Annals of the American Thoracic Society

Rationale: Fibrosing interstitial lung diseases (ILDs), including idiopathic pulmonary fibrosis (IPF), have heterogeneous postdiagnosis courses. Existing prognostic tools often rely on pulmonary function testing, imaging, or laboratory data that may not be uniformly available and rarely provide individualized, time-updated forecasts of multiple clinically relevant trajectory events. Objectives: To determine whether longitudinal healthcare claims can generate test-free, time-updated forecasts of clinically actionable postdiagnosis trajectory events in patients with fibrosing ILD and IPF. Methods: Using de-identified longitudinal administrative claims from the Merative MarketScan Commercial Claims and Encounters and Medicare Supplemental and Coordination of Benefits databases, we constructed code-based digital twins (ZeBRA) encoding each patient's evolving diagnosis, pharmacy, and procedure history. Horizon-specific models forecast seven claims-observable events: supplemental oxygen escalation, pulmonary hypertension, acute respiratory failure/ARDS composite, nausea, diarrhea, liver injury, and gastrointestinal bleeding. The analytic cohort included 345,918 patients with fibrosing ILD, including 17,284 with IPF. Predictions were evaluated in a time-updated follow-up setting at 1-month, 6-month, and 1-year horizons. Results: Predictive discrimination was consistent across events and horizons. In fibrosing ILD, AUC ranged from 0.691 for liver injury at 1 year to 0.912 for oxygen dependence at 1 month, with PPV ranging from 0.189 to 0.714. At 1 month, oxygen dependence achieved an AUC of 0.912 +/- 0.005 with PPV of 0.473 +/- 0.005, and pulmonary hypertension achieved an AUC of 0.881 +/- 0.005 with PPV of 0.539 +/- 0.005. The IPF subcohort showed analogous horizon-dependent performance, with AUC ranging from 0.687 to 0.855 and PPV from 0.245 to 0.817. At 1 month in IPF, PPV was 0.753 +/- 0.015 for oxygen dependence and 0.817 +/- 0.011 for pulmonary hypertension. Conclusions: A test-free digital-twin framework derived from routine longitudinal claims can provide individualized, time-updated forecasts of actionable fibrosing ILD and IPF trajectory events without imaging, pulmonary function tests, laboratory data, clinical notes, or patient-facing data collection. These forecasts may support low-burden reassessment, anticipatory care planning, and earlier recognition of elevated near-term risk for respiratory deterioration or management-altering complications.

Background: Children spend more than 90% of their time indoors, and early childhood education settings (ECEs) are an understudied, high-occupant-density indoor microenvironment where exposure to volatile organic compounds, particulate matter, and other toxicants has been documented. Limited knowledge exists on ECE-specific exposures affecting young children and how they compare to exposures in the home. Methods: This prospective, repeated-measures pilot study targeted enrollment of 44 preschool-aged children and 8 ECE staff across two geographically and sociodemographically distinct ECEs in metropolitan Atlanta, Georgia. Paired silicone wristbands, one home-designated and one ECE-designated, were exchanged between settings across three consecutive days and nights beginning at enrollment to characterize microenvironment-specific exposure. A single spot urine sample was also collected from each child. Continuous indoor air quality monitoring was conducted in two classrooms per site. Caregivers and ECE staff completed structured questionnaires assessing home and ECE environmental characteristics, child respiratory risk, and protocol feasibility and acceptability. Feasibility was evaluated using eight pre-specified indicators spanning recruitment and enrollment, wristband wear duration and loss by microenvironment, urine sample collection completeness, and survey completion by instrument and respondent group. Conclusion: This pilot will establish feasibility and acceptability parameters for a paired, multi-matrix silicone wristband protocol across home and ECE microenvironments. Findings will inform the design, sample size, and power calculations for a subsequent study testing indoor air interventions and pediatric respiratory outcomes in ECEs. Feasibility outcomes are reported in a companion manuscript.

Background: Primary malignant cardiac tumors (PMCTs) are rare and histologically heterogeneous. Objective: To compare demographics, specific ICD-O-3 morphologies, first-course treatment patterns, annual registered case counts, and unadjusted overall survival between soft-tissue and hematologic PMCTs. Methods: We identified 730 PMCT cases diagnosed from 2000 to 2021 in SEER 18 (ICD-O-3 topography C38.0). Histologic lineage was assigned from ICD-O-3 morphology. Comparative analyses included soft-tissue (n=458) and hematologic (n=212) tumors. First-course variables were primary-site surgery, chemotherapy (yes versus no/unknown), and radiotherapy (radiation versus none/unknown). Groups were compared with chi-square tests. Overall survival was estimated with Kaplan-Meier methods; follow-up was truncated at 120 months. Results: Soft-tissue PMCTs occurred predominantly at ages 45-64 years (67.9%), whereas hematologic PMCTs occurred predominantly at age [&ge;]65 years (63.2%; p<0.001). Men comprised 59.9% of hematologic and 49.3% of soft-tissue cases (p=0.014). The leading soft-tissue morphology was hemangiosarcoma/angiosarcoma (ICD-O-3 9120/3; 201/458, 43.9%); synovial sarcoma accounted for 20/458 cases (4.4%). Diffuse large B-cell lymphoma, NOS, accounted for 131/212 hematologic tumors (61.8%). Any primary-site surgery was recorded in 66.6% of soft-tissue versus 15.6% of hematologic cases (p<0.001). Chemotherapy was recorded in 67.5% versus 51.1% (p<0.001), and radiotherapy in 9.0% versus 20.5% (p<0.001). In exploratory Kaplan-Meier analyses, hematologic patients with recorded chemotherapy had higher unadjusted 120-month overall survival than those without recorded chemotherapy (42.0% versus 12.2%; log-rank p=7.5x10-). Radiation-associated survival differences were not statistically significant in either lineage. Conclusions: Soft-tissue and hematologic PMCTs have distinct age distributions, named histologies, and first-course treatment patterns in SEER. These findings describe registry coding and do not establish treatment effectiveness or population incidence.

Background: Environmental noise and air pollution are both shaped by road traffic and the built environment, and exposure assessment increasingly folds them into composite indices or proxies both by traffic exposure. Whether the two share a social distribution has rarely been tested against direct measurement of several exposures in the same communities, and community noise is almost always characterized by A-weighted levels alone, which discount low-frequency energy. Methods: At 176 sites across Rhode Island, spanning the contiguous urban area of Providence, Central Falls, and Pawtucket together with four rural municipalities, we measured the acoustic environment under A- and C-weighting (LAeq, LCeq), fine particulate matter (PM2.5), night-time illuminance, and relative humidity across four session types over roughly one year (704 site-sessions). Exposures were linked to census-tract composition (American Community Survey), and mixed-effects models were fitted for each of eight area-level markers of disadvantage, adjusting for campaign and session. Relative humidity was carried through the identical model as a negative control. Results: A-weighted noise was consistently higher in more disadvantaged tracts, rising with non-White, poverty, renter, and no-vehicle shares and falling with income and older-resident share (six of eight markers significant; 1.3 to 1.8 dBA per standard deviation; 6.6 dBA between the least and most racially diverse neighborhoods). C-weighted levels followed the same gradient on every marker and exceeded their A-weighted counterparts at block-group scale for renter occupancy and vehicle absence. Night-time illuminance was also socially patterned, whereas short-term PM2.5 was roughly an order of magnitude weaker and relative humidity showed no gradient. The acoustic gradient persisted within the urban core alone. Conclusions: Measured burden was carried by the acoustic environment, including its low-frequency component, and by night-time light, not by short-term particulates. The exposure metric and the averaging time determine which disparities are visible at all.

Background: The 2026 American Heart Association/American College of Cardiology (AHA/ACC) guidelines replaced the 2019 European Society of Cardiology (ESC) four-tier pulmonary embolism (PE) risk scheme with five clinical categories (A-E) and subcategories. These categories were set by expert consensus and have not been validated against outcomes. How patients are reclassified relative to ESC, or how the two systems compare prognostically, is unknown. Methods: We utilized three cohorts of patients with confirmed PE using structured electronic health record data, laboratory biomarkers, and large-language-model abstraction of radiology reports: Duke University Health System (n=12,992, drawn from 95,760 consecutive inpatient CT pulmonary angiography studies, 2014-2025, with no referral or registry enrollment step between imaging and cohort entry), INSPECT (Stanford; n=3,870), and MIMIC-IV (Beth Israel Deaconess; n=361). Patients were assigned AHA/ACC categories B through E, subcategorized where data allowed, and mapped to 2019 ESC risk strata. The primary outcome was 30-day mortality; discrimination was assessed with Harrell C-index. Results: Among 17,223 patients with confirmed PE, pooled 30-day mortality rose monotonically across categories: 1.5% (B), 8.9% (C), 15.5% (D), and 31.9% (E), with the ordering preserved in all three cohorts despite differing baseline mortality. Subcategory-level discrimination was reliable only at the high-acuity extreme (D2-E2); across subcategories C1 through D1, mortality did not order monotonically (9.2%, 10.8%, 8.1%, 10.9%), and adding subcategories to category C did not improve discrimination at Duke (C-index 0.699 vs 0.699). Category C patients lacking both echocardiography and biomarker testing (12.7% of category C) had mortality (10.4%) equal to or exceeding classified peers. Relative to ESC, the frameworks were concordant at the extremes, but 5.7%of ESC intermediate-risk patients were reclassified to category D, with modestly higher but non-significant 30-day mortality than those remaining in category C (10.8% versus 8.9%). Conclusions: Across a three-health-system cohort, the 2026 AHA/ACC framework produced a reproducible mortality gradient at the category level, with added subcategory granularity refining risk chiefly at the highest-acuity tiers. Discrimination across the broad intermediate band was limited, and reclassification from ESC fell almost entirely within this range.

Socioeconomic inequality in exposure to air pollution possess a significant public health challenge, yet little is known about how the disparities vary across the various economic status areas in Nairobi. Globally, studies have shown that exposure to air pollution is unequal across communities hence disparities in harm to human health. This study examined the association between socioeconomic characteristics and perceived air quality among residents of low- and high-socioeconomic status areas in Nairobi, Kenya. Two regions within Nairobi County were selected for this study: Mukuru kwa Njenga (representing the Low Socioeconomic Status) and Langata (representing the High Socioeconomic Status) with a sample size of 384 in HSES areas and 368 in LSES areas. A cross-sectional study was conducted among 752 respondents residing in selected LSES and HSES areas of Nairobi. Data was collected using a structured questionnaire assessing sociodemographic characteristics, income, education, employment, perceived air quality, and self-reported health outcomes associated with air pollution exposure. Descriptive statistics were used to summarize participant characteristics and perceived air quality. Chi-square tests were used to examine associations between residential area and categorical health outcomes, while ordinal logistic regression was used to assess the association between socioeconomic characteristics and perceived air-quality ratings. Perceived air quality differed significantly between residential socioeconomic groups. Respondents in LSES areas were more likely to rate air quality as poor or very poor, with 45.4% rating it as very poor, compared with only 1.6% of respondents in HSES areas. In contrast, 12.2% of HSES respondents rated air quality as good compared with 0.3% in LSES areas. The association between area of residence and perceived air-quality rating was statistically significant, {chi}2(3) = 282.672, p < 0.001. In the ordinal logistic regression model, HSES residence was associated with significantly lower odds of reporting poorer perceived air quality compared with LSES residence (OR = 0.135, 95% CI: 0.095-0.190, p < 0.001). Income was also significantly associated with perceived air quality, while respondents with no formal education had higher odds of reporting poorer perceived air quality compared with those with secondary education (OR = 3.254, 95% CI: 1.388-7.638, p = 0.007). Significant differences were also observed for several self-reported health outcomes. Respiratory problems were more prevalent among respondents in LSES areas than HSES areas (72.7% versus 50.4%; {chi}2(1) = 29.081, p < 0.001; Cramer's V = 0.224). However, allergies, eye irritation, and headaches were reported more frequently in HSES areas than in LSES areas, with significant associations observed for allergies ({chi}2(1) = 106.479, p < 0.001; Cramer's V = 0.429), eye irritation ({chi}2(1) = 136.577, p < 0.001; Cramer's V = 0.486), and headaches ({chi}2(1) = 149.180, p < 0.001; Cramer's V = 0.508). No statistically significant association was observed for cardiovascular problems, likely reflecting the very low number of reported cases. Substantial socioeconomic disparities in perceived air quality and self-reported respiratory health outcomes were observed. Residents of low-socioeconomic status areas consistently perceived poorer air quality and reported a higher burden of respiratory problems, highlighting the need for targeted interventions to reduce environmental health inequalities.

Background Elexacaftor-tezacaftor-ivacaftor (ETI) has been demonstrated to improve lung function in clinical trials; however, evidence describing effects on trajectories and whether long-term improvements are sustained (>1-year) is lacking. We estimated within-person lung clearance index (LCI) trajectories before and after ETI initiation, assessing changes in level and rate of change, alongside acute LCI change, up to three years after ETI initiation. Methods Prospective observational study of children at a tertiary hospital. Children aged 3-17 years with [&ge;]2 LCI testing occasions (i) before and (ii) after starting ETI were used to describe lung function trajectories. Children with [&ge;]1 pre-ETI and [&ge;]1 post-ETI LCI occasion(s) were used to describe acute LCI change after ETI initiation. Age-adjusted LCI trajectories for time periods (i) before and (ii) after ETI initiation were estimated using linear mixed-effects models, and pre- and post-ETI LCIs were compared using paired Wilcoxon tests. Results Mean pre-ETI and post-ETI longitudinal changes in LCI were -0.007 (95% CI: -0.28, 0.27; n=35) and 0.12 (95% CI: -0.17, 0.41; n=20) turnovers per year, respectively. Before ETI initiation, 57% (30/53) of patients had an LCI[&ge;]7.1 turnovers (indicating impaired lung function), compared to 26% (14/53) post-ETI, with a median LCI difference of -0.70 (95% CI -0.84, -0.46; p<0.001) turnovers. Within-individual variability in LCI decreased post-ETI. Conclusions Our real-world data within a unique longitudinal study provide a comprehensive picture of ETI benefit by outlining not only acute improvement in LCI but maintained stability in LCI trajectories and improved LCI stability sustained up to three years post-initiation.

Introduction Acute lower respiratory tract disease (aLRTD) is a leading cause of hospitalisation and death, particularly in older adults and adults with comorbidities, with acute lower respiratory tract infection (aLRTI; pneumonia and non-pneumonic LRTI) being a major component. Non-pulmonary complications and functional decline after aLRTI are recognised, but their pathogen-specific burden is poorly described. We aimed to quantify renal, hepatic, thromboembolic and functional complications, and mortality, after aLRTI hospitalisation, by clinical phenotype and pathogen. Methods We conducted a cohort study of adults (>18 years) admitted with aLRTD to two hospitals in Bristol, UK (01 August 2022-31 July 2024). aLRTD was classified as pneumonia, non-pneumonic LRTI (NP-LRTI) or no diagnosis of aLRTI. Pathogens were identified from standard-of-care and research microbiology. Outcomes were acute kidney injury (AKI), acute liver dysfunction, venous thromboembolism (VTE), in-hospital falls, reduced mobility at discharge, increased care requirements, and 30-day and 1-year mortality. Analyses were descriptive. Results Among 246,797 adult admissions, 21,456 aLRTD hospitalisations were included: 10,239 (47.7%) pneumonia, 7,742 (36.1%) NP-LRTI and 3,475 (16.2%) with no evidence of aLRTI. Of 19,152 tested aLRTD admissions, 8,503 (44.4%) had a positive microbiological/virological test, yielding 9,204 pathogen detections; 1,194 (6.2%) had co-infections, and SARS-CoV-2 was most frequent, with influenza the second most common in pneumonia and NP-LRTI. Pneumonia had greater severity than NP-LRTI and no diagnosis of aLRTI (median length of stay 6 vs 4 vs 4 days; ICU admission 3.4% vs 0.7% vs 0.5%, respectively). Overall, 22.2% developed AKI, 6.1% acute liver dysfunction, 0.6% DVT and 2.4% PE; 1.8% had a fall, 11.5% reduced mobility, and 16.6% required increased care at discharge. 30-day and 1-year mortality were highest for pneumonia (14.0% and 32.0%, respectively). Pathogen-specific analyses showed longer stays and higher complications and mortality rates for SARS-CoV-2 and Streptococcus pneumoniae, and shorter stays with lower complication and mortality rates for influenza and Haemophilus influenzae. Conclusions Non-cardiovascular complications and functional decline after aLRTI were common, particularly in pneumonic and SARS-CoV-2 or pneumococcal disease. These findings support routine surveillance for renal, hepatic, thromboembolic events, early mobilisation and rehabilitation, and consideration of multi-system outcomes when evaluating public health and economic value of vaccines and therapies.

Background Hospitalizations and mortality due to heart failure (HF) are rising in rural areas. However, inpatient outcomes for young adults with HF are not well understood. We aimed to compare in-hospital mortality, advanced procedure utilization, length of stay, and total charges among rural and urban HF patients ages 18-45. Methods We analyzed hospitalizations from the National Inpatient Sample (2016-2022), categorizing discharges as rural (National Center for Health Statistics [NCHS] 5-6), small and medium metropolitan (NCHS 3-4), and urban (NCHS 1-2). Generalized estimating equations were used to model outcomes and adjust for demographics, comorbidities, and hospital characteristics. Outcomes are reported as adjusted rate (aIRRs) or risk ratios (aRRs) with 95% confidence intervals. Results Among 79,258 HF hospitalizations among young adults, 45,075 and 10,722 were for patients from urban and rural areas, respectively. Rural patients had higher rates of in-hospital mortality (1.6% vs. 1.2%; aIRR = 1.28, 95% CI = 1.05, 1.56, p = 0.043), advanced cardiac procedure utilization (15.0% vs. 14.8%; aIRR = 1.19, 95% CI = 1.11, 1.28, p < 0.001), and longer hospital stays (aIRR = 1.10, 95% CI = 1.05, 1.14, p = 0.003). Small and medium metropolitan residents had similar outcomes to urban residents. In interaction analyses, the association between rural-urban residence and mortality differed by race (pint = 0.003) and payer type (pint < 0.001). Conclusions Young adults in rural areas may be prone to poor outcomes following hospitalization for HF. Strategies to identify rural adults at risk for HF and provide affordable and timely care may improve disparities.

Background In adults, cold-attributable mortality exceeds heat-attributable mortality roughly 17-fold. Child-specific evidence has begun to emerge only recently - a nationwide Brazilian case-crossover study located the minimum mortality temperature (MMT) for under-five deaths, and a 56-country survey-based analysis linked monthly temperature anomalies to under-five mortality - but no multi-country, climate-zone-resolved estimate of the childhood respiratory-infection MMT exists, and whether temperature variability is independently associated with childhood respiratory mortality at the global scale is unknown. We quantified both. Methods We combined Global Burden of Disease 2023 mortality estimates, lower respiratory infection (LRI) deaths at ages 0-19 years and asthma deaths at ages 0-24 years, 171 countries, 1990-2023 - with 0.5 deg monthly land temperature and diurnal temperature range (DTR) fields from C-LSAT/C-LDTR (1901-2023). Four exposure dimensions (annual mean, DTR, seasonal amplitude, interannual variability) entered two-way fixed-effects models with Driscoll-Kraay standard errors. A quadratic term in mean temperature located the MMT, with percentile confidence intervals from a 300-replication country-cluster bootstrap. Future-exposure leads, country-level detrending, and permutation tests assessed contemporaneous causality, applied to both the linear coefficients and the quadratic term generating the MMT; national pneumococcal conjugate vaccine (PCV3) coverage and ambient PM2.5 exposure series were added as time-varying mechanistic covariates. Results The childhood LRI MMT was 17.1 C (95% CI 14.7-19.8), the 36th percentile of the annual-temperature distribution; zone estimates were 24.7 C in tropical and 15.8 C in subtropical countries, with weak temperate and no subarctic identification. The quadratic term underpinning the MMT, however, failed both falsification checks - future temperatures reproduced the U-shape and country-level detrending erased it - so these MMT values describe a trend-level geographic pattern of the annual construct rather than a contemporaneous dose-response. Interannual temperature variability was positively associated with LRI (+0.278, 95% CI 0.102-0.454; p = 0.002) and asthma mortality (+0.836, 95% CI 0.447-1.226; p = 2.6 x 10^-5) per 1 C, but future-exposure models returned nearly identical significant coefficients and detrending erased significance, supporting only a trend-level association; adjustment for national PCV3 coverage and PM2.5 exposure left these estimates essentially unchanged. Annual mean temperature was likewise inversely associated with both outcomes at the trend level; DTR and seasonal amplitude showed no independent within-country effects. Conclusions This study provides the first multi-country, climate-zone-resolved geography of the optimal temperature for childhood respiratory survival, spanning 171 countries; because the underlying quadratic association is trend-level, the estimates are directional. The observed variability-mortality associations are trend-level signals rather than contemporaneous causal evidence; daily-scale, child-specific designs are required to determine whether short-term thermal variability affects paediatric respiratory mortality.

Abstract Importance: Socially vulnerable patients have a high burden of obstructive sleep apnea, but the stage of the referral pathway at which access barriers arise is uncertain. Objective: To determine whether area-level social deprivation was associated with appointment scheduling, wait time, cancellations, or no-shows among adults referred for specialist obstructive sleep apnea care. Design: This was a cross-sectional study evaluating patients referred from December 1, 2016 through November 30, 2019. Data were analyzed from January 30, 2026 to May 16, 2026. Setting: Foothills Medical Centre Sleep Centre in Calgary, Canada. Participants: Adults referred to a tertiary academic sleep centre in Calgary, Alberta, Canada. Eligible patients had valid provincial health insurance and either a scheduled clinic appointment or home sleep apnea test data available. Exposures: Quintiles of the four Canadian Index of Multiple Deprivation domains: residential instability, economic dependency, ethnocultural composition, and situational vulnerability. Main Outcomes and Measures: The primary outcome was receipt of a scheduled specialist appointment. Secondary outcomes were time from referral to the first attended appointment and number of appointment cancellations or no-shows. Results: Among 3111 patients (mean [SD] age, 53.7 [14.3] years; 40.7% female), 1766 (56.7%) were scheduled and 1647 (52.9%) attended an appointment. Each quintile increase in situational vulnerability was associated with lower odds of scheduling (adjusted odds ratio [95% confidence interval] 0.86 [0.81-0.92]), whereas each quintile increase in ethnocultural composition was associated with higher odds (adjusted odds ratio [95% confidence interval] 1.32 [1.22-1.43]). Residential instability and economic dependency were not associated with scheduling. No deprivation domain was associated with time to the first attended appointment, cancellations, or no-shows. Conclusions and Relevance: In this cohort, area-level deprivation was associated with whether patients were scheduled for an appointment but not with wait time or missed visits after scheduling. These findings suggest that equity interventions should focus on completion of referral and scheduling processes.

Background: The systemic immune responses associated with persistent respiratory symptoms (PRS) after exposure to airborne environmental pollutants remain poorly understood. Objective: To identify immune disturbances associated with PRS, defined as persistent wheeze, cough, or breathlessness, we examined systemic immune responses and airway function in a cross-sectional cohort with detailed histories of airborne pollutant exposure. Methods: Never-smoking post-deployment Veterans with PRS (n=16) or without PRS (n=24) underwent chest computed tomography, pulmonary function testing, and oscillometry to assess structural and functional airway abnormalities. Peripheral blood mononuclear cells (PBMCs) were stimulated with anti-CD3/CD28 antibodies, lipopolysaccharide, or {beta}-glucan, and cytokine production was measured. Correlation analyses evaluated associations between cytokine responses and physiological measures of airway function. Results: Oscillometry, but not conventional pulmonary function testing or chest computed tomography, detected small-airway abnormalities in participants with PRS, including significantly greater frequency dependence of resistance and higher resonant frequency. Baseline PBMC cytokine concentrations were similar between groups. After stimulation, however, PBMCs from participants with PRS showed increased IL-17A production consistent with a type 17 (T17) response; innate stimulation also increased the type 2 (T2) cytokines IL-33 and IL-4. T2/T17 cytokine responses correlated positively with oscillometric measures of small-airway dysfunction. Conclusion: Individuals with PRS exhibited a stimulus-dependent systemic T2/T17 immune signature that was associated with early small-airway dysfunction. Clinical Implication: Stimulus-dependent systemic immune profiling, combined with oscillometry, may help identify early respiratory abnormalities in pollutant-exposed individuals whose conventional pulmonary tests remain normal.

Background: Immunochemotherapy (ICT) is considered standard in regards to care for small-cell lung cancer (SCLC) in extensive stages, yet reliable biomarkers for treatment response remain elusive. While previous univariate analyses suggest specific peripheral lymphocyte subsets correlate with survival, the systemic immune response involves complex, multivariate interactions that require advanced analytical approaches. Methods: This paper analysed high-dimensional flow cytometry data from 32 patients with stage IV SCLC treated with carboplatin, etoposide, and atezolizumab. Peripheral blood was analysed at baseline (V0) and longitudinally during treatment. To identify potential early predictive biomarkers and mitigate sample attrition in later cycles, we focused on baseline and measurements after two cycles of ICT (V1). We employed a rigorous machine learning framework utilising nested cross-validation, bootstrapping, and permutation-based statistical testing to evaluate eleven different regression and survival models. Results: Under model-appropriate metrics, regressors did not generalise (R2 <0); conversely, censoring-aware Random Survival Forests (RSF) successfully extracted robust prognostic signatures. Baseline immune profiles (V0) achieved a concordance index (C-index) of 0.66 (p= 0.015), while dynamic changes from V0 to V1 ({triangleup}V) achieved a C-index of 0.65 (p= 0.022). Crucially, absolute values measured after two cycles of ICT (V1) yielded no significant signal (p= 0.445). Feature importance analysis confirmed the prognostic value of Th17 normalisation and identified Naive Regulatory T cells and Memory B cells as candidate components. Conclusion: Machine learning validation confirms a predictive signal in the peripheral immune profile of SCLC patients. Early dynamic shifts in the balance between regulatory and effector immune arms are associated with prognosis, contrasting with the lack of signal in absolute counts after two cycles of ICT. These findings establish a proof of concept for multivariate liquid biopsy immune profiling, warranting confirmation in larger cohorts and highlighting the necessity of integrating systemic and tumour-intrinsic data.

Introduction: Idiopathic inflammatory myopathy-associated interstitial lung disease (IIM-ILD) is a major cause of morbidity and mortality. We tested whether quantitative myositis-specific autoantibodies and proteomic profiling capture biological heterogeneity and prognosis beyond categorical serology. Methods: Myositis-specific autoantibodies were quantified using the luciferase immunoprecipitation systems assay, and 184 serum proteins were measured in 226 IIM patients; 199 with higher-ILD-risk autoantibodies (Jo-1/MDA5/PL-7/PL-12/EJ), 27 with lower-ILD-risk autoantibodies (Mi-2/NXP2/TIF1{gamma}) and 35 healthy controls. We identified shared and subgroup-specific differences by comparing each subgroup with controls, then correlated quantitative autoantibody and protein levels within higher-risk subgroups. Additional analyses included pathway enrichment, unsupervised clustering, longitudinal lung-function change, and mortality. Results: Higher-ILD-risk subgroups shared interferon-responsive CXCR3 chemokine, IL-6/JAK/STAT3, and apoptosis signaling. Dominant autoantibody subgroup profiles differed: interferon/CXCR3 chemokine signaling with T-cell activation and monocyte recruitment in anti-Jo-1; proteostasis/antigen-processing and vascular/cellular stress signals in anti-MDA5; IL-6/macrophage and profibrotic signals in anti-PL-12; and apoptotic and innate immune activation with metabolic/redox-stress signals in anti-PL-7. Within higher-ILD-risk subgroups, autoantibody levels correlated with interferon-response, profibrotic, and metabolic/vascular proteins (r=0.40-0.74; nominal p<0.05). Unsupervised clustering identified four proteomic endotypes beyond autoantibody type, including an injury-stress endotype associated with worse lung function and poorer survival, and a chemokine/checkpoint-high endotype with relatively preserved lung function. Across 203 participants with 38 deaths, a weighted 10-protein score was associated with all-cause mortality (HR, 3.28; 95% CI, 2.12-5.08; p<0.001). Conclusions: Integrated quantitative autoantibodies and proteomic profiling revealed shared inflammatory biology, autoantibody-associated signatures, and an injury-stress endotype associated with poor survival in IIM-ILD, supporting risk stratification beyond categorical serology.

Background: Blood volume (BV) in patients with chronic heart failure (HF) is characterized by heterogeneity in volume profiles; one profile being "normal BV". While overall intravascular volume may be considered normal clinically, the relative contributions of red blood cell (RBC) mass and plasma volume (PV) may not be. Objective: Assess how normal is a "normal BV" based on quantitative measures of RBC mass and PV. Methods: Retrospective analysis was undertaken in 395 patients with Class II-III HF. BV was quantitated using indicator-dilution methodology. Cohort was stratified by normal and hypervolemic BV. Results: Of the cohort, 31% (123/395) demonstrated normal total BV and 62% (244/395) hypervolemic BV. Of patients with "normal BV", 36% (44/123) demonstrated normal RBC mass and 60% normal PV (74/123). Importantly, 60% (74/123) demonstrated a deficit in RBC mass (true anemia), while a low hemoglobin (<12 g/dL) was present in just 29% (36/123). An excess in RBC mass (erythrocytosis) in 4% (5/123). Notably, true normal BV (i.e., normal RBC mass and normal PV) was observed in only 30% (37/123) of patients with an overall "normal" intravascular volume. Conclusions: Findings reveal that "normal BV" can be misleading by concealing substantial variability in RBC mass (including unrecognized anemia and erythrocytosis) as well as different degrees of PV expansion and contraction. An actual normal BV was identified in a minority of "normal BV" patients. This underscores the importance of looking beyond overall "normal BV" to the contributing elements of RBC mass and PV with significant implications for patient management and outcomes.

Background: General illness-related sick leave among teachers represents a relevant public health and workforce management issue. However, long-term population-based evidence describing its distribution and associated factors in Latin American urban educational systems remains limited. This study aimed to characterize the occurrence, distribution, duration, and sociodemographic, occupational, temporal, and territorial factors associated with general illness-related sick leave among public school teachers in Bogota between 2010 and 2025. Methods: A retrospective cohort study was conducted using integrated administrative databases from the Bogota District Department of Education. The primary outcome was the occurrence of at least one general illness-related sick leave episode in a teacher-month observation. Descriptive analyses were performed to characterize sociodemographic and occupational patterns. A multivariable logistic regression model was used to estimate associations. Month and year were included as temporal fixed effects to account for seasonal patterns, academic-calendar effects, pandemic-related disruption, and secular changes. Results: The cohort included 59,697 unique teachers, contributing 537,025 teacher-year observations from teachers with an active employment record between January 1, 2010, and July 31, 2025. Overall, 41.59% of teacher-year observations included at least one general illness-related sick leave episode, and 83.26% of teachers had at least one episode at any time during follow-up. Respiratory diseases accounted for the largest share of episodes, followed by musculoskeletal and infectious diseases. Mean duration varied substantially by diagnostic category, ranging from short respiratory and infectious episodes to longer absences related to neoplasms, circulatory diseases, injuries, and mental health conditions. In the multivariable teacher-month model, sick leave occurrence was associated with age, sex, occupational role, teaching area, contract type, locality, calendar month, and calendar year. Lower odds were observed among male teachers, principals, and teachers with provisional contracts, while temporal and territorial variation was observed across months, years, and localities. Conclusions: General illness-related sick leave among public school teachers in Bogota showed consistent sociodemographic, occupational, temporal, and territorial patterns. Respiratory and musculoskeletal conditions accounted for the largest share of episodes, while chronic, neoplastic, injury-related, circulatory, and mental health conditions were associated with longer durations. These findings provide population-level evidence to inform occupational health surveillance, seasonal preparedness, and workforce planning strategies within urban educational systems.

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

Ambient particulate matter (PM) is a well-established environmental risk factor for non-communicable diseases, yet its influence on mitochondrial function remains poorly defined. Mitochondrial DNA copy number (mtDNA-CN) serves as a biomarker of mitochondrial biogenesis, making it a candidate exposure biomarker. We conducted the study per PRISMA guidelines (PROSPERO-CRD420261320957) and examined the association between ambient PM exposure and mtDNA-CN. Risk of bias was assessed using Joanna Briggs Institute tools, and relative and absolute changes in mtDNA-CN were pooled using random-effects models, with subgroup analyses by pollutant type and descriptive synthesis of mechanistic evidence. Of 1,224 records identified, 24 studies met inclusion criteria for quantitative analysis, with 12 reporting percentage change and 12 reporting absolute values, covering 13,092 participants. PM exposure was significantly associated with decreased percentage mtDNA-CN (ES: -4.90; 95% CI: -7.97 to -1.82; p = 0.002), while absolute mtDNA-CN levels increased significantly (ES = 0.55; 95% CI: 0.05 to 1.04; p = 0.030). Mechanistic pathways contributing included mtDNA hypermethylation, impaired mitochondrial biogenesis and dynamics. Our findings show ambient PM exposure alters mtDNA-CN, though directionality differs by metric, pointing to the need for larger prospective studies to validate mtDNA-CN as a reliable biomarker of airborne PM and nanoparticulate exposure.

This study documents the derivation and validation of a deterministic algorithm for cause-of-death (COD) ascertainment from longitudinal real-world medical claims data, evaluated against an independent state-level death certificate file. Death certificates are the dominant reference standard in mortality research but carry well-documented limitations, including primary-cause error rates estimated at 20-40\% across empirical studies. A matched analytic cohort of 216,382 individuals (Connecticut death records, 2017--2025, age 25 and above) was constructed after exclusion of mechanism-of-injury cases and removal of ill-defined symptom-code entries from both sources. Concordance between algorithmic and certificate-based COD was assessed through three complementary frameworks: age-stratified positive predictive value (PPV) at the ICD-10-CM chapter level under a full-set concordance scenario; mean absolute rank difference (MARD) for chapters identified by both sources; and analyses of breadth, depth, and code-level specificity of COD reporting. Chapter-level PPV was strongest for individuals aged 55 and above, with all estimates representing conservative lower bounds given the known error rate of the certificate reference standard. The algorithm consistently reported broader and more granular contributing cause profiles than the death certificate, with discordances directionally consistent with the well-documented tendency of certificates to under-report contributing conditions. These findings support the conclusion that algorithmic COD ascertainment from longitudinal claims data is a feasible and scalable alternative to certificate-based attribution and, at population scale, a principled methodology for characterising death certificate error rates beyond what small-sample chart review studies can achieve.

Background: Adults with congenital heart disease (ACHD) represent a rapidly expanding population with evolving mortality patterns. Despite improved survival, excess mortality persists. Objective: To evaluate the incidence, causes, and predictors of mortality in a contemporary ACHD cohort. Methods: We performed a retrospective cohort study of adults (?18 years) first evaluated at Mayo Clinic from 2002?2023. Baseline clinical, imaging, and electrocardiographic data were analyzed. Vital status was determined using institutional records and the Accurint national mortality database. Kaplan-Meier analysis and Cox proportional hazard models were used to evaluate mortality and identify independent predictors of mortality Results: A total of 7,678 ACHD patients were included, with median age of 36.8 years and median follow-up of 11.4 years. During 78,768 patient-years of follow-up, 1,116 patients died (median age at death 57.2 years), corresponding to an annual mortality rate of 1.4%. The cumulative rate of all-cause mortality at 5, 10, 15, and 20 years was 6.9%, 12.0%, 19.0%, and 26.2%, respectively. When stratified by CHD complexity, the annual death rate in patients with severe CHD (2.4%/year) was twice that of patients with moderate or mild CHD (both 1.2%/year). Older age and ACHD subtypes, specifically, cyanotic heart disease (HR 3.9, 95% CI 2.9?5.3) and Fontan physiology (HR 3.2, 95% CI 2.3?4.4), were strongly associated with increased mortality. Additional independent predictors included male sex, ventricular dysfunction, advanced NYHA class, prior heart failure hospitalization, hypertension, smoking, coronary artery disease, renal dysfunction, and abnormal hemoglobin levels. Cardiovascular causes accounted for 57.7% of deaths with known etiology, predominantly heart failure (48.9%) and sudden cardiac death (21.9%), while non-cardiovascular causes were driven mainly by infection and malignancy. Conclusions: In this large contemporary ACHD cohort, mortality was driven by ventricular dysfunction, heart failure, and systemic end-organ involvement in addition to the underlying congenital anatomy. Both cardiovascular and non-cardiovascular causes contributed significantly to mortality. These findings underscore the need for comprehensive multidisciplinary ACHD care focused on early recognition of cardiac functional decline, management of acquired comorbidities, and end-organ dysfunction.