Thorax

Background High-risk subgroups among household contacts of persons with tuberculosis (TB) might benefit from additional interventions. However, the significance of an abnormal baseline chest radiograph (CXR) suggestive of TB, despite negative sputum microbiology, is uncertain. Methods Adults ([≥]18 years) with recent household TB exposure were enrolled at three South African sites (April 2021-September 2022). All participants underwent symptom screening, CXR, and sputum Xpert Ultra and MGIT culture. Pulmonary TB diagnosis was microbiologically-confirmed. Participants without prevalent TB were followed for symptomatic incident TB through 12 months. Multivariable logistic regression identified factors associated with abnormal CXR suggestive of TB. Poisson regression estimated adjusted incidence rate ratios (aIRR) with 95% confidence intervals (95%CI). Results Baseline CXR were available for 795/846 (94.0%) participants without prevalent TB and were abnormal in 157/795 (19.7%); associated with older age (adjusted odds ratio, aOR=1.04, 95%CI 1.02-1.05); prior TB (aOR=6.39, 95%CI 4.18-9.78); and current smoking (aOR=1.61, 95%CI 1.00-2.62). Symptomatic incident TB developed in 8/795 (1.0%) participants, including 7/8 (87.5%) who were asymptomatic and 4/8 (50.0%) with abnormal CXR at baseline. TB incidence was higher in those with abnormal versus normal CXR (aIRR=4.11, 95%CI 1.29-13.09), but after median 12.1 (IQR 11.1-13.1) months follow-up, 153/157 (97.5%) had not progressed to incident TB. Conclusions Adult household contacts with CXR abnormalities, but without prevalent TB, had a four-fold higher incidence of TB within one year, compared to those with normal CXR. This additional risk warrants targeted preventive treatment and extended surveillance, but since most remained TB-free, therapeutic TB treatment is not justified.

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

Background: Wearing facemasks and practising social distancing slow the spread of respiratory pathogens. However, in the event of a new pandemic emerging, the willingness of populations to voluntarily adopt these behaviours is unclear. Methods: A discrete choice experiment was conducted among 2,006 UK-based adults. Participants were presented with hypothetical scenarios describing the emergence of a respiratory virus pandemic and were asked to choose when they would wear facemasks and practise social distancing. A mixed multinomial logit model was used to jointly estimate how disease severity and prevalence, uncertainty in these quantities, and individual-level characteristics influence behavioural choices. Findings: Participants were averse to facemasks and social distancing in the absence of pandemic risk. For each ten-unit increase in severity (10 additional hospitalisations/1,000 infections), the odds of always wearing a facemask outside the home increased by 15.9% (95%CI: 14.3%, 17.5%), relative to rarely/never, and the odds of avoiding all people as much as possible increased by 16.4% (14.6%, 18.2%), relative to not avoiding anyone. Greater disease prevalence, uncertainty in disease severity or disease prevalence, a university education, prior COVID-19 vaccination and non-white ethnicity were also associated with choosing to always wear facemasks and avoid all people as much as possible. The probability of participants choosing to rarely/never wear facemasks varied from 13.4% (11.9%, 14.9%) in the lowest-risk scenario to 1.4% (1.2%, 1.7%) in the highest-risk scenario. Interpretation: Perceived risks of disease and associated uncertainty drive intention of UK adults to adapt their behaviour in a future pandemic.

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.

Background Tuberculosis remains the leading infectious cause of death worldwide. In the WHO African region, declining incidence has coincided with antiretroviral therapy (ART) scale-up, though whether this reflects reduced progression to disease or reduced transmission is unclear. We evaluated how ART and symptom status influence within-household Mycobacterium tuberculosis complex (MTBC) transmission risk. Methods We conducted a case-contact household study in rural South Africa, enrolling index adults with bacteriologically-confirmed pulmonary tuberculosis. MTBC immunoreactivity was measured in all child household contacts (aged 2-14 years) as a proxy measure of within-household transmission. We assessed the influence of index person ART status and symptom status, and explored effect-measure modification of the association between index person HIV status and transmission risk by sex. Results Among 755 child contacts of 296 index persons, effective ART was not associated with within-household MTBC transmission risk (risk ratio [RR], 1.07; 95% CI, 0.66-1.74). Among PLHIV engaged in ART care, WHO TB four-symptom screen (WHO4SS) status was not associated with transmission risk (RR, 0.80; 95% CI, 0.43-1.47), although absence of reported cough reduced risk (RR, 0.61; 95% CI, 0.38-0.96). A pronounced interaction between sex and HIV status was observed: HIV-negative women had the highest within-household MTBC transmission risk (30.5% vs. 14.3% in women with HIV) whereas risks were similar between HIV-positive and HIV-negative men. Conclusions We found no evidence that effective ART or WHO4SS status influenced within-household MTBC transmission risk, though confidence intervals were wide. Absence of reported cough was associated with lower risk, and transmission risk was highest among child contacts of HIV-negative women. These findings suggest reported cough is a useful marker of transmission risk and that routine tuberculosis screening within ART care may reduce transmission from PLHIV; intensified efforts are nonetheless needed to achieve earlier tuberculosis detection in HIV-negative individuals.

Rationale: Preclinical familial pulmonary fibrosis (FPF) represents an early stage of fibrotic lung disease, yet the compartment- and cell-specific molecular programs preceding fibrosis remain poorly understood. Objective: To define spatially organized molecular signatures associated with preclinical FPF and identify tissue-informed circulating biomarkers linked to early fibrotic remodeling. Methods: We performed integrated multi-omic profiling of histologically preserved and remodeled lung regions from subjects with preclinical FPF, Idiopathic Pulmonary Fibrosis (IPF), and controls using spatial transcriptomics, single-nucleus RNA sequencing (snRNAseq), and blood proteomics. Differential expression and pathway enrichment analyses were performed across spatial compartments and epithelial cell states. Results: Histologically preserved lung regions in preclinical FPF demonstrated transcriptional abnormalities including stress-response, ciliary, and extracellular matrix-associated programs despite minimal architectural distortion. Spatial analyses identified alterations in alveolar niche molecular programs accompanied by increasing profibrotic signaling across preserved and tissue remodeled lung compartments. Compared with advanced IPF, preclinical FPF retained epithelial repair and surfactant-associated signatures. Integration with snRNAseq demonstrated enrichment of alveolar and airway epithelial cell dysregulated states associated with transitional phenotypes previously implicated in IPF. Compartment- and epithelial-associated transcriptional signatures identified in lung tissue were partially represented in the peripheral blood. Conclusion: Preclinical FPF is characterized by compartment- and cell-specific molecular programs that precede established fibrosis. We identified distinct alveolar, airway, and vascular molecular signatures and epithelial remodeling states represented in the peripheral blood. These findings provide an initial framework for molecular classification of early stages of pulmonary fibrosis and support future studies evaluating minimally invasive approaches for disease stratification and precision therapeutics.

Background Microbiological confirmation of paediatric pulmonary tuberculosis is frequently unattainable, rendering chest radiography a critical yet underutilised diagnostic tool. Methods We conducted a retrospective diagnostic accuracy study of the qXR version 4.2.1 (Qure.ai), a paediatric optimized computer-aided detection (CAD) algorithm, for pulmonary tuberculosis. Diagnostic performance was assessed against microbiological (MRS) and clinical reference standards (ClRS). Bayesian latent class analysis (LCA) was applied to address the imperfection of both reference standards in children. Performance was quantified using area under the receiver operating characteristic curve (AUROC) and estimates of sensitivity and specificity. Results We included digital chest radiographs of 932 Gambian children (< 15 years) comprising 80 (9%) children with confirmed tuberculosis, 163 (17%) with unconfirmed tuberculosis, and 689 (74%) classified as unlikely tuberculosis. Against MRS, qXR demonstrated AUROC, sensitivity and specificity of 0.68 (95% CI, 0.61 to 0.75), 54% (95% CI, 43 to 64%), and 82% (95% CI, 79 to 84%), respectively. Against ClRS, the AUROC, sensitivity and specificity were 0.73 (95% CI, 0.69 to 0.77), 41% (95% CI, 34 to 49%), and 87% (95% CI, 84 to 89%), respectively. Bayesian LCA, assuming conditional independence, estimated sensitivity of 79% (95% CrI, 65 to 89%) and specificity of 82% (95% CrI, 79 to 84%). Assuming conditional dependence between qXR and expert radiologist, and between culture and Xpert, estimated sensitivity increased to 89% (95% CrI, 71 to 98%), with specificity remaining at 82% (95% CrI, 79 to 84%). Conclusions Paediatric optimized qXR algorithm provides a valuable complementary tool for diagnosis of paediatric pulmonary tuberculosis. Conventional reference standards likely underestimate the true diagnostic performance of CAD systems in children.

Background: Without tuberculosis preventive therapy (TPT), approximately 5% of individuals infected with M. tuberculosis progress to active tuberculosis (TB) disease. Recent studies have identified body mass index (BMI) < 25 kg/m2 as a predictor of TB progression, but additional markers are needed to better identify persons at increased risk. Methods: Close contacts of patients with culture-confirmed pulmonary TB were enrolled in the Regional Prospective Observational Research in Tuberculosis (RePORT)-Brazil cohort from 2015 to 2019 and followed for up to 24 months. Analyses were restricted to interferon-{gamma} release assay (IGRA)-positive contacts who did not receive TPT or received <30 days of isoniazid. Prediction models to identify close contacts at increased TB risk were constructed using two complementary approaches: incremental models used BMI as the base predictor and evaluated whether baseline whole-blood transcriptomic signatures, human genetic polymorphism risk scores derived from low-pass whole-genome sequencing, and BMI-related plasma biomarkers improved model discrimination. Agnostic models did not impose BMI in the model and used penalized regression for predictor selection. Results: Among 285 close contacts, 15 (5%) progressed to TB. The model with BMI as unique predictor had a C-index of 0.66 (95% confidence interval [CI] 0.55; 0.77). Adding Rajan5 or Duffy9 transcriptomic signature scores to BMI improved discrimination compared with BMI alone, with C-indices of 0.78 (95% CI 0.62; 0.99) and 0.75 (95% CI 0.61; 0.89), respectively, but did not further improve discrimination after accounting for adiponectin. Adding adiponectin to BMI increased the C-index to 0.80 (95% CI 0.68; 0.91), while adiponectin alone captured most of the discriminatory performance in agnostic models (C-index, 0.80, 95% CI 0.69; 0.91). Genetic risk scores, leptin, and the adiponectin:leptin ratio did not improve model discrimination compared with the BMI-only model. In exploratory post hoc analyses, higher adiponectin was associated with increased risk of progression to TB, with each two-fold increase associated with a higher hazard of TB (HR 2.91, 95% CI 1.73; 4.91, p < 0.001). Conclusions: Baseline adiponectin strongly predicted progression to TB among close contacts and captured most of the discriminatory information contained in epidemiological and transcriptomic variables. Its consistent selection across modelling approaches supports adiponectin as a promising biomarker for TB risk stratification.

Background: Nitrogen dioxide (NO2) is a surrogate for traffic and industrial air pollution associated with adverse respiratory outcomes. Whether elevated NO2 and temperature jointly influence adult-onset asthma (AOA) risk is unclear, especially among subgroups with varying lifestyle and exposure profiles. We investigated further in the prospective All of Us research program. Methods: Among 596,926 U.S. participants who consented to electronic health record release, annual average NO2 concentrations from satellite data were linked to residential locations for 376,535 individuals. We used multivariable Cox regression to estimate associations between NO2, temperature, and incident AOA, adjusting for co-pollutants and potential confounders. We analyzed 4-category cross-classification variables between NO2 (high>75th percentile vs. low<=75th percentile) and maximum or average temperature (high>median vs. low<=median). We also stratified by sex, age, income, and smoking status. Additive interactions were estimated using Relative Excess Risk due to Interaction, Attributable Proportion, and Synergy Index. Results: We identified 10,413 incident AOA cases over an average 4-year follow-up. Participants with the highest categories of NO2 and temperature exposure had significantly higher risk compared to those with the lowest (HRHigh NO2 x High Max. Temp.=1.37, 95%CI:1.26-1.49; HRHigh NO2 x High Average Temp.=1.49, 95%CI:1.38-1.61). The joint association of high NO2 and high maximum temperature was more pronounced among ever-smokers (HR=1.59, 95%CI:1.40-1.81) than never-smokers (HR=1.26, 95%CI:1.13-1.41). Interaction analyses supported super-additive interactions of high NO2 and high average temperature on AOA risk, particularly among ever smokers, lower-income participants, and younger adults. Conclusion: Our findings highlight the respiratory health threat of long-term joint exposure to elevated NO2 and average temperature, particularly among vulnerable subgroups.

Background Community-wide active case-finding (ACF) is being increasingly implemented as a tuberculosis (TB) elimination intervention. However, conventional site selection strategies may result in low yields from screening. We evaluated whether an artificial intelligence (AI) software guided targeting strategy could improve detection of TB during screening activities (called camps) relative to routine approaches to site selection in the programmatic setting in Pakistan. Methods We conducted a stepped-wedge cluster-randomised trial embedded within Global Fund supported ACF activities implemented by Pakistan s National TB Program and private sector partners. Thirty mobile X-ray van teams operating in 68 districts were randomly assigned to transition from routine site selection approaches (based on field-staff experience and historical data) to an AI-guided targeting strategy, using the software MATCH-AI. We assessed the effect of the intervention on the primary outcome, Camp Positivity Yield, defined as the number of individuals diagnosed with bacteriologically confirmed TB per camp, using generalised linear mixed models. The primary analysis was by intention to treat. Camps conducted within a 5-km radius of the AI selected locations were included in a validated per-protocol analysis. We conducted several district-level subgroup analyses. This trial is registered, number NCT06017843. Findings Between August 2023 and September 2024, 3,936 screening camps were conducted (2,046 control, 1,890 intervention), screening 269,254 individuals. In the intention-to-treat analysis, Camp Positivity Yield was 7% higher in the intervention group relative to the control group, however this difference was not statistically significant (adjusted risk ratio [RR] 1.07, 95% CI: 0.94 -1.22). In the validated per-protocol analysis, Camp Positivity Yield was 32% higher in the intervention group relative to the control group (adjusted RR 1.32, 95% CI: 1.12-1.54). Yields were highest in districts that had moderate baseline yields of 0.5-1% per population screened prior to the trial (adjusted RR: 1.57, 95% CI: 1.13 - 2.18) and in rural districts (adjusted RR 1.43, 95% CI: 1.23 -1.65). Interpretation The use of an AI-guided targeting strategy significantly increased detection of bacteriologically confirmed TB during active case-finding in the validated per-protocol analysis, relative to conventional site-selection approaches employed by field-staff. This software may be considered as a supportive tool to improve the efficiency of community-based TB case-finding interventions in other high burden countries.

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

Background Erythema nodosum leprosum (ENL) is a severe inflammatory complication of lepromatous leprosy characterised by recurrent inflammatory episodes often requiring prolonged immunosuppression. The severity of ENL can be quantified using the validated and reliable ENLIST ENL Severity Scale (EESS). The longitudinal course of ENL and how it is captured using standardised severity measures has not been well described. We prospectively evaluated the changes in ENL severity over time using the EESS in a randomised clinical trial. Methods We conducted a post-hoc analysis of participants enrolled in the Methotrexate and Prednisolone Study in ENL, an international multicentre randomised controlled trial conducted in Ethiopia, India, Indonesia, and Nepal. Adults with severe ENL (EESS score [&ge;]9) were followed for 60 weeks with repeated EESS assessments. Longitudinal trajectories were analysed using mixed-effects regression models. Item-level analyses characterised the clinical phenotype captured by the scale. Associations between EESS score, prednisolone exposure, and dermatology-specific health-related quality of life measured using the Dermatology Life Quality Index (DLQI) were examined. Findings A total of 135 participants contributed 1,958 EESS assessments. Mean EESS declined rapidly during the first four weeks of treatment (-2.10 points/week; 95% CI -2.36 to -1.84; p<0.001), increased modestly during reduction in corticosteroid dose (weeks 4-20), and gradually declined thereafter. Severe ENL (EESS score [&ge;]9) occurred in 20.6% of visits and was characterised primarily by pain and cutaneous inflammatory manifestations. Participants who required additional prednisolone had persistently higher EESS scores and showed limited improvement compared with those who did not receive additional prednisolone. Longitudinal EESS scores were strongly correlated with the DLQI score (Spearmans {rho}=0.75; p<0.001). Conclusion The EESS captures clinically meaningful changes in ENL severity, aligns with treatment decisions, and reflects patient-reported severity over time. These findings support the use of the EESS as a robust tool for monitoring ENL severity in both clinical research and routine care.

Background: As tuberculosis (TB) incidence declines, transmission increasingly concentrates into vulnerable populations. There is an urgent need for affordable surveillance strategies to monitor trends, identify high-risk groups and target interventions. Mycobacterium tuberculosis (Mtb) immunoreactivity surveys indirectly detect transmission and therefore undiagnosed infectious disease. Methods: We conducted a cross-sectional community-based interferon-gamma release assay (IGRA) survey in children aged 1-4 years in Blantyre, Malawi. Community-representative participants were recruited using novel convenience sampling in health facilities alongside random household sampling, and tested for Mtb immunoreactivity using QFT-Plus IGRA. We constructed hierarchical Bayesian logistic regression models for IGRA positivity, with neighbourhood-level random effects. Findings: Of 1,545 participants, 102 (6.6%) had a positive IGRA: an annual risk of Mtb infection (ARTI) of 2.7% (95% CrI 2.2-3.2%). Immunoreactivity was higher in the poorest third of households (8.7% vs 4.9%; adjusted odds ratio: 1.88, 95% CrI 1.08-3.01) compared to the richest, but was not associated with HIV exposure, malnutrition or reported household TB exposure. There was substantial between-neighbourhood heterogeneity (ARTI range 1.1-4.1%). There was no association between neighbourhood-level TB case notifications and ARTI. Interpretation: An innovative convenience sampling approach identified a high burden and substantial spatial variation of recent TB transmission, which did not correspond to case notification rates. This strategy could support identification of high-risk populations, monitoring of trends and targeted public health interventions.

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

Background: Diabetes mellitus (DM) worsens pulmonary tuberculosis (TB) and drives systemic hyper-inflammation, but the underlying mechanisms remain unknown. Neutrophils have key roles in TB immunopathology and lung cavitation. Here, we determine the role of neutrophils in DMTB patients and in driving TB immunopathology. Methods: Sputum and plasma from 30 TB and 30 DMTB patients were analysed for proteases and cytokines using Luminex bead array. Whole blood transcriptomics identified transcriptional differences. Single-cell RNA sequencing characterised neutrophil subsets and dysregulated pathways. Neutrophil function of poorly-controlled DM patients (HbA1c>8%) and healthy controls (HC) were examined following Mycobacterium tuberculosis stimulation, including reactive oxygen species (ROS), neutrophil extracellular traps (NETs), and phagocytosis. Pathways were interrogated using chemical inhibitors, protein array and western blot. Results: Compared to non-diabetic TB patients, poorly-controlled DMTB patients showed up-regulated sputum MMP-8 and MMP-9, associated with increased collagen-destruction and lung cavity formation. Circulating neutrophil count and neutrophil-derived plasma MMP-8 were up-regulated, alongside transcriptional enrichment of extracellular matrix degradation and inflammatory pathways including TNF and RAGE. Single-cell profiling identified reduced cycling neutrophil subset and myelocytes in DMTB, with overall reduced antibacterial and cell-killing signatures. Ex vivo mycobacterial stimulation of DM neutrophils increased ROS and MMP-9 with impaired NETs and delayed phagocytosis. TNFR1, TNFR2, and RAGE were up-regulated. RAGE inhibition with rosiglitazone mitigated Mtb-induced ROS and MMP-8 release. Conclusion: DM worsens neutrophil-driven tissue destruction and inflammation in TB via dysregulated TNF and RAGE-signalling, priming neutrophils towards immunopathology. Targeting RAGE alongside tight glycaemic control may dampen neutrophil hyper-inflammatory responses to limit tissue destruction.

Tobacco control treaties were written for billboards and television, not for the people now selling lifestyles to young Africans. As mobile internet saturates East African cities, social media influencers have become an unmeasured channel, especially when it comes to tobacco promotion. We assessed the prevalence of tobacco use, its association with influencer exposure, and how urban youth interpret that exposure in two capitals with different tobacco laws. We conducted a comparative mixed-methods study among youth aged 18-29 years in Kampala, Uganda, and Nairobi, Kenya (January-August 2025), combining (i) a cross-sectional survey using systematic sampling at youth-dense venues (n=772), (ii) four online focus group discussions (FGDs; n=40), and (iii) content analysis of 30 tobacco-related posts from high-reach influencers (greater than 50,000 followers). We used chi-square tests and multivariable logistic regression, thematic analysis (Braun and Clarke), and descriptive engagement metrics. Ever tobacco use among urban youth in East Africa was 29.3% (226/772), similar in Kampala (30.7%) and Nairobi (28.0%; p=0.409). After adjustment, exposure to influencers promoting tobacco independently predicted ever use (adjusted odds ratio [aOR] 1.90, 95% confidence interval [CI] 1.29-2.82; p=0.001), alongside male sex (aOR 2.35) and age 26-29 years (aOR 1.99). Tertiary education (aOR 0.45) and never seeing tobacco content (aOR 0.26) were protective. Posts framed tobacco as aspirational lifestyle; 77% of sampled comments were positive and 47.5% expressed interest in trying the product. Influencer exposure behaved as a modifiable risk factor of a magnitude comparable to established demographic drivers. Tobacco control in the region must move from print-era advertising bans to platform governance, mandatory disclosure of paid promotion, and youth-led counter-marketing.

Background: Despite rising enthusiasm for active case-finding for TB, there have been concerns about conducting simultaneous HIV screenings due to perceived stigma, although the evidence to support this concern is scarce. We assessed the acceptability of integrated HIV-TB community screening and characterised participants' motivations and prior testing history. Methods: The SLIM study was a non-interventional cross-sectional study conducted in Puducherry (February 2023 to January 2024). In two community health camp-style screening events (one urban and one peri-urban), adults 18 years and older were offered TB screening via portable chest X-ray with AI-assisted interpretation (qXR, Qure.ai), plus sputum testing (Truenat), alongside point-of-care HIV testing. Structured questionnaires captured sociodemographics, prior testing history, and motivations for participation. Acceptability was pre-specified as >50% uptake. Results: Of 273 eligible adults approached, 264 (96.7%) accepted integrated screening, nearly double our pre-specified threshold. Participants were predominantly low-income with limited formal employment. The dominant motivation was a desire to know one's health status (HIV: 74.8%; TB: 73.7%), followed by convenience (16 to 17%). Prior HIV and TB testing was rare (7 to 13% and 15 to 18%, respectively). Participation was uniformly high across demographic groups; however, the screened population skewed older and female (mean age 58 (standard deviation: 12.6) years; 67% female). Men under 45 comprised only 3.7% of participants, substantially below their 24.7% share in the Puducherry population per the most recent census. Conclusions: Integrated HIV-TB screening achieved near-universal uptake in a socioeconomically vulnerable population with little prior testing exposure, contradicting concerns that community HIV screening would be poorly accepted in India. Integrated community-based screening should be scaled up as a cornerstone of TB elimination in high-burden settings. Crucially, because TB incidence in India peaks in the 15 to 45 age group and disproportionately affects men, targeted strategies to bring younger men and women into community screenings are essential.

Background: The choice of hand-drying method affects microbial contamination levels but its economic consequences have not been systematically quantified. Methods: By applying a quantitative microbial risk assessment framework, we translated the documented contamination differential between jet air dryers and paper towels into infection risk estimates, and embedded these into an established health economic model of healthcare-associated infections in NHS hospitals and an illustrative productivity analysis for the EU workforce. Results: The median estimated avoidable HCAI cost attributable to jet air dryer presence in UK NHS clinical areas was 58 million pounds per year, representing 2.1% of total HCAI expenditure for the affected hospital population, with a 50% certainty interval of 33-84 million pounds. Extended to the EU workforce, the same contamination differential implied a median of 1.7 billion euros in annual productivity gains, due to reduced absenteeism, for a shift to use of paper towels in public restrooms. Conclusions: These findings suggest that hand-drying method selection carries measurable economic implications that are not currently reflected in facility management practice. The evidence supports the prioritisation of paper towels in clinical and public settings as a cost-effective infection control measure

Introduction Air pollution is the largest environmental risk to human health. Children are disproportionately affected by air pollution and their exposure is amplified during physical activity. Observed concentrations of nitrogen dioxide in 1 in 4 London school playground exceeds the European limit, but the health impacts of air pollution exposure in London school playgrounds remain unexplored. Our study aims to assess and compare the acute changes in lung function and airway inflammation of primary school-aged children exercising in school playgrounds. Methods and analysis 330 children aged 8 to 11 years from ten London schools will be recruited to complete 90 minutes of physical activity and 90 minutes of rest in their school playground in a randomised crossover design. Pre-, post-, and 24-hour post-exposure oscillometry measurements will be performed with airway resistance at 5 Hz (R5) the primary physiological outcome. Nasal lavage samples will be collected pre-exposure and 24-hour post-exposure for analysis of inflammatory, oxidative, and vascular biomarkers, with IL-6 as the primary biological outcome. Mixed-effects regression models will examine associations between estimated pollutant exposures, exercise and physiological responses.

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