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Background: Despite the increasing use of biologics in severe asthma, there is limited research on their use in asthma-chronic obstructive pulmonary disease overlap (ACO). We compared real-world treatment responses to biologics in ACO and asthma. Methods: We conducted a multicenter, retrospective, cohort study using data from the Precision Medicine Intervention in Severe Asthma (PRISM). ACO was defined as post-bronchodilator forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC) 10 pack-years. Physicians selected biologics (omalizumab, mepolizumab, reslizumab, benralizumab, and dupilumab) based on each United States Food & Drug Administration (FDA) approval criteria. Results: After six-month treatment with biologics, both patients with ACO (N = 13) and asthma (N = 81) showed positive responses in FEV1 (10.69 ± 17.17 vs. 11.25 ± 12.87 %, P = 0.652), Asthma Control Test score (3.33 ± 5.47 vs. 5.39 ± 5.42, P = 0.290), oral corticosteroid use (−117.50 ± 94.38 vs. −115.06 ± 456.85 mg, P = 0.688), fractional exhaled nitric oxide levels (−18.62 ± 24.68 vs. −14.66 ± 45.35 ppb, P = 0.415), sputum eosinophils (−3.40 ± 10.60 vs. −14.48 ± 24.01 %, P = 0.065), blood eosinophils (−36.47 ± 517.02 vs. −363.22 ± 1294.59, P = 0.013), and exacerbation frequency (−3.07 ± 4.42 vs. −3.19 ± 5.11, P = 0.943). The odds ratio for exacerbation and time-to-first exacerbation showed no significant difference after full adjustments, and subgroup analysis according to biologic type was also showed similar results. Conclusions: Biologics treatment response patterns in patients with ACO and asthma were comparable, suggesting that biologics should be actively considered for ACO patients as well.

Background Spread of SARS-CoV2 by aerosol is considered an important mode of transmission over distances >2 m, particularly indoors.Objectives We determined whether SARS-CoV2 could be detected in the air of enclosed/semi-enclosed public spaces.Methods and analysis Between March 2021 and December 2021 during the easing of COVID-19 pandemic restrictions after a period of lockdown, we used total suspended and size-segregated particulate matter (PM) samplers for the detection of SARS-CoV2 in hospitals wards and waiting areas, on public transport, in a university campus and in a primary school in West London.Results We collected 207 samples, of which 20 (9.7%) were positive for SARS-CoV2 using quantitative PCR. Positive samples were collected from hospital patient waiting areas, from hospital wards treating patients with COVID-19 using stationary samplers and from train carriages in London underground using personal samplers. Mean virus concentrations varied between 429 500 copies/m3 in the hospital emergency waiting area and the more frequent 164 000 copies/m3 found in other areas. There were more frequent positive samples from PM samplers in the PM2.5 fractions compared with PM10 and PM1. Culture on Vero cells of all collected samples gave negative results.Conclusion During a period of partial opening during the COVID-19 pandemic in London, we detected SARS-CoV2 RNA in the air of hospital waiting areas and wards and of London Underground train carriage. More research is needed to determine the transmission potential of SARS-CoV2 detected in the air.

Abstract Background The acute respiratory distress syndrome (ARDS) occurs in response to a variety of insults, and mechanical ventilation is life-saving in this setting, but ventilator-induced lung injury can also contribute to the morbidity and mortality in the condition. The Beacon Caresystem is a model-based bedside decision support system using mathematical models tuned to the individual patient’s physiology to advise on appropriate ventilator settings. Personalised approaches using individual patient description may be particularly advantageous in complex patients, including those who are difficult to mechanically ventilate and wean, in particular ARDS. Methods We will conduct a multi-centre international randomised, controlled, allocation concealed, open, pragmatic clinical trial to compare mechanical ventilation in ARDS patients following application of the Beacon Caresystem to that of standard routine care to investigate whether use of the system results in a reduction in driving pressure across all severities and phases of ARDS. Discussion Despite 20 years of clinical trial data showing significant improvements in ARDS mortality through mitigation of ventilator-induced lung injury, there remains a gap in its personalised application at the bedside. Importantly, the protective effects of higher positive end-expiratory pressure (PEEP) were noted only when there were associated decreases in driving pressure. Hence, the pressures set on the ventilator should be determined by the diseased lungs’ pressure-volume relationship which is often unknown or difficult to determine. Knowledge of extent of recruitable lung could improve the ventilator driving pressure. Hence, personalised management demands the application of mechanical ventilation according to the physiological state of the diseased lung at that time. Hence, there is significant rationale for the development of point-of-care clinical decision support systems which help personalise ventilatory strategy according to the current physiology. Furthermore, the potential for the application of the Beacon Caresystem to facilitate local and remote management of large numbers of ventilated patients (as seen during this COVID-19 pandemic) could change the outcome of mechanically ventilated patients during the course of this and future pandemics. Trial registration ClinicalTrials.gov identifier NCT04115709. Registered on 4 October 2019, version 4.0

Abstract In utero exposure to tobacco products, whether maternal or environmental, have harmful effects on first neonatal and later adult respiratory outcomes. These effects have been shown to persist across subsequent generations, regardless of the offsprings’ smoking habits. Established epigenetic modifications induced by in utero exposure are postulated as the mechanism underlying the inherited poor respiratory outcomes. As e-cigarette use is on the rise, their potential to induce similar functional respiratory deficits underpinned by an alteration in the foetal epigenome needs to be explored. This review will focus on the functional and epigenetic impact of in utero exposure to maternal cigarette smoke, maternal environmental tobacco smoke, environmental tobacco smoke and e-cigarette vapour on foetal respiratory outcomes.

Introduction Cigarette smoking and oxidative stress are common risk factors for the multi-morbidities associated with chronic obstructive pulmonary disease (COPD). Elevated levels of advanced glycation endproducts (AGE) increase the risk of cardiovascular disease (CVD) comorbidity and mortality. The enzyme fructosamine-3-kinase (FN3K) reduces this risk by lowering AGE levels.Methods The distribution and expression of FN3K protein in lung tissues from stable COPD and control subjects, as well as an animal model of COPD, was assessed by immunohistochemistry. Serum FN3K protein and AGE levels were assessed by ELISA in patients with COPD exacerbations receiving metformin. Genetic variants within the FN3K and FN3K-RP genes were evaluated for associations with cardiorespiratory function in the Subpopulations and Intermediate Outcome Measures in COPD Study cohort.Results This pilot study demonstrates that FN3K expression in the blood and human lung epithelium is distributed at either high or low levels irrespective of disease status. The percentage of lung epithelial cells expressing FN3K was higher in control smokers with normal lung function, but this induction was not observed in COPD patients nor in a smoking model of COPD. The top five nominal FN3K polymorphisms with possible association to decreased cardiorespiratory function (p

Options to achieve oral corticosteroid (OCS)-sparing have been triggering increasing interest since the 1970s because of the side-effects of OCSs, and this has now become achievable with biologics. The Société de Pneumologie de Langue Française workshop on OCSs aimed to conduct a comprehensive review of the basics for OCS use in asthma and issue key research questions. Pharmacology and definition of regular use were reviewed by the first working group (WG1). WG2 examined whether regular OCS use is associated with T2 endotype. WG3 reported on the specificities of the paediatric area. Key “research statement proposals” were suggested by WG4. It was found that the benefits of regular OCS use in asthma outside episodes of exacerbations are poorly supported by the existing evidence. However, complete OCS elimination couldn’t be achieved in any available studies for all patients and the panel felt that it was too early to conclude that regular OCS use could be declared criminal. Repeated or prolonged need for OCS beyond 1 g·year−1 should indicate the need for referral to secondary/tertiary care. A strategic sequential plan aiming at reducing overall exposure to OCS in severe asthma was then held as a conclusion of the workshop.

Abstract Backbround COPD is a common, highly debilitating disease of the airways, primarily caused by smoking. Chronic inflammation and structural remodelling are key pathological features of this disease caused, in part, by the aberrant function of airway smooth muscle (ASM). We have previously demonstrated that hydrogen sulfide (H2S) can inhibit ASM cell proliferation and CXCL8 release, from cells isolated from non-smokers. Methods We examined the effect of H2S upon ASM cells from COPD patients. ASM cells were isolated from non-smokers, smokers and patients with COPD (n = 9). Proliferation and cytokine release (IL-6 and CXCL8) of ASM was induced by FCS, and measured by bromodeoxyuridine incorporation and ELISA, respectively. Results Exposure of ASM to H2S donors inhibited FCS-induced proliferation and cytokine release, but was less effective upon COPD ASM cells compared to the non-smokers and smokers. The mRNA and protein expression of the enzymes responsible for endogenous H2S production (cystathionine-β-synthase [CBS] and 3-mercaptopyruvate sulphur transferase [MPST]) were inhibited by H2S donors. Finally, we report that exogenous H2S inhibited FCS-stimulated phosphorylation of ERK–1/2 and p38 mitogen activated protein kinases (MAPKs), in the non-smoker and smoker ASM cells, with little effect in COPD cells. Conclusions H2S production provides a novel mechanism for the repression of ASM proliferation and cytokine release. The ability of COPD ASM cells to respond to H2S is attenuated in COPD ASM cells despite the presence of the enzymes responsible for H2S production.

Different phenotypes of asthma from mild to severe are categorized based on diverse clinical features. A guideline for the recognition and treatment of asthma has been provided by Global Initiative for Asthma (GINA). To control symptoms and prevent asthma exacerbation in most patients combinational therapy with inhaled corticosteroids (ICS) and a long acting B2-adrenreceptor agonist (LABA) are recommended. Understanding asthma phenotypes would be helpful to improve asthma diagnosis and treatment. The aim of this study was to verify glucocorticoid receptor glcococorticoid receptor (GR) nuclear translocation in CD4 T cells treated with fluticasone furoate (FF), vilanterol (V) and FF/V combination in severe asthmatic patients compare to patients with moderate asthma and healthy controls using Immunocytochemistry (ICC). After taking blood and separating PBMCs from each subject, CD4 T cells were isolated from PBMCs using CD4+ T cell isolation kit. Isolated CD4 T cells were cultured in presence of FF, V and FF/V combination for 1 hour and after cytocentrifugation, cells were incubated with anti GR-antibody and subsequently stained with FITC bound secondary antibody and GR nuclear translocation was observed under microscope. The results showed significant increasing in GR nuclear translocation in treated CD4 T cells from patients with moderate asthma and controls compare to those severe asthmatic patients, along with treating cells with FF/V combination no significant GR nuclear translocation was observed compare to that of using mono treatment of cells with FF and V. Based on our findings, it can be concluded different mechanisms are responsible for severe asthma and moderate asthma.

Signalling network inference is a central problem in system biology. Previous studies investigate this problem by independently inferring local signalling networks and then linking them together via crosstalk. Since a cellular signalling system is in fact indivisible, this reductionistic approach may have an impact on the accuracy of the inference results. Preferably, a cell-scale signalling network should be inferred as a whole. However, the holistic approach suffers from three practical issues: scalability, measurement and overfitting. Here we make this approach feasible based on two key observations: 1) variations of concentrations are sparse due to separations of timescales; 2) several species can be measured together using cross-reactivity. We propose a method, CCELL, for cell-scale signalling network inference from time series generated by immunoprecipitation using Bayesian compressive sensing. A set of benchmark networks with varying numbers of time-variant species is used to demonstrate the effectiveness of our method. Instead of exhaustively measuring all individual species, high accuracy is achieved from relatively few measurements.

Chronic exposure to high levels of ozone induces emphysema and chronic inflammation in mice. We determined the recovery from ozone-induced injury and whether an antioxidant, N-acetylcysteine (NAC), could prevent or reverse the lung damage.Mice were exposed to ozone (2.5 ppm, 3 hours/12 exposures, over 6 weeks) and studied 24 hours (24h) or 6 weeks (6W) later. Nac (100 mg/kg, intraperitoneally) was administered either before each exposure (preventive) or after completion of exposure (therapeutic) for 6 weeks.After ozone exposure, there was an increase in functional residual capacity, total lung volume, and lung compliance, and a reduction in the ratio of forced expiratory volume at 25 and 50 milliseconds to forced vital capacity (FEV25/FVC, FEV50/FVC). Mean linear intercept (Lm) and airway hyperresponsiveness (AHR) to acetylcholine increased, and remained unchanged at 6W after cessation of exposure. Preventive NAC reduced the number of BAL macrophages and airway smooth muscle (ASM) mass. Therapeutic NAC reversed AHR, and reduced ASM mass and apoptotic cells.Emphysema and lung function changes were irreversible up to 6W after cessation of ozone exposure, and were not reversed by NAC. The beneficial effects of therapeutic NAC may be restricted to the ASM.

Asthma is a complex, heterogeneous and chronic airway inflammatory disease with different clinical phenotypes caused by diverse triggers and pathophysiological mechanisms. Asthma heritability has been established in many genetic studies but it is evident that only genetic elements are not responsible for the development of asthma. Increasing rate of asthma incidence during past decades has implicated the role of epigenetics in development of asthma. Environmental factors perform as initiator signals through epigenetic mechanisms. Three epigenetic mechanisms have been identified, including DNA methylation, histone modifications, and small noncoding RNAs. These mechanisms regulate the immune responses and inflammatory genes expression in asthma and allergy. This review explains the role of epigenetic modifications in controlling Th2 response and IgE production in asthma and also briefly overviews the role of environmental factors such as pollutions, allergens, prenatal exposures and diet in developing asthma. Recognizing environmental risk factors and their effects on epigenetic mechanisms would be of great interest for prognostic and preventive aspect in treatment of asthma.