Thorax

BackgroundPopulation-based spirometry data from sub-Saharan Africa remain limited. We characterised lung function, chronic obstructive pulmonary disease (COPD), lung restriction and associated factors from two Sub-Saharan African countries. MethodsWe performed spirometry using ndd Easy On-PC spirometers among adults aged [&ge;]40 years from population-based cohorts in four communities in Burkina Faso and South Africa from January 2019-April 2022. We included 1,619 participants (936 women, 683 men) with repeatable forced expiratory volume in one second (FEV1) and forced vital capacity (FVC). COPD was defined as FEV1/FVC<0.70 and lung restriction as FEV1/FVC[&ge;]0.70, with FVC<80% predicted. We used multivariable models to test factors associated with lung function measurements (FEV1, FVC and FEV1/FVC), COPD and lung restriction. ResultsMedian FEV1 and FVC ranged from 1.940-2.273L and 2.521-2.883L, respectively. COPD prevalence was 16.1% (95% CI 14.4-18.0; site range 10.8%-24.5%) and lung restriction prevalence was 21.3% (95% CI 19.4-23.4; site range 11.3%-36.2%). Prior tuberculosis was associated with higher odds of COPD (OR 2.86, 95% CI 1.75-4.59) and lower FEV1, FVC and FEV1/FVC. HIV infection was associated with higher COPD odds (OR 1.67, 95% CI 1.01-2.72) and lower FEV1/FVC. Hypertension was associated with higher lung restriction odds (OR 1.46, 95% CI 1.07-2.00) and lower FEV1 and FVC. Diabetes was associated with lower COPD odds (OR 0.50, 95% CI 0.24-0.94), lower FVC and higher FEV1/FVC. Ever-smoking and older age were associated with higher COPD odds (OR 2.21, 95% CI 1.48-3.32; OR 1.05, 95% CI 1.03-1.07, respectively); older age was associated with higher lung restriction odds (OR 1.02, 95% CI 1.00-1.04). ConclusionThis multisite study highlights substantial heterogeneity in COPD and lung restriction prevalence across African populations and identifies respiratory multimorbidity with infectious and cardiometabolic conditions. These findings provide population-based evidence to inform respiratory surveillance in sub-Saharan Africa.

Background Exposure to environmental tobacco smoke (ETS) negatively affects children`s health, but few studies examined parental smoking behaviour in families of children with respiratory diseases. We studied parental smoking prevalence, characteristics, and changes over one year among families in the Swiss Paediatric Airway Cohort (SPAC). Methods We included children aged 0-17 years referred to paediatric respiratory outpatient clinics in Switzerland from 2017 to 2024. Parents answered a questionnaire at the initial clinic visit and again after one year. We used multivariable logistic regression to explore the characteristics of mothers and fathers who smoked and assessed changes in smoking behavior over one year. Results Among 4,199 children (median age 9 years [IQR 5-12]), 31% were exposed to parental smoking at baseline (paternal smoking: 16%; maternal smoking: 6%; both parents smoking: 9%). Mothers were more likely to smoke if they had a lower education level (OR 2.0, 95%CI 1.6-2.5 for compulsory education vs university education), did not have Swiss nationality (OR 1.3, 1.0-1.6) and lived in a socially disadvantaged neighborhood (OR 1.3, 1.0-1.7). Similar associations were observed for fathers. In addition, fathers were more likely to smoke if they were unemployed (OR 2.0, 1.3-3.2 vs having a full-time job. The strongest predictor of smoking was having a partner who smoked, with ORs above 6 for both mothers and fathers. Parents of 2,338 children completed the one-year follow-up questionnaire. Data from 2226 mothers and 1895 fathers showed that among baseline smokers with follow-up data, 225 (78%) mothers and 382 (81%) of fathers continued smoking, and only 63 (22%) of mothers and 90 (19%) of fathers quit. Among baseline non-smokers, 47 (2%) mothers and 54 (3%) fathers started smoking. Conclusions One-third of children consulting respiratory specialists in Switzerland are exposed to parental smoking. ETS exposure was strongly associated with socio-economic factors. Even after visiting a specialized clinic, most parents continued to smoke. This highlights the urgent need for stronger national smoking policies and targeted support to help these parents quit and stay smoke-free.

BackgroundEarly-life air pollution exposure has been associated with childhood asthma, but its relative contribution is poorly characterised in cohorts with repeated indoor measurements. Short sampling windows and seasonal bias limit how well any single measurement can represent cumulative exposure. ObjectiveTo evaluate the association between early-life indoor and outdoor pollutant exposure from birth to 18 months and asthma development at ages 7, 12, and 18 years, while testing potential exposure-exposure and gene-environment interactions. MethodsIn the COPSAC2000 birth cohort (n = 411), indoor PM2.5, black carbon, NO2, NOx and VOCs, and modelled outdoor PM2.5, NO2 and NOx, were assessed at 6, 12 and 18 months of age. Indoor metrics were corrected for pump-flow drift and seasonal bias via a Gaussian process with a periodic kernel. Hierarchical Bayesian logistic regression(HBLR) and calibrated random forests (CRF) were evaluated using stratified nested cross-validation for discrimination using AUC-ROC, Calibration using integrated calibration index (ICI), and Brier skill scores. Exposure-exposure and gene-environment interactions were quantified via Shapley interaction indices. ResultsDiscrimination was weak at all endpoints with test AUC-ROC: 0.58-0.67, BSS near zero (0.012 to 0.05) and ICI: 0.043-0.061 for random forest and AUC-ROC 0.53-0.61, BSS equal to zero and ICI: 0.054-0.067 for hierarchical Bayesian logistic regression (HBLR). No pollutant reached a highest density interval excluding OR = 1. The polygenic risk score(PRS) was the only term non-null at all three ages in the adjusted models. While gene-environment interactions were detected, effect sizes were negligible and statistically indistinguishable from zero. SignificanceWhere ambient pollution is low, cumulative early-life exposure adds little to long-term asthma prediction beyond genetic and contextual factors, and an improved exposure correction does not uncover an effect. ImpactRepeated bedroom measurements across infancy are rare, and short sampling windows make them hard to read as cumulative exposure. We corrected measured concentrations for pump-flow drift and for seasonal sampling bias on the pollutants and used two complementary machine learning models to predict interaction and risk. In this low-exposure Danish cohort, genetic risk and residential context dominated, and the measured pollutants added almost nothing to the asthma risk at 7,12 and 18 years. These null results indicate that early cumulative exposures of indoor and outdoor air pollution contribute little to nothing to asthma up to 18 years.

Background. Sarcopenia is common in chronic obstructive pulmonary disease (COPD) and contributes to adverse outcomes. Alpha-1 antitrypsin deficiency (AATD) is the most common genetic cause of COPD, but its impact on skeletal muscle remains to be determined. Methods. We performed a retrospective analysis of 487,207 participants in the UK Biobank with available SERPINA1 genotyping. Associations between AAT genotypes and measures of skeletal muscle mass were determined using multivariable linear and logistic regression models. Models adjusted for age, sex, smoking status, genetic principal components, lung function (FEV% predicted), and liver fibrosis risk (FIB-4). We determined that the Z-allele was associated with sarcopenia and mortality using regression models and mediation analysis. Results. Compared with PI*MM individuals, carriers of the Z allele (PI*MZ, PI*SZ, PI*ZZ) demonstrated significantly lower fat free mass index (FFMI) and appendicular skeletal muscle index (ASMI), as well as higher odds of sarcopenia by binary definition. Associations persisted after adjustment for lung and liver function. A dose-dependent relationship was observed, with the greatest reductions in muscle mass and highest sarcopenia associated with PI*ZZ individuals (adjusted OR for FFMI-defined sarcopenia 2.02, 95% CI 1.16-3.32). Each additional Z allele was associated with increased mortality risk (adjusted OR 1.09, 95% CI 1.02-1.16), with sarcopenia mediating a modest proportion (~2.6%) of this association. Conclusions. The SERPINA1 Z allele is associated with reduced muscle mass and increased risk for sarcopenia independent of lung and liver disease. Our findings expand the phenotypic spectrum of AATD-related diseases to include skeletal muscle as a modifiable target for intervention.

Study Question. COPD exacerbations with respiratory failure have an outsized impact on morbidity, mortality, and healthcare costs. Physicians treat these severe events with high doses of corticosteroids out of concern for intrinsic corticosteroid resistance. This study was designed to determine whether people who suffer from exacerbations with respiratory failure have intrinsic steroid resistance that could affect that decision. Patients and Methods. A matched, case-control study was performed at University of Colorado. Subjects were enrolled into the Exacerbation group if they were hospitalized for an exacerbation requiring ventilation, or into the Stable COPD group if they had no inpatient exacerbation within 12 months. Stable COPD subjects were frequency-matched to Exacerbation subjects for age, smoking status and FEV1%. Corticosteroid sensitivity was assessed ex vivo and in vivo >45 days following the last exacerbation during a period of relative quiescence. The primary outcome was the group difference in methylprednisolone IC50 for LPS-stimulated IL-8 release by mononuclear cells. Measurements and Main Results. The Exacerbation group (N=8) had more exacerbations in the prior year (6.0 vs. 0.5; p<0.01) and had higher baseline blood lymphocytes (p<0.01) versus Stable controls (N=8). Ex vivo, methylprednisolone equally suppressed IL-8, IL-6, TNFalpha and IL-1bets release by mononuclear cells and whole blood across groups. In vivo, methylprednisolone decreased plasma mediators and mononuclear cells in both groups but had a small differential effect on mononuclear cell gene expression. Answer to the Question. Exacerbations with respiratory failure have persistent lymphocytosis, an altered gene response to corticosteroids, but no corticosteroid resistance to suppress inflammation.

Background: Chronic obstructive pulmonary disease (COPD) is characterized by airway remodeling, which may extend to the central airways and alter tracheal morphology. Whether tracheal shape relates to disease severity, quality of life, functional capacity, or survival is not established. Objective: To determine whether CT-derived tracheal lumen eccentricity is associated with cross-sectional and longitudinal clinical outcomes in COPD. Methods: We analyzed 8,383 participants from the multicenter COPDGene study. At each axial cross-section of the trachea, lumen eccentricity ({epsilon}) was computed from the major and minor axis lengths, and the participant-level value was taken as the arithmetic mean across all tracheal slices; {epsilon} = 0 denotes a circular lumen and values approaching 1 denote progressively elongated ellipses. Baseline outcomes were spirometry, 6-minute walk distance (6MWD), St. George's Respiratory Questionnaire (SGRQ) total score, and modified Medical Research Council (mMRC) dyspnea score. Longitudinal outcomes were annualized change in FEV1 and all-cause mortality. Multivariable linear and Cox proportional hazards models were adjusted for [age, sex, race, BMI, smoking status, pack-years, scanner model]. Results: Tracheal eccentricity rose monotonically with severity of airflow obstruction (0.60{+/-}0.07, 0.61{+/-}0.07, 0.62{+/-}0.07, 0.64{+/-}0.08, and 0.64{+/-}0.08 in GOLD stages 0 through 4, respectively). Higher eccentricity was independently associated with lower FEV1 ({beta} = -0.30 L, 95% CI -0.47 to -0.14; p < 0.001), lower FEV1/FVC ({beta} = -0.06, 95% CI -0.09 to -0.04; p < 0.001), shorter 6MWD ({beta} = -15.7 m, 95% CI -25.2 to -6.2; p = 0.001), higher SGRQ score ({beta} = 16.9, 95% CI 11.2 to 22.5; p < 0.001), higher mMRC dyspnea score ({beta} = 0.4, 95% CI 0.1 to 0.6; p = 0.007), and accelerated lung function decline ({beta} = -23.8 mL/year, 95% CI -45.13 to -2.48; p = 0.029). Eccentricity was also associated with all-cause mortality (adjusted HR 1.81, 95% CI 1.01 to 3.26; p = 0.047). Conclusions: Tracheal lumen eccentricity is associated with worse quality of life, reduced functional capacity, accelerated lung function decline, and mortality in COPD, supporting central airway morphology as a candidate imaging biomarker.

Background: Obesity is associated with airway disease, but the contribution of specific thoracic adipose depots remains unclear. We examined whether intrathoracic adipose tissue (ITAT), defined as adipose tissue within the thoracic cavity excluding pericardial adipose tissue (PAT), was associated with airway phenotypes. Methods: We included Framingham Heart Study participants with CT-derived thoracic adipose tissue measures. Cross-sectional associations of ITAT with CT-based airway wall and lumen measurements, spirometry, and respiratory symptoms were evaluated using multivariable regression. Primary analyses used sex-specific ITAT z-scores and adjusted for waist circumference to account for central obesity. Secondary analyses examined sex-specific ITAT quintiles and compared ITAT and PAT in individual-depot and mutually adjusted models. Results: Among 2,825 adult participants (52.0% female), after adjustment for waist circumference, each 1-SD higher ITAT, relative to the sex-specific distribution, was associated with greater segmental ({beta} [95% CI]: 0.010 mm [0.006, 0.014]) and subsegmental airway wall thickness (0.006 mm [0.002, 0.009]), narrower segmental airway lumen diameter (-0.049 [-0.088, -0.011]), lower FEV1 percent predicted (-1.92 percentage points [-2.72, -1.12]), and higher odds of wheezing (OR [95% CI]: 1.16 [1.02, 1.31]) and dyspnea (1.22 [1.05, 1.42]). Associations were similar after further adjustment for PAT and across ITAT quintiles. In contrast, PAT was not independently associated with airway structural measures after adjustment for ITAT. Conclusion: Higher ITAT volume was associated with greater airway wall thickness and narrower airway lumen, as well as lower FEV1 and greater respiratory symptoms, independent of central obesity and pericardial adiposity. These findings support a depot-specific association of ITAT with airway disease.

Abstract Background Fibrotic interstitial lung disease (F-ILD) has high mortality. Evidence suggests short telomere causality and sex hormone interactions. STARSHIP aimed to assess feasibility for future F-ILD sex hormone trials. Methods Leukocyte telomere length (LTL), complete blood count, sex hormone (testosterone and oestrogen), sex hormone binding globulin (SHBG) and albumin concentrations were determined in 102 F-ILD outpatients (age 49-89, male N=80 [78%]) and age/sex-matched controls (ASMCs). Patients undertook routine pulmonary function tests, 93 (91%) participated in bespoke telephone interviews. Survival was assessed at median 33 (28-39) months. Results 77/79 (97.4%) male patients had haemoglobin and haematocrit below the upper reference limit. Mean LTL was shorter for patients than ASMCs (4.57kb [95%CI:4.46-4.69] vs 4.78kb [95%CI:4.67-4.89]; p<0.006). SHBG concentrations were higher for patients. Mean bioavailable testosterone was lower for N=80 male patients than ASMCs (4.95nmol/L [95%CI:4.50-5.41] vs 6.40nmol/L [95%CI:5.82-6.98]; p<0.0001). Post-menopausal oestrogen concentrations were low for female patients and controls. Mean free androgen index (FAI) was low for female patients but not ASMCs (mean 0.51 [95%CI:0.35-0.67] vs 1.23 [95%CI:0.77-1.69]; p=0.0036, N=22). Age/BMI-adjusted bioavailable testosterone concentration in male patients correlated with both DLCO% (=3.31, p=2.4x10-4) and FVC% (=2.76, p=0.0030). FVC% associated with FAI in females (=34.3, p=0.0029). In all-confounder-adjusted Cox analysis, low free testosterone associated with mortality (HR=2.66, p=0.023, N=77) in male patients. Lower FAI (adjusted for age/lung function) suggested similar effects but more studies needed for females (HR=3.59, p=0.22, N=18). Conclusions ILD patients have low sex hormones concentration(s), which associated with reduced lung function and survival. Sex hormone supplementation studies are needed.

Objectives Genetic testing is increasingly used in the diagnosis and management of respiratory conditions, including pulmonary fibrosis (PF). The perspectives of people with PF and healthcare professionals (HCP) on the use of genetic testing remain largely unexplored. Methods A qualitative study was undertaken. People living with PF, their caregivers, and HCP were invited to undertake a semi-structured interview. Interviews were conducted via videoconference or telephone, audio-recorded, and transcribed verbatim. Data were analysed by two researchers using inductive thematic analysis. Results Thirty-eight participants; 15 people living with PF, 1 caregiver, and 22 HCPs were interviewed. Analysis revealed three key themes. Genetic testing in PF was valued by all groups; people with PF wanted testing now, whilst respiratory physicians were cautious, citing their uncertainty regarding clinical value. All groups desired more information and support; people with PF desired a better understanding of terminology, whilst genetic counsellors wanted to better understand PF. No single model for returning genetic results in PF was identified, however resources, multidisciplinary care, and timely return of results was considered important. Conclusion Genetic testing is valued by people with PF and their HCP, but uncertainties remain regarding whether it should be offered and how results should be best communicated.

Background. Short telomeres are an established cause of idiopathic pulmonary fibrosis (IPF), but the genetic evidence rests on seven instruments, six of which lie at telomere-maintenance loci, and so cannot separate an effect of telomere length from an effect of the telomerase pathway itself - a distinction that determines whether telomere length is a tractable target or only a marker of the pathway. Whether other measures of biological ageing share the effect, and whether accelerated ageing causes immune-mediated disease more generally, has not been tested systematically. Methods. Two-sample Mendelian randomisation of six ageing measures - GrimAge, PhenoAge, Hannum-age and intrinsic epigenetic age acceleration, proteomic age acceleration, and leukocyte telomere length - against six immune-mediated diseases in FinnGen R12: giant cell arteritis (GCA), polymyalgia rheumatica, primary Sjoegren's disease, interstitial lung disease (ILD), Crohn's disease and ulcerative colitis. All 36 pairs were analysed in both directions using inverse-variance weighted (IVW), MR-Egger, weighted-median and weighted-mode estimators, with Cochran's Q, I2, leave-one-out and single-variant diagnostics, a pre-specified analysis excluding HLA-region instruments, and iterative Q-based outlier removal. Instruments were annotated against telomere-maintenance and pulmonary-fibrosis loci and that class excluded. Minimum detectable effects were computed for every pair before estimates were examined. Any pair surviving correction was re-estimated in two independent IPF case-control datasets. A two-step analysis tested mediation of ILD risk by seven gut microbial taxa acting through telomere length. Results. One of 36 forward pairs survived correction. Longer telomeres reduced ILD risk: outlier-robust IVW odds ratio (OR) 0.59 per standard deviation (SD), 95% CI 0.49-0.71, p = 2.7 x 10^-8, on 77 instruments, with no residual heterogeneity (I2 = 6%) and concordance across estimators. Four pleiotropic instruments - in TERT, TERC, APOE and ATM - inflated the unfiltered estimate to OR 0.46 (0.37-0.57) and accounted for all of its heterogeneity. The effect was reproduced in 5,159 clinician-diagnosed European IPF cases (OR 0.18, 0.12-0.25, p = 5.0 x 10^-23) and in 1,210 East Asian cases (OR 0.54, 0.35-0.83, p = 0.005). Excluding every telomere-maintenance and pulmonary-fibrosis locus left OR 0.26 (0.17-0.40), p = 1.6 x 10^-9, on 72 instruments, establishing that the effect does not depend on TERT or TERC. The effect was three times larger for clinically defined IPF than for the broad registry ILD endpoint (p = 1.8 x 10^-9), consistent with dilution of a fibrosis-specific mechanism by case mix. No methylation clock and no proteomic age measure affected any disease; smallest detectable ORs ranged from 1.29 to 5.24 per SD, so these nulls exclude only large effects. The reverse direction could not be tested at informative precision. One apparent clock-autoimmunity association was produced entirely by a single HLA-region instrument. Mediation was null at its first step. Conclusions. Telomere attrition causally increases fibrotic lung disease risk, with an effect that concentrates in clinically defined IPF and that survives removal of every telomere-maintenance locus - shown here for the first time - and is therefore attributable to telomere length rather than to the telomerase genes that dominate conventional instrument sets. Four methylation clocks and proteomic age acceleration show no such effect, so these measures cannot be treated as interchangeable proxies for biological ageing.

Background: Sex differences in asthma are well recognized, but sex-associated airway DNA methylation (DNAm) patterns and their relationships with gene expression remain incompletely characterized. We therefore conducted cis- and trans-expression quantitative trait methylation (eQTM) analyses using sex-stratified and CpG-by-sex interaction models. Methods: We analyzed nasal airway epithelial DNAm and transcriptomic data from 298 participants in the CAAPA discovery cohort. Asthma-associated differentially methylated CpGs (DMCs) were identified using sex-combined and sex-stratified models. Cis- and trans-eQTM analyses were then performed in participants with asthma using sex-combined, sex-stratified, and CpG-by-sex interaction models. To prioritize asthma-associated regulatory relationships, eQTMs that were also significant in non-asthmatic controls were excluded from downstream analyses. Replication in an independent bronchial epithelial cohort was defined by concordant effect direction and P < 0.05. Replicated targets underwent pathway and network analyses. Findings: Asthma-associated DMCs were predominantly hypomethylated in females and hypermethylated in males. Among trans-eQTMs, 379 associations were shared across all four models, whereas the majority were model-specific, indicating extensive sex-dependent regulatory architecture. We replicated 3, 1, 9, and 2 cis-eQTMs and 96, 84, 216, and 41 trans-eQTMs in the sex-combined, female-stratified, male-stratified, and interaction models, respectively. Sex-combined targets implicated innate immune and inflammatory signaling (TNF, IRF8); female-stratified targets implicated cytoskeletal remodeling, focal adhesion, and PI3K-Akt signaling (ITGA10); male-stratified targets implicated transcriptional regulation and post-translational modification (MOV10, HDAC7, CSF1, KAT2A); and interaction targets implicated lipid-mediator metabolism and inflammatory signaling and resolution (CYP2C9, LTB4R, CCL19). Our sex-dependent analyses showed that the majority of eQTMs resided within the trans-regulatory architecture, suggesting that sex-dependent gene expression differences are associated predominantly with trans rather than cis regulatory mechanisms. Pathway analyses revealed enrichment of innate immunity in the sex-combined model, structural remodeling in females, transcriptional control in males, and inflammatory resolution in the sex-interaction model. Interpretation: Sex-specific and sex-dependent airway methylation-expression associations were largely undetected by sex-combined analysis. Sex-aware analytical models may help resolve epigenetic mechanisms underlying sex differences in asthma biology.

Objectives To characterise COVID-19 inpatients with and without bacterial/fungal preceding, co- and secondary infections, and describe the distribution of organisms associated with COVID-19 and antibiotic use. Methods We linked ISARIC/WHO CCP-UK data from hospitals in England (admissions 01/01/2020-18/10/2021) with UK Health Security Agency infections datasets of COVID-19, and bacterial- and fungal-positive specimens using a multi-step hierarchical algorithm. We retained those aged >18 years and categorised COVID-19-associated infection as preceding (2-28 days prior to SARS-CoV-2 PCR positive date), co-infection ({+/-}1 day) or secondary (2-28 days after). Results During the study period, there were 173,947 hospitalised episodes of COVID-19; 5.8% (n=10,017) with a bacterial or fungal preceding, co- or secondary infection. Preceding and co-infections were rare (preceding: 0.7%; co-infection: 1.5%) while secondary infections were more common (3.5%). Escherichia coli (29.6%) and Staphylococcus aureus (15.2%) were the most identified organisms in blood specimens, while S. aureus (22.9%) and Pseudomonas aeruginosa (20.4%) were most common in lower respiratory tract specimens. The 28-day case fatality rate (CFR) remained static (36%) in those with secondary infection, whereas it decreased between early 2020 and mid-2021 in the other infection groups (37% to 27%). Of those with no positive microbiology, 72.8% received antibiotics, though this decreased between January-June 2020 (77.6%) and April-October 2021 (62.6%). Conclusion Bacterial and fungal infections complicated approximately 1-in-17 hospitalised episodes of COVID-19, with CFR of >25%. Antibiotic prescribing was common in those without firm evidence of bacterial infection. We recommend adhering to NICE guidance which discourages empirical antibiotic use for hospitalised COVID-19 patients.

Objectives: To investigate whether the PneumoRator wearable sensor could accurately assess Respiratory Rate (RR) and signs of air hunger (SAH) compared with clinician-observed assessment in adults with and without breathing pattern disorder (BrPD). Design: A pilot cross-sectional observational study. Setting: A research laboratory on a university campus. Participants: Healthy adults aged 18-40, who were not pregnant, no smokers or history of cardiovascular, respiratory or neurological illness. Thirty consented to the study, Twenty-nine had full data for analysis. Interventions: Participants wore the PneumoRator chest-worn sensor continuously for 10 minutes while seated at rest. Main outcome measures: Respiratory Rate was compared between PneumoRator-derived measurements and randomised 1-minute observer manual counts. Clinician-observed SAH and BrPD were assessed using the Breathing Pattern Assessment Tool (BPAT). Participants also completed the Nijmegen Questionnaire. PneumoRator signals were analysed to identify large-volume breaths as potential SAH events. Results: Thirty participants were recruited. Twelve participants met BPAT criteria for BrPD and four met Nijmegen Questionnaire criteria. There was no significant difference between manual and PneumoRator RR measurements (p=0.89). No significant difference was observed between methods for SAH detection (p=0.17). Participants with clinician-observed SAH demonstrated significantly higher PneumoRator signal amplitudes than those without SAH (p=0.035). Conclusion: The PneumoRator produced RR measurements comparable to clinician assessment and demonstrated potential for identifying signs of air hunger. Findings from this pilot study indicate that the PneumoRator device shows promise as a tool for continuous RR monitoring and as an adjunct to BrPD assessment. Larger clinical validation studies are now warranted.

Purpose To evaluate the implementation characteristics of a commercially available chest radiography artificial intelligence (AI) system in a large real-world health check-up cohort using workflow-level, lesion-specific, and exploratory retrospective lung cancer case analyses. Methods This retrospective single-centre study included 298,991 consecutive health check-up chest radiographs from 114,866 individuals obtained between 2019 and 2023 and interpreted under routine double reading by board-certified radiologists. A commercially available AI system was evaluated using two prespecified thresholds: positivity in any of ten findings for the all-score analysis and positivity for nodule or mass for the nodule-focused analysis, both at a manufacturer-recommended score threshold of 15. Because routine radiologist judgement rather than universal CT or pathologic verification served as the reference framework, the primary analyses were interpreted as radiologist-referenced operational concordance analyses. Results Radiologist-referenced sensitivity and specificity were 72.0% and 79.6%, respectively, in the all-score analysis and 87.1% and 91.8%, respectively, in the nodule-focused analysis. Negative predictive values were 99.0% and 100.0%, respectively. Among 48 histopathologically confirmed lung cancer cases, retrospective timeline analyses showed earlier AI positivity than routine radiologist positivity in a subset of cases. These findings should be interpreted as exploratory observations and do not establish prospective clinical benefit. Conclusion In a large health check-up cohort, chest radiography AI demonstrated stable concordance with routine radiologist judgement and high sensitivity for radiologist-reported pulmonary nodules and masses. Exploratory retrospective analyses showed earlier AI positivity in a subset of histopathologically confirmed lung cancer cases, supporting further prospective evaluation of AI-assisted health check-up workflows.

IMPORTANCE: CD4+ T helper (T) 1, T2 and T17 cells have helped identify asthma endotypes in predominantly non-Hispanic White adults. Identifying asthma endotypes in diverse subgroups should help develop personalized medicine in asthma. OBJECTIVE: To characterize asthma endotypes and their association with selected variables and asthma severity/control in adults. DESIGN, SETTING, AND PARTICIPANTS: Cross-sectional and longitudinal analyses of nasal samples from the SOL-Asthma study of Puerto Rican and Dominican adults with (cases, n=313) and without (controls, n=371) asthma in the Bronx (NY) and Chicago (IL), with replication of selected findings in 376 adults of African ancestry in CAAPA. MAIN OUTCOMES AND MEASURES: Our primary outcome was asthma endotypes identified through nasal expression of "signature genes" for 3 T2, 5 T1, and 5 T17 pathways. Multinomial logistic regression was used for the analysis of asthma endotypes (with controls as the reference outcome category) at a baseline visit, as well as for the analysis of severe asthma exacerbations (SAEs) at baseline and during a 1-year follow-up. We attempted to replicate the identified profiles in CAAPA. RESULTS: In SOL-Asthma, cases were more likely to be female, Puerto Rican, and current/former smokers, and to have physician-diagnosed COPD than controls. Five transcriptomic profiles were identified in cases: T2HIGH (n=16 [5.1%]), T1HIGH (n=71 [22.7%]), T17HIGH (n=96 [30.7%]), T1HIGH/T17HIGH (n=53 [16.9%]), and T2LOW/T1LOW/T17LOW (n=77 [24.6%]). In a multivariable analysis, Puerto Ricans were more likely to have a T17HIGH profile than Dominicans (odds ratio [OR]=2.48, 95% confidence interval [CI]=1.08-5.74) and female sex was associated with T1HIGH (OR=3.44, 95% CI=1.33-8.88), T1HIGH/T17HIGH and T2LOW/T1LOW/T17LOW profiles, while COPD was associated with profiles other than T2HIGH or T1HIGH. The T1HIGH profile was associated with [&ge;]1 SAE in the year prior to baseline and during the one-year follow-up (OR=4.31, 95% CI=1.26-14.77). Each profile had unique differentially expressed genes (DEGs), with substantial replication of the profile distribution and DEGs in CAAPA. CONCLUSIONS AND RELEVANCE: Nasal transcriptomics identified profiles corresponding to five asthma endotypes in a cohort of Puerto Rican and Dominican adults. Puerto Rican background, female sex, and physician-diagnosed COPD were associated with non-T2HIGH (T2LOW) asthma endotypes, and T1HIGH asthma was strongly associated with SAEs.

Background Staying physically active is essential for healthy ageing. Exposure to high levels of air pollutants such as particulate matter (PM) is associated with less active, more sedentary lifestyles in older adults. Whether results extend to typical fluctuations in daily PM exposure is unclear. We examined associations of higher-than-usual personal exposure to PM (PM2.5 and PM10) with next-day movement behaviour in older adults, assessed using concurrently worn personal air quality monitors and accelerometers. Methods The present study used 304 days of data from 67 adults aged 50-85 years living in the UK. For five days, participants wore accelerometers 24-hours per day and personal air quality monitors during waking hours. Average daily time spent in movement behaviours (moderate-to-vigorous physical activity [MVPA], light physical activity [LPA], sedentary behaviour [SB]) and step count was extracted from accelerometers, and average daily exposure to PM2.5 from personal air quality monitors. PM10 was examined in secondary exploratory analyses. We used linear mixed models to examine within-person associations of deviation from usual PM exposure with next-day movement outcomes, with estimates presented for 'usual' (individual mean) and 'higher-than-usual' (+1 interquartile range, equivalent to 2.6 g/m3 beyond individual mean PM2.5 exposure and 2.8 g/m3 beyond individual mean PM10 exposure) exposure. Analyses were repeated using area-based PM estimates. Results Compared with usual exposure, higher-than-usual PM2.5 was associated with 8 minutes less LPA (95% CI=-14 to -2) and 483 fewer steps (-855 to -82) on the following day. Exposure to higher than usual PM10 was associated with 8 minutes less LPA (-13 to -3), 8 minutes more SB (0 to 15), and 412 fewer steps (-739 to -85) on the following day. There was no association with MVPA, and no associations when area-level PM estimates were used as opposed to estimates from personal air quality monitors. Conclusions Typical daily variability in PM exposure in a setting with relatively low overall PM levels was associated with modest next-day differences in movement behaviour in older adults. Higher-than-usual PM exposure was associated with less next-day activity and more sedentary time. Personal monitoring may be important for capturing short-term exposure-behaviour associations. Trial registration N/A

Urban air pollution remains a significant public health concern, contributing to premature deaths and adverse health outcomes. However, there is little causal research evaluating the effectiveness of policies designed to improve air quality. This study assesses the impact of all three stages of London's Ultra Low Emission Zone (ULEZ) on air pollution, via PM2.5 levels, and respiratory health, via prescription records for bronchodilator and respiratory corticosteroid medications. Analyses are at general practice level, using a generalised synthetic control method to estimate causal impacts. Stage 1 was associated with a statistically significant but negligible 0.77% reduction in PM2.5 levels, with no corresponding change in prescribing. Stage 2 produced a paradoxical 2.69% increase in PM2.5, alongside a 4.44% decrease in inhaled corticosteroid quantity but a 12.51% increase in average daily quantity (ADQ) usage, suggesting a worsening of disease severity among existing patients. Stage 3 yielded a 2.69% PM2.5 reduction and a modest 2.18% decrease in bronchodilator ADQ usage. Spillover effects beyond the ULEZ boundary were statistically significant, but negligible. We find overall that the ULEZ had minimal effects on both air quality and respiratory prescribing across all three stages. These findings provide new insights into the effectiveness of ULEZ policies in reducing air pollution and its associated health impacts, suggesting the zone's effects are considerably smaller than previously reported, and that integration with broader policy measures may be necessary to achieve meaningful public health gains.

Background: Tuberculosis (TB) preventive treatment is a key component of TB control in low-incidence settings, but uptake remains low. Objective: To explore factors influencing patient decisions to accept or decline preventive treatment for TB infection. Design: Qualitative study using semi-structured interviews, analysed with the Theoretical Domains Framework (TDF). Setting: Routine clinical TB prevention services at two hospitals in London, UK. Participants: Adults (18+) diagnosed with TB infection and offered preventive treatment. Methods: Semi-structured interviews were audio-recorded and transcribed verbatim. The TDF was applied to analyse transcripts using a combined inductive thematic analysis and deductive framework approach. Themes were also mapped to the Capability, Opportunity and Motivation model of Behaviour (COM-B) domains. Results: Twenty-five participants (median age 34 years; 64% male) were included; 56% accepted treatment, 28% declined, and 16% were undecided. Influences on decision-making mapped to 12 of 14 TDF domains. Facilitators of treatment acceptance included perceived risk of TB (beliefs about consequences), desire to protect others' health (social influences and goals), confidence in treatment adherence (beliefs about capabilities), and routine integration strategies (behavioural regulation). Barriers to treatment acceptance included low perceived individual risk and doubts about necessity or effectiveness (beliefs about consequences), concerns about side effects and treatment burden (environmental context and resources) and anticipated stigma (social influences). Knowledge had a mixed influence, primarily shaping perceived necessity, but did not determine decisions alone. Social, environmental and emotional factors further influenced decisions, with participants balancing anticipated benefits against perceived burden and uncertainty across multiple interacting domains. Conclusions: Decisions to accept preventive TB treatment are driven by interacting capability, opportunity and motivation factors rather than knowledge alone. Interventions to improve shared decision making should address perceived risk, treatment burden, self-efficacy and social influences.

Introduction: Childrens exposure to second hand tobacco smoke is a preventable global public health issue, yet there is no consensus on how best to support families to create a smoke free home. This pilot randomised controlled trial tested the feasibility of use of free nicotine replacement therapy combined with telephone delivered support to reduce childrens exposure to second hand smoke in the home, and inform a future full scale trial. Methods: Parents and carers aged 18 and over, who smoke in the home and care for one or more children aged 0 to 16 years were recruited through existing initiatives and social media. Participants were randomised to either the intervention or control arm. Group A received free posted to home nicotine replacement therapy, alongside fortnightly telephone calls to support smoking abstinence in the home. Group B were signposted to the Scottish Government Take it Right Outside website which provides interactive advice on creating a smoke free home. To measure second-hand smoke levels, participants installed an air quality monitor in their living room for 7 days to measure fine particulate matter at baseline and 12 week follow-up. Results: Approximately one-quarter (27 of 100) of the intended sample size was recruited. Median fine particulate matter concentrations reduced in both the intervention (by 36mg per cubic metre) and control (by 16mg per cubic metre) groups. Retention rates and adherence rates to nicotine replacement therapy were 70 percent and above, with no risks and or safety concerns reported, suggesting this approach is feasible and acceptable to participants. The estimated cost of delivering this 12 week intervention was two hundred and forty four pounds per individual. Conclusions: Although recruitment rates were insufficient to recommend progression to a larger trial to test effectiveness of this approach in Scotland, this study could inform trial development in other countries where smoking in the home is commonplace. Insights regarding the alignment of smoke free home interventions with broader smoking cessation initiatives could inform future policy and public health approaches.

Importance: Acute mountain sickness (AMS) is a common high-altitude illness partly preventable by acetazolamide, but sex-specific efficacy and tolerability have not been prospectively evaluated. Objective: To test the a priori hypothesis that preventive acetazolamide achieves a 20% greater relative risk reduction (RRR) of AMS in female vs male lowlanders ascending to 3600 m. Design: Randomized, double-blind, placebo-controlled, parallel-group trial conducted from March 2024 to August 2025; participants, outcome assessors, and statistician were blinded until analysis was complete. Setting: Baseline at 760 m in Bishkek and altitude exposure at the Kumtor High Altitude Facility (3600 m), Kyrgyz Republic. Participants: Healthy female and male low-altitude residents (age 18-44 years, BMI 18-30 kg/m2, residence <1000 m); females were premenopausal, eumenorrheic, and not using hormonal contraception. Exclusion criteria included pre-existing disease, regular medication, pregnancy, anaemia, and altitude sojourn >2500 m within 4 weeks. Intervention: Acetazolamide 125 mg or matching placebo twice daily, from 24 hours before ascent and throughout the 2-day, 2-night stay at 3600 m. Main Outcomes and Measures: Primary outcome was the between-sex difference in RRR of AMS, defined as a 2018 revised Lake Louise Score of 3 or higher including headache. Secondary outcomes included absolute risk reduction (ARR) and drug tolerability. Results: Of 303 randomized participants (180 females, 123 males; mean [SD] age, 23 [4] years), AMS incidence under placebo (n=155) was 34% (females 42% vs males 23%; P=.02) and under acetazolamide (n=148) was 24% (females 30% vs males 14%; P=.02). Overall RRR was 31% (95% CI, 0% to 52%) and ARR was 10% (95% CI, 0% to 22%). Sex-stratified RRR was 27% (95% CI, -9% to 52%) in females and 42% (95% CI, -28% to 74%) in males; between-sex RRR difference, -15% (95% CI, -65% to 57%). Females had a 4.8-fold higher risk of moderate-to-severe drug-related side effects than males. Conclusions and Relevance: Preventive acetazolamide reduced overall AMS incidence at 3600 m, but the pre-specified 20% greater RRR in females (trial powered at 90%) was not observed. The nearly 5-fold higher risk of moderate-to-severe side effects in females warrants further investigation of sex-specific dosing. Trial Registration: ClinicalTrials.gov Identifier: NCT06499727