Dixner Rengifo Trigoso - Academia.edu (original) (raw)

Papers by Dixner Rengifo Trigoso

Social Science Research Network, 2019

Environmental enteric dysfunction (EED) is associated with chronic undernutrition. Efforts to ide... more Environmental enteric dysfunction (EED) is associated with chronic undernutrition. Efforts to identify minimally invasive biomarkers of EED reveal an expanding number of candidate analytes. An analytic strategy is reported to select among candidate biomarkers and systematically express the strength of each marker's association with linear growth in infancy and early childhood. 180 analytes were quantified in fecal, urine and plasma samples taken at 7, 15 and 24 months of age from 258 subjects in a birth cohort in Peru. Treating the subjects' length-forage Z-score (LAZ-score) over a 2-month lag as the outcome, penalized linear regression models with different shrinkage methods were fitted to determine the bestfitting subset. These were then included with covariates in linear regression models to obtain estimates of each biomarker's adjusted effect on growth. Transferrin had the largest and most statistically significant adjusted effect on short-term linear growth as measured by LAZ-score-a coefficient value of 0.50 (0.24, 0.75) for each log 2 increase in plasma transferrin concentration. Other biomarkers with large effect size estimates included adiponectin, arginine, growth hormone, proline and serum amyloid P-component. The selected subset explained up to 23.0% of the variability in LAZ-score. Penalized regression modeling approaches can be used to select subsets from large panels of candidate biomarkers of EED. There is a need to systematically express the strength of association of biomarkers with linear growth or other outcomes to compare results across studies.

The American Journal of Clinical Nutrition, Jul 1, 2017

Background: Environmental enteropathy (EE) impairs the gut's absorptive capacity and immune funct... more Background: Environmental enteropathy (EE) impairs the gut's absorptive capacity and immune function and causes decelerations in statural growth that manifest gradually over time. Objective: To illustrate an approach for assessing emerging biomarkers of EE, we separately assessed the associations between 3 such markers and subsequent nutritional status. Design: Stool samples were routinely collected between January 2010 and November 2014 from a cohort of 303 Peruvian infants and analyzed for concentrations of the biomarkers a-1-antitrypsin (AAT), myeloperoxidase, and neopterin. For each marker, a mixed-effects linear regression model was fitted for length-forage z scores (LAZs) obtained from anthropometric assessments that incorporated covariate predictors, polynomial terms for age, and product interaction terms to test associations over varying lag lengths. The biomarkers' contribution to the models was assessed with the use of the likelihood ratio test and partial R 2 statistics. Results: Test statistics for the combined inclusion of the 4-model terms that involved the biomarker were highly statistically significant for AAT (28.71; P , 0.0001) and myeloperoxidase (62.79; P , 0.0001) over a 3-mo lag and moderately so for neopterin (13.97; P = 0.0074). AAT and myeloperoxidase seemed to interact strongly with age, with the magnitude and direction of the effect varying considerably over the first 3 y of life. The largest proportion of the variance explained by any biomarker (2.8%) and the largest difference in LAZ predicted between the 5th and 95th percentile (0.25) was by myeloperoxidase over a 2-mo lag. Conclusions: Of the 3 fecal biomarkers studied, 2 that related to intestinal function-AAT and myeloperoxidase-were associated with small but highly statistically significant differences in future statural growth trajectories in infants in this cohort, lending further evidence to the EE hypothesis that increased gut permeability and inflammation adversely affects subsequent nutritional status. This association exhibited a complex interaction with age. This trial was registered at clinicaltrials.gov as NCT02441426.

Journal of Developmental Origins of Health and Disease, Mar 7, 2017

Environmental enteropathy (EE) is a syndrome of altered small intestine structure and function hy... more Environmental enteropathy (EE) is a syndrome of altered small intestine structure and function hypothesized to be common among individuals lacking access to improved water and sanitation. There are plausible biological mechanisms, both inflammatory and non-inflammatory, by which EE may alter the cardiometabolic profile. Here, we test the hypothesis that EE is associated with the cardiometabolic profile among young children living in an environment of intense enteropathogen exposure. In total, 156 children participating in the Peruvian cohort of a multicenter study on childhood infectious diseases, growth and development were contacted at 3–5 years of age. The urinary lactulose:mannitol ratio, and plasma antibody to endotoxin core were determined in order to assess intestinal permeability and bacterial translocation. Blood pressure, anthropometry, fasting plasma glucose, insulin, and cholesterol and apolipoprotein profiles were also assessed. Extant cohort data were also used to relate biomarkers of EE during the first 18 months of life to early child cardiometabolic profile. Lower intestinal surface area, as assessed by percent mannitol excretion, was associated with lower apolipoprotein-AI and lower high-density lipoprotein concentrations. Lower intestinal surface area was also associated with greater blood pressure. Inflammation at 7 months of age was associated with higher blood pressure in later childhood. This study supports the potential for a relationship between EE and the cardiometabolic profile.

American Journal of Tropical Medicine and Hygiene, Jan 6, 2021

Using previously validated microbial source tracking markers, we detected and quantified fecal co... more Using previously validated microbial source tracking markers, we detected and quantified fecal contamination from avian species and avian exposure, dogs, and humans on household cooking tables and floors. The association among contamination, infrastructure, and socioeconomic covariates was assessed using simple and multiple ordinal logistic regressions. The presence of Campylobacter spp. in surface samples was linked to avian markers. Using molecular methods, animal feces were detected in 75.0% and human feces in 20.2% of 104 households. Floors were more contaminated than tables as detected by the avian marker Av4143, dog marker Bactcan, and human marker Bachum. Wood tables were consistently more contaminated than non-wood surfaces, specifically with the mitochondrial avian markers ND5 and CytB, fecal marker Av4143, and canine marker Bactcan. Final multivariable models with socioeconomic and infrastructure characteristics included as covariates indicate that detection of avian feces and avian exposure was associated with the presence of chickens, maternal age, and length of tenancy, whereas detection of human markers was associated with unimproved water source. Detection of Campylobacter in surface samples was associated with the avian fecal marker Av4143. We highlight the critical need to detect and measure the burden of animal fecal waste when evaluating household water, hygiene, and sanitation interventions, and the possibility of decreasing risk of exposure through the modification of surfaces to permit more effective household disinfection practices. Animals may be a more important source of household fecal contamination than humans in many low-resource settings, although interventions have historically focused almost exclusively on managing human waste.

American Journal of Tropical Medicine and Hygiene, Apr 4, 2018

Poor child gut health, resulting from a lack of access to an improved toilet or clean water, has ... more Poor child gut health, resulting from a lack of access to an improved toilet or clean water, has been proposed as a biological mechanism underlying child stunting and oral vaccine failure. Characteristics related to household sanitation, water use, and hygiene were measured among a birth cohort of 270 children from peri-urban Iquitos Peru. These children had monthly stool samples and urine samples at four time points and serum samples at (2-4) time points analyzed for biomarkers related to intestinal inflammation and permeability. We found that less storage of fecal matter near the household along with a reliable water connection were associated with reduced inflammation, most prominently the fecal biomarker myeloperoxidase (MPO) (no sanitation facility compared with those with an onsite toilet had −0.43 log MPO, 95% confidence interval [CI]: −0.74, −0.13; and households with an intermittent connection versus those with a continuous supply had +0.36 log MPO, 95% CI: 0.08, 0.63). These results provide preliminary evidence for the hypothesis that children less than 24 months of age living in unsanitary conditions will have elevated gut inflammation.

medRxiv (Cold Spring Harbor Laboratory), Mar 11, 2021

Early-life enteric infection and enteropathy markers are associated with changes in adipokine, ap... more Early-life enteric infection and enteropathy markers are associated with changes in adipokine, apolipoprotein and cytokine profiles later in childhood consistent with those of an adverse cardiometabolic disease risk profile in a Peruvian birth cohort.

PLOS Neglected Tropical Diseases, Nov 15, 2019

Environmental enteric dysfunction (EED) is associated with chronic undernutrition. Efforts to ide... more Environmental enteric dysfunction (EED) is associated with chronic undernutrition. Efforts to identify minimally invasive biomarkers of EED reveal an expanding number of candidate analytes. An analytic strategy is reported to select among candidate biomarkers and systematically express the strength of each marker's association with linear growth in infancy and early childhood. 180 analytes were quantified in fecal, urine and plasma samples taken at 7, 15 and 24 months of age from 258 subjects in a birth cohort in Peru. Treating the subjects' length-forage Z-score (LAZ-score) over a 2-month lag as the outcome, penalized linear regression models with different shrinkage methods were fitted to determine the bestfitting subset. These were then included with covariates in linear regression models to obtain estimates of each biomarker's adjusted effect on growth. Transferrin had the largest and most statistically significant adjusted effect on short-term linear growth as measured by LAZ-score-a coefficient value of 0.50 (0.24, 0.75) for each log 2 increase in plasma transferrin concentration. Other biomarkers with large effect size estimates included adiponectin, arginine, growth hormone, proline and serum amyloid P-component. The selected subset explained up to 23.0% of the variability in LAZ-score. Penalized regression modeling approaches can be used to select subsets from large panels of candidate biomarkers of EED. There is a need to systematically express the strength of association of biomarkers with linear growth or other outcomes to compare results across studies.

Clinical Infectious Diseases, Sep 17, 2019

Rouhani et al on pages 989-99 and the Editorial commentary by colin Stine on pages 1008-9.) Backg... more Rouhani et al on pages 989-99 and the Editorial commentary by colin Stine on pages 1008-9.) Background. Campylobacter infection is associated with impaired growth of children, even in the absence of symptoms. To examine the underlying mechanisms, we evaluated associations between Campylobacter infection, linear growth, and fecal microbial community features in a prospective birth cohort of 271 children with a high burden of diarrhea and stunting in the Amazonian lowlands of Peru. Methods. Campylobacter was identified using a broadly reactive, genus-specific enzyme-linked immunosorbent assay. 16S rRNAbased analyses were used to identify bacterial taxa in fecal samples at ages 6, 12, 18, and 24 months (N = 928). Associations between infection, growth, and gut microbial community composition were investigated using multiple linear regression adjusting for withinchild correlations, age, and breastfeeding. Indicator species analyses identified taxa specifically associated with Campylobacter burden. Results. Ninety-three percent (251) of children had Campylobacter present in asymptomatic fecal samples during the follow-up period. A 10% increase in the proportion of stools infected was associated with mean reductions of 0.02 length-forage z scores (LAZ) at 3, 6, and 9 months thereafter (P < .01). We identified 13 bacterial taxa indicative of cumulative Campylobacter burden and 14 taxa significantly associated with high or low burden of enteroaggregative Escherichia coli, norovirus, or Giardia. Conclusions. Campylobacter infection is common in this cohort and associated with changes in microbial community composition. These results support the notion that disruptions to the fecal microbiota may help explain the observed effects of asymptomatic infections on growth in early life.

Universidad Nacional de la Amazonía Peruana, 2008

The present work's objective was to identify RAPD markers linked to sex of “aguaje” Mauritia ... more The present work's objective was to identify RAPD markers linked to sex of “aguaje” Mauritia flexuosa L. f. from DNA mixtures of male and female plants. The sampling area were the community of Quistococha (latitude 03°49'28.66 " S length 73° 19'18.98" W, with 96 msnm) and Santa Clara (latitude 03°46'50.5" S, longitude 73 °18'25.3" W, with 118 msnm); 10 male and 10 female sexually differentiated plants were selected, Collecting leaves, roots and / or pneumatophores and transported to the Research Laboratory of the Biological Sciences School and the Research Laboratory of Natural Antiparasitic Products of the Amazon (LIPNAA) of the National University of the Peruvian Amazon (UNAP), DNA was extracted and mixed by sex , performing RAPD PCR tests with 38 random primers; of Which, 11 primers (E -36, E -37, D1, UNAP1, F1, F5xFa, R5xFma, UNR, PLF, FAR' and EXT5) generated 31 polymorphic amplification products (21 differential bands on female plants and 10 male) with sizes between 182 to 1.552bp; six bands presented better resolution (502bp, 513bp, 610bp, 762bp, 871bp and 975bp) and the F5xFa primer revealed a greater number of differential bands with the female sex. Therefore; the female sex plants are more polymorphic than the male sex and probably can identify sex with RAPD PCR technique early in M. flexuosa.

Clinical Infectious Diseases, Sep 17, 2019

See the Editorial commentary by colin Stine on pages 1008-9 and the Major Article by Rouhani et a... more See the Editorial commentary by colin Stine on pages 1008-9 and the Major Article by Rouhani et al on pages 1000-7.) Background. Detrimental effects of diarrhea on child growth and survival are well documented, but details of the underlying mechanisms remain poorly understood. Recent evidence demonstrates that perturbations to normal development of the gut microbiota in early life may contribute to growth faltering and susceptibility to related childhood diseases. We assessed associations between diarrhea, gut microbiota configuration, and childhood growth in the Peruvian Amazon. Methods. Growth, diarrhea incidence, illness, pathogen infection, and antibiotic exposure were assessed monthly in a birth cohort of 271 children aged 0-24 months. Gut bacterial diversity and abundances of specific bacterial taxa were quantified by sequencing 16S rRNA genes in fecal samples collected at 6, 12, 18, and 24 months. Linear and generalized linear models were used to determine whether diarrhea was associated with altered microbiota and, in turn, if features of the microbiota were associated with the subsequent risk of diarrhea. Results. Diarrheal frequency, duration, and severity were negatively associated with bacterial diversity and richness (P < .05). Children born stunted (length-forage z-score [LAZ] ≤ −2) who were also severely stunted (LAZ ≤ −3) at the time of sampling exhibited the greatest degree of diarrhea-associated reductions in bacterial diversity and the slowest recovery of bacterial diversity after episodes of diarrhea. Increased bacterial diversity was predictive of reduced subsequent diarrhea from age 6 to 18 months. Conclusions. Persistent, severe growth faltering may reduce the gut microbiota's resistance and resilience to diarrhea, leading to greater losses of diversity and longer recovery times. This phenotype, in turn, denotes an increased risk of future diarrheal disease and growth faltering.

Journal of Developmental Origins of Health and Disease, 2017

Environmental enteropathy (EE) is a syndrome of altered small intestine structure and function hy... more Environmental enteropathy (EE) is a syndrome of altered small intestine structure and function hypothesized to be common among individuals lacking access to improved water and sanitation. There are plausible biological mechanisms, both inflammatory and non-inflammatory, by which EE may alter the cardiometabolic profile. Here, we test the hypothesis that EE is associated with the cardiometabolic profile among young children living in an environment of intense enteropathogen exposure. In total, 156 children participating in the Peruvian cohort of a multicenter study on childhood infectious diseases, growth and development were contacted at 3–5 years of age. The urinary lactulose:mannitol ratio, and plasma antibody to endotoxin core were determined in order to assess intestinal permeability and bacterial translocation. Blood pressure, anthropometry, fasting plasma glucose, insulin, and cholesterol and apolipoprotein profiles were also assessed. Extant cohort data were also used to rela...

The American Journal of Tropical Medicine and Hygiene

ABSTRACT. Metabolic syndrome is a cluster of risk factors for cardiovascular disease afflicting m... more ABSTRACT. Metabolic syndrome is a cluster of risk factors for cardiovascular disease afflicting more than 1 billion people worldwide and is increasingly being identified in younger age groups and in socioeconomically disadvantaged settings in the global south. Enteropathogen exposure and environmental enteropathy in infancy may contribute to metabolic syndrome by disrupting the metabolic profile in a way that is detectable in cardiometabolic markers later in childhood. A total of 217 subjects previously enrolled in a birth cohort in Amazonian Peru were monitored annually from ages 2 to 5 years. A total of 197 blood samples collected in later childhood were analyzed for 37 cardiometabolic biomarkers, including adipokines, apolipoproteins, cytokines, which were matched to extant early-life markers of enteropathy ascertained between birth and 2 years. Multivariate and multivariable regression models were fitted to test for associations, adjusting for confounders. Fecal and urinary mark...

The American Journal of Tropical Medicine and Hygiene, 2021

ABSTRACTUsing previously validated microbial source tracking markers, we detected and quantified ... more ABSTRACTUsing previously validated microbial source tracking markers, we detected and quantified fecal contamination from avian species and avian exposure, dogs, and humans on household cooking tables and floors. The association among contamination, infrastructure, and socioeconomic covariates was assessed using simple and multiple ordinal logistic regressions. The presence ofCampylobacterspp. in surface samples was linked to avian markers. Using molecular methods, animal feces were detected in 75.0% and human feces in 20.2% of 104 households. Floors were more contaminated than tables as detected by the avian markerAv4143, dog markerBactcan, and human markerBachum. Wood tables were consistently more contaminated than non-wood surfaces, specifically with the mitochondrial avian markersND5and CytB, fecal marker Av4143, and canine markerBactcan. Final multivariable models with socioeconomic and infrastructure characteristics included as covariates indicate that detection of avian feces...

The American Journal of Clinical Nutrition, 2021

Background Breastfeeding is known to reduce the risk of enteropathogen infections, but protection... more Background Breastfeeding is known to reduce the risk of enteropathogen infections, but protection from specific enteropathogens is not well characterized. Objective The aim was to estimate the association between full breastfeeding (days fed breast milk exclusively or with nonnutritive liquids) and enteropathogen detection. Methods A total of 2145 newborns were enrolled at 8 sites, of whom 1712 had breastfeeding and key enteropathogen data through 6 mo. We focused on 11 enteropathogens: adenovirus 40/41, norovirus, sapovirus, astrovirus, and rotavirus, enterotoxigenic Escherichia coli (ETEC), Campylobacter spp., and typical enteropathogenic E. coli as well as entero-aggregative E. coli, Shigella and Cryptosporidium. Logistic regression was used to estimate the risk of enteropathogen detection in stools and survival analysis was used to estimate the timing of first detection of an enteropathogen. Results Infants with 10% more days of full breastfeeding within the preceding 30 d of a ...

The present work's objective was to identify RAPD markers linked to sex of “aguaje” Mauritia ... more The present work's objective was to identify RAPD markers linked to sex of “aguaje” Mauritia flexuosa L. f. from DNA mixtures of male and female plants. The sampling area were the community of Quistococha (latitude 03°49'28.66 " S length 73° 19'18.98" W, with 96 msnm) and Santa Clara (latitude 03°46'50.5" S, longitude 73 °18'25.3" W, with 118 msnm); 10 male and 10 female sexually differentiated plants were selected, Collecting leaves, roots and / or pneumatophores and transported to the Research Laboratory of the Biological Sciences School and the Research Laboratory of Natural Antiparasitic Products of the Amazon (LIPNAA) of the National University of the Peruvian Amazon (UNAP), DNA was extracted and mixed by sex , performing RAPD PCR tests with 38 random primers; of Which, 11 primers (E -36, E -37, D1, UNAP1, F1, F5xFa, R5xFma, UNR, PLF, FAR' and EXT5) generated 31 polymorphic amplification products (21 differential bands on female plant...

BackgroundMetabolic syndrome is a cluster of risk factors for cardiovascular disease thought to a... more BackgroundMetabolic syndrome is a cluster of risk factors for cardiovascular disease thought to afflict over a billion people worldwide and is increasingly being identified in younger age groups and socio-economically disadvantaged settings in the global south. Enteropathogen exposure and environmental enteropathy in infancy may lead to metabolic syndrome by disrupting the metabolic profile in a way that is detectable in cardiometabolic markers later in childhood.Methods217 subjects previously enrolled in a birth cohort in Amazonian Peru were followed up annually from ages 2 to 5 years. Blood samples collected in later childhood were analyzed for a panel of 37 cardiometabolic biomarkers, including adipokines, apolipoproteins, cytokines, and other analytes. These were matched to extant early-life markers of enteropathy ascertained between birth and 2 years of age. Multivariate and multivariable regression models were fitted to test for associations adjusting for confounders.ResultsFe...

Background: Undernutrition in early childhood has historically been considered irreversible after... more Background: Undernutrition in early childhood has historically been considered irreversible after 2-3 years of age and has been associated with morbidity and mortality over the short-term and poor economic and cognitive outcomes over the long-term. We used longitudinal data to determine which factors are associated with positive changes in absolute and relative differences in height and weight from the WHO Growth Standards from 24 to 60 months of age.Methods: Across six MAL-ED sites, 942 children had anthropometry data at 24 and 60 months, as well as information about socioeconomic status, maternal height, gut permeability (lactulose-mannitol z-score (LMZ)), dietary intake from 9-24 months, and micronutrient status. Anthropometric changes were categorized as positive changes in height- or weight-for-age z-score (HAZ, WAZ) or their absolute difference from the growth standard median (HAD (cm), WAD (kg)), as well as recovery from stunting/underweight. Outcomes were modeled using multi...

PLOS Neglected Tropical Diseases, 2019

Environmental enteric dysfunction (EED) is associated with chronic undernutrition. Efforts to ide... more Environmental enteric dysfunction (EED) is associated with chronic undernutrition. Efforts to identify minimally invasive biomarkers of EED reveal an expanding number of candidate analytes. An analytic strategy is reported to select among candidate biomarkers and systematically express the strength of each marker's association with linear growth in infancy and early childhood. 180 analytes were quantified in fecal, urine and plasma samples taken at 7, 15 and 24 months of age from 258 subjects in a birth cohort in Peru. Treating the subjects' length-forage Z-score (LAZ-score) over a 2-month lag as the outcome, penalized linear regression models with different shrinkage methods were fitted to determine the bestfitting subset. These were then included with covariates in linear regression models to obtain estimates of each biomarker's adjusted effect on growth. Transferrin had the largest and most statistically significant adjusted effect on short-term linear growth as measured by LAZ-score-a coefficient value of 0.50 (0.24, 0.75) for each log 2 increase in plasma transferrin concentration. Other biomarkers with large effect size estimates included adiponectin, arginine, growth hormone, proline and serum amyloid P-component. The selected subset explained up to 23.0% of the variability in LAZ-score. Penalized regression modeling approaches can be used to select subsets from large panels of candidate biomarkers of EED. There is a need to systematically express the strength of association of biomarkers with linear growth or other outcomes to compare results across studies.

The American Journal of Clinical Nutrition, 2019

ABSTRACTBackgroundEnvironmental enteric dysfunction (EED) is thought to increase the risk of micr... more ABSTRACTBackgroundEnvironmental enteric dysfunction (EED) is thought to increase the risk of micronutrient deficiencies, but few studies adjust for dietary intakes and systemic inflammation.ObjectiveWe 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.MethodsUsing 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 ...

The American Journal of Tropical Medicine and Hygiene, 2018

Poor child gut health, resulting from a lack of access to an improved toilet or clean water, has ... more Poor child gut health, resulting from a lack of access to an improved toilet or clean water, has been proposed as a biological mechanism underlying child stunting and oral vaccine failure. Characteristics related to household sanitation, water use, and hygiene were measured among a birth cohort of 270 children from peri-urban Iquitos Peru. These children had monthly stool samples and urine samples at four time points and serum samples at (2-4) time points analyzed for biomarkers related to intestinal inflammation and permeability. We found that less storage of fecal matter near the household along with a reliable water connection were associated with reduced inflammation, most prominently the fecal biomarker myeloperoxidase (MPO) (no sanitation facility compared with those with an onsite toilet had −0.43 log MPO, 95% confidence interval [CI]: −0.74, −0.13; and households with an intermittent connection versus those with a continuous supply had +0.36 log MPO, 95% CI: 0.08, 0.63). These results provide preliminary evidence for the hypothesis that children less than 24 months of age living in unsanitary conditions will have elevated gut inflammation.

Social Science Research Network, 2019

Environmental enteric dysfunction (EED) is associated with chronic undernutrition. Efforts to ide... more Environmental enteric dysfunction (EED) is associated with chronic undernutrition. Efforts to identify minimally invasive biomarkers of EED reveal an expanding number of candidate analytes. An analytic strategy is reported to select among candidate biomarkers and systematically express the strength of each marker's association with linear growth in infancy and early childhood. 180 analytes were quantified in fecal, urine and plasma samples taken at 7, 15 and 24 months of age from 258 subjects in a birth cohort in Peru. Treating the subjects' length-forage Z-score (LAZ-score) over a 2-month lag as the outcome, penalized linear regression models with different shrinkage methods were fitted to determine the bestfitting subset. These were then included with covariates in linear regression models to obtain estimates of each biomarker's adjusted effect on growth. Transferrin had the largest and most statistically significant adjusted effect on short-term linear growth as measured by LAZ-score-a coefficient value of 0.50 (0.24, 0.75) for each log 2 increase in plasma transferrin concentration. Other biomarkers with large effect size estimates included adiponectin, arginine, growth hormone, proline and serum amyloid P-component. The selected subset explained up to 23.0% of the variability in LAZ-score. Penalized regression modeling approaches can be used to select subsets from large panels of candidate biomarkers of EED. There is a need to systematically express the strength of association of biomarkers with linear growth or other outcomes to compare results across studies.

The American Journal of Clinical Nutrition, Jul 1, 2017

Background: Environmental enteropathy (EE) impairs the gut's absorptive capacity and immune funct... more Background: Environmental enteropathy (EE) impairs the gut's absorptive capacity and immune function and causes decelerations in statural growth that manifest gradually over time. Objective: To illustrate an approach for assessing emerging biomarkers of EE, we separately assessed the associations between 3 such markers and subsequent nutritional status. Design: Stool samples were routinely collected between January 2010 and November 2014 from a cohort of 303 Peruvian infants and analyzed for concentrations of the biomarkers a-1-antitrypsin (AAT), myeloperoxidase, and neopterin. For each marker, a mixed-effects linear regression model was fitted for length-forage z scores (LAZs) obtained from anthropometric assessments that incorporated covariate predictors, polynomial terms for age, and product interaction terms to test associations over varying lag lengths. The biomarkers' contribution to the models was assessed with the use of the likelihood ratio test and partial R 2 statistics. Results: Test statistics for the combined inclusion of the 4-model terms that involved the biomarker were highly statistically significant for AAT (28.71; P , 0.0001) and myeloperoxidase (62.79; P , 0.0001) over a 3-mo lag and moderately so for neopterin (13.97; P = 0.0074). AAT and myeloperoxidase seemed to interact strongly with age, with the magnitude and direction of the effect varying considerably over the first 3 y of life. The largest proportion of the variance explained by any biomarker (2.8%) and the largest difference in LAZ predicted between the 5th and 95th percentile (0.25) was by myeloperoxidase over a 2-mo lag. Conclusions: Of the 3 fecal biomarkers studied, 2 that related to intestinal function-AAT and myeloperoxidase-were associated with small but highly statistically significant differences in future statural growth trajectories in infants in this cohort, lending further evidence to the EE hypothesis that increased gut permeability and inflammation adversely affects subsequent nutritional status. This association exhibited a complex interaction with age. This trial was registered at clinicaltrials.gov as NCT02441426.

Journal of Developmental Origins of Health and Disease, Mar 7, 2017

Environmental enteropathy (EE) is a syndrome of altered small intestine structure and function hy... more Environmental enteropathy (EE) is a syndrome of altered small intestine structure and function hypothesized to be common among individuals lacking access to improved water and sanitation. There are plausible biological mechanisms, both inflammatory and non-inflammatory, by which EE may alter the cardiometabolic profile. Here, we test the hypothesis that EE is associated with the cardiometabolic profile among young children living in an environment of intense enteropathogen exposure. In total, 156 children participating in the Peruvian cohort of a multicenter study on childhood infectious diseases, growth and development were contacted at 3–5 years of age. The urinary lactulose:mannitol ratio, and plasma antibody to endotoxin core were determined in order to assess intestinal permeability and bacterial translocation. Blood pressure, anthropometry, fasting plasma glucose, insulin, and cholesterol and apolipoprotein profiles were also assessed. Extant cohort data were also used to relate biomarkers of EE during the first 18 months of life to early child cardiometabolic profile. Lower intestinal surface area, as assessed by percent mannitol excretion, was associated with lower apolipoprotein-AI and lower high-density lipoprotein concentrations. Lower intestinal surface area was also associated with greater blood pressure. Inflammation at 7 months of age was associated with higher blood pressure in later childhood. This study supports the potential for a relationship between EE and the cardiometabolic profile.

American Journal of Tropical Medicine and Hygiene, Jan 6, 2021

Using previously validated microbial source tracking markers, we detected and quantified fecal co... more Using previously validated microbial source tracking markers, we detected and quantified fecal contamination from avian species and avian exposure, dogs, and humans on household cooking tables and floors. The association among contamination, infrastructure, and socioeconomic covariates was assessed using simple and multiple ordinal logistic regressions. The presence of Campylobacter spp. in surface samples was linked to avian markers. Using molecular methods, animal feces were detected in 75.0% and human feces in 20.2% of 104 households. Floors were more contaminated than tables as detected by the avian marker Av4143, dog marker Bactcan, and human marker Bachum. Wood tables were consistently more contaminated than non-wood surfaces, specifically with the mitochondrial avian markers ND5 and CytB, fecal marker Av4143, and canine marker Bactcan. Final multivariable models with socioeconomic and infrastructure characteristics included as covariates indicate that detection of avian feces and avian exposure was associated with the presence of chickens, maternal age, and length of tenancy, whereas detection of human markers was associated with unimproved water source. Detection of Campylobacter in surface samples was associated with the avian fecal marker Av4143. We highlight the critical need to detect and measure the burden of animal fecal waste when evaluating household water, hygiene, and sanitation interventions, and the possibility of decreasing risk of exposure through the modification of surfaces to permit more effective household disinfection practices. Animals may be a more important source of household fecal contamination than humans in many low-resource settings, although interventions have historically focused almost exclusively on managing human waste.

American Journal of Tropical Medicine and Hygiene, Apr 4, 2018

Poor child gut health, resulting from a lack of access to an improved toilet or clean water, has ... more Poor child gut health, resulting from a lack of access to an improved toilet or clean water, has been proposed as a biological mechanism underlying child stunting and oral vaccine failure. Characteristics related to household sanitation, water use, and hygiene were measured among a birth cohort of 270 children from peri-urban Iquitos Peru. These children had monthly stool samples and urine samples at four time points and serum samples at (2-4) time points analyzed for biomarkers related to intestinal inflammation and permeability. We found that less storage of fecal matter near the household along with a reliable water connection were associated with reduced inflammation, most prominently the fecal biomarker myeloperoxidase (MPO) (no sanitation facility compared with those with an onsite toilet had −0.43 log MPO, 95% confidence interval [CI]: −0.74, −0.13; and households with an intermittent connection versus those with a continuous supply had +0.36 log MPO, 95% CI: 0.08, 0.63). These results provide preliminary evidence for the hypothesis that children less than 24 months of age living in unsanitary conditions will have elevated gut inflammation.

medRxiv (Cold Spring Harbor Laboratory), Mar 11, 2021

Early-life enteric infection and enteropathy markers are associated with changes in adipokine, ap... more Early-life enteric infection and enteropathy markers are associated with changes in adipokine, apolipoprotein and cytokine profiles later in childhood consistent with those of an adverse cardiometabolic disease risk profile in a Peruvian birth cohort.

PLOS Neglected Tropical Diseases, Nov 15, 2019

Environmental enteric dysfunction (EED) is associated with chronic undernutrition. Efforts to ide... more Environmental enteric dysfunction (EED) is associated with chronic undernutrition. Efforts to identify minimally invasive biomarkers of EED reveal an expanding number of candidate analytes. An analytic strategy is reported to select among candidate biomarkers and systematically express the strength of each marker's association with linear growth in infancy and early childhood. 180 analytes were quantified in fecal, urine and plasma samples taken at 7, 15 and 24 months of age from 258 subjects in a birth cohort in Peru. Treating the subjects' length-forage Z-score (LAZ-score) over a 2-month lag as the outcome, penalized linear regression models with different shrinkage methods were fitted to determine the bestfitting subset. These were then included with covariates in linear regression models to obtain estimates of each biomarker's adjusted effect on growth. Transferrin had the largest and most statistically significant adjusted effect on short-term linear growth as measured by LAZ-score-a coefficient value of 0.50 (0.24, 0.75) for each log 2 increase in plasma transferrin concentration. Other biomarkers with large effect size estimates included adiponectin, arginine, growth hormone, proline and serum amyloid P-component. The selected subset explained up to 23.0% of the variability in LAZ-score. Penalized regression modeling approaches can be used to select subsets from large panels of candidate biomarkers of EED. There is a need to systematically express the strength of association of biomarkers with linear growth or other outcomes to compare results across studies.

Clinical Infectious Diseases, Sep 17, 2019

Rouhani et al on pages 989-99 and the Editorial commentary by colin Stine on pages 1008-9.) Backg... more Rouhani et al on pages 989-99 and the Editorial commentary by colin Stine on pages 1008-9.) Background. Campylobacter infection is associated with impaired growth of children, even in the absence of symptoms. To examine the underlying mechanisms, we evaluated associations between Campylobacter infection, linear growth, and fecal microbial community features in a prospective birth cohort of 271 children with a high burden of diarrhea and stunting in the Amazonian lowlands of Peru. Methods. Campylobacter was identified using a broadly reactive, genus-specific enzyme-linked immunosorbent assay. 16S rRNAbased analyses were used to identify bacterial taxa in fecal samples at ages 6, 12, 18, and 24 months (N = 928). Associations between infection, growth, and gut microbial community composition were investigated using multiple linear regression adjusting for withinchild correlations, age, and breastfeeding. Indicator species analyses identified taxa specifically associated with Campylobacter burden. Results. Ninety-three percent (251) of children had Campylobacter present in asymptomatic fecal samples during the follow-up period. A 10% increase in the proportion of stools infected was associated with mean reductions of 0.02 length-forage z scores (LAZ) at 3, 6, and 9 months thereafter (P < .01). We identified 13 bacterial taxa indicative of cumulative Campylobacter burden and 14 taxa significantly associated with high or low burden of enteroaggregative Escherichia coli, norovirus, or Giardia. Conclusions. Campylobacter infection is common in this cohort and associated with changes in microbial community composition. These results support the notion that disruptions to the fecal microbiota may help explain the observed effects of asymptomatic infections on growth in early life.

Universidad Nacional de la Amazonía Peruana, 2008

The present work's objective was to identify RAPD markers linked to sex of “aguaje” Mauritia ... more The present work's objective was to identify RAPD markers linked to sex of “aguaje” Mauritia flexuosa L. f. from DNA mixtures of male and female plants. The sampling area were the community of Quistococha (latitude 03°49'28.66 " S length 73° 19'18.98" W, with 96 msnm) and Santa Clara (latitude 03°46'50.5" S, longitude 73 °18'25.3" W, with 118 msnm); 10 male and 10 female sexually differentiated plants were selected, Collecting leaves, roots and / or pneumatophores and transported to the Research Laboratory of the Biological Sciences School and the Research Laboratory of Natural Antiparasitic Products of the Amazon (LIPNAA) of the National University of the Peruvian Amazon (UNAP), DNA was extracted and mixed by sex , performing RAPD PCR tests with 38 random primers; of Which, 11 primers (E -36, E -37, D1, UNAP1, F1, F5xFa, R5xFma, UNR, PLF, FAR' and EXT5) generated 31 polymorphic amplification products (21 differential bands on female plants and 10 male) with sizes between 182 to 1.552bp; six bands presented better resolution (502bp, 513bp, 610bp, 762bp, 871bp and 975bp) and the F5xFa primer revealed a greater number of differential bands with the female sex. Therefore; the female sex plants are more polymorphic than the male sex and probably can identify sex with RAPD PCR technique early in M. flexuosa.

Clinical Infectious Diseases, Sep 17, 2019

See the Editorial commentary by colin Stine on pages 1008-9 and the Major Article by Rouhani et a... more See the Editorial commentary by colin Stine on pages 1008-9 and the Major Article by Rouhani et al on pages 1000-7.) Background. Detrimental effects of diarrhea on child growth and survival are well documented, but details of the underlying mechanisms remain poorly understood. Recent evidence demonstrates that perturbations to normal development of the gut microbiota in early life may contribute to growth faltering and susceptibility to related childhood diseases. We assessed associations between diarrhea, gut microbiota configuration, and childhood growth in the Peruvian Amazon. Methods. Growth, diarrhea incidence, illness, pathogen infection, and antibiotic exposure were assessed monthly in a birth cohort of 271 children aged 0-24 months. Gut bacterial diversity and abundances of specific bacterial taxa were quantified by sequencing 16S rRNA genes in fecal samples collected at 6, 12, 18, and 24 months. Linear and generalized linear models were used to determine whether diarrhea was associated with altered microbiota and, in turn, if features of the microbiota were associated with the subsequent risk of diarrhea. Results. Diarrheal frequency, duration, and severity were negatively associated with bacterial diversity and richness (P < .05). Children born stunted (length-forage z-score [LAZ] ≤ −2) who were also severely stunted (LAZ ≤ −3) at the time of sampling exhibited the greatest degree of diarrhea-associated reductions in bacterial diversity and the slowest recovery of bacterial diversity after episodes of diarrhea. Increased bacterial diversity was predictive of reduced subsequent diarrhea from age 6 to 18 months. Conclusions. Persistent, severe growth faltering may reduce the gut microbiota's resistance and resilience to diarrhea, leading to greater losses of diversity and longer recovery times. This phenotype, in turn, denotes an increased risk of future diarrheal disease and growth faltering.

Journal of Developmental Origins of Health and Disease, 2017

Environmental enteropathy (EE) is a syndrome of altered small intestine structure and function hy... more Environmental enteropathy (EE) is a syndrome of altered small intestine structure and function hypothesized to be common among individuals lacking access to improved water and sanitation. There are plausible biological mechanisms, both inflammatory and non-inflammatory, by which EE may alter the cardiometabolic profile. Here, we test the hypothesis that EE is associated with the cardiometabolic profile among young children living in an environment of intense enteropathogen exposure. In total, 156 children participating in the Peruvian cohort of a multicenter study on childhood infectious diseases, growth and development were contacted at 3–5 years of age. The urinary lactulose:mannitol ratio, and plasma antibody to endotoxin core were determined in order to assess intestinal permeability and bacterial translocation. Blood pressure, anthropometry, fasting plasma glucose, insulin, and cholesterol and apolipoprotein profiles were also assessed. Extant cohort data were also used to rela...

The American Journal of Tropical Medicine and Hygiene

ABSTRACT. Metabolic syndrome is a cluster of risk factors for cardiovascular disease afflicting m... more ABSTRACT. Metabolic syndrome is a cluster of risk factors for cardiovascular disease afflicting more than 1 billion people worldwide and is increasingly being identified in younger age groups and in socioeconomically disadvantaged settings in the global south. Enteropathogen exposure and environmental enteropathy in infancy may contribute to metabolic syndrome by disrupting the metabolic profile in a way that is detectable in cardiometabolic markers later in childhood. A total of 217 subjects previously enrolled in a birth cohort in Amazonian Peru were monitored annually from ages 2 to 5 years. A total of 197 blood samples collected in later childhood were analyzed for 37 cardiometabolic biomarkers, including adipokines, apolipoproteins, cytokines, which were matched to extant early-life markers of enteropathy ascertained between birth and 2 years. Multivariate and multivariable regression models were fitted to test for associations, adjusting for confounders. Fecal and urinary mark...

The American Journal of Tropical Medicine and Hygiene, 2021

ABSTRACTUsing previously validated microbial source tracking markers, we detected and quantified ... more ABSTRACTUsing previously validated microbial source tracking markers, we detected and quantified fecal contamination from avian species and avian exposure, dogs, and humans on household cooking tables and floors. The association among contamination, infrastructure, and socioeconomic covariates was assessed using simple and multiple ordinal logistic regressions. The presence ofCampylobacterspp. in surface samples was linked to avian markers. Using molecular methods, animal feces were detected in 75.0% and human feces in 20.2% of 104 households. Floors were more contaminated than tables as detected by the avian markerAv4143, dog markerBactcan, and human markerBachum. Wood tables were consistently more contaminated than non-wood surfaces, specifically with the mitochondrial avian markersND5and CytB, fecal marker Av4143, and canine markerBactcan. Final multivariable models with socioeconomic and infrastructure characteristics included as covariates indicate that detection of avian feces...

The American Journal of Clinical Nutrition, 2021

Background Breastfeeding is known to reduce the risk of enteropathogen infections, but protection... more Background Breastfeeding is known to reduce the risk of enteropathogen infections, but protection from specific enteropathogens is not well characterized. Objective The aim was to estimate the association between full breastfeeding (days fed breast milk exclusively or with nonnutritive liquids) and enteropathogen detection. Methods A total of 2145 newborns were enrolled at 8 sites, of whom 1712 had breastfeeding and key enteropathogen data through 6 mo. We focused on 11 enteropathogens: adenovirus 40/41, norovirus, sapovirus, astrovirus, and rotavirus, enterotoxigenic Escherichia coli (ETEC), Campylobacter spp., and typical enteropathogenic E. coli as well as entero-aggregative E. coli, Shigella and Cryptosporidium. Logistic regression was used to estimate the risk of enteropathogen detection in stools and survival analysis was used to estimate the timing of first detection of an enteropathogen. Results Infants with 10% more days of full breastfeeding within the preceding 30 d of a ...

The present work's objective was to identify RAPD markers linked to sex of “aguaje” Mauritia ... more The present work's objective was to identify RAPD markers linked to sex of “aguaje” Mauritia flexuosa L. f. from DNA mixtures of male and female plants. The sampling area were the community of Quistococha (latitude 03°49'28.66 " S length 73° 19'18.98" W, with 96 msnm) and Santa Clara (latitude 03°46'50.5" S, longitude 73 °18'25.3" W, with 118 msnm); 10 male and 10 female sexually differentiated plants were selected, Collecting leaves, roots and / or pneumatophores and transported to the Research Laboratory of the Biological Sciences School and the Research Laboratory of Natural Antiparasitic Products of the Amazon (LIPNAA) of the National University of the Peruvian Amazon (UNAP), DNA was extracted and mixed by sex , performing RAPD PCR tests with 38 random primers; of Which, 11 primers (E -36, E -37, D1, UNAP1, F1, F5xFa, R5xFma, UNR, PLF, FAR' and EXT5) generated 31 polymorphic amplification products (21 differential bands on female plant...

BackgroundMetabolic syndrome is a cluster of risk factors for cardiovascular disease thought to a... more BackgroundMetabolic syndrome is a cluster of risk factors for cardiovascular disease thought to afflict over a billion people worldwide and is increasingly being identified in younger age groups and socio-economically disadvantaged settings in the global south. Enteropathogen exposure and environmental enteropathy in infancy may lead to metabolic syndrome by disrupting the metabolic profile in a way that is detectable in cardiometabolic markers later in childhood.Methods217 subjects previously enrolled in a birth cohort in Amazonian Peru were followed up annually from ages 2 to 5 years. Blood samples collected in later childhood were analyzed for a panel of 37 cardiometabolic biomarkers, including adipokines, apolipoproteins, cytokines, and other analytes. These were matched to extant early-life markers of enteropathy ascertained between birth and 2 years of age. Multivariate and multivariable regression models were fitted to test for associations adjusting for confounders.ResultsFe...

Background: Undernutrition in early childhood has historically been considered irreversible after... more Background: Undernutrition in early childhood has historically been considered irreversible after 2-3 years of age and has been associated with morbidity and mortality over the short-term and poor economic and cognitive outcomes over the long-term. We used longitudinal data to determine which factors are associated with positive changes in absolute and relative differences in height and weight from the WHO Growth Standards from 24 to 60 months of age.Methods: Across six MAL-ED sites, 942 children had anthropometry data at 24 and 60 months, as well as information about socioeconomic status, maternal height, gut permeability (lactulose-mannitol z-score (LMZ)), dietary intake from 9-24 months, and micronutrient status. Anthropometric changes were categorized as positive changes in height- or weight-for-age z-score (HAZ, WAZ) or their absolute difference from the growth standard median (HAD (cm), WAD (kg)), as well as recovery from stunting/underweight. Outcomes were modeled using multi...

PLOS Neglected Tropical Diseases, 2019

Environmental enteric dysfunction (EED) is associated with chronic undernutrition. Efforts to ide... more Environmental enteric dysfunction (EED) is associated with chronic undernutrition. Efforts to identify minimally invasive biomarkers of EED reveal an expanding number of candidate analytes. An analytic strategy is reported to select among candidate biomarkers and systematically express the strength of each marker's association with linear growth in infancy and early childhood. 180 analytes were quantified in fecal, urine and plasma samples taken at 7, 15 and 24 months of age from 258 subjects in a birth cohort in Peru. Treating the subjects' length-forage Z-score (LAZ-score) over a 2-month lag as the outcome, penalized linear regression models with different shrinkage methods were fitted to determine the bestfitting subset. These were then included with covariates in linear regression models to obtain estimates of each biomarker's adjusted effect on growth. Transferrin had the largest and most statistically significant adjusted effect on short-term linear growth as measured by LAZ-score-a coefficient value of 0.50 (0.24, 0.75) for each log 2 increase in plasma transferrin concentration. Other biomarkers with large effect size estimates included adiponectin, arginine, growth hormone, proline and serum amyloid P-component. The selected subset explained up to 23.0% of the variability in LAZ-score. Penalized regression modeling approaches can be used to select subsets from large panels of candidate biomarkers of EED. There is a need to systematically express the strength of association of biomarkers with linear growth or other outcomes to compare results across studies.

The American Journal of Clinical Nutrition, 2019

ABSTRACTBackgroundEnvironmental enteric dysfunction (EED) is thought to increase the risk of micr... more ABSTRACTBackgroundEnvironmental enteric dysfunction (EED) is thought to increase the risk of micronutrient deficiencies, but few studies adjust for dietary intakes and systemic inflammation.ObjectiveWe 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.MethodsUsing 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 ...

The American Journal of Tropical Medicine and Hygiene, 2018

Poor child gut health, resulting from a lack of access to an improved toilet or clean water, has ... more Poor child gut health, resulting from a lack of access to an improved toilet or clean water, has been proposed as a biological mechanism underlying child stunting and oral vaccine failure. Characteristics related to household sanitation, water use, and hygiene were measured among a birth cohort of 270 children from peri-urban Iquitos Peru. These children had monthly stool samples and urine samples at four time points and serum samples at (2-4) time points analyzed for biomarkers related to intestinal inflammation and permeability. We found that less storage of fecal matter near the household along with a reliable water connection were associated with reduced inflammation, most prominently the fecal biomarker myeloperoxidase (MPO) (no sanitation facility compared with those with an onsite toilet had −0.43 log MPO, 95% confidence interval [CI]: −0.74, −0.13; and households with an intermittent connection versus those with a continuous supply had +0.36 log MPO, 95% CI: 0.08, 0.63). These results provide preliminary evidence for the hypothesis that children less than 24 months of age living in unsanitary conditions will have elevated gut inflammation.