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The nasal cellular epigenome may serve as biomarker of airway disease and environmental response. Here we collect nasal swabs from the anterior nares of 547 children (mean-age 12.9 y), and measure DNA methylation (DNAm) with the Infinium MethylationEPIC BeadChip. We perform nasal Epigenome-Wide Association analyses (EWAS) of current asthma, allergen sensitization, allergic rhinitis, fractional exhaled nitric oxide (FeNO) and lung function. We find multiple differentially methylated CpGs (FDR < 0.05) and Regions (DMRs; ≥ 5-CpGs and FDR < 0.05) for asthma (285-CpGs), FeNO (8,372-CpGs; 191-DMRs), total IgE (3-CpGs; 3-DMRs), environment IgE (17-CpGs; 4-DMRs), allergic asthma (1,235-CpGs; 7-DMRs) and bronchodilator response (130-CpGs). Discovered DMRs annotated to genes implicated in allergic asthma, Th2 activation and eosinophilia ( EPX , IL4, IL13 ) and genes previously associated with asthma and IgE in EWAS of blood ( ACOT7, SLC25A25 ). Asthma, IgE and FeNO were associated with nasal epigenetic age acceleration. The nasal epigenome is a sensitive biomarker of asthma, allergy and airway inflammation. Epigenetic differences in nasal epithelium have been proposed as a biomarker for lower airway disease and asthma. Here, in epigenome-wide association studies for asthma and other airway traits using nasal swabs, the authors identify differentially methylated CpGs that highlight genes involved in T H 2 response.

Cystic fibrosis-related diabetes (CFRD) is one of the most common non-pulmonary complications in people living with cystic fibrosis (pwCF), seen in up to 50% of adults. Even when correcting for severity of CFTR mutations, those with CFRD have more pulmonary exacerbations, lower lung function, and increased mortality than those with normal glucose tolerance (NGT). Expectorated sputum samples were collected from 63 pwCF during routine outpatient visits (29 with CFRD, 12 with IGT and 22 with NGT). Oral glucose tolerance test results, A1c levels, and pulmonary function tests closest to the time of sputum collection were obtained from the medical record. Samples underwent metagenomics sequencing and raw reads were processed through the bioBakery workflow for taxonomic profiling at the species level as well as predicted functional profiling and antibiotic resistance profiling. Viral profiling was performed with Marker-MAGu. Differences in alpha diversity, beta diversity, and differential abundance were assessed. Microbiome and phage signatures of CFRD were generated using sparse partial least squares models which were subsequently used as a primary predictor of lung function using multivariate linear regression. In linear models, CFRD status compared to NGT was associated with a lower alpha diversity (reciprocal Simpson -1.98 [-3.80,-0.16], p = 0.033) and differences in microbial community composition (Bray Curtis dissimilarity PERMANOVA R2 0.17, p = 0.011). Pseudomonas aeruginosa and Streptococcus gordonii had higher relative abundance in CRFD vs NGT participants (2.43 [0.027, 4.82], unadjusted p = 0.056 and 1.11 [0.58, 1.64] unadjusted p= < .001 respectively). There were global differences between CFRD vs NGT in both functional pathways and antibiotic resistance genes. In multivariate models adjusting for age, sex, antibiotic use, and modulator therapies, virome but not microbiome signatures of CFRD were associated with lower FEV1 percent predicted (-6.4 [95% CI -10.2, -2.6]%, p = 0.001 for each 10% increase in virome score). Differences in the airway microbiome in those with dysglycemia in CF are associated with poorer lung function.

Multisystem inflammatory syndrome in children (MIS-C) evolves in some pediatric patients following acute infection with SARS-CoV-2 by hitherto unknown mechanisms. Whereas acute-COVID-19 severity and outcomes were previously correlated with Notch4 expression on Tregs, here, we show that Tregs in MIS-C were destabilized through a Notch1-dependent mechanism. Genetic analysis revealed that patients with MIS-C had enrichment of rare deleterious variants affecting inflammation and autoimmunity pathways, including dominant-negative mutations in the Notch1 regulators NUMB and NUMBL leading to Notch1 upregulation. Notch1 signaling in Tregs induced CD22, leading to their destabilization in a mTORC1-dependent manner and to the promotion of systemic inflammation. These results identify a Notch1/CD22 signaling axis that disrupts Treg function in MIS-C and point to distinct immune checkpoints controlled by individual Treg Notch receptors that shape the inflammatory outcome in SARS-CoV-2 infection.

To characterize the microbial environment of workers in academic mouse research facilities using endotoxin, 16S qPCR, and 16S amplicon sequencing. To determine whether the work microbiome contributes to the human microbiome of workers. We performed area air sampling from the animal rooms, dirty, middle, and setup cage wash locations in four academic mouse research facilities. 10 workers in the dirty cage wash area underwent personal air sampling as well as repeated collection of nasal, oral, and skin samples before and after the work shift. Environmental samples underwent measurement of endotoxin, mouse allergen, bacteria copy number via 16S qPCR, and microbial identification via 16S rDNA sequencing. 16S rDNA sequencing was also performed on human samples before and after the work shift. SourceTracker was used to identify the contribution of the work microbiome to the human microbiome. Median endotoxin levels ranged from undetectable to 1.0 EU/m3. Significant differences in mouse allergen levels, bacterial copy number, microbial richness, and microbial community structure were identified between animal, dirty, middle, and setup cage wash locations. Endotoxin levels had only a moderate correlation with microbial composition. Location within a facility was a stronger predictor of microbial community composition (R2 = 0.41, p = 0.002) than facility. The contribution of the work microbiome to the pre-shift human microbiome of workers was estimated to be 0.1 ± 0.1% for the oral microbiome; 3.1 ± 1.9% for the nasal microbiome; and 3.0 ± 1.5% for the skin microbiome. The microbial environment of academic animal care facilities varies significantly by location rather than facility. Endotoxin is not a proxy for assessment of environmental microbial exposures using 16S qPCR or 16S rDNA sequencing. The work microbiome contributes to the composition of the nasal and skin microbiome of workers; the clinical implications of this observation should be further studied.

[This corrects the article DOI: 10.1371/journal.pone.0229699.].

Antibiotic use for livestock is presumed to be a contributor to the acquisition of antimicrobial resistance (AMR) genes in humans, yet studies do not capture AMR data before and after livestock introduction. We performed a feasibility study by recruiting a subset of women in a delayed-start randomized controlled trial of small-scale chicken farming to examine the prevalence of clinically-relevant AMR genes. Stool samples were obtained at baseline and one year post-randomization from five intervention women who received chickens at the start of the study, six control women who did not receive chickens until the end of the study, and from chickens provided to the control group at the end of the study. Stool was screened for 87 clinically significant AMR genes using a commercially available qPCR array (Qiagen). Chickens harbored 23 AMR genes from classes found in humans as well as additional vancomycin and β-lactamase resistance genes. AMR patterns between intervention and control women appeared more similar at baseline than one year post randomization (PERMANOVA R2 = 0.081, p = 0.61 at baseline, R2 = 0.186, p = 0.09 at 12 months) Women in the control group who had direct contact with the chickens sampled in the study had greater similarities in AMR gene patterns to chickens than those in the intervention group who did not have direct contact with chickens sampled (p = 0.01). However, at one year there was a trend towards increased similarity in AMR patterns between humans in both groups and the chickens sampled (p = 0.06). Studies designed to evaluate human AMR genes in the setting of animal exposure should account for high baseline AMR rates. Concomitant collection of animal, human, and environmental samples over time is recommended to determine the directionality and source of AMR genes. ClinicalTrials.gov Identifier NCT02619227.

Background The gut microbiome is a critical modulator of host immunity and is linked to the immune response to respiratory viral infections. However, few studies have gone beyond describing broad compositional alterations in severe COVID-19, defined as acute respiratory or other organ failure. Methods We profiled 127 hospitalized patients with COVID-19 ( n  = 79 with severe COVID-19 and 48 with moderate) who collectively provided 241 stool samples from April 2020 to May 2021 to identify links between COVID-19 severity and gut microbial taxa, their biochemical pathways, and stool metabolites. Results Forty-eight species were associated with severe disease after accounting for antibiotic use, age, sex, and various comorbidities. These included significant in-hospital depletions of Fusicatenibacter saccharivorans and Roseburia hominis , each previously linked to post-acute COVID syndrome or “long COVID,” suggesting these microbes may serve as early biomarkers for the eventual development of long COVID. A random forest classifier achieved excellent performance when tasked with classifying whether stool was obtained from patients with severe vs. moderate COVID-19, a finding that was externally validated in an independent cohort. Dedicated network analyses demonstrated fragile microbial ecology in severe disease, characterized by fracturing of clusters and reduced negative selection. We also observed shifts in predicted stool metabolite pools, implicating perturbed bile acid metabolism in severe disease. Conclusions Here, we show that the gut microbiome differentiates individuals with a more severe disease course after infection with COVID-19 and offer several tractable and biologically plausible mechanisms through which gut microbial communities may influence COVID-19 disease course. Further studies are needed to expand upon these observations to better leverage the gut microbiome as a potential biomarker for disease severity and as a target for therapeutic intervention.

Energy poverty is prevalent in resource-limited settings, leading households to use inefficient fuels and appliances that contribute to household air pollution. Randomized controlled trials of household energy interventions in low and middle income countries have largely focused on cooking services. Less is known about the adoption and impact of clean lighting interventions. We conducted an explanatory sequential mixed methods study as part of a randomized controlled trial of home solar lighting systems in rural Uganda in order to identify contextual factors determining the use and impact of the solar lighting intervention. We used sensors to track usage, longitudinally assessed household lighting expenditures and health-related quality of life, and performed cost-effectiveness analyses. Qualitative interviews were conducted with all 80 trial participants and coded using reflexive thematic analysis. Uptake of the intervention solar lighting system was high with daily use averaging 8.23 ± 5.30 h d −1 . The intervention solar lighting system increased the EQ5D index by 0.025 (95% CI 0.002–0.048) and led to an average monthly change in household lighting costs by −1.28 (−2.52, −0.85) US dollars, with higher savings in users of fuel-based lighting. The incremental cost-effectiveness ratio for the solar lighting intervention was $2025.72 US dollars per quality adjusted life year gained making the intervention cost-effective when benchmarked against the gross domestic product per capita in Uganda. Thematic analysis of qualitative data from individual interviews showed that solar lighting was transformative and associated with numerous benefits that fit within a social determinants of health (SDOH) framework. The benefits included improved household finances, improved educational performance of children, increased household safety, improved family and community cohesion, and improved perceived household health. Our findings suggest that household solar lighting interventions may be a cost-effective approach to improve health-related quality of life by addressing SDOH.

IntroductionTuberculosis (TB) is significantly associated with multiple postinfectious, non-communicable diseases after microbiological cure. For example, those with a history of TB disease have a higher risk of developing chronic lung diseases at a younger age. However, the extent and nature of post-TB complications are not well described. Here, we present a protocol for a systematic review and meta-analysis, which aims to synthesise literature on the burden of post-TB lung disease (PTLD) in sub-Saharan Africa, describe phenotypes, long-term outcomes and the health-related quality of life of people with PTLD.Methods and analysisA systematic search will be conducted using PubMed, EMBASE, Web of Science, African Journals Online and the Cochrane Library of Systematic Reviews. Papers published in English and French languages that report the prevalence, clinical features, quality of life and long-term outcomes of people with PTLD in sub-Saharan Africa will be considered. We will assess and critically appraise the methodological quality of all studies using the modified covidence. Qualitative and quantitative (network and meta-analysis) synthesis will be performed and STATA V.16 will be used to estimate the burden of PTLD.Ethics and disseminationEthical approval is not required for this systematic review and meta-analysis. Our results will be published in peer-reviewed journals.PROSPERO registration numberCRD42021274018.

Background Most of the global burden of pollution-related morbidity and mortality is believed to occur in resource-limited settings, where HIV serostatus and sex may influence the relationship between air pollution exposure and respiratory morbidity. The lack of air quality monitoring networks in these settings limits progress in measuring global disparities in pollution-related health. Personal carbon monoxide monitoring may identify sub-populations at heightened risk for air pollution-associated respiratory morbidity in regions of the world where the financial cost of air quality monitoring networks is prohibitive. Methods From September 2015 through May 2017, we measured 48-h ambulatory carbon monoxide (CO) exposure in a longitudinal cohort of HIV-infected and uninfected adults in rural southwestern Uganda. We fit generalized mixed effects models to identify correlates of CO exposure exceeding international air quality thresholds, quantify the relationship between CO exposure and respiratory symptoms, and explore potential effect modification by sex and HIV serostatus. Results Two hundred and sixty study participants completed 419 sampling periods. Personal CO exposure exceeded international thresholds for 50 (19%) participants. In covariate-adjusted models, living in a home where charcoal was the main cooking fuel was associated with CO exposure exceeding international thresholds (adjusted odds ratio [AOR] 11.3, 95% confidence interval [95%CI] 4.7–27.4). In sex-stratified models, higher CO exposure was associated with increased odds of respiratory symptoms among women (AOR 3.3, 95%CI 1.1–10.0) but not men (AOR 1.3, 95%CI 0.4–4.4). In HIV-stratified models, higher CO exposure was associated with increased odds of respiratory symptoms among HIV-infected (AOR 2.5, 95%CI 1.01–6.0) but not HIV-uninfected (AOR 1.4, 95%CI 0.1–14.4) participants. Conclusions In a cohort in rural Uganda, personal CO exposure frequently exceeded international thresholds, correlated with biomass exposure, and was associated with respiratory symptoms among women and people living with HIV. Our results provide support for the use of ambulatory CO monitoring as a low-cost, feasible method to identify subgroups with heightened vulnerability to pollution-related respiratory morbidity in resource-limited settings and identify subgroups that may have increased susceptibility to pollution-associated respiratory morbidity.