Thorax

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.

IntroductionPredictive biomarkers for symptomatic tuberculosis (TB) progression would transform targeted prevention efforts. Although interferon-gamma release assays (IGRAs), including QuantiFERON(R) TB-Gold Plus (QFT-Plus), have been studied for this purpose, systematic evaluation of the QFT-Plus TB1 and TB2 Interferon-Gamma (IFN{gamma}) concentrations remains limited, particularly in high-burden TB settings. MethodsBaseline TB1 and TB2 IFN{gamma} concentrations from 5,259 participants in TB-endemic regions were analyzed in relation to subsequent TB outcomes over a median of 525 days follow-up. Participants were categorized as controls (no TB), suspected TB (no microbiological confirmation), or laboratory-confirmed TB, including a subset meeting a stringent case definition ([&ge;]2 positive microbiologic tests). Associations between baseline IFN{gamma} concentrations and progression to symptomatic TB were assessed. ResultsIn the full cohort (IGRA+/-participants), baseline TB2 IFN{gamma} concentrations were significantly higher compared to controls among participants who developed suspected TB (p=0.01), laboratory-confirmed TB (p=0.01), or met the stringent case definition (p<0.0001). In IGRA+ participants, baseline TB2 concentrations were significantly higher than controls in suspected (p=0.01) and laboratory-confirmed (p=0.02) groups. Associations with baseline TB1 IFN{gamma} concentrations and TB progression were observed for participants meeting the stringent case definition within the full cohort (p=0.009). Among stringent definition cases, TB2 concentrations achieved an area under the Receiver Operating Characteristic curve of 0.84, with a sensitivity of 80% and specificity of 78%. ConclusionsQuantitative IFN{gamma} concentrations from QFT-Plus, particularly TB2, were associated with progression to symptomatic TB, met or exceeded WHO-recommended sensitivity and specificity thresholds for predictive biomarkers, and may support biomarker-based stratification in TB clinical research. SummaryIn an exploratory analysis from a global tuberculosis (TB) epidemiology study, higher QuantiFERON-TB Gold Plus IFN{gamma} concentrations were associated with progression to symptomatic TB and met WHO predictive biomarker thresholds, supporting their potential value for risk stratification in TB research.

BackgroundInterstitial lung abnormalities (ILA) are radiologic findings of increased lung density or fibrosis in individuals without clinical interstitial lung disease (ILD) and are associated with increased mortality and progression to ILD. Understanding physiologic trajectories of lung function preceding ILA diagnosis may illuminate early mechanisms of lung injury. MethodsWe recruited participants from the Coronary Artery Risk Development in Young Adults (CARDIA) Lung Study, a prospective cohort of adults enrolled at ages 18-30 years and followed longitudinally for 25 years. Percent predicted forced vital capacity (ppFVC) was measured at five study visits over 20 years. Individual ppFVC trajectories were estimated using random coefficient models. Person-specific slopes were incorporated into logistic regression models to examine associations with visually detected ILA on chest CT at exam year 25. Models were adjusted for age, sex, race, body mass index, pack-years of smoking, and study center. ResultsAmong 3,136 participants with complete data, 57 (1.8%) had ILA at mean age 51 years. In univariable and multivariable models, individuals with ILA had greater cumulative decline in ppFVC over the 20 years preceding diagnosis. Each 10% absolute decline in ppFVC was associated with more than twice the odds of ILA (adjusted OR 2.21, 95% confidence interval 1.47-3.31, p = 0.0001). ConclusionsGreater longitudinal decline in FVC from early adulthood was strongly associated with the presence of ILA at midlife. These findings suggest that physiologic impairments precede radiologic evidence of subclinical parenchymal lung abnormalities, underscoring the potential of life course lung function trajectories to identify individuals at risk for developing ILD.

RationaleIdiopathic pulmonary fibrosis (IPF) is a rare, chronic, progressive lung disease with high mortality and few treatment options. Using an additive genetic model, genome-wide association studies (GWAS) have identified multiple risk loci highlighting new genes and pathways of interest. Since IPF risk could also be influenced by non-additive effects, we hypothesised that association analyses using alternative genetic models may provide additional mechanistic insight. ObjectivesTo perform GWAS of IPF susceptibility to detect associations where the underlying effects are consistent with recessive or dominant genetic models. MethodsWe performed GWAS of IPF susceptibility, with logistic regression assuming dominant or recessive genetic models, including 5,159 IPF cases, from clinically-curated sources, and 27,459 controls. We functionally annotated independent signals and performed variant-to-gene mapping, applying fine-mapping to define potentially causal variants and genes. We assessed differential expression levels of genes of interest in publicly available single cell RNAseq data and in primary cells derived from IPF donors and controls. Main ResultsWe identified five genome-wide significant signals, under a recessive model, that had not been reported previously. These included exonic variants in the cell-cycle gene Polyamine-Modulated Factor 1 (PMF1) and in Epsin 3 (EPN3) genes. We also observed evidence of increased PMF1 expression in airway basal cells of IPF patients compared to controls. ConclusionsUsing alternative genetic models in IPF susceptibility GWAS identified new signals and genes, providing new insights into IPF pathogenesis and potential future therapies.

BackgroundPulmonary TB (PTB) patients present with a wide range of pre-treatment Mycobacterium tuberculosis (Mtb) burdens, which predict poor treatment outcomes. We sought to identify immune pathways and biomarkers associated with pre-treatment Mtb burden. MethodsWe conducted whole-blood RNA sequencing in 295 Vietnamese adults with PTB, quantifying bacterial load using GeneXpert Ct values. Weighted gene co-expression network analysis (WGCNA) identified gene modules, pathways, and hub genes associated with Mtb burden. Deconvolution analysis assessed contributions of immune cell types. Key findings were validated in independent PTB (n=171) and TB meningitis (TBM, n=281) cohorts, and publicly available animal datasets. We used non-linear regression for variable selection to identify gene predictors of Mtb burden and hurdle regression to model Mtb loads below the detection limit. FindingsHigher Mtb burden correlated with prolonged symptom duration, elevated neutrophil and monocyte counts, and severe lung pathology. WGCNA identified a 1,093-gene module associated with Mtb burden, characterized by coordinated innate-adaptive pathway interactions. Within this module, IFN-{gamma} signaling participates in modulating the increase of innate signaling (Toll-like, Nod-like receptors, TNF) and the decrease of adaptive signaling (T- and B-cell receptor) pathways in high-burden patients. These responses were primarily driven by neutrophils and classical monocytes. CNIH4 emerged as the strongest hub-gene and a top predictor of bacterial burden, with consistent validation across independent PTB and TBM cohorts. InterpretationOur study reveals systemic innate-adaptive immune dynamics underlying bacterial burden in PTB and identifies CNIH4 as a potential biomarker for treatment monitoring as well as a therapeutic target. FundingNational Institute of Health; Wellcome Trust, UK. Research in ContextO_ST_ABSEvidence before this studyC_ST_ABSWe searched PubMed from Jan 1, 2000, to Dec 10, 2025, without language restrictions, for human studies examining the relationship between Mycobacterium tuberculosis (Mtb) burden and host blood transcriptional responses in pulmonary tuberculosis. Search terms were used in combination as follows: ("Tuberculosis, Pulmonary" OR "pulmonary tuberculosis" OR PTB) AND ("Mycobacterium tuberculosis" OR mycobacter*) AND ("bacterial load" OR "bacterial burden" OR "sputum smear" OR "smear grade" OR xpert OR genexpert OR "cycle threshold" OR ct OR "time to positivity" OR TTP OR CFU OR "molecular bacterial load" OR MBLA)) AND (blood OR "whole blood" OR "peripheral blood") AND (RNA-seq OR "RNA sequencing" OR transcriptom* OR "gene expression" OR microarray). We included studies of active pulmonary tuberculosis that measured quantitative or semi-quantitative bacterial burden and profiled host blood transcriptome-wide responses at baseline, reporting either differential expression by burden strata or associations between bacterial burden and host gene expression. We excluded studies limited to latent tuberculosis, animal or in vitro models, diagnostic or prognostic signature studies without bacterial burden measurement, studies focused on treatment response, and studies using targeted assays without transcriptome-wide profiling. This search identified 12 articles describing blood transcriptional signatures for tuberculosis diagnosis, prognosis, and treatment response. However, only one study directly examined the relationship between pre-treatment bacterial burden and whole-blood transcriptome-wide profiles. That study demonstrated differences in systemic gene expression between patients with higher and lower sputum mycobacterial load and proposed a 20-gene blood signature associated with bacterial burden. However, the analysis was limited by small sample size, lack of pathway-level and cellular interpretation or assessment of correlation between signature with bacterial load. Added value of this studyOur study advances existing evidence by leveraging the wide spectrum of pre-treatment bacterial burden observed in routine clinical populations, quantified using GeneXpert Ct values, and integrating this with whole-blood RNA sequencing in large, well-characterized clinical cohorts. Through network-based transcriptomic analysis, immune cell deconvolution, and non-linear modelling, we identify a bacterial burden-associated gene network characterized by enhanced innate inflammatory signaling and relative suppression of adaptive immune pathways, predominantly driven by neutrophils and classical monocytes and modulated by IFN-{gamma} signaling. Within this network, CNIH4 emerges as a central hub gene and a robust predictor of bacterial burden, with consistent validation across independent pulmonary tuberculosis and tuberculous meningitis cohorts. Implications of all the available evidenceTaken together, the available evidence indicates that host blood transcriptional responses correlate with bacterial burden in pulmonary tuberculosis, but previous studies have provided limited insight into the underlying immune processes. Our findings strengthen the biological link between pre-treatment mycobacterial burden and systemic immune dysregulation, showing that higher bacterial burden is associated with transcriptional state marked by coordinated upregulation of innate immune responses and downregulation of adaptive immune pathways. These results support the use of host transcriptomic profiling as a biologically informative complement to sputum-based measures of bacterial burden and highlight burden-associated immune pathways, particularly CNIH4, as a potential target for treatment monitoring and host-directed therapeutic development.

ObjectiveMyositis-associated interstitial lung disease (myositis-ILD) consists of two predominant radiologic patterns of lung injury--nonspecific interstitial pneumonia (NSIP) and organizing pneumonia (OP)--that oftentimes coexist. However, it remains unclear whether either is associated with clinical outcomes. We aimed to assess the therapeutic response in patients with NSIP-compared to those with OP-predominant myositis-ILD. MethodsThis retrospective, single-center cohort study recruited participants from the Northwestern University ILD Registry with a circulating myositis-associated antibody, ILD, and at least 6 months of follow-up while on immunomodulatory therapy during a 24-month observation period after diagnosis. Two thoracic radiologists determined the predominant radiologic pattern (NSIP or OP). The primary outcome was the absolute change in forced vital capacity (FVC) at 24 months post-diagnosis. Secondary outcomes included changes in the diffusing capacity of the lung for carbon monoxide (DLCO) and radiologic qualitative and quantitative measures of lung injury. ResultsForty-one participants were included in analyses. 71% had an OP-predominant while 29% had an NSIP-predominant radiologic pattern of lung injury. Both exposure cohorts had improvement in mean absolute FVC (OP cohort = +0.18L [p=0.005], NSIP cohort = +0.24L [p=0.07]) over the 24-month observation period. The OP (p<0.05) but not the NSIP cohort (p=0.20) had an increase in DLCO. The OP cohort demonstrated improvement in the qualitative assessment of follow-up imaging (p<0.05), driven by quantitative improvement in groundglass/consolidative opacities (p=0.006). A subset of participants demonstrated features of NSIP/OP overlap and had greater baseline radiologic severity of lung injury. ConclusionPatients with circulating myositis-associated antibodies and an OP-predominant pattern of lung injury may have a more favorable response to therapy than those with NSIP. Further studies are needed to validate our findings and delineate other features cognate with these associations. Significance and InnovationsO_LIRadiologic phenotyping may predict therapeutic response in myositis-ILD. This study demonstrates that an OP-predominant computed tomography (CT) pattern of lung injury is associated with greater improvement in lung function and radiologic signs of inflammation over 24 months on at least 6 months of immunomodulatory therapy compared with an NSIP-predominant pattern, suggesting that CT pattern may provide clinically meaningful prognostic information. C_LIO_LIFirst study to integrate blinded qualitative radiologic adjudication with quantitative CT scoring in myositis-ILD. By combining dual-radiologist review with Kazerooni quantitative scoring and longitudinal pulmonary function testing, this study offers a rigorous and multidimensional assessment of treatment response. C_LIO_LIExpands risk stratification beyond antibody-based toward imaging-based phenotyping strategies. In a heterogeneous population defined by diverse myositis-associated antibodies, this work introduces radiologic pattern as a practical and accessible framework for anticipating treatment responsiveness. C_LIO_LIProvides hypothesis-generating data for precision management in myositis-ILD. The findings support the concept that imaging-defined subgroups may exhibit differential therapeutic trajectories, laying groundwork for future multicenter studies integrating CT phenotype, antibody profile, and treatment strategy. C_LI

BackgroundIn extensively drug-resistant and pre-extensively drug-resistant TB, bacteriology-based monitoring often fails to capture structural lung recovery and patient-reported functional health. We aimed to characterize multidomain treatment response and examine host inflammatory and transcriptional features associated with incomplete recovery. MethodsWe conducted an ancillary analysis of a prospective, open-label, pilot study evaluating adjunctive ibuprofen in XDR-TB (NCT02781909). Participants were assessed at baseline and during treatment using TBS, chest radiography, sputum culture, SGRQ, blood cell indices, plasma cytokines, and whole-blood transcriptomic profiling. Clinical and laboratory measures were compared across outcome groups, and blood transcriptional profiles were analyzed in relation to treatment outcomes. ResultsHere we show that microbiological and symptomatic improvement occurred earlier than radiological and functional recovery. Higher baseline systemic inflammation, including elevated NLR, SII, and IL-6, as well as increased expression of interferon-related genes such as CD274 and GBP5, were associated with poorer radiological and SGRQ outcomes at 6 months. In contrast, transient elevations of IL-8 and IL-4 were associated with early bacteriological clearance. IL-8 was the only plasma biomarker consistently correlated with symptom severity, radiological findings, and functional health. ConclusionsTreatment response in drug-resistant TB is asynchronous across biological domains. Integrated host profiling identifies inflammatory and transcriptional features associated with incomplete structural and functional recovery, supporting the use of multidimensional endpoints to better capture long-term outcomes and inform individualized patient management. Plain Language SummaryPeople with highly drug-resistant tuberculosis can clear the infection but still experience lung damage and reduced quality of life after treatment. In this study, we examined recovery using several measures, including symptoms, chest X-rays, blood markers of inflammation, and gene activity, in addition to tests for tuberculosis bacteria. We analyzed data and stored samples from a small clinical trial to see how these measures changed over time. We found that lung structure and quality of life improved more slowly than bacterial clearance. People with higher levels of inflammation before treatment were more likely to have ongoing lung changes and poorer quality of life later. These results suggest that tuberculosis care should look beyond bacterial clearance and include monitoring inflammation to better support long-term recovery.

BACKGROUNDDiagnostic performance of tongue swab Mycobacterium tuberculosis PCR has been evaluated for facility-based triage of symptomatic tuberculosis (TB). It is unknown whether tongue swab performance differs for detection of asymptomatic TB in community-based screening. METHODSTongue swabs were collected from adult household contacts of TB patients (HHC Cohort), and symptomatic adults presenting to clinics with presumptive TB (Clinic Cohort), at eight South African sites. TB Cases were defined by positive sputum Xpert Ultra or liquid culture, performed in all participants; and matched [~]1:3 (HHC Cohort) or [~]1:2 (Clinic Cohort) to Controls without TB. Tongue swabs in both cohorts were tested by high-volume qPCR; and in the Clinic Cohort, also by sequence-specific magnetic capture (SSMaC) with qPCR. RESULTSThe Clinic Cohort included 217 TB Cases (100% symptomatic) and 437 Controls. The HHC Cohort included 44 TB Cases (84.1% asymptomatic) and 136 Controls. In the Clinic Cohort, sensitivity of SSMaC with qPCR was 73.2% (specificity 94.6%), but not significantly higher than high-volume qPCR (63.8%; p = 0.14) (specificity 94.4%). Sensitivity of high-volume qPCR in the Clinic Cohort (63.8%) was significantly higher than the HHC Cohort (34.1%; p = 0.0007) (specificity 91.9%). Among HHC, high-volume qPCR sensitivity was 35.1% for asymptomatic TB; 52.2% for TB with abnormal CXR; and 100% for TB with High sputum Xpert Ultra grade. CONCLUSIONSSensitivity of tongue swab high-volume qPCR for community-based, household screening for asymptomatic TB was low, approximately half that of facility-based triage for symptomatic TB, but increased with radiographic severity and sputum bacillary load. Key pointsSensitivity of tongue swab high-volume qPCR for community tuberculosis screening among primarily asymptomatic household contacts was low and approximately half that of facility-based triage for symptomatic tuberculosis. Sensitivity was lowest in individuals with normal chest radiography and low bacillary burden.

BackgroundHousehold contact investigation for tuberculosis (TB) is limited by referral for clinic-based testing services. We evaluated the performance of in-home tongue swab (TS) testing among symptom-agnostic household contacts (HHC) to inform HCI screening strategies. MethodsWe conducted a prospective cohort study among HHC of TB patients in Eastern Cape, South Africa. In-home testing of sputum and TSs, with TSs pooled from up to three HHCs, was performed using Xpert Ultra on portable GeneExpert devices. Outcomes included diagnostic performance of TS testing relative to sputum and linkage-to-care outcomes. FindingsBetween June 2021 and October 2024, 909 HHC were enrolled; 99{middle dot}1% provided s TS, 31{middle dot}6% provided sputum. Overall sensitivity and specificity of TS testing was 61{middle dot}9% (95% CI: 38{middle dot}4%-81{middle dot}9%) and 100% (98{middle dot}9%-100%), respectively; sensitivity was 100% (47{middle dot}8%-100%) for individually tested swabs. Among two-swab and three-swab pools where 21 individual was sputum positive, 55{middle dot}6% (21{middle dot}2%-86{middle dot}3%) and 42{middle dot}9% (9{middle dot}9%-81{middle dot}6%) tested positive, respectively; TS sensitivity declined with decreasing sputum Ultra semi-quantitative category. 27 of 439 (6{middle dot}2%) households had an indictation of secondary TB; 13 (3{middle dot}0%) by sputum and TS, 11 (2{middle dot}5%) by sputum only, 3 (0{middle dot}7%) by TS only. Sputum testing identified 29 HHC with TB (yield=3{middle dot}2%); 25/29 (86{middle dot}2%) linked to care (median 1 day [IQR 1-2]). InterpretationWhile in-home molecular testing of sputum supported rapid linkage-to-care, and TSs enabled near-universal testing of symptom-agnostic HHCs, efficiency gains through pooled TS testing must be balance against sensitivity trade-offs. FundingU.S. NIH; Australian Department of Foreign Affairs and Trade; UK Foreign, Commonwealth and Development Office RESEARCH IN CONTEXTO_ST_ABSEvidence Before This StudyC_ST_ABSHousehold contacts (HHCs) of people with TB are prioritized for active case-finding (ACF) strategies due to their increased risk of developing TB disease. Household contact investigation (HCI), a widely recommended ACF strategy, is constrained by attrition from referral-based cascades and sputum-based testing. We searched PubMed and Embase for studies published in English from January 1, 2010 to January 31, 2026, using combinations of the terms "tuberculosis" or "TB" with "household contact," "contact tracing," "contact investigation," "screening," "triage," "in-home testing," "molecular testing," and "tongue swab." We also reviewed references listed in relevant articles. There are limited data describing microbiological testing strategies targeting HHCs conducted outside clinic settings, and fewer still that explore the integration of HCI and in-home molecular TB testing. Tongue swabs have emerged as a promising non-invasive, non-sputum specimen type for molecular TB diagnosis. However, most tongue swab performance data have been generated in clinic-based or symptom-prompted populations, with a marked paucity of data generated in populations at high risk for asymptomatic or paucibacillary TB, including HHC. Before this study, published work exploring the use of tongue swabs within in-home TB testing strategies was limited to two papers, both from our group, which focused on acceptability, feasibility, and preliminary costing and modeling analyses. To date, no published studies have assessed the diagnostic performance of tongue swab-based molecular testing relative to sputum-based testing among HHC, the use of tongue swab specimens as part of in-home testing strategies, nor the implication of pooled tongue swab testing to inform household-level screening and diagnostic escalation strategies. In addition, evidence describing verified linkage to TB treatment services following in-home sputum molecular testing was limited to one pilot study paper. Added Value of This StudyThis study is the first to evaluate in-home molecular TB testing using tongue swab specimens, and to incorporate household-level pooling of tongue swabs from multiple household members as a primary screening strategy. Near-universal swab collection substantially expanded access to microbiological testing in a population with limited sputum production. Although pooled swab testing exhibited reduced sensitivity compared with individual-level sputum testing, stratified analyses of tongue swab tests by sputum Xpert Ultra semi-quantitative categories demonstrate that this reduction reflects a biological gradient associated with low mycobacterial burden. Importantly, pooled swab testing identified TB among contacts unable to produce sputum, increasing diagnostic yield beyond sputum-dependent approaches. The study also documents the increase in diagnostic yield when implementing a symptom-agnostic testing strategy among HHC, and rapid, verified linkage to clinic-based TB treatment services following in-home sputum testing. Implications of All the Available EvidenceCollectively, the available evidence supports reframing TB household contact investigation from individual-level referral for clinic-based testing toward in-home testing models, including the use of household-level screening with diagnostic escalation. Near-universal, in-home collection of tongue swab specimens enables substantially broader microbiological assessment than sputum-dependent strategies and facilitates detection of TB among asymptomatic and sputum-scarce HHCs, individuals frequently missed by referral-based approaches for clinic-based sputum collection and testing. Our findings show that the reduced sensitivity associated with pooled tongue swab testing follows a predictable biological gradient related to mycobacterial burden rather than a technical failure of pooling. Pooled swab testing should therefore be understood as a household-level screening strategy within a sequential diagnostic algorithm, not a replacement for individual diagnosis. For TB programs, efficiency gains and expanded coverage achieved through pooling must be balance against sensitivity trade-offs. Household-level screening using pooled specimens can focus downstream referrals and may improve programmatic efficiency without requiring universal individual testing. Future research should evaluate optimized diagnostic algorithms that integrate pooled, non-sputum testing with diagnostic escalation, assess impact on linkage-to-care and prevention outcomes, and define the role of pooled testing within scalable, community-based TB case-finding strategies.

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.

Purpose: We systematically reviewed the evidence for three questions on screening for lung cancer with computed tomography (CT): benefits (from randomized trials) and harms of screening versus no screening/minimal intervention or alternative screening approaches (e.g., selection criteria, screening intervals); relative importance that informed patients place on the potential benefits and harms of screening (patient preferences); and comparative effects from observational studies of different screening selection criteria (using risk prediction models) or nodule classification systems compared with those used in the screening trials. Methods: A working group of primary care and specialist clinicians (previously members of Canadian Task Force on Preventive Health Care) and topic experts provided input into the eligibility criteria and key potential effect moderators, rated outcomes for their importance to decision making, and developed decision thresholds for use when making conclusions and assessing certainty of the evidence. Critical outcomes of screening effects included all-cause mortality, lung-cancer mortality, and overdiagnosis (via excess cancer incidence from screening). For patient preferences, we sought direct preference data via (i) disutilities of relevant health states (measuring their impact on ones health-related quality of life on a scale of 0 [perfect health] to 1 [death], mainly using EQ-5D), and (ii) other preference-based data, such as outcome trade-offs, as well as indirect preference data via (iii) the relative importance of benefits versus harms inferred from attitudes, intentions, and behaviors towards screening among eligible patients informed with estimates of the outcomes. For screening benefits and harms and for patient preferences, we searched three databases (MEDLINE, Embase, and Central & MEDLINE, Scopus, and EconLit, respectively) to July 11, 2025. For screening studies published prior to 2015 we relied on searches for other reviews, and for patient preferences our search was limited to 2012-onwards. For comparative effects, we searched MEDLINE and Embase from 2019 to September 23, 2025, with reliance on other reviews for studies published 2012-2018. Reference lists were scanned and trial registries searched. For the main searches, two independent reviewers screened titles and abstracts and then full texts; for search updates we applied AI to assist with title and abstract screening. Data extraction and analysis were undertaken by single reviewers, with verification; risk of bias and GRADE certainty assessments were undertaken independently by at least two reviewers. Data were pooled where suitable using random effects methods appropriate to the outcome metric and prevalence. Subgroup analyses explored heterogeneity (e.g., sex, number of rounds, type of comparator, sensitivity of nodule management, type of utility measurement). When not pooled (e.g., patient preferences based on screening intentions) data were analyzed by grouping studies based on factors such as population, setting, exposure, and outcomes, with consideration of study size and risk of bias. Conclusions and certainty assessments for screening effects were based on estimates of absolute effects. Results: We included 85 studies (N=640,537; 13 trials) on screening benefits and harms, 59 on patient preferences (33 [N=42,219] on disutilities and 26 [N=10,829] other studies), and 16 for comparing trial (National Lung Screening Trial [NLST]) and LungRADs nodule management, either directly (2 studies, N=26,978) or indirectly (14 studies, N=1,102,285). Screening benefits and harms: Findings from nine trials (N=94,530) examining low-dose CT (LDCT) screening on all-cause (RR 0.97, 95% CI 0.93 to 1.01; 3.7 fewer [8.5 fewer to 1.2 more] per 1000) and lung-cancer mortality (RR 0.87, 95% CI 0.79 to 0.96; 4.0 fewer [1.2 to 6.4 fewer] per 1000) offered low and moderate certainty, respectively, that screening previous/current 20-30 pack-year smokers 50-74 years old 3-4 times will probably result in at least 1 (all-cause) and 2 (cause-specific) fewer deaths per 1000 screened after 10-12 years. The absolute effects may not apply to participants at the lowest baseline risk for lung-cancer incidence (e.g., <1.5% over 6 years) or death. Seven trials (N=35,161) contributed to meta-analysis for overdiagnosis (RR 1.19, 95% CI 1.03 to 1.37; 8.4 [1.3 to 16.3] per 1000), and our certainty was moderate that LDCT screening 3-4 times will probably result in at least 2.5 cases of overdiagnosis per 1000 screened over 10 years. For important outcomes, we had high certainty that screening 3-4 times results in at least 75 people per 1000 screened (and probably at least 225) having at least one benign biopsy/false positive, 150 having one or more incidental findings (likely at least 450), and 50 (probably at least 100) having a clinically significant/actionable incidental finding, but probably does not have an important impact on major complications or death from invasive testing among those without cancer. Though undergoing a LDCT scan probably causes little-to-no psychosocial harm, having a positive screening result likely causes at least a small degree of harm (i.e., 4-8% change from baseline), especially for the 10-15% having to undergo invasive procedures where some may experience moderate harm. Among those without cancer, these effects may last for several months while the diagnostic process is underway, though moderate certainty evidence found little-to-no effects remaining after 6 months from diagnostic resolution. Comparative effects: Findings from applying different baseline predicted risks for lung-cancer incidence or mortality to the trial populations (i.e., alternative selection criteria) were considered with the effects from screening benefits and harms. Using LungRADs instead of NLST nodule management (among NLST eligible people) probably reduces the false positive rate substantially (about half), though the number of false positives still exceeded the decision threshold of 75 per 1000 and the effects for benefits or other harm outcomes are not known. Patient preferences: Findings showed little-to-no disutility (i.e., <0.04) from a positive screening test (moderate certainty) or a false positive result (low certainty). Low-certainty evidence found there may be little-to-no disutility from a stage I-IIIA cancer diagnosis (before treatment) but small but important disutilities from a stage IIIB/IV diagnosis, during first-line treatment of any stage (though possibly moderate disutility of about 0.09 for stage IIIB/IV), and after treatment for stage IIIB/IV but not stage I-IIIA (without progression) where effects were inconsistent but indicated that any disutility may not be long-lasting. Findings for stage I-IIIA are likely most relevant for understanding the consequences of overdiagnosis. For stated preferences between outcomes, there was low certainty evidence that a small majority (51-75%) of people may accept 69-122 false positives and at least 1.3 cases of overdiagnosis per prevented lung-cancer death, and think that the reduction in lung-cancer mortality is more important than experiencing one of the relevant harms. After being informed about anticipated benefits and harms from screening (with the largest screening effects shown to those at higher baseline risk), progressively more people preferred screening (mainly via intentions) as the net benefit of screening improved from low [25-50% preferred] to moderate [51-75%] to high [>75%]. Conclusions: This review provides contemporary data on the benefits and harms of LDCT screening after at least a decade of follow-up and makes conclusions based on absolute effects while considering thresholds for decision making. Across the reviews, findings indicate that screening those aged 50-74 years with 3-4 rounds of LDCT will lead to benefits and harms for which a majority, but not all, eligible people probably find acceptable and worthwhile. While current nodule management using LungRADs likely reduces false positives, whether it impacts the benefits of screening is less certain and worth further research. Further, comparative prospective studies are lacking to determine the effects from screening for those not meeting the minimum age (50 years) and smoking history criteria in the trials, despite having an equivalent risk for lung cancer.

Background: Lung cancer screening can reduce lung cancer mortality through early detection, but uptake of the NHS Targeted Lung Health Check (TLHC) programme remains low. Behaviourally informed invitation messages have been proposed as a low-cost approach to increase attendance, but evidence of their effectiveness in lung cancer screening is mixed. Few intervention studies used evidence-based behaviour change frameworks, and rarely tailored invitation strategies to empirically identified barriers and enablers. Methods: In an online experiment, 3,274 adults aged 55-74 years and with a history of smoking were randomised to see one of four behaviourally informed invitation messages or a control message. Participants then rated their intention to attend a TLHC appointment, and selected barriers and enablers to attending from a pre-defined list, which were classified according to the Theoretical Domains Framework. Invitation messages were mapped to Behaviour Change Techniques using the Theory and Techniques Tool. Message conditions were compared on intention to attend TLHC using bootstrapped ANOVA followed by pairwise comparisons. Exploratory counterfactual mediation analyses examined the role of fear in intention to attend. Results: Behaviourally informed invitation messages did not meaningfully increase intention to attend TLHC compared with the control message. While a GP-endorsed message showed a small potential benefit relative to the other conditions, this finding was not robust after adjustment for multiple comparisons. Participants most frequently reported barriers related to Emotion (particularly fear), Social Influence, and Knowledge, while Beliefs about Consequences emerged as the primary enabler of attendance. Only around half of reported barriers and enablers were addressed by the invitation messages. Exploratory analyses found that fear was associated with lower intention to attend a TLHC appointment, yet none of the behaviourally informed messages appeared to reduce fear compared to the control message. Conclusions: Improving lung cancer screening uptake will likely require invitation messages that directly address emotional concerns, particularly fear, alongside credible recommendations. These findings highlight the importance of systematically aligning invitation message content with empirically identified behavioural influences when designing scalable interventions to improve lung cancer screening uptake.

Background: Our group previously reported that lung cancer (LC) screening history results and subsequent timing of diagnosis are associated with significant differences in survival outcomes. As a follow-up study, we sought to develop novel personalized risk models that considered screening history for incidence cancers, interval LCs, and prevalence LCs. Methods: Using data from the CT-arm of the NLST, four independent case-control analyses were conducted to develop parsimonious risk models. Controls (n=26,038) were those never diagnosed with LC. The four LC case groups were 270 prevalence LCs, 44 interval LCs, 206 screen-detected LCs (SDLCs) that had a baseline positive screen, and 164 SDLCs that had a baseline negative screen. For each case-control analysis, univariable analyses identified statistically significant covariates from 48 variables and then significant covariates were included into a stepwise backward selection approach to identify a model with the most informative covariates. Results: For prevalence LCs, the model (AUC=0.711) included age, pack-years smoked, BMI, smoking status, smoking onset age, personal history of cancer, family history of LC, alcohol consumption, and milling occupation. For interval LCs, the model (AUC=0.734) included age, smoking status, smoking onset age, cigar smoking, marital status, and asbestos occupation. For baseline positive SDLCs, the model (AUC=0.685) included age, pack-years smoked, BMI, emphysema, chemicals/plastics exposure, and milling occupation. For baseline negative SDLCs, the model (AUC=0.701) included age, pack-years smoked, BMI, smoking status, emphysema, sarcoidosis, and sandblasting occupation. Conclusions: Besides smoking and age, which are inclusion criteria for screening, these models identified other important risk factors which could be used to provide personalized LC risk assessment and screening management.

BACKGROUNDRapid, interoperable whole-genome tools for Mycobacterium tuberculosis complex (MTBC) surveillance remain limited for harmonised lineage assignment across recognised lineages and simultaneous resistance-associated variant detection. AIMTo develop and validate Pathotypr, an alignment-free tool for harmonised MTBC lineage assignment and resistance genotyping from assemblies and raw reads. METHODSWe reconstructed an MTBC phylogeny from 26,813 genomes using 609,003 polymorphic sites, derived an updated lineage marker backbone, and implemented a k-mer/Random Forest framework with marker-based lineage and WHO catalogue-based resistance calling. Performance was evaluated on 498 RefSeq assemblies, 88,071 UShER-TB typed sequencing samples, 162 clinical read sets for closest-reference matching, and 7,148 CRyPTIC isolates with phenotypic drug susceptibility data. RESULTSPathotypr supported all 14 currently recognised MTBC lineages (L1-L10, A1-A4). On 498 complete genomes, marker-based and alignment-free lineage calls were 100% concordant, and prediction accuracy remained 100% on 254 independent assemblies. In 88,071 non-ambiguous UShER-TB samples, root-lineage concordance with TB-Profiler was 100%, while Pathotypr additionally identified lineage 10, A1 and A2. Resistance predictions showed 85.0% genotype-phenotype concordance overall, with high performance for rifampicin (95.8% sensitivity, 95.0% specificity) and isoniazid (93.0%, 97.9%). Runtime was about 1 second per sample, enabling analysis of 88,071 samples in approximately 24 hours on four threads. In the MDR-enriched CRyPTIC collection, Pathotypr supported reconstruction of 135 probable introduction events into Germany, Italy and Ukraine; 33.7% of introduction-associated isolates carried MDR/pre-XDR genotypes. CONCLUSIONPathotypr enables rapid, harmonised MTBC lineage assignment and high-confidence resistance screening, supporting near real-time and cross-border tuberculosis surveillance.

Introduction: Current tuberculosis (TB) screening tools, such as the WHO four-symptom screen (W4SS), lack sufficient sensitivity and specificity for effective community-based active case finding, contributing to both missed diagnoses and unnecessary diagnostic evaluations. This study aimed to develop and validate a machine learning (ML) model to improve TB risk prediction among persons aged >=15 years in community settings of Zambia and South Africa. Methods: A large, harmonized dataset was created from four community-based TB prevalence surveys in South Africa and Zambia (N=169,813), restricted to individuals not under treatment at the time of survey. A binary reference outcome was defined based on available microbiological and radiographic data, grouping individuals as either 'Possible TB' or 'Unlikely TB'. An XGBoost model was trained on 80% (N=135,854) of the data using demographic, clinical, and socio-economic variables, and model interpretability was assessed using SHapley Additive exPlanations (SHAP) values. Internal validation was performed using a 20% hold-out test set (N=33,959). Model performance was assessed using discrimination, calibration, and clinical utility measures compared to the W4SS and against WHO's 2025 Target Product Profile (TPP) for a tool in a two-step screening algorithm. Results: Overall, 16,413 (9.7%) of individuals were labelled as 'Possible TB'. On the test set, the XGBoost model yielded an area under the curve (AUC) of 79.7% (95% CI: 78.7, 80.7), outperforming the W4SS (AUC 57.0%; 95% CI: 56.1, 57.8). The XGBoost model achieved 81.5% sensitivity (95% CI: 77.6, 84.9) at a 60% specificity threshold. This exceeded the W4SS, which achieved only 38.2% sensitivity (95% CI: 36.5, 39.9) on the same dataset. SHAP analysis identified age, previous TB treatment, times treated for TB and unemployment as the primary contributors to risk. Conclusion: The ML XGBoost model shows promise as a screening tool to support community-based active case finding activities prior to diagnostic testing. However, as performance remained below TPP targets, and adding variables, e.g. on geolocation, could be considered.

BackgroundProgressive pulmonary fibrosis carries poor prognosis despite availability of antifibrotics. Current progression criteria rely on functional decline (FVC [&ge;]10% decline over 6-12 months), which detects disease worsening after significant structural damage. Previous quantitative CT (qCT) methods using fixed Hounsfield unit (HU) thresholds or volume-only measurements have shown inconsistent sensitivity for early progression. We hypothesized that a hybrid approach combining HU thresholding with Z-score normalization would detect qualitative progression (tissue densification) before quantitative territorial expansion. MethodsWe developed a novel hybrid CT analysis method integrating: (1) HU threshold-based fibrosis detection (>-600 HU), (2) Z-score normalization for severity stratification (mild Z=1-2, moderate Z=2-3, severe Z[&ge;]3), and (3) five clinical progression criteria including qualitative worsening ({Delta}Z-score [&ge;]0.5). The method was validated in two ILD patients with serial CT at short intervals (3.5 and 10 months). Automated lung segmentation, fibrosis quantification, and clinical decision support were implemented in Python (scikit-image, SimpleITK, NumPy). ResultsIn the index case (progressive COPD-fibrosis overlap, 3.5-month interval), traditional volume-based analysis showed minimal change (+1 mL, +2%), below significance threshold. However, the hybrid method detected significant qualitative progression: Z-score increased from 2.35 to 2.87 (+0.52 SD, p<0.05 criterion threshold), with emergence of 24 mL new severe fibrosis (Z[&ge;]3). This represented redistribution from mild/moderate to severe categories despite stable total volume. The qualitative progression criterion triggered clinical recommendation for antifibrotic consideration, which volume-only analysis would have missed. In a comparative case (10-month interval), massive quantitative progression (+136 mL, +191.5%) with moderate qualitative component ({Delta}Z +0.24) was detected, demonstrating method sensitivity across extreme progression patterns (pure densification vs dominant territorial expansion). ConclusionsThe hybrid HU-Z-score method overcomes critical limitations of previous qCT approaches by detecting qualitative fibrosis progression (tissue densification) independent of territorial expansion. This enables identification of "Phase 1 progression" (densification) at 3-6 month intervals, earlier than functional criteria (6-12 months) or traditional volumetric CT analysis. The method provides objective, standardized clinical decision support for antifibrotic therapy initiation, addressing a critical gap in progressive fibrosing ILD management. Prospective validation in larger cohorts is warranted to establish optimal {Delta}Z-score thresholds and evaluate impact on clinical outcomes.

Introduction: Although 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. Methods: Symptomatic, 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. Results: Of 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 [&ge;]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%. Conclusions: Home 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.

Background Scalable, non invasive tools are critically needed to improve early lung cancer detection and optimize primary care referral pathways. We evaluated Inflammacheck, a point-of-care device utilizing exhaled breath condensate (EBC) H2O2 and physiological parameters with machine learning, for non-invasive lung cancer detection in a real-world screening population. Methods ExPeL study participants, from the UK Targeted Lung Health Check (TLHC) programme, included individuals with suspected lung cancer and low-risk ever-smoker controls. EBC was collected via Inflammacheck, measuring H2O2;, end-tidal CO2;, humidity, temperature, and exhalation flow rate. Multivariate analyses (PCA, LDA, Mahalanobis distance) assessed intrinsic group separation. SMOTE-balanced data trained supervised machine learning models (stacked and voting ensembles), which were then evaluated on held-out test sets. In parallel, untargeted LCMS metabolomics was performed to identify discriminatory molecular features. Results Analysing 34 participants with valid EBC data, 83% of cancer cases were early-stage (I or II), reflecting a screening population. Multivariate analysis clearly separated lung cancer and controls across PCA, LDA, and Mahalanobis mapping. The voting ensemble model achieved: Accuracy 85.7%, Sensitivity 80%, Specificity 100%, Precision (PPV) 100%, ROC AUC 0.90, MCC 0.73. Crucially, no false positives were identified. EBC variables revealed greater dispersion in cancer patients, reflecting physiological heterogeneity missed by univariate analysis. Untargeted metabolomics identified 2,132 features, with four key metabolites yielding an AUC of 0.969 for cancer discrimination. Discussion Inflammacheck effectively distinguishes early-stage lung cancer via a rapid, non-invasive breath test, findings which are highly relevant for primary care and screening triage, where non-specific symptoms and low prevalence pose challenges.

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 Higher levels of sedentary behaviour, such as leisure screen time (LST), and lower levels of physical activity are associated with diseases across multiple body systems which contribute to a large global health burden. Whether these associations are causal is unclear. The primary aim of this study is to investigate the causal effects of higher LST (given greater power) and, secondarily, lower moderate-to-vigorous intensity physical activity (MVPA), on a wide range of diseases in a hypothesis-free approach. Methods A two-sample Mendelian randomisation phenome-wide association study was conducted for the main analyses. Genetic single nucleotide polymorphisms (SNPs) were first selected as exposure genetic instruments for LST (hours of television watched per day; 117 SNPs) and MVPA (higher vs. lower; 18 SNPs) based on the genome-wide significant threshold (p < 5*10-8) from the largest relevant genome-wide association study (GWAS). For disease outcomes, we used summary results from FinnGen GWAS, including 1,719 diseases defined by hospital discharge International Classification of Diseases (ICD) codes in 453,733 European participants. For the main analyses, we used the inverse-variance weighting method with a Bonferroni corrected p-value of p [&le;] 3.47*10-4. Sensitivity analyses included Steiger filtering, MR-Egger and weighted median analyses, and data from UK Biobank were used to explore replication. Findings Genetically predicted higher LST was associated with increased risk of 87 (5.1% of the 1,719) diseases. Most of these diseases were in musculoskeletal and connective tissue (n=37), genitourinary (n=12) and respiratory (n=8) systems. Genetic liability to lower MVPA was associated with six diseases: three in musculoskeletal and connective tissue and genitourinary systems (with greater risk of these diseases also identified with higher LST), and three in respiratory and genitourinary systems. Sensitivity analyses largely supported the main analyses. Results replicated in UK Biobank, where data available. Conclusions Higher levels of sedentary behaviour, and lower levels of physical activity, causally increase the risk of diseases across multiple body systems, making them promising targets for reducing multimorbidity.