from young children in rural Tanzania. We surveyed temporal stability in antibiotic resistance in 2492 E. coli isolated from fecal samples obtained from young children in rural Tanzania collected over a 6 month period. Enteroaggregative, enteropathogenic, and enterotoxigenic E. coli contribute significantly to the burden of diarrheal infections particularly in developing countries. Antibiotic resistance is increasingly common among bacterial pathogens including pathogenic E. coli. We assessed the relationship between pathogenic E. coli carriage and resistance to 6 antibiotics in E. coli isolated from young children in rural Tanzania. We surveyed temporal stability in antibiotic resistance in 2492 E. coli isolated from fecal samples obtained from young children in rural Tanzania collected over a 6 month period. Approximately half of the 377 children sampled were exposed to an azithromycin mass treatment program for trachoma control and half resided in control villages. Children were sampled at baseline, 1-, 3- and 6 months following azithromycin treatment. We compared resistance to 6 antibiotics in pathogenic and non-pathogenic strains at the population level, within fecal specimens, and within individuals over time using chi-square tests, paired odds ratios, and logistic regression, respectively. Resistance to ampicillin and trimethoprim/sulfamethoxazole was highly prevalent (>65%). Resistance to 5 of 6 antibiotics tested and multi-drug resistance occurred more frequently in pathogenic isolates (p≤0.001) within fecal specimens and overall. Azithromycin mass treatment exposure was significantly associated with increased odds of carriage of isolates resistant to erythromycin (OR 3.64, p

Growth and development shortfalls that are disproportionately prevalent in children living in poor environmental conditions are postulated to result, at least in part, from abnormal gut function. Using data from The Etiology, Risk Factors, and Interactions of Enteric Infections and Malnutrition and the Consequences for Child Health and Development (MAL-ED) longitudinal cohort study, we examine biomarkers of gut inflammation and permeability in relation to environmental exposures and feeding practices. Trends in the concentrations of three biomarkers, myeloperoxidase (MPO), neopterin (NEO), and α-1-antitrypsin (AAT), are described from fecal samples collected during the first 2 years of each child's life. A total of 22,846 stool samples were processed during the longitudinal sampling of 2,076 children 0–24 months of age. Linear mixed models were constructed to examine the relationship between biomarker concentrations and recent food intake, symptoms of illness, concurrent enteropathogen infection, and socioeconomic status. Average concentrations of MPO, NEO, and AAT were considerably higher than published references for healthy adults. The concentration of each biomarker tended to decrease over the first 2 years of life and was highly variable between samples from each individual child. Both MPO and AAT were significantly elevated by recent breast milk intake. All three biomarkers were associated with pathogen presence, although the strength and direction varied by pathogen. The interpretation of biomarker concentrations is subject to the context of their collection. Herein, we identify that common factors (age, breast milk, and enteric infection) influence the concentration of these biomarkers. Within the context of low- and middle-income communities, we observe concentrations that indicate gut abnormalities, but more appropriate reference standards are needed.

We evaluated the effect of a single mass distribution of azithromycin for trachoma on the risk of acute lower respiratory infection (ALRI) during a 6-month period among young children living in 8 communities in rural Tanzania.In 8 communities, a cohort of randomly selected children (n = 1036) was followed for incidence of ALRI episodes. Mass treatment for trachoma using a single dose of oral azithromycin was provided in 4 of the 8 communities where trachoma prevalence was .10%. All children were followed with biweekly surveillance at home for 6 months. Incidence of ALRI episodes was calculated for 0 to 1 month, 1 to 3 months, and 3 to 6 months posttreatment and in comparable time points in the nontreated villages.In the multivariate analysis, living in a MDA village was associated with a 38% (rate ratio 5 0.62, 95% confidence interval [CI] = 0.43-0.91) decreased risk of ALRI in the 0- to 1-month follow-up period as compared with those in the untreated communities after adjusting for covariates and clustering. There were no significant differences in ALRI incidence by exposure status in the 1- to 3-month (rate ratio = 0.91, 95% CI = 0.69-1.20) and in the 3- to 6-month (rate ratio = 1.00, 95% CI = 0.76-1.30) follow-up periods.Mass distribution of a single dose of oral azithromycin for trachoma is associated with a significant short-term reduction in ALRI morbidity among young children.

A cohort study was designed to assess the impact of mass distribution of azithromycin (MDA) for trachoma control on incidence over six months of pediatric diarrhea in eight communities in rural Tanzania. A single dose of azithromycin was offered to all residents in four communities, where trachoma prevalence was ≥ 10%. Four geographically matched communities had trachoma prevalences < 10% and did not receive MDA. All randomly selected children (n = 1036) were followed-up for six months post-MDA with bi-weekly surveillance at home. In the 0–1-month and 1–3-month periods, MDA exposure was associated with a 39% (rate ratio = 0.61, 95% confidence interval = 0.39–0.95) and 24% (rate ratio = 0.76, 95% confidence interval = 0.54–1.07) lower risk of diarrhea, respectively, compared with those unexposed, after adjustment for clustering and covariates. By the 3–6-month period, diarrhea incidence was comparable between groups. Thus, MDA was associated with a short-term reduction in diarrheal morbidity in children.