The acquisition of antimicrobial resistance (AR) genes has rendered important pathogens nearly or... more The acquisition of antimicrobial resistance (AR) genes has rendered important pathogens nearly or fully unresponsive to antibiotics. It has been suggested that pathogens acquire AR traits from the gut microbiota, which collectively serve as a global reservoir for AR genes conferring resistance to all classes of antibiotics. However, only a subset of AR genes confers resistance to clinically relevant antibiotics, and, although these AR gene profiles are wellcharacterized for common pathogens, less is known about their taxonomic associations and transfer potential within diverse members of the gut microbiota. We examined a collection of 14,850 human metagenomes and 1666 environmental metagenomes from 33 countries, in addition to nearly 600,000 isolate genomes, to gain insight into the global prevalence and taxonomic range of clinically relevant AR genes. We find that several of the most concerning AR genes, such as those encoding the cephalosporinase CTX-M and carbapenemases KPC, IMP, NDM, and VIM, remain taxonomically restricted to Proteobacteria. Even cfiA, the most common carbapenemase gene within the human gut microbiome, remains tightly restricted to Bacteroides, despite being found on a mobilizable plasmid. We confirmed these findings in gut microbiome samples from India, Honduras, Pakistan, and Vietnam, using a high-sensitivity single-cell fusion PCR approach. Focusing on a set of genes encoding carbapenemases and cephalosporinases, thus far restricted to Bacteroides species, we find that few mutations are required for efficacy in a different phylum, raising the question of why these genes have not spread more widely. Overall, these data suggest that globally prevalent, clinically relevant AR genes have not yet established themselves across diverse commensal gut microbiota. Preventing the spread of multidrug-and pandrug-resistant pathogenic bacteria remains a primary focus of global health efforts 1 . Recognition that the commensal gut microbiota harbor extensive numbers of diverse AR genes [4] , engage in horizontal gene transfer (HGT) at higher rates than microbiota in other environments , and may serve as a stable reservoir for pathogenic acquisition has prompted broader AR surveillance beyond clinical isolates . The potential for the spread of AR genes between taxa through HGT 14-17 has raised further concern, especially for mcr genes, which confer resistance against colistin, and carbapenemases. However, many of the annotated AR genes observed to transfer within microbiomes, including many common Class A betalactamase variants 18 , do not confer phenotypic resistance to clinically relevant antibiotics. Understanding the global spread and HGT potential of clinically relevant AR genes-particularly those associated
The phenomenon of children raising children, or older children caretaking for younger children is... more The phenomenon of children raising children, or older children caretaking for younger children is underinvestigated and can signi cantly impact child development and family wellbeing outcomes. The perceptions and practices of 150 parents towards sibling caretaking in rural Pakistan were explored through mixed methods surveys and interviews. 73% of parents assign sibling caretaking responsibilities to their daughters primarily, and 89% ask the eldest child to care for younger siblings, while only 2% reported never assigning this responsibility to a child. Caretaking responsibilities include feeding, bathing, disciplining, and putting the younger siblings to sleep. 95% reported assigning these responsibilities to their eldest child as their personal choice; 79% reported sibling caretaking is aligned with traditional practices/beliefs, although 89% agreed it is unrelated to religious obligations. The ndings hold implications for provision of nurturing care services for young children to support their health, education, childcare, social engagement in resource-constrained settings where children are expected to care for their siblings.
Growth faltering in children (low length for age or low weight for length) during the first 1,000... more Growth faltering in children (low length for age or low weight for length) during the first 1,000 days of life (from conception to 2 years of age) influences short-term and long-term health and survival1,2. Interventions such as nutritional supplementation during pregnancy and the postnatal period could help prevent growth faltering, but programmatic action has been insufficient to eliminate the high burden of stunting and wasting in low- and middle-income countries. Identification of age windows and population subgroups on which to focus will benefit future preventive efforts. Here we use a population intervention effects analysis of 33 longitudinal cohorts (83,671 children, 662,763 measurements) and 30 separate exposures to show that improving maternal anthropometry and child condition at birth accounted for population increases in length-for-age z-scores of up to 0.40 and weight-for-length z-scores of up to 0.15 by 24 months of age. Boys had consistently higher risk of all forms ...
Impact of diarrhoea and acute respiratory infection on environmental enteric dysfunction and growth of malnourished children in Pakistan: a longitudinal cohort study
SummarySustainable Development Goal 2.2, to end malnutrition by 2030, includes elimination of chi... more SummarySustainable Development Goal 2.2, to end malnutrition by 2030, includes elimination of child wasting, defined as weight-for-length more than 2 standard deviations below international standards. Prevailing methods to measure wasting rely on cross-sectional surveys that cannot measure onset, recovery, and persistence — key features that inform preventive interventions and disease burden estimates. We analyzed 21 longitudinal cohorts to show wasting is a highly dynamic process of onset and recovery, with incidence peaking between birth and 3 months. By age 24 months 29.2% of children had experienced at least one wasting episode, more than 5-fold higher than point prevalence (5.6%), demonstrating that wasting affects far more children than can be inferred through cross-sectional surveys. Children wasted before 6 months had faster recovery and shorter episodes than children wasted at older ages, but early wasting increased the risk of later growth faltering, including concurrent w...
Characterize Respiratory Pathogens Endemic to Pakistan
Abstract : The objective of this study was to determine the incidence of respiratory viruses asso... more Abstract : The objective of this study was to determine the incidence of respiratory viruses associated with severe pneumonia among children in the rural district of Matiari in Sindh, Pakistan. The study was a community-based prospective cohort of active surveillance for two years, and a total of 817 participants were followed. Of the nasopharyngeal swabs collected, 77.8 percent (179/230) were positive for one or more respiratory viruses. The incidence of viral-associated pneumonia was 11.9 per 100 child-years of follow up. Enterovirus/Rhinovirus was detected in 51.7 patients, followed by parainfluenza virus type III (8.3 percent), and RSV (5.7 percent ). Of the blood cultures collected, 1.4 percent (5/356) were positive for a bacterial pathogen.
Background The reduction in severe and moderate acute malnutrition (SAM and MAM) rates in Pakista... more Background The reduction in severe and moderate acute malnutrition (SAM and MAM) rates in Pakistan has been sub-optimal compared to other low-and middle-income countries (LMICs). Specially-formulated products have been designed globally to manage SAM and MAM, such as ready-to-use therapeutic food (RUTF) and ready-to-use supplementary food (RUSF), with variable efficacies. RUTF is primarily produced and patented in industrialized countries, raising supply challenges in resource-constrained regions with a high burden of acute malnutrition. RUSF minimizes costs by using locally-available ingredients while providing similar nutritional value. In this study, we compared the efficacy, side effects, and compliance of two months of supplementation with either RUTF or RUSF. Methods Children aged nine months in the rural district of Matiari, Pakistan, with a weight-for-height z-score (WHZ) <-2 received either RUTF (500 kcal sachet) for two months in 2015 or RUSF (520 kcal sachet) for two m...
The American Journal of Tropical Medicine and Hygiene
Environmental enteric dysfunction (EED) is a subclinical enteropathy prevalent in resource-limite... more Environmental enteric dysfunction (EED) is a subclinical enteropathy prevalent in resource-limited settings, hypothesized to be a consequence of chronic exposure to environmental enteropathogens, resulting in malnutrition, growth failure, neurocognitive delays, and oral vaccine failure. This study explored the duodenal and colonic tissues of children with EED, celiac disease, and other enteropathies using quantitative mucosal morphometry, histopathologic scoring indices, and machine learning–based image analysis from archival and prospective cohorts of children from Pakistan and the United States. We observed villus blunting as being more prominent in celiac disease than in EED, as shorter lengths of villi were observed in patients with celiac disease from Pakistan than in those from the United States, with median (interquartile range) lengths of 81 (73, 127) µm and 209 (188, 266) µm, respectively. Additionally, per the Marsh scoring method, celiac disease histologic severity was in...
Introduction: Environmental enteropathy is an important contributor to childhood malnutrition in ... more Introduction: Environmental enteropathy is an important contributor to childhood malnutrition in the developing world. Chronic exposure to fecal pathogens leads to alteration in intestinal structure and function, resulting in impaired gut immune function, malabsorption, and growth faltering leading to environmental enteropathy. Methods: A community-based intervention study was carried out on children till 24 months of age in Matiari district, Pakistan. Blood and fecal specimens were collected from the enrolled children aged 3-6 and 9 months. A real-time PCR-based TaqMan array card (TAC) was used to detect enteropathogens. Results: Giardia, Campylobacter spp., enteroaggregative Escherichia coli (EAEC), Enteropathogenic Escherichia coli (EPEC), Enterotoxigenic Escherichia coli (ETEC), and Cryptosporidium spp. were the most prevailing enteropathogens in terms of overall positivity at both time points. Detection of protozoa at enrollment and 9 months was negatively correlated with rate of change in height-forage Z (HAZ) scores during the first and second years of life. A positive association was found between Giardia, fecal lipocalin (LCN), and alpha 1-Acid Glycoprotein (AGP), while Campylobacter spp. showed positive associations with neopterin (NEO) and myeloperoxidase (MPO). Conclusion: Protozoal colonization is associated with a decline in linear growth velocity during the first 2 years of life in children living in Environmental enteric dysfunction (EED) endemic settings. Mechanistic studies exploring the Frontiers in Nutrition 01 frontiersin.org Kabir et al. 10.3389/fnut.2022.1081833 role of cumulative microbial colonization, their adaptations to undernutrition, and their influence on gut homeostasis are required to understand symptomatic enteropathogen-induced growth faltering.
Additional file 2: of Study of Environmental Enteropathy and Malnutrition (SEEM) in Pakistan: protocols for biopsy based biomarker discovery and validation
Informed consent forms for recruitment of healthy and malnourished children.
Additional file 1: of Study of Environmental Enteropathy and Malnutrition (SEEM) in Pakistan: protocols for biopsy based biomarker discovery and validation
Figure S1. Urine and fecal sample collection protocol. Panel A describes the urine collection pro... more Figure S1. Urine and fecal sample collection protocol. Panel A describes the urine collection protocol followed by the community health workers (CHWs), and Panel B describes the fecal collection protocol followed by the CHWs for instant transport of fecal samples in a dry shipper for long term storage and preservation for microbiome analysis. Please note: L:R Lactose Rhamnose ratio, mL milliliter, CHW Community Health Worker, AKU Aga Khan University, IDRL Infectious Diseases Research Laboratory.
Environmental enteric dysfunction (EED) is a subclinical condition of intestinal inflammation, ba... more Environmental enteric dysfunction (EED) is a subclinical condition of intestinal inflammation, barrier dysfunction and malabsorption associated with growth faltering in children living in poverty. This study explores association of altered duodenal permeability (lactulose, rhamnose and their ratio) with higher burden of enteropathogen in the duodenal aspirate, altered histopathological findings and higher morbidity (diarrhea) that is collectively associated with linear growth faltering in children living in EED endemic setting. In a longitudinal birth cohort, 51 controls (WHZ > 0, HAZ > −1.0) and 63 cases (WHZ< -2.0, refractory to nutritional intervention) were recruited. Anthropometry and morbidity were recorded on monthly bases up to 24 months of age. Dual sugar assay of urine collected after oral administration of lactulose and rhamnose was assessed in 96 children from both the groups. Duodenal histopathology (n = 63) and enteropathogen analysis of aspirate via Taqman ar...
International Journal of Environmental Research and Public Health, 2021
The relationship between environmental factors and child health is not well understood in rural P... more The relationship between environmental factors and child health is not well understood in rural Pakistan. This study characterized the environmental factors related to the morbidity of acute respiratory infections (ARIs), diarrhea, and growth using geographical information systems (GIS) technology. Anthropometric, address and disease prevalence data were collected through the SEEM (Study of Environmental Enteropathy and Malnutrition) study in Matiari, Pakistan. Publicly available map data were used to compile coordinates of healthcare facilities. A Pearson correlation coefficient (r) was used to calculate the correlation between distance from healthcare facilities and participant growth and morbidity. Other continuous variables influencing these outcomes were analyzed using a random forest regression model. In this study of 416 children, we found that participants living closer to secondary hospitals had a lower prevalence of ARI (r = 0.154, p < 0.010) and diarrhea (r = 0.228, p ...
The Study of Environmental Enteropathy (EE) and Malnutrition in Pakistan (SEEM) is a community in... more The Study of Environmental Enteropathy (EE) and Malnutrition in Pakistan (SEEM) is a community intervention trial designed to understand the pathophysiology of EE and its associated clinical phenotypes in children less than two years of age. Undernutrition is the underlying cause of three million deaths annually, accounting for 45% of all deaths among children under five years of age. Linear growth stunting affects a further 165 million. In Pakistan, where our study is focused, an estimated one in three children are underweight and nearly half are stunted. This manuscript summarizes the challenges faced by the field team and the solutions employed for achieving our research objectives at the rural field site, Matiari. Our study design involved a longitudinal collection of field data and biological samples which required constant engagement of field staff with the participating families. Challenges faced in SEEM included: 1) quality assurance parameters of anthropometry data; 2) 24-...
Infectious disease is the leading cause of mortality in children under five. This study has inves... more Infectious disease is the leading cause of mortality in children under five. This study has investigated environmental factors related to the morbidity of acute respiratory infections (ARIs), diarrhea, and growth using geographical information systems (GIS) technology. Anthropometric, address and disease prevalence data were collected through the SEEM study in Matiari, Pakistan. Publicly available map data was used to compile coordinates of healthcare facilities. A Pearson correlation coefficient (r) was used to calculate the correlation between distance from healthcare facilities and participant growth and morbidity. Other continuous variables influencing these outcomes were analyzed using a random forest regression model. In this study of 416 children, we found participants living closer to secondary hospitals had lower prevalence of ARI (r=0.154, p<0.010) and diarrhea (r=0.228, p<0.001) as well as participants living closer to Maternal Health Centers (MHCs): ARI (r=0.185, p...
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Papers by Fayaz Umrani