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Introduction Understanding human mobility’s role in malaria transmission is critical to successful control and elimination. However, common approaches to measuring mobility are ill-equipped for remote regions such as the Amazon. This study develops a network survey to quantify the effect of community connectivity and mobility on malaria transmission.Methods We measure community connectivity across the study area using a respondent driven sampling design among key informants who are at least 18 years of age. 45 initial communities will be selected: 10 in Brazil, 10 in Ecuador and 25 in Peru. Participants will be recruited in each initial node and administered a survey to obtain data on each community’s mobility patterns. Survey responses will be ranked and the 2–3 most connected communities will then be selected and surveyed. This process will be repeated for a third round of data collection. Community network matrices will be linked with each country’s malaria surveillance system to test the effects of mobility on disease risk.Ethics and dissemination This study protocol has been approved by the institutional review boards of Duke University (USA), Universidad San Francisco de Quito (Ecuador), Universidad Peruana Cayetano Heredia (Peru) and Universidade Federal Minas Gerais (Brazil). Results will be disseminated in communities by the end of the study.

Malaria transmission is influenced by climate and land use/land cover change (LULC). This study examines the impact of climate and LULC on malaria risk in the Ecuadorian Amazon. Weekly malaria surveillance data between 2008 and 2019 from Ecuador's Ministry of Public Health were combined with hydrometeorological and LULC data. Cross-correlation analyses identified time lags. Bayesian spatiotemporal models estimated annual LULC rates of change (ARC) by census area and assessed the effects on Plasmodium vivax and Plasmodium falciparum incidence. ARC for the five land cover classes (forest, agriculture, urban, shrub vegetation, water) ranged from -1 to 4% with agriculture increasing across areas. Forest and shrub vegetation ARC were significantly associated with both Plasmodium vivax and Plasmodium falciparum. Temperature and terrestrial water content showed consistent negative relationships with both species. Precipitation had varying effects on Plasmodium vivax (null) and Plasmodium falciparum (increase) incidence. Shrubs and forest expansion, increased temperature, and terrestrial water content reduced malaria incidence, while increased precipitation had varying effects. Relationships between malaria, LULC, and climate are complex, influencing risk profiles. These findings aid decision-making and guide further research in the region.

[This corrects the article DOI: 10.1371/journal.pone.0287412.].

Artisanal and small-scale gold mining (ASGM) is the largest global anthropogenic mercury (Hg) source and is widespread in the Peruvian Amazon. Consuming Hg-laden foods exposes people to this potent neurotoxin. While numerous studies have examined fish Hg content near ASGM, Hg accumulation in other commonly consumed animal-and plant-based foods from terrestrial environments is often overlooked. In this study, we aim to address understudied dietary Hg exposures. To understand Hg exposure from food staples in the Peruvian Amazon, we measured total and methyl Hg in local crops, fish, chicken meat, chicken feathers, and eggs from ASGM-impacted and upstream (reference) communities. Diet surveys were used to estimate probable weekly Hg intake from each food. Fish and chicken stable carbon and nitrogen isotope signatures were analyzed to evaluate trophic magnification. Though few crops exceeded food safety recommendations, rice methyl Hg proportions were high (84%). Trophic level was an expected key predictor of fish Hg content. 81% (17 of 21) of local carnivorous fish exceeded WHO and EPA recommendations. Compared to upstream communities, mining-impacted communities demonstrated elevated total Hg in crops (1.55 (interquartile ranges (IQR): 0.60–3.03) μ g kg ^−1 upstream versus 3.38 (IQR: 1.62–11.58) in mining areas), chicken meats (2.69 (IQR: BDL–9.96) μ g kg ^−1 versus 19.68 (IQR: 6.33–48.1)), and feathers (91.20 (IQR: 39.19–216.13) μ g kg ^−1 versus 329.99 (IQR: 173.22–464.99)). Chicken meats from mining areas exhibited over double the methyl Hg concentrations of those upstream. Methyl Hg fractions in chicken muscle tissue averaged 93%. Egg whites and livers exceeded Hg recommendations most frequently. Proximity to mining, but not trophic position, was a predictor of chicken Hg content. Our results demonstrate that terrestrial and aquatic foods can accumulate Hg from mining activity, introducing additional human Hg exposure routes. However, locally sourced carnivorous fish was the largest contributor to an estimated three-fold exceedance of the provisional tolerable weekly Hg intake.

Gulf War Illness (GWI) is a major health problem for approximately 250,000 Gulf War (GW) veterans, but the etiology of GWI is unclear. We hypothesized that mitochondrial dysfunction is an important contributor to GWI, based on the similarity of some GWI symptoms to those occurring in some mitochondrial diseases; the plausibility that certain pollutants to which GW veterans were exposed affect mitochondria; mitochondrial effects observed in studies in laboratory models of GWI; and previous evidence of mitochondrial outcomes in studies in GW veterans. A primary role of mitochondria is generation of energy via oxidative phosphorylation. However, direct assessment of mitochondrial respiration, reflecting oxidative phosphorylation, has not been carried out in veterans with GWI. In this case-control observational study, we tested multiple measures of mitochondrial function and integrity in a cohort of 114 GW veterans, 80 with and 34 without GWI as assessed by the Kansas definition. In circulating white blood cells, we analyzed multiple measures of mitochondrial respiration and extracellular acidification, a proxy for non-aerobic energy generation; mitochondrial DNA (mtDNA) copy number; mtDNA damage; and nuclear DNA damage. We also collected detailed survey data on demographics; deployment; self-reported exposure to pesticides, pyridostigmine bromide, and chemical and biological warfare agents; and current biometrics, health and activity levels. We observed a 9% increase in mtDNA content in blood in veterans with GWI, but did not detect differences in DNA damage. Basal and ATP-linked oxygen consumption were respectively 42% and 47% higher in veterans without GWI, after adjustment for mtDNA amount. We did not find evidence for a compensatory increase in anaerobic energy generation: extracellular acidification was also lower in GWI (12% lower at baseline). A subset of 27 and 26 veterans returned for second and third visits, allowing us to measure stability of mitochondrial parameters over time. mtDNA CN, mtDNA damage, ATP-linked OCR, and spare respiratory capacity were moderately replicable over time, with intraclass correlation coefficients of 0.43, 0.44, 0.50, and 0.57, respectively. Other measures showed higher visit-to-visit variability. Many measurements showed lower replicability over time among veterans with GWI compared to veterans without GWI. Finally, we found a strong association between recalled exposure to pesticides, pyridostigmine bromide, and chemical and biological warfare agents and GWI (p < 0.01, p < 0.01, and p < 0.0001, respectively). Our results demonstrate decreased mitochondrial respiratory function as well as decreased glycolytic activity, both of which are consistent with decreased energy availability, in peripheral blood mononuclear cells in veterans with GWI.

IntroductionThe Taenia solium tapeworm is responsible for cysticercosis, a neglected tropical disease presenting as larvae in the body of a host following taenia egg ingestion. Neurocysticercosis (NCC), the name of the disease when it affects the human central nervous system, is a major cause of epilepsy in developing countries, and can also cause intracranial hypertension, hydrocephalus and death. Simulation models can help identify the most cost-effective interventions before their implementation. Modelling NCC should enable the comparison of a broad range of interventions, from treatment of human taeniasis (presence of an adult taenia worm in the human intestine) to NCC mitigation. It also allows a focus on the actual impact of the disease, rather than using proxies as is the case for other models.MethodsThis agent-based model is the first model that simulates human NCC and associated pathologies. It uses the output of another model, CystiAgent, which simulates the evolution of pig cysticercosis and human taeniasis, adding human and cyst agents, including a model of cyst location and stage, human symptoms, and treatment. CystiHuman also accounts for delays in the appearance of NCC-related symptoms. It comprises three modules detailing cyst development, seizure probability and timing, and intracranial hypertension/hydrocephalus, respectively. It has been implemented in Java MASON and calibrated in three endemic villages in Peru, then applied to another village (Rica Playa) to compare simulation results with field data in that village.Results and discussionDespite limitations in available field data, parameter values found through calibration are plausible and simulated outcomes in Rica Playa are close to actual values for NCC prevalence and the way it increases with age and cases with single lesions. Initial simulations further suggest that short-term interventions followed by a rapid increase in taeniasis prevalence back to original levels may have limited impacts on NCC prevalence.

The pork tapeworm, Taenia solium, is the cause of a preventable zoonotic disease, cysticercosis, affecting both pigs and humans. Continued endemic transmission of T. solium is a major contributor of epilepsy and other neurologic morbidity, and the source of important economic losses, in many rural areas of developing countries. Simulation modelling can play an important role in aiding the design and evaluation of strategies to control or even eliminate transmission of the parasite. In this paper, we present a new agent based model of local-scale T. solium transmission and a new, non-local, approach to the model calibration to fit model outputs to observed human taeniasis and pig cysticercosis prevalence simultaneously for several endemic villages. The model fully describes all relevant aspects of T. solium transmission, including the processes of pig and human infection, the spatial distribution of human and pig populations, the production of pork for human consumption, and the movement of humans and pigs in and out in several endemic villages of the northwest of Peru. Despite the high level of uncertainty associated with the empirical measurements of epidemiological data associated with T. solium, the non-local calibrated model parametrization reproduces the observed prevalences with an acceptable precision. It does so not only for the villages used to calibrate the model, but also for villages not included in the calibration process. This important finding demonstrates that the model, including its calibrated parametrization, can be successfully transferred within an endemic region. This will enable future studies to inform the design and optimization of T. solium control interventions in villages where the calibration may be prevented by the limited amount of empirical data, expanding the possible applications to a wider range of settings compared to previous models.

BackgroundThe pork tapeworm (Taenia solium) is a parasitic helminth that imposes a major health and economic burden on poor rural populations around the world. As recognized by the World Health Organization, a key barrier for achieving control of T. solium is the lack of an accurate and validated simulation model with which to study transmission and evaluate available control and elimination strategies. CystiAgent is a spatially-explicit agent based model for T. solium that is unique among T. solium models in its ability to represent key spatial and environmental features of transmission and simulate spatially targeted interventions, such as ring strategy.Methods/principal findingsWe validated CystiAgent against results from the Ring Strategy Trial (RST)-a large cluster-randomized trial conducted in northern Peru that evaluated six unique interventions for T. solium control in 23 villages. For the validation, each intervention strategy was replicated in CystiAgent, and the simulated prevalences of human taeniasis, porcine cysticercosis, and porcine seroincidence were compared against prevalence estimates from the trial. Results showed that CystiAgent produced declines in transmission in response to each of the six intervention strategies, but overestimated the effect of interventions in the majority of villages; simulated prevalences for human taenasis and porcine cysticercosis at the end of the trial were a median of 0.53 and 5.0 percentages points less than prevalence observed at the end of the trial, respectively.Conclusions/significanceThe validation of CystiAgent represented an important step towards developing an accurate and reliable T. solium transmission model that can be deployed to fill critical gaps in our understanding of T. solium transmission and control. To improve model accuracy, future versions would benefit from improved data on pig immunity and resistance, field effectiveness of anti-helminthic treatment, and factors driving spatial clustering of T. solium infections including dispersion and contact with T. solium eggs in the environment.

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.

Abstract Background Models can be used to study and predict the impact of interventions aimed at controlling the spread of infectious agents, such as Taenia solium, a zoonotic parasite whose larval stage causes epilepsy and economic loss in many rural areas of the developing nations. To enhance the credibility of model estimates, calibration against observed data is necessary. However, this process may lead to a paradoxical dependence of model parameters on location-specific data, thus limiting the model’s geographic transferability. Methods In this study, we adopted a non-local model calibration approach to assess whether it can improve the spatial transferability of CystiAgent, our agent-based model of local-scale T. solium transmission. The calibration dataset for CystiAgent consisted of cross-sectional data on human taeniasis, pig cysticercosis and pig serology collected in eight villages in Northwest Peru. After calibration, the model was transferred to a second group of 21 destination villages in the same area without recalibrating its parameters. Model outputs were compared to pig serology data collected over a period of 2 years in the destination villages during a trial of T. solium control interventions, based on mass and spatially targeted human and pig treatments. Results Considering the uncertainties associated with empirical data, the model produced simulated pre-intervention pig seroprevalences that were successfully validated against data collected in 81% of destination villages. Furthermore, the model outputs were able to reproduce validated pig seroincidence values in 76% of destination villages when compared to the data obtained after the interventions. The results demonstrate that the CystiAgent model, when calibrated using a non-local approach, can be successfully transferred without requiring additional calibration. Conclusions This feature allows the model to simulate both baseline pre-intervention transmission conditions and the outcomes of control interventions across villages that form geographically homogeneous regions, providing a basis for developing large-scale models representing T. solium transmission at a regional level. Graphical Abstract

The Peruvian Amazon is facing the highest known input of mercury pollution of any ecosystem globally. Intact forests located near artisanal gold mining are particularly at risk from this toxin.

Abstract Background American cutaneous leishmaniasis (CL) is a neglected tropical disease typically associated with men working in remote, sylvatic environments. We sought to identify CL risk factors in a highly deforested region where anecdotal reports suggested an atypical proportion of women and children were infected with CL raising concern among authorities that transmission was shifting towards domestic spaces and population centers. Methods We describe the characteristics of CL patients from four participating clinics after digitizing up to 10 years of patient data from each clinic’s CL registries. We assessed risk factors of CL associated with intradomestic, peridomestic, or non-domestic transmission through a matched case-control study with 63 patients who had visited these same clinics for CL (cases) or other medical reasons (controls) between January 2014 and August 2016. The study consisted of an in-home interview of participants by a trained field worker using a standard questionnaire. Risk factors were identified using bivariable and multivariable conditional logistic regression. Results Between 2007 and 2016, a total of 529 confirmed CL positives were recorded in the available CL registries. Children and working aged women made up 58.6% of the cases. Our final model suggests that the odds of sleeping in or very near an agricultural field were five times greater in cases than controls (p = 0.025). Survey data indicate that women, children, and men have similar propensities to both visit and sleep in or near agricultural fields. Conclusions Women and children may be underappreciated as CL risk groups in agriculturally dependent regions. Despite the age-sex breakdown of clinical CL patients and high rates of deforestation occurring in the study area, transmission is mostly occurring outside of the largest population centers. Curbing transmission in non-domestic spaces may be limited to decreasing exposure to sandflies during the evening, nighttime, and early morning hours. Our paper serves as a cautionary tale for those relying solely on the demographic information obtained from clinic-based data to understand basic epidemiological trends of vector-borne infections.

Background: In-utero exposure to mercury and other trace metals pose a significant threat to child health and development, but exposures and health impacts in artisanal and small-scale gold mining (ASGM) environments are poorly defined. Objectives: We describe the CONAMAD study design, a prospective birth cohort consisting of multiparous women (18 and over) living in rural and peri-urban Peruvian Amazon communities exposed to ASGM. Methods: Pregnant women are enrolled from health posts across four zones of Madre de Dios, Peru. Data are collected at enrollment, childbirth, and (planned) 36-48 months. At enrollment, hair samples for mercury assessment, demographic and clinical data are obtained. At birth, we obtain venous and cord blood, placenta, hair, toenails, and saliva. Findings: Two hundred seventy mothers were enrolled at an average 20 weeks gestational age with no differences in maternal characteristics across zones. Two hundred fifteen mothers were successfully followed at birth. We obtained 214 maternal and cord blood samples, 211 maternal and 212 infant hair samples, 212 placenta samples, 210 infant saliva samples, and 214 infant dried blood spots. Data collected will allow for testing our primary hypotheses of maternal malnutrition modifying ratios of cord:maternal blood total mercury (tHg), cord blood:maternal hair tHg, and infant:maternal hair tHg, and whether chemical mixtures (Hg, Pb, Cd) have synergistic effects on infant neurodevelopment. Conclusions: CONAMAD is designed to collect and store samples for future processing and hypothesis testing associated with in-utero mercury exposure and child development. We have completed the exposure assessments and will conduct a follow-up of mothers to evaluate early child development outcomes, including developmental delay and growth. These data offer insights into disease mechanisms, exposure prevention, and policy guidance for countries where ASGM is prevalent.

Background: In Peru, anemia has been a persistent health problem that is known to lead to irreversible cognitive and developmental deficits in children. The Peruvian government has recently made anemia a primary health concern by passing legislation in 2017 that makes anemia an intersectoral priority. This new legislation fortifies previous programs while creating new programs that target specific age groups. Objectives: Evaluate the effectiveness of government programs in Madre de Dios, Peru to reduce anemia prevalence and increase hemoglobin levels among children ages 2–11 years old. Methods: Propensity scores are used to match 688 children enrolled in 2018, after the legislation, and 2,140 children enrolled in previous studies our team conducted in the region between 2014 and 2017, based on sex, age (years), intervention status (prior/post), community income, presence of a health post in the community (yes/no), community type (indigenous, non-indigenous rural, non-indigenous urban) and road access (fraction of the number of months out of the year with road access). A pseudo matched case-control analysis to evaluate changes in anemia prevalence and hemoglobin was conducted using t-tests and multivariate models. Program effectiveness is evaluated overall, by age groups (2–4, 5–7 and 8–11 years old), and community type (indigenous vs. urban). Findings: The adjusted odds ratio indicated lower odds of anemia (OR = 0.31, 95%CI 0.17–0.54) for children exposed to the anemia prevention programs vs. those not exposed. The effect was not significantly different across age groups; however, the intervention effects significantly differed by community type among children 8–11 years old, with urban children less likely to benefit from anemia interventions (OR = 0.69, 95% CI 0.38–1.25) compared to indigenous children (OR = 0.21, 95% CI 0.08–0.56). Conclusion: Government programs to reduce anemia in Madre de Dios were found to be associated with reduced anemia prevalence in the study communities. However, the lack of program monitoring precludes the attribution of anemia decline to specific interventions or program components. In addition, regional anemia prevalence remains high according to the 2019 Demographic and Health Survey, suggesting impaired population impact. Program monitoring and evaluation is a key component of health interventions to improve program implementation effectiveness.

Abstract Children living near artisanal and small‐scale gold mining (ASGM) are at risk of exposure to mercury, a neurotoxicant. It is not certain whether such exposures are harming development, as they occur in underresourced contexts entwined with other stressors, such as malnutrition and enteric infection. This study sought to investigate the association between hair‐mercury levels and visual‐motor, cognitive, and physical development among children living near ASGM in the Peruvian Amazon. Total hair‐mercury levels were measured in 164 children ages 5–12 living in Madre de Dios, Peru. Primary outcomes included Visual‐Motor Integration assessed via the Beery‐VMI Developmental Test, General Cognitive Ability assessed via the Batería‐III Woodcock‐Munoz (Spanish‐language Woodcock‐Johnson Tests of Cognitive Abilities), and Physical Health assessed via anthropometry/hemoglobin counts. Mean (SD) hair‐mercury level was 2.06 (2.43) μg/g. Fifty‐four children (32.9%) had hair‐mercury levels above the World Health Organization reference level of 2.0 μg/g. After controlling for sex, child age, maternal education, and family socioeconomic status, each one unit increase in log hair‐mercury level was associated with a 1.01 unit decrease in Visual‐Motor Integration (95%CI: −2.06, 0.05, p = 0.061), a 2.59 unit decrease in General Cognitive Ability (95%CI: −4.52, −0.66, p = 0.012), and a 2.43 unit decrease in Physical Health (95%CI: −5.34, 0.49, p = 0.096). After adjustment for covariates, children with hair‐mercury levels exceeding the World Health Organization reference level scored 4.68 IQ points lower in Cognitive Ability than their peers. Mercury exposures related to ASGM may be harming child development in the Peruvian Amazon. Children in this region may benefit from intervention to reach their full developmental potential.

Background: Environmental enteropathy (EE), the adverse impact of frequent and numerous enteric infections on the gut resulting in a state of persistent immune activation and altered permeability, has been proposed as a key determinant of growth failure in children in low- and middle-income populations. A theory-driven systems model to critically evaluate pathways through which enteropathogens, gut permeability, and intestinal and systemic inflammation affect child growth was conducted within the framework of the Etiology, Risk Factors and Interactions of Enteric Infections and Malnutrition and the Consequences for Child Health and Development (MAL-ED) birth cohort study that included children from eight countries. Methods: Non-diarrheal stool samples (N = 22,846) from 1253 children from multiple sites were evaluated for a panel of 40 enteropathogens and fecal concentrations of myeloperoxidase, alpha-1-antitrypsin, and neopterin. Among these same children, urinary lactulose:mannitol (L:M) (N = 6363) and plasma alpha-1-acid glycoprotein (AGP) (N = 2797) were also measured. The temporal sampling design was used to create a directed acyclic graph of proposed mechanistic pathways between enteropathogen detection in non-diarrheal stools, biomarkers of intestinal permeability and inflammation, systemic inflammation and change in length- and weight- for age in children 0–2 years of age. Findings: Children in these populations had frequent enteric infections and high levels of both intestinal and systemic inflammation. Higher burdens of enteropathogens, especially those categorized as being enteroinvasive or causing mucosal disruption, were associated with elevated biomarker concentrations of gut and systemic inflammation and, via these associations, indirectly associated with both reduced linear and ponderal growth. Evidence for the association with reduced linear growth was stronger for systemic inflammation than for gut inflammation; the opposite was true of reduced ponderal growth. Although Giardia was associated with reduced growth, the association was not mediated by any of the biomarkers evaluated. Interpretation: The large quantity of empirical evidence contributing to this analysis supports the conceptual model of EE. The effects of EE on growth faltering in young children were small, but multiple mechanistic pathways underlying the attribution of growth failure to asymptomatic enteric infections had statistical support in the analysis. The strongest evidence for EE was the association between enteropathogens and linear growth mediated through systemic inflammation. Funding: Bill & Melinda Gates Foundation.