HIV infection and domestic smoke exposure, but not human papillomavirus, are risk factors for esophageal squamous cell carcinoma in Zambia: a case-control study

(c) 2015 The Authors. Cancer Medicine published by John Wiley & Sons Ltd. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited

Characterizing the metabolic phenotype of intestinal villus blunting in Zambian children with severe acute malnutrition and persistent diarrhea

Background: Environmental enteric dysfunction (EED) is widespread throughout the tropics and in children is associated with stunting and other adverse health outcomes. One of the hallmarks of EED is villus damage. In children with severe acute malnutrition (SAM) the severity of enteropathy is greater and short term mortality is high, but the metabolic consequences of enteropathy are unknown. Here, we characterize the urinary metabolic alterations associated with villus health, classic enteropathy biomarkers and anthropometric measurements in severely malnourished children in Zambia. Methods/Principal findings: We analysed 20 hospitalised children with acute malnutrition aged 6 to 23 months in Zambia. Small intestinal biopsies were assessed histologically (n = 15), anthropometric and gut function measurements were collected and the metabolic phenotypes were characterized by 1H nuclear magnetic resonance (NMR) spectroscopy. Endoscopy could not be performed on community controls children. Growth parameters were inversely correlated with enteropathy biomarkers (p = 0.011) and parameters of villus health were inversely correlated with translocation and permeability biomarkers (p = 0.000 and p = 0.015). Shorter villus height was associated with reduced abundance of metabolites related to gut microbial metabolism, energy and muscle metabolism (p = 0.034). Villus blunting was also related to increased sucrose excretion (p = 0.013). Conclusions/Significance: Intestinal villus blunting is associated with several metabolic perturbations in hospitalized children with severe undernutrition. Such alterations include altered muscle metabolism, reinforcing the link between EED and growth faltering, and a disruption in the biochemical exchange between the gut microbiota and host. These findings extend our understanding on the downstream consequences of villus blunting and provide novel non-invasive biomarkers of enteropathy dysfunction. The major limitations of this study are the lack of comparative control group and gut microbiota characterization

Hospitalizations and Costs Incurred at the Facility Level After Scale-Up of Malaria Control: Pre-Post Comparisons From Two Hospitals in Zambia

There is little evidence on the impact of malaria control on the health system, particularly at the facility level. Using retrospective, longitudinal facility-level and patient record data from two hospitals in Zambia, we report a pre-post comparison of hospital admissions and outpatient visits for malaria and estimated costs incurred for malaria admissions before and after malaria control scale-up. The results show a substantial reduction in inpatient admissions and outpatient visits for malaria at both hospitals after the scale-up, and malaria cases accounted for a smaller proportion of total hospital visits over time. Hospital spending on malaria admissions also decreased. In one hospital, malaria accounted for 11% of total hospital spending before large-scale malaria control compared with \u3c 1% after malaria control. The findings demonstrate that facility-level resources are freed up as malaria is controlled, potentially making these resources available for other diseases and conditions

Transcriptomic analysis of enteropathy in Zambian children with severe acute malnutrition.

BACKGROUND: Children with severe acute malnutrition (SAM), with or without diarrhoea, often have enteropathy, but there are few molecular data to guide development of new therapies. We set out to determine whether SAM enteropathy is characterised by specific transcriptional changes which might improve understanding or help identify new treatments. METHODS: We collected intestinal biopsies from children with SAM and persistent diarrhoea. mRNA was extracted from biopsies, sequenced, and subjected to a progressive set of complementary analytical approaches: NOIseq, Gene Set Enrichment Analysis (GSEA), and correlation analysis of phenotypic data with gene expression. FINDINGS: Transcriptomic profiles were generated for biopsy sets from 27 children of both sexes, under 2 years of age, of whom one-third were HIV-infected. NOIseq analysis, constructed from phenotypic group extremes, revealed 66 differentially expressed genes (DEGs) out of 21,386 mapped to the reference genome. These DEGs include genes for mucins and mucus integrity, antimicrobial defence, nutrient absorption, C-X-C chemokines, proteases and anti-proteases. Phenotype - expression correlation analysis identified 1221 genes related to villus height, including increased cell cycling gene expression in more severe enteropathy. Amino acid transporters and ZIP zinc transporters were specifically increased in severe enteropathy, but transcripts for xenobiotic metabolising enzymes were reduced. INTERPRETATION: Transcriptomic analysis of this rare collection of intestinal biopsies identified multiple novel elements of pathology, including specific alterations in nutrient transporters. Changes in xenobiotic metabolism in the gut may alter drug disposition. Both NOIseq and GSEA identified gene clusters similar to those differentially expressed in pediatric Crohn's disease but to a much lesser degree than those identified in coeliac disease. FUND: Bill & Melinda Gates Foundation OPP1066118. The funding agency had no role in study design, data collection, data analysis, interpretation, or writing of the report

Gene expression profiles compared in environmental and malnutrition enteropathy in Zambian children and adults

Background:: Environmental enteropathy (EE) contributes to growth failure in millions of children worldwide, but its relationship to clinical malnutrition has not been elucidated. We used RNA sequencing to compare duodenal biopsies from adults and children with EE, and from children with severe acute malnutrition (SAM), to define key features of these malnutrition-related enteropathies. Methods:: RNA was extracted and sequenced from biopsies of children with SAM in hospital (n=27), children with non-responsive stunting in the community (n=30), and adults living in the same community (n=37) using an identical sequencing and analysis pipeline. Two biopsies each were profiled and differentially expressed genes (DEGs) were computed from the comparisons of the three groups. DEG lists from these comparisons were then subjected to analysis with CompBio software to assemble a holistic view of the biological landscape and IPA software to interrogate canonical pathways. Findings:: Dysregulation was identified in goblet cell/mucin production and xenobiotic metabolism/detoxification for both cohorts of children, versus adults. Within the SAM cohort, substantially greater induction of immune response and barrier function, including NADPH oxidases was noted, concordant with broadly reduced expression of genes associated with the brush border and intestinal structure/transport/absorption. Interestingly, down regulation of genes associated with the hypothalamic-pituitary-adrenal axis was selectively observed within the cohort of children with stunting. Interpretation:: Gene expression profiles in environmental enteropathy and severe acute malnutrition have similarities, but SAM has several distinct transcriptional features. The intestinal capacity to metabolise drugs and toxins in malnourished children requires further study. Funding:: Bill & Melinda Gates Foundation (OPP1066118

Single-cell profiling of environmental enteropathy reveals signatures of epithelial remodeling and immune activation

Environmental enteropathy (EE) is a subclinical condition of the small intestine that is highly prevalent in low- and middle-income countries. It is thought to be a key contributing factor to childhood malnutrition, growth stunting, and diminished oral vaccine responses. Although EE has been shown to be the by-product of a recurrent enteric infection, its full pathophysiology remains unclear. Here, we mapped the cellular and molecular correlates of EE by performing high-throughput, single-cell RNA-sequencing on 33 small intestinal biopsies from 11 adults with EE in Lusaka, Zambia (eight HIV-negative and three HIV-positive), six adults without EE in Boston, United States, and two adults in Durban, South Africa, which we complemented with published data from three additional individuals from the same clinical site. We analyzed previously defined bulk-transcriptomic signatures of reduced villus height and decreased microbial translocation in EE and showed that these signatures may be driven by an increased abundance of surface mucosal cells-a gastric-like subset previously implicated in epithelial repair in the gastrointestinal tract. In addition, we determined cell subsets whose fractional abundances associate with EE severity, small intestinal region, and HIV infection. Furthermore, by comparing duodenal EE samples with those from three control cohorts, we identified dysregulated WNT and MAPK signaling in the EE epithelium and increased proinflammatory cytokine gene expression in a T cell subset highly expressing a transcriptional signature of tissue-resident memory cells in the EE cohort. Together, our work elucidates epithelial and immune correlates of EE and nominates cellular and molecular targets for intervention

Retinoic acid elicits a coordinated expression of gut homing markers on T lymphocytes of Zambian men receiving oral Vivotif, but not Rotarix, Dukoral or OPVERO vaccines

This work was supported by the Bill and Melinda Gates Foundation through a Grand Challenges Explorations grant (OPP1043696)

Conceptualising Drivers of Illegal Hunting by Local Hunters Living in or Adjacent to African Protected Areas: A Scoping Review

Illegal hunting of wildlife by community members abutting African protected areas contributes to unsustainable use of wildlife, resulting in significant declines in wildlife populations. Contemporary intervention measures have largely been ineffective, leading to pervasive and persistent illegal hunting. Such illegal hunting of wildlife is partly exacerbated by poor understanding of what motivates people to hunt illegally. Applying a scoping review approach, this study aims at developing concepts for drivers of illegal hunting and how they influence illegal hunting behaviour by local hunters living in or adjacent to African protected areas. A total of 30 publications were included for review analysis from 1014 publications retrieved using data base searches on Google Scholar and ScienceDirect. The study identified 12 proximate and five underlying drivers, which were categorised into 10 thematic drivers of illegal hunting by local hunters. The need for survival and sustaining livelihoods was conceptualised as the key thematic driver of illegal hunting by local hunters. The study represents a novel work of conceptualising drivers of illegal hunting by local hunters with implications on the persistence of illegal hunting in Africa

Contribution of Schistosoma mansoni to systemic inflammation and microbial translocation among people with HIV in Zambia.

BACKGROUND: Schistosoma mansoni is hyperendemic in many rural areas of Zambia where up to 77% of people are positive for infection via serologic evaluation. Zambia also has a high prevalence of HIV infection. Individually, S. mansoni and HIV infection impair gastrointestinal barrier integrity and induce inflammation, but the effects of coinfection are not well understood. We set out to test the hypothesis that HIV would exacerbate intestinal barrier failure in patients with S. mansoni infection. METHODS: Adults attending medical outpatient clinics in Kaoma, Western Province, Zambia, were enrolled in a case-control study to determine the relative contributions of schistosomiasis and HIV to microbial translocation (measured as soluble CD14 [sCD14] and lipopolysaccharide binding protein [LBP]) and inflammation (measured as CRP). RESULTS: Among 152 adults evaluated, 74 (49%) were HIV-seropositive, 45 (29%) were shedding schistosome ova (Kato-Katz), 120 (81%) were seropositive for schistosome antibodies (i.e. prior or current infection, with or without egg shedding) and 16 (11%) were HIV/schistosome coinfected (defined by Kato-Katz). HIV infection was associated with higher circulating sCD14 concentrations (p=0.003 by Kruskal-Wallis test), but schistosomiasis was not. HIV infection was associated with greater exposure to schistosomes assessed serologically (OR=2.48, 95% CI 1.05 to 5.86; p=0.03), but reduced likelihood of egg shedding (OR 0.47, 95% CI 0.21 to 1.01; p=0.03). CONCLUSIONS: There was no evidence for a compounding or synergistic effect of coinfection on microbial translocation that appeared to be correlated with HIV infection. Further studies are needed to understand how the increase in LBP secondary to HIV infection may decrease schistosome egg excretion in coinfected individuals