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.

IMPORTANCE Home aeroallergen exposure is associated with increased asthma morbidity in children, yet little is known about the contribution of school aeroallergen exposures to such morbidity.OBJECTIVE To evaluate the effect of school-specific aeroallergen exposures on asthma morbidity among students, adjusting for home exposures. DESIGN, SETTING, AND PARTICIPANTSThe School Inner-City Asthma Study was a prospective cohort study evaluating 284 students aged 4 to 13 years with asthma who were enrolled from 37 inner-city elementary schools in the northeastern United States between March 1, 2008, and August 31, 2013. Enrolled students underwent baseline clinical evaluations before the school year started and were then observed clinically for 1 year. During that same school year, classroom and home dust samples linked to the students were collected and analyzed for common indoor aeroallergens. Associations between school aeroallergen exposure and asthma outcomes during the school year were assessed, adjusting for home exposures.EXPOSURES Indoor aeroallergens, including rat, mouse, cockroach, cat, dog, and dust mites, measured in dust samples collected from inner-city schools. MAIN OUTCOMES AND MEASURESThe primary outcome was maximum days in the past 2 weeks with asthma symptoms. Secondary outcomes included well-established markers of asthma morbidity, including asthma-associated health care use and lung function, measured by forced expiratory volume in 1 second. RESULTS Among 284 students (median age, 8 years [interquartile range, 6-9 years]; 148 boys and 136 girls), exposure to mouse allergen was detected in 441 (99.5%) of 443 school dust samples, cat allergen in 420 samples (94.8%), and dog allergen in 366 samples (82.6%). Levels of mouse allergen in schools were significantly higher than in students' homes (median settled dust level, 0.90 vs 0.14 μg/g; P < .001). Exposure to higher levels of mouse allergen in school (comparing 75th with 25th percentile) was associated with increased odds of having an asthma symptom day (odds ratio, 1.27; 95% CI, 1.05-1.54; P = .02) and 4.0 percentage points lower predicted forced expiratory volume in 1 second (95% CI, -6.6 to -1.5; P = .002). This effect was independent of allergic sensitization. None of the other indoor aeroallergens were associated with worsening asthma outcomes. CONCLUSIONS AND RELEVANCEIn this study of inner-city students with asthma, exposure to mouse allergen in schools was associated with increased asthma symptoms and decreased lung function. These findings demonstrate that the school environment is an important contributor to childhood asthma morbidity. Future school-based environmental interventions may be beneficial for this important public health problem.

A cardinal feature of COVID-19 is lung inflammation and respiratory failure. In a prospective multi-country cohort of COVID-19 patients, we found that increased Notch4 expression on circulating regulatory T (Treg) cells was associated with disease severity, predicted mortality, and declined upon recovery. Deletion of Notch4 in Treg cells or therapy with anti-Notch4 antibodies in conventional and humanized mice normalized the dysregulated innate immunity and rescued disease morbidity and mortality induced by a synthetic analog of viral RNA or by influenza H1N1 virus. Mechanistically, Notch4 suppressed the induction by interleukin-18 of amphiregulin, a cytokine necessary for tissue repair. Protection by Notch4 inhibition was recapitulated by therapy with Amphiregulin and, reciprocally, abrogated by its antagonism. Amphiregulin declined in COVID-19 subjects as a function of disease severity and Notch4 expression. Thus, Notch4 expression on Treg cells dynamically restrains amphiregulin-dependent tissue repair to promote severe lung inflammation, with therapeutic implications for COVID-19 and related infections.

Background: Limited data exist regarding ventilation in patients with class III obesity [body mass index (BMI) > 40 kg/m 2 ] and acute respiratory distress syndrome (ARDS). The aim of the present study was to determine whether an individualized titration of mechanical ventilation according to cardiopulmonary physiology reduces the mortality in patients with class III obesity and ARDS. Methods: In this retrospective study, we enrolled adults admitted to the ICU from 2012 to 2017 who had class III obesity and ARDS and received mechanical ventilation for > 48 h. Enrolled patients were divided in two cohorts: one cohort (2012-2014) had ventilator settings determined by the ARDSnet table for lower positive end-expiratory pressure/higher inspiratory fraction of oxygen (standard protocol-based cohort); the other cohort (2015-2017) had ventilator settings determined by an individualized protocol established by a lung rescue team (lung rescue team cohort). The lung rescue team used lung recruitment maneuvers, esophageal manometry, and hemodynamic monitoring. Results: The standard protocol-based cohort included 70 patients (BMI = 49 ± 9 kg/m 2 ), and the lung rescue team cohort included 50 patients (BMI = 54 ± 13 kg/m 2 ). Patients in the standard protocol-based cohort compared to lung rescue team cohort had almost double the risk of dying at 28 days [31% versus 16%, P = 0.012; hazard ratio (HR) 0.32; 95% confidence interval (CI95%) 0.13-0.78] and 3 months (41% versus 22%, P = 0.006; HR 0.35; CI95% 0.16-0.74), and this effect persisted at 6 months and 1 year (incidence of death unchanged 41% versus 22%, P = 0.006; HR 0.35; CI95% 0.16-0.74). Conclusion: Individualized titration of mechanical ventilation by a lung rescue team was associated with decreased mortality compared to use of an ARDSnet table.

Background Home-based interventions to improve indoor air quality have demonstrated benefits for asthma morbidity, yet little is known about the effect of environmental interventions in the school setting. Objective We piloted the feasibility and effectiveness of a classroom-based air cleaner intervention to reduce particulate pollutants in classrooms of children with asthma. Methods In this pilot randomized controlled trial, we assessed the effect of air cleaners on indoor air particulate pollutant concentrations in 18 classrooms (9 control, 9 intervention) in 3 urban elementary schools. We enrolled 25 asthmatic children (13 control, 12 intervention) aged 6–10 years old. Classroom air pollutant measurements and spirometry were completed once prior to and twice after randomization. Asthma symptoms were surveyed every 3 months. Results Baseline classroom levels of fine particulate matter (PM2.5) and black carbon (BC) were 6.3 μg/m3 and 0.41 μg/m3, respectively. When comparing the intervention to the control group, classroom PM2.5 levels were reduced by 49% and 42%, and BC levels were reduced by 58% and 55% in the first and second follow-up periods, respectively (p < 0.05 for all comparisons). When comparing the children randomized to intervention and control classrooms, there was a modest improvement in peak flow, but no significant changes in forced expiratory volume in 1 second (FEV1) and asthma symptoms. Conclusion In this pilot study, a classroom-based air cleaner intervention led to significant reductions in PM2.5 and BC. Future large-scale studies should comprehensively evaluate the effect of school-based environmental interventions on pediatric asthma morbidity.

Purpose of review Over 60 million people worldwide work in the textile or clothing industry. Recent studies have recognized the contribution of workplace exposures to chronic lung diseases, in particular chronic obstructive pulmonary disease (COPD). Early studies in textile workers have focused on the relationship between hemp or cotton dust exposure and the development of a syndrome termed Byssinosis. The purpose of this review is to evaluate the effect of long term exposure to organic dust in textile workers on chronic respiratory disease in the broader context of disease classifications such as reversible or irreversible obstructive lung disease (i.e. asthma or COPD), and restrictive lung disease. Recent findings Cessation of exposure to cotton dusts leads to improvement in lung function. Recent animal models have suggested a shift in the lung macrophage:dendritic cell population as a potential mechanistic explanation for persistent inflammation in the lung due to repeated cotton-dust related endotoxin exposure. Other types of textile dust, such as silk, may contribute to COPD in textile workers. Summary Textile dust related obstructive lung disease has characteristics of both asthma and COPD. Significant progress has been made in the understanding of chronic lung disease due to organic dust exposure in textile workers.

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IntroductionLittle is known about the antimicrobial susceptibility of common bacteria responsible for wound infections from many countries in sub-Saharan Africa.MethodsWe performed a retrospective review of microbial isolates collected based on clinical suspicion of wound infection between 2004 and 2016 from Mercy Ships, a non-governmental organisation operating a single mobile surgical unit in Benin, Congo, Liberia, Madagascar, Sierra Leone and Togo. Antimicrobial resistant organisms of interest were defined as methicillin-resistant Staphylococcus aureus (MRSA) or Enterobacteriaceae resistant to third-generation cephalosporins. Generalised mixed-effects models accounting for repeated isolates in a patient, potential clustering by case mix for each field service, age, gender and country were used to test the hypothesis that rates of antimicrobial resistance differed between countries.Results3145 isolates from repeated field services in six countries were reviewed. In univariate analyses, the highest proportion of MRSA was found in Benin (34.6%) and Congo (31.9%), while the lowest proportion was found in Togo (14.3%) and Madagascar (14.5%); country remained a significant predictor in multivariate analyses (P=0.002). In univariate analyses, the highest proportion of third-generation cephalosporin-resistant Enterobacteriaceae was found in Benin (35.8%) and lowest in Togo (14.3%) and Madagascar (16.3%). Country remained a significant predictor for antimicrobial-resistant isolates in multivariate analyses (P=0.009).ConclusionA significant proportion of isolates from wound cultures were resistant to first-line antimicrobials in each country. Though antimicrobial resistance isolates were not verified in a reference laboratory and these data may not be representative of all regions of the countries studied, differences in the proportion of antimicrobial-resistant isolates and resistance profiles between countries suggest site-specific surveillance should be a priority and local antimicrobial resistance profiles should be used to guide empiric antibiotic selection.