CHEST

Obstructive sleep apnea (OSA) is associated with a wide range of comorbidities, but the extent to which these follow predictable, age-dependent patterns is not well understood. Identifying such patterns could provide insight into OSA heterogeneity and its links to physiological measures of OSA. We trained age-dependent topic models (ATM) on longitudinal electronic health records from 36,426 patients with OSA in the Mass General Brigham Biobank. ATM organizes incident diagnoses into distinct comorbidity "topics," whose age-specific disease loadings represent predictive patterns linking related diagnoses across the life course. We applied the trained model to compute individual-level topic scores in independent data: a cohort of 11,689 OSA cases and 22,695 matched controls, and a cohort of 6,220 patients with polysomnography (PSG)-derived physiological measures. We identified 19 distinct age-dependent comorbidity profiles, all significantly associated with OSA case status (FDR-adjusted p<0.05). Topics reflected recognizable clusters including metabolic, neuropsychiatric, and immune-mediated conditions, and several were distinguished by age-of-onset of key comorbidities, such as early- vs late-onset asthma. Seventeen of the 19 topics were significantly associated with at least one of 13 PSG-derived physiological measures, including associations between cardiometabolic topics and the apnea-hypopnea index, sleep apnea specific hypoxic burden, and respiratory event-specific heart rate burden. These findings indicate that age-dependent comorbidity patterns distinguish meaningful OSA subtypes with differing prognoses and endophenotype associations. ATM offers insight into complex OSA comorbidity and suggests that age-informed, topic-based stratification may improve individualized risk assessment, interpretation of PSG findings, and targeting of clinical interventions.

Background: Chronic obstructive pulmonary disease (COPD) is a leading cause of global morbidity and mortality, and its heterogeneity demands better biomarkers of severity and progression risk. Extracellular vesicles (EVs) are promising blood-based biomarkers, but have not been examined for COPD severity and outcomes in a large multicentre cohort. Methods: We analysed 600 COSYCONET participants (up to 54 months of follow-up). EV surface markers were profiled with the MACSPlex EV Kit IO. Cross-sectional associations with severity (GOLD, FEV1) were primary (ordinal and linear regression); longitudinal trajectories and all-cause mortality were prespecified exploratory endpoints. Results: Six EV markers showed robust associations with cross-sectional severity: CD29, CD49e and CD31 increased with severity (a cell-adhesion/matrix-remodelling signal), whereas CD81 and CD8 decreased; HLA-ABC (increasing) was less specific. No marker was linked to FEV1 decline. After FDR correction, lower levels of three markers with higher 54-month mortality (all HR<1): CD25 (HR 0.77, 95% CI 0.65-0.90, q=0.018), CD56 (HR 0.75, 95% CI 0.63-0.89, q=0.018) and CD142 (HR 0.74, 95% CI 0.60-0.90, q=0.024). CD25 and CD142 also improved reclassification, CD56 did not; a CD25 + CD69 combination showed the largest incremental signal ({Delta}C 0.017, 95% CI 0.002-0.032, p=0.027). Conclusion: Circulating EV surface markers are associated with cross-sectional COPD severity. Exploratory analyses nominate CD25, CD142 and CD25 + CD69 as candidate prognostic markers requiring external validation, suggesting minimally invasive EV profiling could complement clinical assessment in COPD.

ABSTRACT Background: Corticosteroids reduce mortality in severe COVID-19 requiring oxygen or invasive mechanical ventilation, yet emerging data suggest that SARS-CoV-2-associated acute lung injury is biologically heterogeneous and that treatment response may vary across molecularly defined disease states. Lung-derived molecular endotypes of severe COVID-19-associated acute lung injury have been described, but direct molecular profiling is not routinely available at the bedside. We evaluated whether a clinical predictor of previously defined lung molecular endotype identifies heterogeneity in corticosteroid treatment effect among mechanically ventilated patients with COVID-19. Methods: We utilized a single-center cohort of 5,000 patients with COVID-19 treated at the University of North Carolina Hospital between January 1, 2020, and December 31, 2022, to emulate a target trial assessing the effect of corticosteroid receipt on mortality, length of stay, and incident organ support. Confounding was addressed through inverse probability of treatment weighting (IPTW). Outcomes for severely ill patients requiring mechanical ventilation were compared to the RECOVERY trial results, with subsequent moderation analysis and stratified analysis by clinically predicted lung molecular endotype and vaccination status. The primary outcome was 28-day mortality. Secondary Outcomes were time to discharge alive and progression to additional organ support. Results: This emulated target trial showed a directionally favorable but non-statistically significant association between corticosteroid treatment and reduced 28-day mortality in patients requiring mechanical ventilation for SARS-CoV-2 infection. A clinical predictor of lung molecular endotype moderated the effect of corticosteroids on 28-day mortality (p-value for interaction 0.038) and identified distinct predicted endotype-specific treatment effect. Corticosteroid treatment was associated with lower 28-day mortality in the predicted Hyper-Inflammatory endotype (OR 0.62, 95% CI 0.39, 0.99) but not in the predicted Metabolic Dysregulation endotype (OR 1.15, 95% CI 0.82, 1.61). We did not detect significant effect modification by vaccination status (p-value for interaction 0.65), although inference was limited by the small, vaccinated subgroup (28-mortality OR 0.78, 95% CI 0.37, 1.65 in vaccinated vs 0.94, 95% CI 0.70, 1.26 in unvaccinated). Conclusions: In this target trial emulation of mechanically ventilated patients with severe COVID-19, corticosteroid treatment showed a directionally favorable but non-statistically significant association with reduced 28-day mortality in the overall cohort. However, a clinical predictor of lung molecular endotype identified significant heterogeneity in treatment effect, with benefit concentrated in the predicted Hyper-Inflammatory endotype and no apparent benefit in the predicted Metabolic Dysregulation endotype. These findings support prospective validation of clinically deployable endotype-guided corticosteroid treatment strategies in acute lung injury and ARDS.

Machine-learning survival models are increasingly proposed for intensive-care mortality prediction and are almost always selected and reported using the concordance index, a ranking metric averaged over follow-up. Yet most bedside decisions hinge on a probability at a specific time, such as 60- or 180-day mortality. We asked whether ranking-optimized models remain competitive at fixed clinical horizons against two reference points clinicians actually rely on: unaided attending-physician judgment and the original 1995 SUPPORT logistic model. Reanalyzing the SUPPORT2 cohort (9,105 critically ill adults from five United States centers, 1989-1994) under a stratified 70/15/15 split, we compared a gradient-boosted survival model, the physician's recorded prognosis, and the 1995 model at 60 and 180 days, alongside several alternative learners. The survival model achieved competitive ranking concordance (0.705) yet underperformed both comparators at fixed horizons: at 60 days its area under the ROC curve was 0.750, against 0.808 for physicians on the matched sample and 0.827 for the 1995 model, a gap that held across eight independent data splits and remained statistically reliable after multiplicity correction. The shortfall was not miscalibration, since post-hoc recalibration left discrimination unchanged, nor limited capacity, since neural networks, a deep ranking model, and two timepoint-aware discrete-time models also failed to close it; replacing the ranking objective with timepoint-matched binary training recovered roughly half the gap, pointing to an objective-horizon mismatch. Discrimination was equitable across sex, race, and age, but leave-one-disease-out validation exposed severe failure for disease groups absent from training, and the physician advantage was conditional on a physician electing to provide an estimate. We recommend reporting timepoint-specific discrimination alongside concordance, timepoint-matched training when fixed-horizon predictions drive care, leave-one-subgroup validation, and distribution-free prediction intervals to support selective deployment.

Rationale: Air trapping in functional areas of the lung is common in chronic obstructive pulmonary disease (COPD). We developed a novel music-based intervention, Engagement of Music for Pulmonary Obstruction With Expiratory Restoration (EMPOWER) aimed at reducing air trapping and functional small airways disease (fSAD) in patients with COPD. Objectives: We conducted a pilot study to assess if air trapping and fSAD in COPD patients are reduced by our targeted EMPOWER music-based singing intervention. Methods: Participants completed four weeks of singing and vocalizing with a board-certified music therapist. Pre- and post-intervention assessments of standard pulmonary function tests (PFTs), and quantitative computed tomography (qCT) lung imaging documented changes in air trapping. Pre- and post-intervention change in psychological and patient-reported outcomes of hope, emotional wellbeing, agency and COPD symptom burden were also obtained. Main Results: All five adult participants with COPD who enrolled completed the study and reported strong interest in continuing with a similar program. Additionally, we observed trends toward improvement in qCT-measured fSAD, six-minute walk distance, and patient-reported symptoms on the COPD Assessment Test. Conclusion: Results of this preliminary study showed improvements in both patient-reported and imaging-indicated respiratory outcomes, suggesting that targeted singing components in music-based interventions such as the EMPOWER intervention may support physiological lung function changes in COPD patients.

Background: Computer vision-enabled airway workflows can turn airway video into timestamped model-observation fields, but later blinded review and training studies require source-video linkage, run identifiers, quality-control status, and app/model provenance. Objective: To audit whether a public post-reconciliation 30-run manikin evidence package from a computer vision-enabled video laryngoscopy workflow preserved prespecified, video-linked procedural telemetry in structured JSON, while keeping detection accuracy, report quality, and reviewer agreement outside the current claim. Methods: Thirty manikin runs were captured on a HEALTHIBLE Intubation Simulator using an IntuBlade device connected to an iPhone 15 Pro Max. Six predefined conditions were tested with five runs each in planned round-robin order by a board-certified emergency physician operator. The author-affiliated team analyzed corrected Study Metrics JSON exports, the video manifest, app/model metadata, QC fields, and the frozen package checker after reconciliation against the assigned run guide. Blinded video review, independent analysis, and report-quality adjudication were not performed. Results: After reconciliation, all 30 rows contained parseable Study Metrics JSON, a companion videoFilename, run-named Drive video status, QC pass status, and corrected identifiers matching assigned row labels (30/30 for each completeness field; descriptive exact binomial 95% CI, 88.4% to 100.0%). App/model metadata were complete: appVersion 3.3.0 (75), source revision b94cd63, Navigation model, model version 31, and detection threshold 0.1. The exported JSON target-state flag was true in 25 of 25 target-condition rows (95% CI, 86.3% to 100.0%) and false in 5 of 5 no-target controls (95% CI, 47.8% to 100.0%), with zero glottic-detected frames and zero acceptable-view time in no-target controls. Among target-condition rows, median time to first model-detected glottic target was 2 seconds (IQR 1 to 3), median acceptable-view duration was 2.2 seconds (IQR 1.0 to 3.8), and median glottic visibility was 35.8% (IQR 25.8 to 45.6). Interpretation: The corrected package supports a bounded formative claim: simulated airway video can be represented as specified, video-linked computer-vision procedural telemetry after documented reconciliation. It supports package completeness, traceability, and assigned-condition consistency only; it does not establish native uncorrected export reliability, computer-vision detection accuracy, report quality, reviewer agreement, training effectiveness, autonomous guidance, tube-placement confirmation, clinical efficacy, or patient outcomes.

ObjectiveTo test whether machine learning (ML) models trained on tidal breathing flow time series can discriminate between individuals with and without respiratory disease and predict lung function indices obtained from conventional pulmonary function testing. BackgroundAccurate assessment of respiratory function in infants and young children is challenging because conventional pulmonary function testing requires sophisticated equipment and/or active patient cooperation. Tidal breathing measurements, in contrast, can be obtained non-invasively with little or no patient cooperation and at low cost, yet their clinical utility has been limited. We hypothesized that sufficiently long tidal breathing flow time series contain clinically relevant information that can be extracted using a recurrent neural network known as a long short-term memory (LSTM) network. ApproachWe evaluated LSTM models in two scenarios within the Basel-Bern Infant Lung Development cohort. First, we assessed the ability of a model trained on flow and derived volume time series to detect bronchopulmonary dysplasia (BPD) in 329 infants. Second, we examined whether a model trained on tidal breathing flow alone could predict forced expiratory volume in one second (FEV1) in 135 school-age children. Signals were filtered and normalized prior to model training, and performance was evaluated on held-out test datasets. Main resultsFor BPD detection, the model achieved 97.0% accuracy, 100% specificity, 91.7% sensitivity, 100% precision, and an F1-score of 95.7%. For FEV1 prediction, Bland-Altman analysis showed a mean bias of -0.009 L (95% CI -0.091 to 0.074), with limits of agreement of -0.416 L and 0.399 L. The mean relative prediction error was 13.7%. SignificanceThese findings demonstrate that temporal patterns in tidal breathing flow signals contain diagnostically and functionally relevant information. ML applied to tidal breathing measurements may provide a low-burden, minimal-cooperation approach for early respiratory disease detection and functional assessment across early life stages.

Rationale: Pulmonary artery (PA) enlargement is a non-invasive imaging biomarker associated with pulmonary hypertension and mortality in COPD; however, its genetic determinants remain incompletely understood. Objectives: To characterize the genetic architecture of PA size across COPD-enriched and population-based cohorts. Methods: We performed genome-wide association analyses of PA diameter using whole-genome sequencing in COPDGene (n=9,418) and ECLIPSE (n=1,859), and imputed-genotype data from the UK Biobank (n=37,073). We replicated lead variants in the Framingham Heart Study (FHS; n=3,289), incorporated all four studies into a joint meta-analysis, and identified independent signals through conditional analyses. Candidate effector genes were prioritized using coding variant annotation, colocalization, and integrative regulatory evidence. Measurements and Main Results: We identified 44 independent genome-wide significant PA diameter signals within 39 loci, including 8 variants replicated in FHS, novel associations near FRMD4B, SLC20A2, BORCS7-ASMT, and KCNRG, and 5 signals in conditional analysis including multiple signals at ANO1. Genetic effects were concordant across imaging modalities and cohorts of differing COPD burden. Effector-gene prioritization nominated ABCC8, PDGFD, HMCN1, CCNE1, and TBX20, implicating pathways in vascular remodeling, developmental regulation, smooth muscle and endothelial function, ion-channel signaling, and extracellular matrix organization. Colocalization with pulse pressure GWAS demonstrated substantial shared causal variation between pulmonary and systemic vascular biology. Conclusions: In this largest genetic study of pulmonary vascular imaging to date, PA diameter exhibits a polygenic architecture consistent across imaging modalities and cohorts of differing COPD burden. The prioritized effector genes bridge rare-variant pulmonary hypertension biology with common-variant systemic vascular biology.

In idiopathic pulmonary fibrosis (IPF), the lung is remodeled through coordinated epithelial, stromal, and immune-associated programs, but individual transcriptomic cohorts are often too small to separate shared disease signals from demographic and study-level variation. To increase statistical power while preserving study-aware interpretation, we integrated raw bulk lung RNA sequencing (RNA-seq) data from five well-annotated studies and analyzed 223 samples in a common framework that modeled sex, age, library layout and repeated sampling. IPF showed a broad and reproducible expression shift, with 2,443 genes meeting the differential-expression threshold of false discovery rate (FDR) <0.05 and absolute log_2 fold change at least 1. The dominant program combined extracellular matrix remodeling, stromal and epithelial activation, complement and B-cell-related pathways, cilium-associated processes, and relative depletion of oxidative phosphorylation and proteasome pathways. Sex-stratified analyses recovered a shared fibrotic core with smaller sex-skewed components, whereas age-related disease effects were weaker and centered on immune activation. A leave-one-study-out elastic-net analysis using fixed disease-gene panels classified IPF across held-out studies, supporting cross-study portability of the core signature. This integrated reanalysis strengthens evidence for a stable matrix-immune IPF program and reinforces the view that core disease-associated transcriptional programs are reproducible across heterogeneous cohorts.

BackgroundEsophageal pressure (Pes) measurement has been used successfully over the past half-century to delineate the respiratory systems physiology and mechanics. However, there is no information about the importance of Pes monitoring in different scenarios. We aimed to assess the importance and frequency of Pes monitoring in different scenarios according to health professionals and its importance in decision-making. MethodCross-sectional study with an international survey. We included healthcare professionals dedicated to patients receiving invasive and non-invasive ventilation without limits of age, gender, experience and seniority in the position or country of residence. We used non-probabilistic snowball sampling. ResultsWe included 152 participants, with 54.61% (83) males. The response rate to the survey questions ranged from 100% to 71.71%. Of the included participants, 91/139 (65.47%) were respiratory therapists, and 31/139 (22.30%) were Physicians. Most participants worked in mixed ICU. 109/121 (90.08%) participants considered Pes monitoring very important or extremely important for teaching or research. Only 32/112 (28.57%) reported using Pes frequently for these proposals. 49/109 (40.50%) participants considered Pes monitoring very important or extremely important during non-invasive ventilatory support. Only 17/112 (15.18%) reported using Pes frequently for these proposals. Regarding MV individualisation in ARDS during total ventilatory support, 94/121 (77.69%) participants considered Pes monitoring very important or extremely important. Only 33/112 (29.46%) reported using Pes frequently in this scenario. 90/121 (74.38%) also considered it very important or extremely important for MV individualisation in obese patients without ARDS, and 108/121 (89.26%) considered it very important or extremely important for MV individualisation in obese patients with ARDS during total ventilatory support. Only 25/112 (22.32%) and 39/112 (34.82%) reported using Pes frequently in these scenarios, respectively. ConclusionsPes monitoring was considered very important or extremely important for most assessed scenarios. Conversely, most participants rarely or never used it, although it changed therapeutic decisions often when implemented.

BackgroundMultiple-choice questions (MCQs) are widely used in medical education, but are criticized for cueing and guessing. Very short answer questions (VSAQs), which require students to generate responses independently, may better assess knowledge. While VSAQs demonstrate higher item discrimination within individual exams, their effectiveness in distinguishing academic performance across multiple assessments remains unclear - representing a key gap in the validation of VSAQs under Messicks framework, specifically the category of "relations to other variables". This study examines whether VSAQs or MCQs more effectively distinguish students of varying performance levels across multiple summative examinations. MethodsWe analyzed retrospective data from six mixed-format examinations with VSAQs and MCQs of three cohorts of first- and second-year medical students. Academic performance was measured using grade point average (GPA) across assessments. Linear regression assessed the relationship of each question format with GPA, while ROC curves and C-statistics evaluated their ability to identify poor and excellent performing students (lowest and highest quintile of GPA). ResultsVSAQs showed higher item discrimination (Rir-values) than MCQs in all exams. VSAQs also had a stronger positive association with GPA compared to MCQs, and higher C-statistics, indicating superior discriminative ability. ConclusionVSAQs outperform MCQs in distinguishing academic performance levels across multiple assessments. Their integration into examinations enhances discriminative ability and may facilitate earlier identification of poor and excellent performing students, enabling targeted interventions and support of students.

Rationale: Conventional measures of obstructive sleep apnea severity, particularly the apnea-hypopnea index, do not adequately capture event-level neurophysiologic responses to respiratory events. Whether post-apnea/hypopnea arousal dynamics provide prognostic information beyond established metrics remains unknown. Objectives: To determine whether post-apnea/hypopnea arousal dynamics are associated with all-cause and cardiovascular mortality. Methods: We conducted a retrospective analysis of in-home polysomnography data from 8,053 adults across four community-based cohorts. Peak time (PT; latency to maximal arousal probability), peak height (PH; maximal arousal probability), and area under the curve (AUC; cumulative arousal probability) were derived from peri-stimulus time histograms aligned to event termination. Associations with mortality were examined using multivariable Cox models and random-effects meta-analysis. Measurements and Main Results: PT, but not PH or AUC, was associated with mortality. In pooled analyses, each 1-second delay in PT was associated with higher all-cause mortality in males (hazard ratio [HR], 1.04; 95% confidence interval [CI], 1.02-1.06) and females (HR, 1.03; 95% CI, 1.00-1.06). For cardiovascular mortality, each 1-second delay in PT was associated with higher risk in males (HR, 1.05; 95% CI, 1.02-1.08) but not females (HR, 1.04; 95% CI, 0.99-1.10). Associations were driven primarily by non-rapid eye movement sleep and remained materially unchanged after additional adjustment for apnea-hypopnea index, arousal index, and hypoxic burden. Conclusions: Delayed arousal timing after apnea/hypopnea termination was associated with increased mortality risk independent of conventional measures of obstructive sleep apnea severity. Event-level arousal timing may provide prognostic information beyond count-based and hypoxemia-based metrics.

Tobacco smoke shapes mutations, selection and clonal expansion in lung epithelial cells. Smoking cessation leads to divergent epidemiology in the two most common lung cancers: squamous cell carcinoma risk declines sharply, while adenocarcinoma risk is preserved. To investigate this discrepancy, we analysed 806 genomes of alveolar type II (AT2) cells and found persistently elevated mutation burdens after cessation. In contrast, in the proximal airway, rare basal stem cells with near- normal mutation burden expand after cessation, protecting against squamous cell carcinoma. Targeted single-molecule DNA sequencing of AT2 cells revealed positive selection for TP53 and cell cycle and MAPK genes, supporting continued cancer risk. A multistage carcinogenesis model emphasised the importance of a small population of hypermutated cells in the alveoli and reproduced the divergent epidemiological trajectories following cessation due to distinct regenerative dynamics. Our findings suggest that differences in mutational burden and clonal regeneration explain post-cessation trends in lung cancer subtypes.

Despite its high prevalence and the discovery of hundreds of genetic associations, the genetic determinants and heterogeneous manifestations of asthma remain incompletely understood. Incorporating polygenic risk scores (PRS) into asthma research offers a powerful approach to quantify inherited susceptibility, refine risk profiles, and advance mechanistic understanding of disease development. For this study, we leveraged whole-genome sequencing (WGS) data from two family-based cohorts of childhood asthma - the Genetics of Asthma in Costa Rica Study (GACRS) and the Childhood Asthma Management Program (CAMP) - to examine the transmission profiles of externally derived asthma PRS and their associations with clinical phenotypes in children with asthma. To further elucidate molecular mechanisms, we integrated large-scale external genome-wide association study (GWAS) summary statistics and genetic prediction models of protein abundance in a two-step proteome-wide association study (PWAS) of asthma. Our findings provide robust evidence supporting the validity of externally derived asthma PRS (asthma PRS association p-value p={10}^{-24} [GACRS and CAMP trios combined] for the Global Biobank Meta-analysis Initiative [GBMI]) and reveal consistent associations with spirometry measures and atopy markers across both studies, as 13 of 21 traits (62%) were significantly associated with the GBMI-PRS in the meta-analysis after multiple-testing correction. Moreover, the results of the integrative proteomic analysis implicate IL-1 signaling in the etiology of asthma, reinforcing the candidacy of IL1R1 antagonists for drug repurposing.

Background: Biologically distinct asthma subgroups may obscure genetic effects when analyzed as a single phenotype. We examined whether asthma susceptibility signals are shared, heterogeneous, or stratum-specific across ancestry, obesity status, and sex. Methods: We performed ancestry-specific GWAS meta-analyses in African ancestry participants (9,965 asthma cases; 37,391 controls) and European ancestry participants (6,074 cases; 116,255 controls), followed by obesity- and sex-stratified analyses. Analyses used imputed dosages and fixed-effect meta-analysis within ancestry. Results: Stratification detected asthma association signals that were less apparent in the combined phenotype. Shared cross-ancestry loci implicated epithelial antiviral susceptibility and immune regulation, represented by signals near CDHR3 and FOXO1. An ancestry-heterogeneous signal at the 17q21 locus, harboring ORMDL3/GSDMB, supported population-dependent effects at an epithelial inflammatory locus. Obesity stratification mapped the genome-wide significant burden to asthma without obesity. Sex stratification detected genome-wide significant signals in AFR females with asthma and obesity and in both sex strata with asthma without obesity, with the strongest signal burden in EU females without obesity. Conclusions: Asthma genetic architecture differed by ancestry, obesity status, and sex. Stratified analyses identified group-specific susceptibility related to epithelial and immune regulation, airway inflammation, remodeling, and neural signaling, supporting precision approaches to asthma.

Background: The chromosome 1q31 Th2 pathway-associated interval has been linked to asthma, but its phenotype specificity and cross-ancestry architecture remain unclear. Methods: We analyzed African (AFR) and European (EU) ancestry datasets, including 9,965 asthma cases and 37,391 controls of AFR, and 6,074 cases and 116,255 controls of EU ancestry. Imputed dosage-based association analyses were performed for asthma, steroid-dependent asthma (SDA), and non-steroid-dependent asthma, followed by QC-filtered SDA remapping, leave-one-batch-out analysis, cross-ancestry comparison, and functional enrichment. Results: Strong regional association was observed only for SDA. After quality-control (QC) filtering, the SDA signal remained significant in both ancestries, with 2,280 genome-wide significant variants in AFR and 859 in EU. Cross-ancestry comparison identified 3,129 significant variants: 10 shared, 2,270 AFR-specific, and 849 EU-specific. Shared variants showed concordant effects, whereas 237 variants showed nominal heterogeneity. AFR-specific signals included PTPRC variants with larger effects in AFR. Functional enrichment suggested different biological emphases within the same interval: immune and contractile airway-wall biology in AFR, and additional neuroaxonal components in EU. Conclusions: The 1q31 interval is strongly associated with SDA in both AFR and EU populations, and its fine-scale architecture differs by ancestry. These findings highlight population-specific effects within a shared SDA susceptibility interval, with potential implications for population-informed precision medicine in steroid responsiveness and asthma management.

BackgroundOnline professional learning offers a scalable alternative to traditional face-to-face learning, but there are doubts regarding how well it works and when it works best. This review assessed the effectiveness of online professional learning interventions on healthcare professionals knowledge and skill acquisition. MethodsWe conducted a systematic review and meta-analysis of randomised controlled trials that compared online professional learning against static controls or face-to-face controls. We searched MEDLINE Complete, Scopus, Embase, CENTRAL, and PsycINFO from inception to January 31, 2025. Eligible studies included practising healthcare professionals in any clinical setting that measured knowledge or skill acquisition related to patient care. Data was extracted in duplicate, with disagreements resolved through discussion or by a third reviewer. We used multilevel meta-analyses to estimate the overall effect size and conducted moderation analyses for pre-specified factors. The study protocol was pre-registered on the Open Science Framework (OSF; https://osf.io/46zav). FindingsOf 55,376 records; 171 studies (391 effects, 25,412 participants) met the inclusion criteria. Online learning significantly improved knowledge and skill acquisition compared to static controls (g = 0.93, 95% CI [0.78,1.07], p < 0.001; I{superscript 2} = 89.8%), with larger effects in lower-middle income countries (g = 1.30, 95% CI [0.88, 1.72]) than in high income (g = 0.75, 95% CI [0.63, 0.86]). Online learning also significantly improves outcomes compared to face-to-face instruction (g = 0.45, 95% CI [0.31,0.59], p < 0.001; I{superscript 2} = 85.92%), with larger effects for knowledge outcomes (g = 0.46, 95% CI [0.33, 0.59]) than skills outcomes (g = 0.20, 95% CI [0.04, 0.36]). Effects did not differ significantly by profession, clinician experience, clinical setting, intervention characteristics or the learning design features (all p > 0.05). No studies had low overall risk of bias, and some evidence of publication bias was found. InterpretationFrom this body of evidence, we identified that online learning appears to improve healthcare professionals knowledge and skill acquisition, exceeding traditional teaching methods. Healthcare organisations can be confident implementing or expanding online professional learning to improve knowledge and skill acquisition. FundingNo funding

BackgroundRecent guidelines differ in how fractional exhaled nitric oxide (FeNO) is used to diagnose school-age asthma, either as one of several tests with a cut-off at 25 ppb or as a single rule-in test at 35 ppb. Evidence on its diagnostic performance and clinical utility in subgroups remain limited. MethodsWe analysed data from 1,979 school-age children in the Swiss Paediatric Airway Cohort referred for suspected asthma. We investigated FeNO performance with diagnosis by paediatric pulmonologists as reference standard using receiver operating characteristics curves, selected cut-offs and simulated predictive values across different prevalence. Subgroup analyses considered allergic sensitisation with allergic rhinitis and current inhaled corticosteroid (ICS) use. ResultsIn the overall cohort (asthma diagnosis 70%), FeNO showed poor discrimination for asthma (AUC 0.66; 95% CI 0.64-0.68) with an optimal cut-off at 22 ppb. At 25 and 35 ppb, sensitivity was low (43%, 95% CI 40-46; 31%, 95% CI 29-34) and specificity moderate to high (84%, 95% CI 77-84; 90%, 95% CI 87-92). Positive predictive value at 35 ppb was 88% and was 57% when simulated at a prevalence of 30%. FeNO had no diagnostic value in non-sensitised children and lower performance in sensitised children with allergic rhinitis than in those without (AUC 0.59 vs 0.68). Current ICS use did not influence performance. ConclusionFeNO has limited diagnostic performance as a stand-alone test for school-age asthma, and underlying asthma prevalence and allergic characteristics should be considered in the interpretation.

Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease in which the earliest cellular events driving fibrosis remain poorly defined. Here, we analyzed lung samples from three independent and unique cohorts of patients with early disease and preserved lung function (Florence, NIH, Forli), applying an integrated multi-modal approach combining single-nucleus RNA sequencing, bulk transcriptomics, immunostaining, and spatial transcriptomics. Single nuclear RNA sequencing of samples obtained by diagnostic bronchoscopic cryobiopsy (Florence, n= 22) revealed that early IPF is characterized by a marked shift in alveolar epithelial composition, with loss of AT1 and AT2 cells and the emergence of aberrant basaloid cells and alveolar epithelial intermediate cells. These populations exhibited transcriptional programs associated with epithelial plasticity and profibrotic signaling and closely resembled those observed in end-stage IPF. Higher proportions of aberrant basaloid and alveolar epithelial intermediate cells were associated with subsequent disease progression, whereas AT2 cell abundance correlated with preserved lung function. Fibrotic CTHRC1+ fibroblasts are largely restricted to advanced disease, while endothelial remodeling and inflammatory fibroblast states are already evident in early IPF. Spatial transcriptomic analyses confirmed early disruption of the alveolar niche, with replacement of normal epithelial-capillary interactions by aberrant epithelial and venous endothelial cells (Forli, n= 24); the findings were replicated through single cell RNA sequencing of samples obtained by video assisted thoracoscopy two decades earlier (NIH n=9). Together, these findings identify that alveolar niche remodeling with loss of its normal components, and emergence of aberrant basaloid cells are features of early IPF, highlighting epithelial dysfunction as a key potential target for therapeutic interventions in early disease.

BackgroundTBX4 variants are a recognised cause of paediatric pulmonary hypertension (PH), often associated with interstitial lung disease (ILD). Evidence for ILD-directed therapy in this group is lacking. MethodsWe conducted a retrospective study of children ([&le;]18 years) with TBX4-associated PH at a national centre (2001-2025). ILD was defined using ChILD-EU criteria. Patients treated with pulsed intravenous methylprednisolone were assessed for response using ChILD-EU categories. Secondary outcomes included respiratory severity score (RSS), functional class (FC), echocardiographic measures, and NT-proBNP. ResultsOf 21 children, 11 (52%) had ILD; 9 received corticosteroids. Median age at treatment was 0.8 years. A clear or best response occurred in 7/9 (78%). RSS improved in 6/9 (p=0.02), with all children on respiratory support showing partial or complete weaning. Functional class improved in all with FC III/IV at baseline (p=0.02). Right ventricular function improved (TAPSE z-score +1.65, p=0.04), and elevated NT-proBNP normalised. Key clinical milestones included ECMO weaning, transplant delisting, and discontinuation of prostacyclin therapy. No significant adverse effects were observed. Untreated children showed no early improvement. ConclusionsCorticosteroids were associated with meaningful improvements in respiratory and PH outcomes in TBX4-associated PH with ILD. Prospective evaluation is warranted.