BMJ Open Respiratory Research

Purpose: Obstructive sleep apnea (OSA) is a treatable chronic condition associated with significant health and societal consequences. Primary care providers (PCPs) often manage OSA with support from sleep specialists but face challenges navigating a complex system of care. By developing a Journey Map, we sought to identify factors influencing primary care OSA management and the associated PCPs' perspectives and emotions. Methods: Twenty-one Calgary-based PCPs were interviewed as part of a study evaluating a primary care management pathway for OSA. We used conventional content analysis, utilizing inductive coding to define journey phases and deductive coding via the Theoretical Domains Framework (TDF) to identify barriers and enablers. These were then mapped onto journey phases for OSA management to create a Journey Map. Results: The Journey Map included five phases of OSA care. PCPs described feeling neutral during the Learning phase and expressed neutral to positive emotions during the Patient Encounter and Diagnosing OSA phases. In contrast, the Initial Treatment and Ongoing Management phases were associated with neutral to negative emotional experiences. Barriers included limited OSA-related training and education, unclear roles among provider groups, and low patient engagement. Enablers included accessible knowledge resources, a shared key role in OSA screening, and availability of sleep testing. Opportunities to enhance primary care OSA management were identified at each step. Conclusion: This study identified several behavioural factors influencing PCP decision-making across the OSA care continuum. The Journey Map illustrates how high diagnostic confidence of PCPs shifts to escalating challenges and negative sentiment during treatment and long-term management of OSA. Keywords: obstructive sleep apnea; primary health care; health service delivery; process assessments; attitude of health personnel

BackgroundSocial deprivation impacts chronic disease and acute admission outcomes. In interstitial lung disease (ILD), prior British Thoracic Society registry data for idiopathic pulmonary fibrosis has shown high deprivation was associated with poorer long-term outcomes. However, its impact on acute admissions in ILD is not known. MethodsWe undertook a multicentre, retrospective study of ILD-related admissions between 1st January 2017 and 31st December 2019 across 11 hospitals in the North West of England, utilising available real-world data. We determined social deprivation geographically by the 2019 English Indices of Deprivation deciles. The primary outcome was 90-day all-cause mortality. Results999 admissions met the inclusion criteria. 327/999 (32.7%) of admissions came from individuals geographically in the most deprived 20%. Across 999 admissions, in unadjusted survival analysis we observed a non-linear relationship between deprivation and 90-day all-cause mortality. In complete case multivariate modelling, deprivation demonstrated borderline significant association with all-cause mortality (HR 1.038, 95% CI 1.00 - 1.077, p = 0.050). However, this effect was lost in pooled analysis using multiple imputation (HR 1.001, 95% CI 0.971 - 1.033, p = 0.928). Male sex and pre-admission long-term oxygen were consistently associated with increased 90-day all-cause mortality across both models. Lower TLCO values were significantly associated with increased 90-day mortality in pooled analysis. ConclusionWe observe a high burden of acute ILD-related hospital admission amongst the most deprived 20%, suggesting geographical deprivation may impact acute healthcare seeking behaviours. Once admitted, the impact of deprivation appears more complex and multifactorial. Further studies which assess geographical and individual-level deprivation are needed to validate our findings. Key Messages What is already known on the topic?The British Thoracic Society idiopathic pulmonary fibrosis registry has previously demonstrated that higher social deprivation is associated with worse long-term outcomes. In other respiratory diseases, social deprivation impacts acute admission patterns and outcomes. What this study addsTo the best of our knowledge, this is the first study examining the relationship between social deprivation and acute ILD-related admission outcomes. This study demonstrates high acute admission burden from the geographically most deprived 20%. Once admitted, the association between geographical social deprivation and mortality outcomes appears complex and multifactorial in our modelling. How this may affect research, practice or policyThis study highlights the acute admission burden from highly deprived communities and the need for additional research to further understand the individual-level and geographical-level deprivation patients with ILD experience. We suggest the need for community outreach to build trust with deprived communities, alongside increasing awareness amongst patients, caregivers and primary care physicians in such communities. Deprivation must remain an important consideration in any new service or intervention to prevent worsening of health inequalities.

IntroductionAlthough temporal variation is the hallmark of asthma, recommended diagnostic approaches largely rely on single clinic-based measurements. Ambulatory monitoring captures diurnal and day-to-day variability and may therefore enhance diagnostic accuracy. We evaluated the clinical feasibility and potential utility of home spirometry and fractional exhaled nitric oxide (FeNO) monitoring in asthma diagnosis. MethodsSymptomatic, untreated adults with GP-suspected asthma underwent diagnostic tests including bronchodilator reversibility, in-clinic FeNO, blood eosinophil counts and bronchial challenge. Participants measured spirometry and FeNO four times daily over one week; during the second week spirometry were measured twice daily. The reference standard was provided (asthma/not-asthma) by an expert panel of at least two asthma specialists based on clinical history and the results of all in-clinic testing; home spirometry (except for peak expiratory flow) and FeNO measurements were blinded to the panel. ResultsOf 67 eligible participants, 51(76%) were recruited, and 38 had asthma confirmed or excluded by the panel. 1058 home spirometry measurements were obtained from 37(73%) participants; 848 home FeNO readings were obtained from 39(76%) participants. Among those completing at least one home measurement, median (IQR) adherence was 66.7(58.6-97.6)% for spirometry and 78.5(51.8-103.6)% for FeNO. Collection of health impact data for economic evaluation was feasible. In participants with a confirmed diagnostic outcome who completed home measurements (FeNO: n=32; spirometry: n=28), the putative home-testing metrics demonstrated high sensitivities at [≥]90% specificity, and outperformed peak expiratory flow diurnal variability. Incorporating home testing into the BTS/NICE/SIGN 2024 diagnostic pathway had the potential to reduce reliance on bronchial challenge testing by 57%. ConclusionsHome spirometry and FeNO testing and the prospective collection of health-economic data in the diagnostic setting were feasible. Home-based testing strategy showed early potential to improve asthma diagnosis and pathway efficiency. These findings support further evaluation through an adequately powered diagnostic accuracy study and health-economic assessment. Key messagesO_LIWhat is already known on this topic: Asthma can be difficult to diagnose, as objective tests may be normal when assessments are performed during periods of minimal or intermittent symptoms. C_LIO_LIWhat this study adds: Our data suggest that home spirometry and FeNO monitoring could be successfully implemented within a diagnostic accuracy trial. Participants were able to perform these tests reliably in the home environment. C_LIO_LIHow this study might affect research, practice or policy: The early findings suggest that home-based physiological monitoring may offer additive diagnostic value beyond standard clinic-based assessments and could reduce reliance on bronchial challenge testing. These results provide a clear rationale for larger diagnostic accuracy trials and for undertaking early health-economic modelling to assess the potential impact on clinical pathways and resource utilisation. C_LI

RationaleObstructive sleep apnea (OSA) is a common, treatable chronic disease with significant health and societal consequences. Many patients face barriers to care due to systemic inequality, poverty, and other contributors to social vulnerability, leading to delayed diagnosis and more severe disease at presentation. Several studies have examined the impacts of social vulnerability on OSA severity using individual-level factors. However, there is comparatively limited work examining how neighbourhood-level indicators may influence OSA severity. This study aimed to determine whether social vulnerability, measured using a neighbourhood-level multidimensional index, is associated with OSA severity at referral to a tertiary sleep centre. MethodsWe conducted a retrospective observational study of adult patients referred to an academic hospital in Calgary, Canada for evaluation of OSA between November 2016 and November 2019. Patient data were linked using residential postal codes to the Canadian Index of Multiple Deprivation (CIMD), a census-based tool designed to reflect dimensions of social vulnerability in Canadian populations. CIMD divides social vulnerability into four dimensions including residential instability, ethnocultural composition, economic dependency, and situational vulnerability. We employed both linear and logistic mixed-effects models to assess the impact of neighbourhood-level social vulnerability on sleep apnea severity, using postal code as the grouping variable. OSA severity was based on home sleep apnea test (HSAT) derived oxygen desaturation index (ODI). Secondary outcomes included severe OSA (ODI [&ge;] 30), sleepiness based on Epworth Sleepiness Scale (ESS), and severe sleepiness (ESS > 15). ResultsThe study included 2,232 patients, 80% of whom had at least mild OSA. ODI was positively associated with situational vulnerability (p < 0.01) and inversely associated with ethnocultural composition (p < 0.01), though both associations lost significance after adjusting for BMI. ESS was independently associated with situational vulnerability (p < 0.01) and inversely with ethnocultural composition (p = 0.01), independent of BMI and ODI. Severe sleepiness was associated with situational vulnerability (p < 0.01) and residential instability (p = 0.02). ConclusionLiving in a socially deprived area was associated with OSA severity at time of referral, though this relationship appeared to be mediated by BMI. Deprivation dimensions were independently associated with sleepiness, highlighting the broader impact of social-related factors on sleepiness. These findings demonstrate the complex interplay between social vulnerability and sleep disorders and suggest that composite indices like the CIMD can enhance our understanding of these relationships.

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.

AimCystic fibrosis (CF) care has been transformed by CFTR modulator therapies, yet most efficacy data arise from clinical trials with restrictive eligibility criteria. Real-world registry data can capture treatment outcomes in broader, more diverse patient populations. We used the Cystic Fibrosis Foundation Patient Registry (CFFPR) data to evaluate longitudinal clinical outcomes, and care benchmarking at a single Adult CF Program Center over a decade. MethodsA retrospective, descriptive analysis of CFFPR data (2011-2022) was performed to assess trends in modulator use, lung function (ppFEV1), body mass index (BMI), respiratory microbiology, and pulmonary exacerbations (PEx). Comparative Effectiveness Research (CER) methods were applied to compare outcomes across peak modulator eras: pre-modulator (2011), ivacaftor (2015), mixed-modulator (2019), and elexacaftor/tezacaftor/ivacaftor (ELE/TEZ/IVA) (2021). Program-level outcomes were benchmarked against national network metrics to assess adherence to guideline-based care. ResultsOver ten years, median ppFEV1 improved from 63.4% (2011) to 78.8% (2021), and BMI increased from 22.3 to 24.8 kg/m2. The proportion of adults experiencing more than one PEx annually declined from 39.7% to 19.5%, while Pseudomonas aeruginosa (P.a.) culture positivity decreased from 79% to 47%. ELE/TEZ/IVA therapy was associated with greatest clinical improvements. Program-level performance remained comparable to national network benchmarks, reflecting high adherence to standard care metrics. ConclusionRegistry-based CER provides valuable real-world insights into CF care effectiveness and quality improvement. This decade-long analysis demonstrates significant clinical gains associated with modulator therapies and highlights the importance of patient registries in monitoring outcomes, benchmarking care, and informing global CF care models and standards for rare disease management. Key Messages{square} Real-world registry data enables decade-long evaluation of CFTR modulator effectiveness. {square}Elexacaftor/tezacaftor/ivacaftor demonstrates the greatest clinical benefit among modulator therapies. {square}Benchmarking Adult CF Program performance against the Network of Adult CF Programs facilitates quality improvement and standard care guideline adherence. {square}Patient registries provide insights for personalized care, program-level decision-making, and international standards for rare disease management.

Purpose: To understand how the Philips PAP device recall affected patient experiences, clinical practice, and health system responses. Methods: From November 2022 to August 2023, we interviewed individuals with OSA, physicians, respiratory therapists and health system leaders. We also received emailed responses from Health Canada. Interviews explored participants' experiences with the recall announcement and communication, their own responses and perceptions of actions taken by others, the overall impact of the recall and suggestions for improving future recall processes. Interviews were analyzed using an inductive thematic approach. Results: We interviewed 47 participants (16 individuals with OSA, 10 physicians, 17 public or private respiratory therapists, five health system leaders). Themes were organized into four domains: recall communication, execution, participant experiences, and the policy and regulatory context. Participants were confused due to inadequate information from Philips throughout the process. The burden of notifying patients and tracing devices mostly fell to healthcare providers and vendors, while replacement efforts were disorganized and frustrating. Individuals with OSA experienced emotional distress over therapy decisions and difficulties navigating the recall. Healthcare providers described moral distress from being unable to support patients adequately, and vendors faced additional logistical and financial strain. While regulatory authorities reported that Philips followed standard procedures, participants expressed a loss of trust in both the manufacturer and oversight systems. Conclusions: Interviews revealed that poor communication and execution of the Philips recall caused confusion, frustration and significant emotional and financial burden. Collaborative, context-specific strategies are required to improve future recalls.

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.

Abstract Background: The association between chronic lung disease (CLD) and osteoporosis (OP) is well-recognized, but the direction and magnitude of this relationship remain debated, particularly in aging populations. We aimed to quantify the bidirectional association between CLD (including COPD and asthma) and incident OP using a two-stage individual participant data (IPD) meta-analysis of three large longitudinal cohorts. Methods: We harmonized and analyzed individual-level data from the Health and Retirement Study (HRS, USA), the Survey of Health, Ageing and Retirement in Europe (SHARE, Europe), and the English Longitudinal Study of Ageing (ELSA, UK), all comprising adults aged greater than or equal to[&ge;]50 years. In the first stage, Cox proportional hazards models were fitted separately in each cohort to estimate hazard ratios (HRs) for the forward (CLD[-&gt;]OP) and reverse (OP[-&gt;]CLD) associations, adjusting for a comprehensive set of confounders (demographics, lifestyle, comorbidities, functional status). In the second stage, cohort-specific log HRs were pooled using fixed-effect meta-analysis. Heterogeneity was assessed with the I-squared statistic. Results: A total of 40,050 participants were included across the three cohorts. The pooled HR for incident OP among individuals with baseline CLD was 1.37 (95% confidence interval [CI] 1.24-1.51), with similar estimates for COPD (HR 1.47, 95% CI 1.27-1.69) and asthma (HR 1.35, 95% CI 1.22-1.50). For the reverse association, baseline OP was associated with increased risk of incident CLD (pooled HR 1.16, 95% CI 1.05-1.29), COPD (HR 1.28, 95% CI 1.11-1.47), and asthma (HR 1.17, 95% CI 1.05-1.30). Heterogeneity was low across all analyses (I2[&le;]7.5%). Conclusion: This two-stage IPD meta-analysis provides robust evidence of a bidirectional relationship between CLD and OP in older adults. These findings underscore the need for integrated screening and management of both conditions in aging populations.

Rationale: Sputum-based testing using Xpert MTB/RIF Ultra (Xpert) is the most common molecular testing method for diagnosing tuberculosis (TB). Objectives: To evaluate whether sputum quality influences Xpert positivity and diagnostic accuracy. Methods: We screened consecutive people for presumptive TB in India, the Philippines, Vietnam, Nigeria, South Africa, Uganda, and Zambia as part of the R2D2 TB Network and ADAPT studies. Participants provided 2-3 sputum samples for Xpert and culture reference testing. The quality of the first sputum sample was graded following standardized procedures by trained research staff and used for Xpert testing. We performed logistic regression to evaluate whether sputum grade was independently associated with Xpert positivity, and calculated sensitivity and specificity of Xpert against a culture-based microbiological reference standard (MRS). Measurements and Main Results: Among 1,855 participants, 798 (43%) were female, 348 (19%) were living with HIV (PLHIV), and 1795 (97%) had a cough of [&ge;]2 weeks. Overall, 313 (17%) had a positive Xpert result. Most sputum samples were salivary (83%). Xpert positivity was lowest among salivary samples (16.1%) and highest among purulent samples (31.2%). After adjusting for demographic and clinical variables, there was no significant association between any sputum grade and Xpert positivity. Xpert sensitivity (salivary: 89%, mucoid: 91%, mucopurulent: 87%, purulent: 100%) and specificity (>98%) were high across sputum grades. Conclusions: Sputum quality was not independently associated with Xpert positivity and Xpert sensitivity was high across all sputum grades. These findings support molecular testing of all sputum samples for TB diagnosis regardless of macroscopic appearance.

BackgroundCystic Fibrosis (CF) is a lethal genetic condition affecting over 100,000 people worldwide, characterised by multi-organ dysfunction and a progressive lethal lung disease. The disease occurs due to faulty cystic fibrosis transmembrane conductance regulator (CFTR) ion channels effecting flow of chloride, bicarbonate and water out of cells. This causes thick mucus with repeated bacterial infections, systemic inflammation and a decrease in lung function. CFTR modulator therapies have shown variable improvements in lung function and reduction in exacerbation frequency. Basal cells within the lung act as a stem cell for repair following injury and can repopulate the epithelial layer. This process is dysfunctional in CF causing progressive damage. Spontaneous lung repair is well described but not well characterised. Nothing is known about the effects of CFTR modulator therapy on these cells, but this could be of major consequence for people with CF (pwCF). AimsTo determine the effects of CFTR modulator therapy on the activity of CF basal cells and relate this to progenitor function and to study the effects of CFTR modulators on systemic inflammation and clinical outcomes. MethodsClinical information, blood and nasal brushes were obtained from pwCF prior to commencing modulator therapy and at multiple time points up until 1 year of treatment. 10 pwCF were recruited to undertake thoracic CT scans pre-treatment and at 1 year of therapy. Nasal samples were used to isolate basal cells and serum to study systemic markers of inflammation. RNA sequencing of basal cells was undertaken by Ilumina Novoseq to a depth of 20 million read pairs and gene ontology analysis was performed. Functional assays of basal cell activity were carried out. Proteomic analysis and ELISAs were undertaken to determine changes in inflammatory cytokines within the serum across the first year of treatment. Quantitative results were generated by Lung Quantification (LungQ) analysis with qualitative reports from independent radiologists. Results were compared with clinical outcomes. Results110 pwCF were recruited in total who commenced a commercially available CFTR modulator therapy. Serum samples were collected from 77pwCF, nasal brushes obtained from 40 pwCF and 10 completed their CT scans following 1 year of highly effective CFTR modulator therapy. Systemic IL-6, CRP and calprotectin (a biomarker of CF exacerbation) were all significantly reduced with highly effective CFTR modulator treatment. Clinical results were in keeping with those seen in published CFTR modulator clinical trials with improvement in lung function, weight, and exacerbation frequency. Subjective improvements were seen in all 10 CT scans following 1 year of modulator therapy. Significant reductions were seen in airway wall thickening and reduction in thoracic lymphadenopathy were also observed. Basal cell RNA sequencing showed that the relative expression of 2570 genes were significantly different following treatment with CFTR modulators. Ontology analysis showed enrichment in multiple pathways including cilliagenesis and Notch signalling, a key pathway in lung tissue development and homeostasis. Functional assays exhibited a deficit in repair mechanisms of the CF basal cell compared to healthy controls, and reduction in progenitor function. ConclusionsAlthough CFTR modulators improve multiple clinical and radiological outcomes, they also have impacts on basal cell function. There are however, limited impacts on systemic inflammation and more work is needed in this area to understand the disease process.

BackgroundChronic obstructive pulmonary disease (COPD) is a chronic lung condition characterised by accelerated lung aging. Extracellular vesicles (EVs), which can be categorised into large EVs (LEVs) and small EVs (SEVs), may play a critical role in intercellular communication. They contribute to the pathogenesis of COPD by transporting and transferring microRNAs (miRNAs). This study profiles cells and EV-associated miRNAs from both healthy and COPD small airway (SA)-epithelial cells and SA-fibroblasts and identifies the biological pathways associated with these miRNAs. MethodsEVs were isolated from conditioned media of healthy and COPD SA-epithelial cells and SA-fibroblasts, both at baseline and following H2O2 exposure. MiRNAs were extracted from cells and EVs and analysed by small RNA (smRNA) sequencing. ResultsSmRNA sequencing of COPD SA-epithelial cells and EVs revealed that four miRNAs were upregulated and fourteen were downregulated in the cells compared to healthy controls. COPD LEVs displayed nine upregulated and ten downregulated miRNAs, while SEVs showed ten upregulated and eleven downregulated miRNAs. Only one miRNA consistently upregulated in COPD SA-epithelial cells, LEVs, and SEVs. The various differentially expressed miRNAs were primarily associated with cellular senescence pathways. In SA-fibroblasts 39 miRNAs were upregulated in COPD compared to healthy cells. 14 miRNAs were upregulated in COPD LEVs and 11 downregulated, whereas SEVs exhibited twenty upregulated and eleven downregulated miRNAs. Overlap was limited, with only three miRNAs consistently upregulated in SA-fibroblasts and EVs. These miRNAs were linked to pathways related to fibrosis and cellular senescence. Furthermore, oxidative stress alters the miRNA profiles detected in cells and EVs differently between cells from healthy individuals and COPD patients. ConclusionsCOPD alters miRNA signatures in cells and their EVs, with limited overlap between compartments. These COPD-associated miRNAs are enriched in pathways driving cellular senescence and fibrosis, suggesting a potential role in disease progression.

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.

BackgroundIdiopathic pulmonary fibrosis (IPF) is a progressive and fatal lung disease characterized by aberrantly activated, apoptosis-resistant profibrotic lung (myo)fibroblasts. Prior research has demonstrated that lung fibroblasts from patients with IPF exhibit resistance to DNA damage, suggesting that this behavior contributes to their persistent survival and continuous proliferation. We propose that elevated levels of the DNA damage repair protein RAD51 regulate myofibroblast activation and apoptosis and provide a potential therapeutic target to impede fibrosis progression. MethodsHuman lung fibroblasts were transfected with siRNA against RAD51 or treated with RAD51-specific inhibitor B02 and markers of fibrosis, DNA damage, apoptosis, metabolic reprogramming, and mitochondrial dynamics were assessed. The preclinical efficacy of B02 was evaluated in human precision cut lung slices (PCLS) and in a mouse model of pulmonary fibrosis. FindingsRAD51 expression was significantly upregulated in the lungs and lung fibroblasts of IPF patients. Knockdown or inhibition of RAD51 in fibroblasts reduced profibrotic marker expression, suppressed mTORC1 signaling and mitochondrial function, and increased apoptosis susceptibility. Pharmacological inhibition of RAD51 shifted the profibrotic phenotype towards a fibrosis-resolving state in human and mouse PCLS, and in a bleomycin-induced mouse model of lung fibrosis. InterpretationThe inhibition of RAD51 exerts therapeutic benefits in lung fibrosis by promoting apoptosis. Our findings identify that inhibiting RAD51 with B02 in fibroblasts impairs DNA repair and induces metabolic reprogramming, making it a potential therapeutic target. Research in contextO_ST_ABSEvidence before this studyC_ST_ABSPulmonary fibrosis (PF) is characterized by excessive fibroblast activation and subsequent deposition of extracellular matrix (ECM) proteins, which ultimately disrupt normal lung architecture. A significant contributing factor to the pathogenesis of pulmonary fibrosis is the presence of fibroblasts that are resistant to apoptosis, preventing normal wound healing. Recent studies highlight the DNA repair protein RAD51 as effective in protecting fibroblasts from death induced by chemotherapy and ionizing radiation. These finding suggested that RAD51 could have a role in fibroblast activation and apoptosis resistance in pulmonary fibrosis. Added value of this studyWe demonstrated that RAD51 is important for maintaining apoptosis-resistant fibrotic fibroblasts and their metabolic abnormalities. Our findings indicated that TGF{beta}-mediated upregulation of RAD51 reduces DNA damage, activates multiple pathways related to fibroblast activation and proliferation, and induces metabolic reprogramming, ultimately regulating apoptosis. Mechanistically, RAD51 inhibition enhanced p53 acetylation at lysine 120 and upregulated the expression proapoptotic proteins PUMA/BAK in mitochondria, promoting apoptosis. Pharmacological inhibition of RAD51 using the specific inhibitor B02 during the fibrotic phase of experimental lung disease effectively ameliorated pulmonary fibrosis. Implications of all the available evidenceOur findings establish that RAD51 plays an important role in the survival of apoptosis-resistant fibrotic fibroblasts. We propose that reducing RAD51 expression leads to the metabolic reprogramming of activated fibroblasts, resulting in decreased mitochondrial respiration, reduced ATP levels, and diminished glycolysis or glutaminolysis. These observations suggest that targeting energy metabolism through RAD51 inhibition could be a viable strategy to enhance apoptosis, thereby creating a therapeutically targetable pathway in fibrotic cells. These findings highlight the potential of RAD51 as a therapeutic target for the treatment of IPF.

Background: Chronic Obstructive Pulmonary Disease (COPD) is the third leading cause of global mortality, with persistent lung inflammation contributing to disease progression. This inflammation is partly associated with reduced levels of histone deacetylase 2 (HDAC2). Previous studies suggest that Vitamin D may modulate HDAC2 levels. This study aimed to evaluate the effect of Vitamin D supplementation on HDAC2 expression in stable COPD patients. This experimental study aimed to evaluate the effect of vitamin D supplementation on HDAC2 expression in stable COPD patients at Jemursari Islamic Hospital. Methods: Five COPD patients received a daily dose of 5000 IU of Vitamin D for three months. Serum levels of 25(OH)D3 and HDAC2 were measured before and after the intervention. Results: Vitamin D supplementation resulted in a significant increase in both 25(OH)D and HDAC2 levels. Pulmonary function parameters showed an increasing trend, however, no statistically significant differences were observed. Conclusion: Vitamin D supplementation was associated with increased HDAC2 levels, suggesting a potential anti-inflammatory effect. However, no significant improvement in pulmonary function was observed. Further studies are needed to determine its clinical impact.

Background Genetic studies to date are yet to define the major portion of the genetic risk for adult-onset pulmonary fibrosis (PF). Further the dearth of knowledge of clinically actionable variants for PF is hampering efforts to implement genetic testing to aid early diagnosis and improve disease management. Here we evaluated the contribution of rare and common variants to PF in cohorts with and without a family history of PF. Method Whole genome sequencing (WGS) was performed in a familial cohort comprising PF cases and their family members (85 individuals representing 55 families); and 122 cases from the Australian IPF Registry (AIPFR) with and without a self-reported family history of PF. WGS data were interrogated for rare potentially PF-causing variants in 33 genes previously associated with PF. Variants that were rare and predicted to be likely causative were formally curated using the American College of Medical Genetics and Association for Molecular Pathology (ACMG-AMP) guidelines. Additionally, to examine the common risk variant contribution, a weighted polygenic risk score (PRS) was generated using 16 previously IPF-associated common SNPs. PRS were generated from WGS for the 85 clinically confirmed familial cases and 122 AIPFR cases. In the remaining 202 AIPFR cases, PRS were generated from TaqMan genotyping data. Results Interrogation of WGS generated from 207 individuals with PF revealed multiple rare putative pathogenic variants in both familial and AIPFR cohorts. Formal curation revealed pathogenic (P) or likely pathogenic (LP) variants confirmed in TERT or RTEL1 in four families (7.3%) with the majority of remaining variants classified as variants of uncertain significance (VUS; 12.7%) in seven additional families. Amongst AIPFR participants, four variants met the threshold for classification as P/LP variants (3.3%), with a further six individuals found to harbour VUS following curation (4.9%). Overall weighted PRS did not differ significantly between individuals with familial PF or with no reported family history. However, PRS in all patient groups were significantly elevated compared with population controls. Conclusion VUS remain the major portion of rare variants identified in known PF -related genes. For ~80% individuals with a confirmed family history no potentially causative variants were identified in known PF related genes nor was there evidence that a high burden of common variants contributed to risk in these families. Similarly, we found no evidence that a high burden of common variants contributes to a significant proportion of risk PF in those individuals with no reported family history.

BackgroundPleuroparenchymal fibroelastosis (PPFE) is a rare, fibrotic lung disease with poor prognosis, usually affecting adults which most commonly occurs idiopathically. Biallelic pathogenic variants in DGUOK cause mitochondrial DNA (mtDNA) depletion syndrome, predominantly affecting infants with severe hepatic and neurological symptoms. Detailed description of pulmonary manifestations with late-onset presentation have not been reported. MethodsWe describe nine patients with PPFE and DGUOK-associated mitochondriopathy. Clinical, radiological, histopathological, and genetic data were systematically collected from all patients. Functional studies, single nucleus RNA sequencing (snRNAseq), immunofluorescence staining, transmission electron microscopy and respiratory chain enzyme activity assays were conducted on patient-derived fibroblasts, muscle or lung tissues. mtDNA content quantification was performed on whole genome sequencing (WGS) data. ResultsAll patients (ages 5-36) presented with progressive dyspnea, weight loss and some with spontaneous pneumothoraces. Chest computed tomography and lung biopsies showed features of PPFE. Biallelic pathogenic DGUOK variants were identified in all patients, seven of them carry an unreported intronic variant leading to mtDNA depletion. snRNAseq of lung tissue from four pediatric patients identified Aberrant Basaloid cells and intermediate cells as their precursor localized at the fibrotic edge. Mitochondrial alterations were identified by electron microscopy. ConclusionPPFE in children and young adults is associated with DGUOK-related mitochondriopathy. For the first time, we demonstrate Aberrant Basaloid cells in pediatric fibrotic lung tissue. Since pulmonary involvement may be underrecognized or misinterpreted and the clinical presentation may not always be typical of a mitochondriopathy, we recommend genetic testing in all patients with PPFE of unknown origin.

Background: The determinants of immunoglobulin E (IgE) remain poorly understood in older adults, a population with an increasing burden of chronic diseases. Identifying IgE's determinants may improve its clinical interpretation in the evaluation of allergic and IgE-related conditions. Objective: To investigate age, sex, smoking, alcohol, body mass index (BMI), corticosteroid use, and season as potential determinants of total IgE (tIgE) and inhaled allergen-specific IgE (sIgE). Methods: Using Rotterdam Study data, we investigated the determinants of tIgE and sIgE using multivariable linear regression. Longitudinal changes and the effects of corticosteroids were assessed with linear mixed models. Results: We included 8769 participants, of which 478 had repeated IgE measurements. Age showed a U-shaped relationship with tIgE and L-shaped relationship with sIgE (both p<0.001). Women had lower tIgE (OR [95%CI]: 0.69 [0.65-0.74]), whereas current smokers (1.34 [1.23-1.46]), higher BMI (1.01 [1.01-1.02]), topical corticosteroid users (1.27 [1.07-1.50]) and inhaled corticosteroid users (1.93 [1.64-2.26]) showed higher tIgE. Women (0.96 [0.92-1.00]), former smokers (0.87 [0.83-0.91]) and current smokers (0.72 [0.68-0.76]) had lower sIgE, whereas topical corticosteroid users (1.20 [1.07-1.35]) and inhaled corticosteroid users (1.20 [1.07-1.35]) showed higher sIgE. Over time, tIgE and sIgE decreased (p<0.001) but did not significantly change after corticosteroid use. Conclusion: We identified age, sex, smoking, BMI, season and topical and inhaled corticosteroids as determinants of tIgE and sIgE. Incorporating these determinants may improve IgE's clinical interpretation for the diagnosis and management of allergic and IgE-related conditions. Future research should investigate how these determinants shape IgE's relationship with chronic diseases in aging populations.

BackgroundThe COVID-19 pandemic exposed critical shortages of mechanical ventilators, particularly in low-resource settings. Disruptions in global supply chains and dependence on specialized components highlighted the need for scalable, locally manufacturing alternatives for emergency respiratory support. AimTo describe and evaluate a simplified, supply-chain-independent mechanical ventilator assembled from widely available automotive and simple hardware components, and intended as a last-resort solution. MethodsThe ventilator is based on a reciprocating air pump driven by an automotive windshield wiper motor coupled to parallel shaft bellows and readily assembled passive membrane valves, only requiring materials available from standard hardware retailers, minimal tools, and basic manual skills. Ventilator performance was assessed through bench testing using a patient model simulating severe lung disease in an adult (R=20 cmH2O{middle dot}s/L, C=15 mL/cmH2O) and pediatric (R=50 cmH2O{middle dot}s/L, C=10 mL/cmH2O) patients. Realistic proof of concept was performed in four mechanically ventilated 50-kg pigs. ResultsThe device delivered tidal volumes up to 600 mL and respiratory rates up to 45 breaths/min with PEEP up to 10 cmH2O, covering pediatric and adult ventilation ranges. In vivo testing showed that the ventilator maintained arterial blood gases within the targeted range. Technical details for ventilator construction are provided in an open-source video tutorial. DiscussionThis low-cost ventilator demonstrated adequate performance under demanding conditions. Although not a substitute for commercial intensive care ventilators, its simplicity, autonomy, and independence from fragile supply chains provide a potentially life-saving option in resource-constrained emergency scenarios.

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.