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Mickaël Martin,1 Natalie Almeras,1 Jean-Pierre Després,1 Harvey O Coxson,2 George R Washko,3 Isabelle Vivodtzev,4 Emiel FM Wouters,5 Erica Rutten,6 Michelle C Williams,7 John T Murchison,8 William MacNee,7 Don D Sin,2 François Maltais1 On behalf of the Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) Study Group 1Research Centre, Institut universitaire de cardiologie et de pneumologie de Québec, Université Laval, Québec, QC, 2Department of Radiology, University of British Columbia, Vancouver, BC, Canada; 3Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA; 4Hypoxia Pathophysiology Laboratory, Grenoble University Hospital, Grenoble, France; 5Department of Respiratory Medicine, Maastricht University Medical Center, Maastricht, 6Research and Development, CIRO, Horn, the Netherlands; 7Department of Respiratory Medicine, University of Edinburgh, 8Department of Radiology, Royal Infirmary of Edinburgh, Edinburgh, UK Background: Obesity is increasingly associated with COPD, but little is known about the prevalence of ectopic fat accumulation in COPD and whether this can possibly be associated with poor clinical outcomes and comorbidities. The Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) substudy tested the hypothesis that COPD is associated with increased ectopic fat accumulation and that this would be associated with COPD-related outcomes and comorbidities.Methods: Computed tomography (CT) images of the thorax obtained in ECLIPSE were used to quantify ectopic fat accumulation at L2–L3 (eg, cross-sectional area [CSA] of visceral adipose tissue [VAT] and muscle tissue [MT] attenuation, a reflection of muscle fat infiltration) and CSA of MT. A dose–response relationship between CSA of VAT, MT attenuation and CSA of MT and COPD-related outcomes (6-minute walking distance [6MWD], exacerbation rate, quality of life, and forced expiratory volume in 1 second [FEV1] decline) was addressed with the Cochran–Armitage trend test. Regression models were used to investigate possible relationships between CT body composition indices and comorbidities.Results: From the entire ECLIPSE cohort, we identified 585 subjects with valid CT images at L2–L3 to assess body composition. CSA of VAT was increased (P

BackgroundPulmonary endothelial damage has been shown to precede the development of emphysema in animals, and vascular changes in humans have been observed in COPD and emphysema.Research questionIs intraparenchymal vascular pruning associated with longitudinal progression of emphysema on CT imaging or decline in lung function over 5 years?Study design and methodsThe Genetic Epidemiology of COPD Study enrolled ever smokers with and without COPD from 2008 through 2011. The percentage of emphysema-like lung, or "percent emphysema," was assessed at baseline and after 5 years on noncontrast CT imaging as the percentage of lung voxels < -950 Hounsfield units. An automated CT imaging-based tool assessed and classified intrapulmonary arteries and veins. Spirometry measures are postbronchodilator. Pulmonary arterial pruning was defined as a lower ratio of small artery volume (< 5 mm2 cross-sectional area) to total lung artery volume. Mixed linear models included demographics, anthropomorphics, smoking, and COPD, with emphysema models also adjusting for CT imaging scanner and lung function models adjusting for clinical center and baseline percent emphysema.ResultsAt baseline, the 4,227 participants were 60 ± 9 years of age, 50% were women, 28% were Black, 47% were current smokers, and 41% had COPD. Median percent emphysema was 2.1 (interquartile range, 0.6-6.3) and progressed 0.24 percentage points/y (95% CI, 0.22-0.26 percentage points/y) over 5.6 years. Mean FEV1 to FVC ratio was 68.5 ± 14.2% and declined 0.26%/y (95% CI, -0.30 to -0.23%/y). Greater pulmonary arterial pruning was associated with more rapid progression of percent emphysema (0.11 percentage points/y per 1-SD increase in arterial pruning; 95% CI, 0.09-0.16 percentage points/y), including after adjusting for baseline percent emphysema and FEV1. Arterial pruning also was associated with a faster decline in FEV1 to FVC ratio (-0.04%/y per 1-SD increase in arterial pruning; 95% CI, -0.008 to -0.001%/y).InterpretationPulmonary arterial pruning was associated with faster progression of percent emphysema and more rapid decline in FEV1 to FVC ratio over 5 years in ever smokers, suggesting that pulmonary vascular differences may be relevant in disease progression.Trial registryClinicalTrials.gov; No.: NCT00608764; URL: www.clinicaltrials.gov.

Rationale: The role of 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (statins) in the development or progression of interstitial lung disease (ILD) is controversial.Objectives: To evaluate the association between statin use and ILD.Methods: We used regression analyses to evaluate the association between statin use and interstitial lung abnormalities (ILA) in a large cohort of smokers from COPDGene. Next, we evaluated the effect of statin pretreatment on bleomycin-induced fibrosis in mice and explored the mechanism behind these observations in vitro.Measurements and Main Results: In COPDGene, 38% of subjects with ILA were taking statins compared with 27% of subjects without ILA. Statin use was positively associated in ILA (odds ratio, 1.60; 95% confidence interval, 1.03-2.50; P = 0.04) after adjustment for covariates including a history of high cholesterol or coronary artery disease. This association was modified by the hydrophilicity of statin and the age of the subject. Next, we demonstrate that statin administration aggravates lung injury and fibrosis in bleomycin-treated mice. Statin pretreatment enhances caspase-1-mediated immune responses in vivo and in vitro; the latter responses were abolished in bone marrow-derived macrophages isolated from Nlrp3(-/-) and Casp1(-/-) mice. Finally, we provide further insights by demonstrating that statins enhance NLRP3-inflammasome activation by increasing mitochondrial reactive oxygen species generation in macrophages.Conclusions: Statin use is associated with ILA among smokers in the COPDGene study and enhances bleomycin-induced lung inflammation and fibrosis in the mouse through a mechanism involving enhanced NLRP3-inflammasome activation. Our findings suggest that statins may influence the susceptibility to, or progression of, ILD. Clinical trial registered with www.clinicaltrials.gov (NCT 00608764). [ABSTRACT FROM AUTHOR]

Rationale and Objectives: To evaluate the correlations of tracheal volume and collapsibility on inspiratory and end-expiratory computed tomography (CT) with lung volume and with lung function in smokers.Materials and Methods: The institutional review board approved this study at each institution. 85 smokers (mean age 68, range 45-87 years; 40 females and 45 males) underwent pulmonary function tests and chest CT at full inspiration and end-expiration. On both scans, intrathoracic tracheal volume and lung volume were measured. Collapsibility of the trachea and the lung was expressed as expiratory/inspiratory (E/I) ratios of these volumes. Correlations of the tracheal measurements with the lung measurements and with lung function were evaluated by the linear regression analysis.Results: Tracheal volume showed moderate or strong, positive correlations with lung volume on both inspiratory (r = 0.661, P < .0001) and end-expiratory (r = 0.749, P < .0001) scans. The E/I ratio of tracheal volume showed a strong, positive correlation with the E/I ratio of lung volume (r = 0.711, P < .0001). A weak, negative correlation was found between the E/I ratio of tracheal volume and the ratio of forced expiratory volume in the first second to forced vital capacity (r = -0.436, P < .0001). Also, a weak, positive correlation was observed between the E/I ratio of tracheal volume and the ratio of residual volume to total lung capacity (r = 0.253, P = .02).Conclusions: Tracheal volume and collapsibility, measured by inspiratory and end-expiratory CT scans, is related to lung volume and collapsibility. The highly collapsed trachea on end-expiratory CT does not indicate more severe airflow limitation or air-trapping in smokers. [ABSTRACT FROM AUTHOR]

Rationale: Previous investigations have identified several potential predictors of outcomes from lung volume reduction surgery (LVRS). A concern regarding these studies has been their small sample size, which may limit generalizability. We therefore sought to examine radiographic and physiologic predictors of surgical outcomes in a large, multicenter clinical investigation, the National Emphysema Treatment Trial.Objectives: To identify objective radiographic and physiological indices of lung disease that have prognostic value in subjects with chronic obstructive pulmonary disease being evaluated for LVRS.Methods: A subset of the subjects undergoing LVRS in the National Emphysema Treatment Trial underwent preoperative high-resolution computed tomographic (CT) scanning of the chest and measures of static lung recoil at total lung capacity (SRtlc) and inspiratory resistance (Ri). The relationship between CT measures of emphysema, the ratio of upper to lower zone emphysema, CT measures of airway disease, SRtlc, Ri, the ratio of residual volume to total lung capacity (RV/TLC), and both 6-month postoperative changes in FEV(1) and maximal exercise capacity were assessed.Measurements and Main Results: Physiological measures of lung elastic recoil and inspiratory resistance were not correlated with improvement in either the FEV(1) (R = -0.03, P = 0.78 and R = -0.17, P = 0.16, respectively) or maximal exercise capacity (R = -0.02, P = 0.83 and R = 0.08, P = 0.53, respectively). The RV/TLC ratio and CT measures of emphysema and its upper to lower zone ratio were only weakly predictive of postoperative changes in both the FEV(1) (R = 0.11, P = 0.01; R = 0.2, P < 0.0001; and R = 0.23, P < 0.0001, respectively) and maximal exercise capacity (R = 0.17, P = 0.0001; R = 0.15, P = 0.002; and R = 0.15, P = 0.002, respectively). CT assessments of airway disease were not predictive of change in FEV(1) or exercise capacity in this cohort.Conclusions: The RV/TLC ratio and CT measures of emphysema and its distribution are weak but statistically significant predictors of outcome after LVRS. [ABSTRACT FROM AUTHOR]

Rationale: Vascular alteration of small pulmonary vessels is one of the characteristic features of pulmonary hypertension in chronic obstructive pulmonary disease. The in vivo relationship between pulmonary hypertension and morphological alteration of the small pulmonary vessels has not been assessed in patients with severe emphysema.Objectives: We evaluated the correlation of total cross-sectional area of small pulmonary vessels (CSA) assessed on computed tomography (CT) scans with the degree of pulmonary hypertension estimated by right heart catheterization.Methods: In 79 patients with severe emphysema enrolled in the National Emphysema Treatment Trial (NETT), we measured CSA less than 5 mm(2) (CSA(<5)) and 5 to 10 mm(2) (CSA(5-10)), and calculated the percentage of total CSA for the lung area (%CSA(<5) and %CSA(5-10), respectively). The correlations of %CSA(<5) and %CSA(5-10) with pulmonary arterial mean pressure (Ppa) obtained by right heart catheterization were evaluated. Multiple linear regression analysis using Ppa as the dependent outcome was also performed.Measurements and Main Results: The %CSA(<5) had a significant negative correlation with Ppa (r = -0.512, P < 0.0001), whereas the correlation between %CSA(5-10) and Ppa did not reach statistical significance (r = -0.196, P = 0.083). Multiple linear regression analysis showed that %CSA(<5) and diffusing capacity of carbon monoxide (DL(CO)) % predicted were independent predictors of Ppa (r(2) = 0.541): %CSA (<5) (P < 0.0001), and DL(CO) % predicted (P = 0.022).Conclusions: The %CSA(<5) measured on CT images is significantly correlated to Ppa in severe emphysema and can estimate the degree of pulmonary hypertension. [ABSTRACT FROM AUTHOR]

Rationale: Debate exists about the immunogenicity and protective efficacy of antibodies produced by the 23-valent pneumococcal polysaccharide vaccine (PPSV23) in chronic obstructive pulmonary disease (COPD). The 7-valent diphtheria-conjugated pneumococcal polysaccharide vaccine (PCV7) induces a more robust immune response than PPSV23 in healthy elderly adults.Objectives: We hypothesized that serotype-specific IgG antibody concentration and functional antibody activity would be superior after PCV7 vaccination compared with PPSV23 in moderate to severe COPD. We also posited that older age and prior PPSV23 vaccination would be associated with reduced vaccine responsiveness.Methods: One hundred twenty patients with COPD were randomized to PPSV23 (63 subjects) or PCV7 (57 subjects). IgG concentrations were determined by ELISA; functional antibody activity was assayed with a standardized opsonophagocytosis assay and reported as an opsonization killing index (OPK). Increases in serotype-specific IgG and OPK at 1 month post vaccination were compared within and between vaccine groups.Measurements and Main Results: Both vaccines were well tolerated. Within each study group, postvaccination IgG and OPK were higher than baseline (P < 0.01) for all serotypes. Adjusted for baseline levels, postvaccination IgG was higher in the PCV7 group than the PPSV23 group for all seven serotypes, reaching statistical significance for five (P < 0.05). PCV7 resulted in a higher OPK for six of seven serotypes (statistically greater for four) compared with PPSV23. In multivariate analyses, younger age, vaccine naivety, and receipt of PCV7 were associated with increased OPK responses.Conclusions: PCV7 induces a superior immune response at 1 month post vaccination compared with PPSV23 in COPD. Older age and prior PPSV23 reduce vaccine responsiveness. Clinical trial registered with www.clinicaltrials.gov (NCT00457977). [ABSTRACT FROM AUTHOR]

Monocyte-derived alveolar macrophages drive lung injury and fibrosis in murine models and are associated with pulmonary fibrosis in humans. Monocyte-derived alveolar macrophages have been suggested to develop a phenotype that promotes lung repair as injury resolves. We compared single-cell and cytokine profiling of the alveolar space in a cohort of 35 patients with post-acute sequelae of COVID-19 who had persistent respiratory symptoms and abnormalities on a computed tomography scan of the chest that subsequently improved or progressed. The abundance of monocyte-derived alveolar macrophages, their gene expression programs, and the level of the monocyte chemokine CCL2 in bronchoalveolar lavage fluid positively associated with the severity of radiographic fibrosis. Monocyte-derived alveolar macrophages from patients with resolving or progressive fibrosis expressed the same set of profibrotic genes. Our findings argue against a distinct reparative phenotype in monocyte-derived alveolar macrophages, highlighting their utility as a biomarker of failed lung repair and a potential target for therapy., (© 2024. The Author(s).)

Rationale: Quantitative interstitial abnormalities (QIAs) are a computed tomography (CT) measure of early parenchymal lung disease associated with worse clinical outcomes, including exercise capacity and symptoms. The presence of pulmonary vasculopathy in QIAs and its role in the QIA-outcome relationship is unknown. Objectives: To quantify radiographic pulmonary vasculopathy in QIAs and determine whether this vasculopathy mediates the QIA-outcome relationship. Methods: Ever-smokers with QIAs, outcomes, and pulmonary vascular mediator data were identified from the Genetic Epidemiology of COPD (COPDGene) study cohort. CT-based vascular mediators were right ventricle-to-left ventricle ratio, pulmonary artery-to-aorta ratio, and preacinar intraparenchymal arterial dilation (pulmonary artery volume, 5-20 mm 2 in cross-sectional area, normalized to total arterial volume). Outcomes were 6-minute walk distance and a modified Medical Council Research Council Dyspnea Scale score of 2 or higher. Adjusted causal mediation analyses were used to determine whether the pulmonary vasculature mediated the QIA effect on outcomes. Associations of preacinar arterial dilation with select plasma biomarkers of pulmonary vascular dysfunction were examined. Measurements and Main Results: Among 8,200 participants, QIA burden correlated positively with vascular damage measures, including preacinar arterial dilation. Preacinar arterial dilation mediated 79.6% of the detrimental impact of QIA on 6-minute walk distance (56.2-100%; P  < 0.001). Pulmonary artery-to-aorta ratio was a weak mediator, and right ventricle-to-left ventricle ratio was a suppressor. Similar results were observed in the relationship between QIA and modified Medical Council Research Council dyspnea score. Preacinar arterial dilation correlated with increased pulmonary vascular dysfunction biomarker levels, including angiopoietin-2 and N-terminal brain natriuretic peptide. Conclusions: Parenchymal QIAs deleteriously impact outcomes primarily through pulmonary vasculopathy. Preacinar arterial dilation may be a novel marker of pulmonary vasculopathy in QIAs.

Rationale: Accelerated decline in lung function is associated with incident COPD, hospitalizations and death. However, identifying this trajectory with longitudinal spirometry measurements is challenging in clinical practice., Objective: To determine whether a proteomic risk score trained on accelerated decline in lung function can assess risk of future respiratory disease and mortality., Methods: In CARDIA, a population-based cohort starting in young adulthood, longitudinal measurements of FEV1 percent predicted (up to six timepoints over 30 years) were used to identify accelerated and normal decline trajectories. Protein aptamers associated with an accelerated decline trajectory were identified with multivariable logistic regression followed by LASSO regression. The proteomic respiratory susceptibility score was derived based on these circulating proteins and applied to the UK Biobank and COPDGene studies to examine associations with future respiratory morbidity and mortality., Measurements and Results: Higher susceptibility score was independently associated with all-cause mortality (UKBB: HR 1.56, 95%CI 1.50-1.61; COPDGene: HR 1.75, 95%CI 1.63-1.88), respiratory mortality (UKBB: HR 2.39, 95% CI 2.16-2.64; COPDGene: HR 1.83, 95%CI 1.33-2.51), incident COPD (UKBB: HR 1.84, 95%CI 1.71-1.98), incident respiratory exacerbation (COPDGene: OR 1.11, 95%CI 1.03-1.20), and incident exacerbation requiring hospitalization (COPDGene: OR 1.18, 95%CI 1.08-1.28)., Conclusions: A proteomic signature of increased respiratory susceptibility identifies people at risk of respiratory death, incident COPD, and respiratory exacerbations. This susceptibility score is comprised of proteins with well-known and novel associations with lung health and holds promise for the early detection of lung disease without requiring years of spirometry measurements.

Rationale: Some with interstitial lung abnormalities (ILA) have suspected interstitial lung disease (ILD), a subgroup with adverse outcomes. Rates of development and progression of suspected ILD and their effect on mortality are unknown., Objectives: To determine rates of development and progression of suspected ILD and assess effects of individual ILD and progression criteria on mortality., Methods: Participants from COPDGene were included. ILD was defined as ILA and fibrosis and/or FVC <80% predicted. Prevalent ILD was assessed at enrollment, incident ILD and progression at 5-year follow-up. CT progression was assessed visually and FVC decline as relative change. Multivariable Cox regression tested associations between mortality and ILD groups., Results: Of 9,588 participants at enrollment, 267 (2.8%) had prevalent ILD. Those with prevalent ILD had 52% mortality after median 10.6 years, which was higher than ILA (33%; HR=2.0; p<0.001). The subgroup of prevalent ILD with fibrosis only had worse mortality (59%) than ILA (HR=2.2; p<0.001). 97 participants with prevalent ILD completed 5-year follow-up: 32% had stable CT and relative FVC decline <10%, 6% FVC decline ≥10% only, 39% CT progression only, and 22% both CT progression and FVC decline ≥10%. Mortality rates were 32%, 50%, 45%, and 46% respectively; those with CT progression only had worse mortality than ILA (HR=2.6; p=0.005). At 5-year follow-up, incident ILD occurred in 168/4,843 participants without prevalent ILD and had worse mortality than ILA (HR=2.5; p<0.001)., Conclusion: Rates of mortality and progression are high among those with suspected ILD in COPDGene; fibrosis and radiologic progression are important predictors of mortality.

Low muscle mass is associated with numerous adverse outcomes independent of other associated comorbid diseases. We aimed to predict and understand an individual's risk for developing low muscle mass using proteomics and machine learning. We identified eight biomarkers associated with low pectoralis muscle area (PMA). We built three random forest classification models that used either clinical measures, feature selected biomarkers, or both to predict development of low PMA. The area under the receiver operating characteristic curve for each model was: clinical-only = 0.646, biomarker-only = 0.740, and combined = 0.744. We displayed the heterogenetic nature of an individual's risk for developing low PMA and identified two distinct subtypes of participants who developed low PMA. While additional validation is required, our methods for identifying and understanding individual and group risk for low muscle mass could be used to enable developments in the personalized prevention of low muscle mass., (© 2024. The Author(s).)

Objective: To compare longitudinal changes in spirometric measures between patients with rheumatoid arthritis (RA) and non-RA comparators., Methods: We analysed longitudinal data from two prospective cohorts: the UK Biobank and COPDGene. Spirometry was conducted at baseline and a second visit after 5-7 years. RA was identified based on self-report and disease-modifying antirheumatic drug use; non-RA comparators reported neither. The primary outcomes were annual changes in the per cent-predicted forced expiratory volume in 1 s (FEV 1 %) and per cent predicted forced vital capacity (FVC%). Statistical comparisons were performed using multivariable linear regression. The analysis was stratified based on baseline smoking status and the presence of obstructive pattern (FEV 1 /FVC <0.7)., Results: Among participants who underwent baseline and follow-up spirometry, we identified 233 patients with RA and 37 735 non-RA comparators. Among never-smoking participants without an obstructive pattern, RA was significantly associated with more FEV 1 % decline (β=-0.49, p=0.04). However, in ever smokers with ≥10 pack-years, those with RA exhibited significantly less FEV 1 % decline than non-RA comparators (β=0.50, p=0.02). This difference was more pronounced among those with an obstructive pattern at baseline (β=1.12, p=0.01). Results were similar for FEV 1 /FVC decline. No difference was observed in the annual FVC% change in RA versus non-RA., Conclusions: Smokers with RA, especially those with baseline obstructive spirometric patterns, experienced lower FEV 1 % and FEV 1 /FVC decline than non-RA comparators. Conversely, never smokers with RA had more FEV 1 % decline than non-RA comparators. Future studies should investigate potential treatments and the pathogenesis of obstructive lung diseases in smokers with RA., Competing Interests: Competing interests: PAJ reports grant funding and other support from Novartis, Galapagos and Boehringer Ingelheim, unrelated to this work. MM reports institutional grant support from Bayer and Honoraria from Chickasaw Nation. MHC has received grant funding from Bayer, unrelated to this work. TJD received support from Bayer and has been part of a clinical trial funded by Genentech, unrelated to this study. PFD reports grant funding from Bristol Myers Squibb. ZW has received grant funding from Bristol-Myers Squibb and Principia/Sanofi and consulting fees from Viela Bio, Zenas BioPharma, Horizon Therapeutics, Sanofi, MedPace, BioCryst, Amgen, Nkarta, Inc, Adicet Bio, and Therapeutic’s and participation in data safety monitoring board or advisory board for Sanofi, Horizon, Novartis, Visterra/Otsuka and Shionogi, unrelated to this work. GMH reports consulting fees from Boehringer-Ingelheim, and the Gerson Lehrman Group, unrelated to this work. EKS has received grant support from Bayer and Northpond Laboratories, unrelated to this work. SYA reports consulting fees from Verona Pharmaceuticals and Vertex Pharmaceuticals and is cofounder and co-owner of Quantitative Imaging Solutions. RSJE reports contracts from Lung Biotechnology and Insmed, received a grant support from Boehringer Ingelheim and is cofounder and an equity holder of Quantitative Imaging Solutions. GRW reports grants from Boehringer Ingelheim, consultancy for Pulmonx, Janssen Pharmaceuticals, Novartis, and Vertex, and is founder and co-owner of Quantitative Imaging Solutions. JS has received research support from Bristol Myers Squibb and performed consultancy for AbbVie, Amgen, Boehringer Ingelheim, Bristol Myers Squibb, Gilead, Inova Diagnostics, Janssen, Optum, Pfizer, ReCor, Sobi, and UCB, unrelated to this work. Other authors report no competing interests., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Rationale: The term "pre-chronic obstructive pulmonary disease" ("pre-COPD") refers to individuals at high risk of developing COPD who do not meet conventional spirometric criteria for airflow obstruction. New approaches to identifying these individuals are needed, particularly in younger populations. Objectives: To determine whether lung function thresholds and respiratory symptoms can be used to identify individuals at risk of developing COPD. Methods: The Tasmanian Longitudinal Health Study comprises a population-based cohort first studied in 1968 (at age 7 yr). Respiratory symptoms, pre- and post-bronchodilator (BD) spirometry, diffusing capacity, and static lung volumes were measured in a subgroup at age 45, and the incidence of COPD was assessed at age 53. For each lung function measure, z -scores were calculated using Global Lung Function Initiative references. The optimal threshold for best discrimination of COPD incidence was determined by the unweighted Youden index. Measurements and Main Results: Among 801 participants who did not have COPD at age 45, the optimal threshold for COPD incidence by age 53 was pre-BD FEV 1 /FVC z -score less than -1.264, corresponding to the lowest 10 th percentile. Those below this threshold had a 36-fold increased risk of developing COPD over an 8-year follow-up period (risk ratio, 35.8; 95% confidence interval, 8.88 to 144), corresponding to a risk difference of 16.4% (95% confidence interval, 3.7 to 67.4). The sensitivity was 88%, and the specificity was 87%. Positive and negative likelihood ratios were 6.79 and 0.14, respectively. Respiratory symptoms, post-BD spirometry, diffusing capacity, and static lung volumes did not improve on the classification achieved by pre-BD FEV 1 /FVC alone. Conclusions: This is the first study, to our knowledge, to evaluate the discriminatory accuracy of spirometry, diffusing capacity, and static lung volume thresholds for COPD incidence in middle-aged adults. Our findings support the inclusion of pre-BD spirometry in the physiological definition of pre-COPD and indicate that pre-BD FEV 1 /FVC at the 10th percentile accurately identifies individuals at high risk of developing COPD in community-based settings.

Rationale: Quantitative interstitial abnormalities (QIAs) are early measures of lung injury automatically detected on chest computed tomography scans. QIAs are associated with impaired respiratory health and share features with advanced lung diseases, but their biological underpinnings are not well understood. Objectives: To identify novel protein biomarkers of QIAs using high-throughput plasma proteomic panels within two multicenter cohorts. Methods: We measured the plasma proteomics of 4,383 participants in an older, ever-smoker cohort (COPDGene [Genetic Epidemiology of Chronic Obstructive Pulmonary Disease]) and 2,925 participants in a younger population cohort (CARDIA [Coronary Artery Disease Risk in Young Adults]) using the SomaLogic SomaScan assays. We measured QIAs using a local density histogram method. We assessed the associations between proteomic biomarker concentrations and QIAs using multivariable linear regression models adjusted for age, sex, body mass index, smoking status, and study center (Benjamini-Hochberg false discovery rate-corrected P  ⩽ 0.05). Measurements and Main Results: In total, 852 proteins were significantly associated with QIAs in COPDGene and 185 in CARDIA. Of the 144 proteins that overlapped between COPDGene and CARDIA, all but one shared directionalities and magnitudes. These proteins were enriched for 49 Gene Ontology pathways, including biological processes in inflammatory response, cell adhesion, immune response, ERK1/2 regulation, and signaling; cellular components in extracellular regions; and molecular functions including calcium ion and heparin binding. Conclusions: We identified the proteomic biomarkers of QIAs in an older, smoking population with a higher prevalence of pulmonary disease and in a younger, healthier community cohort. These proteomics features may be markers of early precursors of advanced lung diseases.

Background Acute respiratory disease (ARD) events are often thought to be airway-disease related, but some may be related to quantitative interstitial abnormalities (QIAs), which are subtle parenchymal abnormalities on CT scans associated with morbidity and mortality in individuals with a smoking history. Purpose To determine whether QIA progression at CT is associated with ARD and severe ARD events in individuals with a history of smoking. Materials and Methods This secondary analysis of a prospective study included individuals with a 10 pack-years or greater smoking history recruited from multiple centers between November 2007 and July 2017. QIA progression was assessed between baseline (visit 1) and 5-year follow-up (visit 2) chest CT scans. Episodes of ARD were defined as increased cough or dyspnea lasting 48 hours and requiring antibiotics or corticosteroids, whereas severe ARD episodes were those requiring an emergency room visit or hospitalization. Episodes were recorded via questionnaires completed every 3 to 6 months. Multivariable logistic regression and zero-inflated negative binomial regression models adjusted for comorbidities (eg, emphysema, small airway disease) were used to assess the association between QIA progression and episodes between visits 1 and 2 (intercurrent) and after visit 2 (subsequent). Results A total of 3972 participants (mean age at baseline, 60.7 years ± 8.6 [SD]; 2120 [53.4%] women) were included. Annual percentage QIA progression was associated with increased odds of one or more intercurrent (odds ratio [OR] = 1.29 [95% CI: 1.06, 1.56]; P = .01) and subsequent (OR = 1.26 [95% CI: 1.05, 1.52]; P = .02) severe ARD events. Participants in the highest quartile of QIA progression (≥1.2%) had more frequent intercurrent ARD (incidence rate ratio [IRR] = 1.46 [95% CI: 1.14, 1.86]; P = .003) and severe ARD (IRR = 1.79 [95% CI: 1.18, 2.73]; P = .006) events than those in the lowest quartile (≤-1.7%). Conclusion QIA progression was independently associated with higher odds of severe ARD events during and after radiographic progression, with higher frequency of intercurrent severe events in those with faster progression. Clinical trial registration no. NCT00608764 © RSNA, 2024 Supplemental material is available for this article . See also the editorial by Little in this issue.

Background: Chronic obstructive pulmonary disease (COPD) is a significant public health concern and intercepting the development of emphysema is vital for COPD prevention. Smokers are a high-risk population for emphysema with limited prevention strategies. We aimed to determine if adherence to a nutritionally rich, plant-centered diet among young ever-smokers is associated with reduced risk of future radiographic emphysema., Methods: We studied participants from the Coronary Artery Risk Development in Young Adults (CARDIA) Lung Prospective Cohort Study who were 18-30 years old at enrollment and followed for 30 years. We analyzed 1706 adults who reported current or former smoking by year 20. Repeated measures of diet history were used to calculate A Priori Diet Quality Scores (APDQSs), and categorized into quintiles, with higher quintiles representing higher nutritionally rich plant-centered food intake. Emphysema was assessed at year 25 (n=1351) by computed tomography (CT). Critical covariates were selected, acknowledging potential residual confounding., Results: Emphysema was observed in 13.0% of the cohort, with a mean age of 50.4 ± 3.5 years. The prevalence of emphysema was 4.5% in the highest APDQS quintile (nutritionally rich), compared with 25.4% in the lowest quintile. After adjustment for multiple covariates, including smoking, greater adherence to a plant-centered diet was inversely associated with emphysema (highest versus lowest quintile odds ratio: 0.44, 95% CI 0.19-0.99, p trend =0.008)., Conclusion: Longitudinal adherence to a nutritionally rich, plant-centered diet was associated with a decreased risk of emphysema development in middle adulthood, warranting further examination of diet as a strategy for emphysema prevention in a high-risk smoking population., (JCOPDF © 2024.)

Introduction/rationale: Protein biomarkers may help enable the prediction of incident interstitial features on chest CT., Methods: We identified which protein biomarkers in a cohort of smokers (COPDGene) differed between those with and without objectively measured interstitial features at baseline using a univariate screen (t-test false discovery rate, FDR p<0.001), and which of those were associated with interstitial features longitudinally (multivariable mixed effects model FDR p<0.05). To predict incident interstitial features, we trained four random forest classifiers in a two-thirds random subset of COPDGene: (1) imaging and demographic information, (2) univariate screen biomarkers, (3) multivariable confirmation biomarkers and (4) multivariable confirmation biomarkers available in a separate testing cohort (Pittsburgh Lung Screening Study (PLuSS)). We evaluated classifier performance in the remaining one-third of COPDGene, and, for the final model, also in PLuSS., Results: In COPDGene, 1305 biomarkers were available and 20 differed between those with and without interstitial features at baseline. Of these, 11 were associated with feature progression over a mean of 5.5 years of follow-up, and of these 4 were available in PLuSS, (angiopoietin-2, matrix metalloproteinase 7, macrophage inflammatory protein 1 alpha) over a mean of 8.8 years of follow-up. The area under the curve (AUC) of classifiers using demographics and imaging features in COPDGene and PLuSS were 0.69 and 0.59, respectively. In COPDGene, the AUC of the univariate screen classifier was 0.78 and of the multivariable confirmation classifier was 0.76. The AUC of the final classifier in COPDGene was 0.75 and in PLuSS was 0.76. The outcome for all of the models was the development of incident interstitial features., Conclusions: Multiple novel and previously identified proteomic biomarkers are associated with interstitial features on chest CT and may enable the prediction of incident interstitial diseases such as idiopathic pulmonary fibrosis., Competing Interests: Competing interests: SA reports equity/dividends from Quantitative Imaging Solutions and consulting for Vertex Pharmaceuticals, Verona Pharmaceuticals and Triangulate Knowledge, all unrelated to the current work. TJD has received grant support from Bristol Myers Squibb, consulting fees from Boehringer Ingelheim and L.E.K. consulting, and has been part of a clinical trial funded by Genentech, unrelated to the current work. BC reports consulting fees from Quantitative Imaging Solutions, unrelated to the current work. RuSJE reports consulting fees from Quantitative Imaging Solutions, unrelated to the current work. VC reports no competing interests. NE reports no competing interests. RK reports grants and personal fees from AstraZeneca, personal fees from CVS Caremark, personal fees from Aptus Health, grants and personal fees from GlaxoSmithKline, personal fees from Boston Scientific, personal fees from Boston Consulting Group, all outside the submitted work. GL reports no competing interests. RB reports no competing interests. DOW reports advisory board membership and shareholder of Online Disruptive Technologies, unrelated to the current work. RaSJE reports equity/dividends from Quantitative Imaging Solutions, unrelated to the current work. IOR reports no competing interests. GRW reports grants from Boehringer Ingelheim, BTG Interventional Medicine and Janssen Pharmaceuticals; consultancies/advisory board participation for Boehringer Ingelheim, Janssen Pharmaceuticals, Pulmonx, Novartis, Philips, CSL Behring and Vertex; and equity/dividends from Quantitative Imaging Solutions, unrelated to the current work, all outside the submitted work. GRW’s wife works for Biogen., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Lung function throughout adulthood predicts morbidity and mortality even among adults without chronic respiratory disease. Diet quality may represent a modifiable risk factor for lung function impairment later in life. We investigated associations between nutritionally-rich plant-centered diet and lung function across early and middle adulthood from the Coronary Artery Risk Development in Young Adults (CARDIA) Study., Methods: Diet was assessed at baseline and years 7 and 20 of follow-up using the validated CARDIA diet history questionnaire. Plant-centered diet quality was scored using the validated A Priori Diet Quality Score (APDQS), which weights food groups to measure adherence to a nutritionally-rich plant-centered diet for 20 beneficially rated foods and 13 adversely rated foods. Scores were cumulatively averaged over follow-up and categorized into quintiles. The primary outcome was lung function decline, including forced expiratory volume in 1 s (FEV 1 ) and forced vital capacity (FVC), measured at years 0, 2, 5, 10, 20, and 30. We estimated the association of APDQS with annual pulmonary function changes and cross-sectional differences in a repeated measures regression model, adjusting for clinically relevant covariates., Results: The study included 3,787 Black and White men and women aged 18-30 in 1985-86 and followed for 30 years. In multivariable repeated measures regression models, individuals in the lowest APDQS quintile (poorest diet) had declines in FEV 1 that were 1.6 ml/year greater than individuals in the highest quintile (35.0 vs. 33.4 ml/year, ß ± SE per 1 SD change APDQS 0.94 ± 0.36, p = 0.009). Additionally, declines in FVC were 2.4 ml/year greater in the lowest APDQS quintile than those in the highest quintile (37.0 vs 34.6 ml/year, ß ± SE per 1 SD change APDQS 1.71 ± 0.46, p < 0.001). The association was not different between never and ever smokers (p int  = 0.07 for FVC and 0.32 for FEV 1 ). In sensitivity analyses where current asthma diagnosis and cardiorespiratory fitness were further adjusted, results remained similar. Cross-sectional analysis at each exam year also showed significant differences in lung function according to diet after covariate adjustment., Conclusions: In this 30-year longitudinal cohort study, long-term adherence to a nutritionally-rich plant-centered diet was associated with cross-sectional differences in lung function as well as slower decline in lung function, highlighting diet quality as a potential treatable trait supporting long-term lung health., (© 2024. The Author(s).)

Rationale: The mean pulmonary arterial wedge pressure (mPAWP) is the critical hemodynamic factor differentiating group 1 pulmonary arterial hypertension (PAH) from group 2 pulmonary hypertension associated with left heart disease. Despite the discrepancy between the mPAWP upper physiologic normal and current PAH definitions, the implications of the initial mPAWP for PAH clinical trajectory are poorly understood. Objectives: To model longitudinal mPAWP trajectories in PAH over 10 years and examine the clinical and hemodynamic factors associated with trajectory membership. Methods: Adult patients with PAH with two or more right heart catheterizations were identified from a multiinstitution healthcare system in eastern Massachusetts. mPAWP trajectories were constructed via group-based trajectory modeling. Feature selection was performed in least absolute shrinkage and selection operator regression. Logistic regression was used to assess associations between trajectory membership, baseline characteristics, and transplant-free survival. Measurements and Main Results: Among 301 patients with PAH, there were two distinct mPAWP trajectories, termed "mPAWP-high" ( n  = 71; 23.6%) and "mPAWP-low" ( n  = 230; 76.4%), based on the ultimate mPAWP value. Initial mPAWP clustered around median 12 mm Hg (interquartile range [IQR], 8-14 mm Hg) in the mPAWP-high and 9 mm Hg (IQR, 6-11 mm Hg) in the mPAWP-low trajectories ( P  < 0.001). After feature selection, initial mPAWP ⩾12 mm Hg predicted an mPAWP-high trajectory (odds ratio, 3.2; 95% confidence interval, 1.4-6.1; P  = 0.0006). An mPAWP-high trajectory was associated with shorter transplant-free survival (vs. mPAWP-low, median, 7.8 vs. 11.3 yr; log-rank P  = 0.017; age-adjusted P  = 0.217). Conclusions: Over 10 years, the mPAWP followed two distinct trajectories, with 25% evolving into group 2 pulmonary hypertension physiology. Using routine baseline data, longitudinal mPAWP trajectory could be predicted accurately, with initial mPAWP ⩾12 mm Hg as one of the strongest predictors.

Background: Abnormal lung function trajectories are associated with increased risk of chronic obstructive pulmonary disease (COPD) and premature mortality; several risk factors for following these trajectories have been identified. Airway under-sizing dysanapsis (small airway lumens relative to lung size), is associated with an increased risk for COPD. The relationship between dysanapsis and lung function trajectories at risk for adverse outcomes of COPD is largely unexplored. We test the hypothesis that dysanapsis differentially affects distinct lung function trajectories associated with adverse outcomes of COPD., Methods: To identify lung function trajectories, we applied Bayesian trajectory analysis to longitudinal FEV1 and FVC Z-scores in the COPDGene Study, an ongoing longitudinal study that collected baseline data from 2007 to 2012. To ensure clinical relevance, we selected trajectories based on risk stratification for all-cause mortality and prospective exacerbations of COPD (ECOPD). Dysanapsis was measured in baseline COPDGene CT scans as the airway lumen-to-lung volume (a/l) ratio. We compared a/l ratios between trajectories and evaluated their association with trajectory assignment, controlling for previously identified risk factors. We also assigned COPDGene participants for whom only baseline data is available to their most likely trajectory and repeated our analysis to further evaluate the relationship between trajectory assignment and a/l ratio measures., Findings: We identified seven trajectories: supranormal, reference, and five trajectories at increased risk for mortality and exacerbations. Three at-risk trajectories are characterized by varying degrees of concomitant FEV1 and FVC impairments and exhibit airway predominant COPD patterns as assessed by quantitative CT imaging. These trajectories have lower a/l ratio values and increased risk for mortality and ECOPD compared to the reference trajectory. Two at-risk trajectories are characterized by disparate levels of FEV1 and FVC impairment and exhibit mixed airway and emphysema COPD patterns on quantitative CT imaging. These trajectories have markedly lower a/l ratio values compared to both the reference trajectory and airway-predominant trajectories and are at greater risk for mortality and ECOPD compared to the airway-predominant trajectories. These findings were observed among the participants with baseline-only data as well., Interpretation: The degree of dysanapsis appears to portend patterns of progression leading to COPD. Assignment of individuals-including those without spirometric obstruction-to distinct trajectories is possible in a clinical setting and may influence management strategies. Strategies that combine CT-assessed dysanapsis together with spirometric measures of lung function and smoke exposure assessment are likely to further improve trajectory assignment accuracy, thereby improving early detection of those most at risk for adverse outcomes., Funding: United States National Institute of Health, COPD Foundation, and Brigham and Women's Hospital., Competing Interests: Dr. Ross reports grants from National Heart Lung and Blood Institute, during the conduct of the study. Dr. San José Estepar reports grants from NHLBI, during the conduct of the study; other from Lung Biotechnology, from Insmed, grants from Boehringer Ingelheim, outside the submitted work; and co-founder and stock holder of Quantitative Imaging Solutions, an imaging analytics company in the lung cancer space. Dr. Ash reports grants from NHLBI, during the conduct of the study; other from Quantitative Imaging Solutions, other from Verona Pharmaceuticals, other from Vertex Pharmaceuticals, other from Triangulate Knowledge, other from Boehringer Ingelheim, outside the submitted work. Dr. Pistenmaa reports grants from NIH/NHLBI, during the conduct of the study. Dr. Han reports grants from NIH NHLBI, during the conduct of the study; grants from NIH, personal fees from Sanofi, personal fees from Novartis, personal fees from Nuvaira, personal fees from Sunovion, personal fees from Gala Therapeutics, grants from COPD Foundation, personal fees from AstraZeneca, grants from American Lung Association, personal fees from Boehringer Ingelheim, personal fees from Biodesix, personal fees from GlaxoSmithKline, personal fees from Pulmonx, personal fees from Teva, personal fees from Verona, personal fees from Merck, personal fees from Mylan, personal fees from DevPro, personal fees from Aerogen, personal fees from Polarian, personal fees from United Therapeutics, personal fees from Regeneron, personal fees from Altesa BioPharma, personal fees from Amgen, personal fees from Roche, personal fees from Cipla, personal fees from Chiesi, personal fees from Medscape, personal fees from Integrity, personal fees from NACE, personal fees from Medwiz, outside the submitted work. Novartis, Medtronic (participation on data safety monitoring board/advisory board)—funds paid to institution. Leadership/fiduciary role on the following: COPD Foundation Board, COPD Foundation Scientific Advisory Committee, ALA advisory committee, American Thoracic Society journal editor, ALA volunteer spokesperson, GOLD scientific committee, Emerson School Board (Ann Arbor, MI). Stock or stock options: Meissa Vaccines, Altesa BioPharma. Writing support: GSK, Boehringer Ingelheim, AstraZeneca, Novartis. Royalties from Uptodate, Norton Publishing, and Penguin Random House. Dr. Bhatt reports grants and personal fees from Sanofi, grants and personal fees from Regeneron, personal fees from Boehringer Ingelheim, personal fees from GSK, outside the submitted work. Dr. Bodduluri has nothing to disclose. Dr. Sparrow has nothing to disclose. Dr. Charbonnier reports personal fees and other from Thirona, outside the submitted work. Dr. Washko reports grants from NHLBI, grants from Boehringer Ingelheim, grants from DoD, other from Vertex Pharmaceuticals, other from Pieris Therapeutics, other from Intellia Therapeutics, other from Sanofi, outside the submitted work; and Dr. Washko is a co-founder and equity share holder in Quantitative Imaging Solutions, a company that provides consulting services for image and data analytics. Dr. Washko's spouse works for Biogen. Dr. Diaz reports grants from National Heart Lung and Blood Institute, during the conduct of the study; personal fees from Boehringer Ingelheim, outside the submitted work; in addition, Dr. Diaz has a patent “Methods and Compositions Relating to Airway Dysfunction” pending., (© 2023 The Authors.)

Background CT attenuation is affected by lung volume, dosage, and scanner bias, leading to inaccurate emphysema progression measurements in multicenter studies. Purpose To develop and validate a method that simultaneously corrects volume, noise, and interscanner bias for lung density change estimation in emphysema progression at CT in a longitudinal multicenter study. Materials and Methods In this secondary analysis of the prospective Genetic Epidemiology of Chronic Obstructive Pulmonary Disease (COPDGene) study, lung function data were obtained from participants who completed baseline and 5-year follow-up visits from January 2008 to August 2017. CT emphysema progression was measured with volume-adjusted lung density (VALD) and compared with the joint volume-noise-bias-adjusted lung density (VNB-ALD). Reproducibility was studied under change of dosage protocol and scanner model with repeated acquisitions. Emphysema progression was visually scored in 102 randomly selected participants. A stratified analysis of clinical characteristics was performed that considered groups based on their combined lung density change measured by VALD and VNB-ALD. Results A total of 4954 COPDGene participants (mean age, 60 years ± 9 [SD]; 2511 male, 2443 female) were analyzed (1329 with repeated reduced-dose acquisition in the follow-up visit). Mean repeatability coefficients were 30 g/L ± 0.46 for VALD and 14 g/L ± 0.34 for VNB-ALD. VALD measurements showed no evidence of differences between nonprogressors and progressors (mean, -5.5 g/L ± 9.5 vs -8.6 g/L ± 9.6; P = .11), while VNB-ALD agreed with visual readings and showed a difference (mean, -0.67 g/L ± 4.8 vs -4.2 g/L ± 5.5; P < .001). Analysis of progression showed that VNB-ALD progressors had a greater decline in forced expiratory volume in 1 second (-42 mL per year vs -32 mL per year; Tukey-adjusted P = .002). Conclusion Simultaneously correcting volume, noise, and interscanner bias for lung density change estimation in emphysema progression at CT improved repeatability analyses and agreed with visual readings. It distinguished between progressors and nonprogressors and was associated with a greater decline in lung function metrics. Clinical trial registration no. NCT00608764 © RSNA, 2024 Supplemental material is available for this article. See also the editorial by Goo in this issue.

Objectives: There have been limited investigations of the prevalence and mortality impact of quantitative computed tomography (QCT) parenchymal lung features in rheumatoid arthritis (RA). We examined the cross-sectional prevalence and mortality associations of QCT features, comparing RA and non-RA participants., Methods: We identified participants with and without RA in COPDGene, a multicentre cohort study of current or former smokers. Using a k-nearest neighbor quantifier, high resolution CT chest scans were scored for percentage of normal lung, interstitial changes, and emphysema. We examined associations between QCT features and RA using multivariable linear regression. After dichotomizing participants at the 75th percentile for each QCT feature among non-RA participants, we investigated mortality associations by RA/non-RA status and quartile 4 vs quartiles 1-3 of QCT features using Cox regression. We assessed for statistical interactions between RA and QCT features., Results: We identified 82 RA cases and 8820 non-RA comparators. In multivariable linear regression, RA was associated with higher percentage of interstitial changes (β = 1.7 ± 0.5, p= 0.0008) but not emphysema (β = 1.3 ± 1.7, p= 0.44). Participants with RA and >75th percentile of emphysema had significantly higher mortality than non-RA participants (HR 5.86, 95%CI 3.75-9.13) as well as RA participants (HR 5.56, 95%CI 2.71-11.38) with ≤75th percentile of emphysema. There were statistical interactions between RA and emphysema for mortality (multiplicative p= 0.014; attributable proportion 0.53, 95%CI 0.30-0.70)., Conclusions: Using machine learning-derived QCT data in a cohort of smokers, RA was associated with higher percentage of interstitial changes. The combination of RA and emphysema conferred >5-fold higher mortality., (© The Author(s) 2023. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Quantitative interstitial abnormalities (QIA) are an automated computed tomography (CT) finding of early parenchymal lung disease, associated with worse lung function, reduced exercise capacity, increased respiratory symptoms, and death. The metabolomic perturbations associated with QIA are not well known. We sought to identify plasma metabolites associated with QIA in smokers. We also sought to identify shared and differentiating metabolomics features between QIA and emphysema, another smoking-related advanced radiographic abnormality., Methods: In 928 former and current smokers in the Genetic Epidemiology of COPD cohort, we measured QIA and emphysema using an automated local density histogram method and generated metabolite profiles from plasma samples using liquid chromatography-mass spectrometry (Metabolon). We assessed the associations between metabolite levels and QIA using multivariable linear regression models adjusted for age, sex, body mass index, smoking status, pack-years, and inhaled corticosteroid use, at a Benjamini-Hochberg False Discovery Rate p-value of ≤ 0.05. Using multinomial regression models adjusted for these covariates, we assessed the associations between metabolite levels and the following CT phenotypes: QIA-predominant, emphysema-predominant, combined-predominant, and neither- predominant. Pathway enrichment analyses were performed using MetaboAnalyst., Results: We found 85 metabolites significantly associated with QIA, with overrepresentation of the nicotinate and nicotinamide, histidine, starch and sucrose, pyrimidine, phosphatidylcholine, lysophospholipid, and sphingomyelin pathways. These included metabolites involved in inflammation and immune response, extracellular matrix remodeling, surfactant, and muscle cachexia. There were 75 metabolites significantly different between QIA-predominant and emphysema-predominant phenotypes, with overrepresentation of the phosphatidylethanolamine, nicotinate and nicotinamide, aminoacyl-tRNA, arginine, proline, alanine, aspartate, and glutamate pathways., Conclusions: Metabolomic correlates may lend insight to the biologic perturbations and pathways that underlie clinically meaningful quantitative CT measurements like QIA in smokers., (© 2023. The Author(s).)

Nonalcoholic fatty liver disease (NAFLD) is common and partially heritable and has no effective treatments. We carried out a genome-wide association study (GWAS) meta-analysis of imaging (n = 66,814) and diagnostic code (3,584 cases versus 621,081 controls) measured NAFLD across diverse ancestries. We identified NAFLD-associated variants at torsin family 1 member B (TOR1B), fat mass and obesity associated (FTO), cordon-bleu WH2 repeat protein like 1 (COBLL1)/growth factor receptor-bound protein 14 (GRB14), insulin receptor (INSR), sterol regulatory element-binding transcription factor 1 (SREBF1) and patatin-like phospholipase domain-containing protein 2 (PNPLA2), as well as validated NAFLD-associated variants at patatin-like phospholipase domain-containing protein 3 (PNPLA3), transmembrane 6 superfamily 2 (TM6SF2), apolipoprotein E (APOE), glucokinase regulator (GCKR), tribbles homolog 1 (TRIB1), glycerol-3-phosphate acyltransferase (GPAM), mitochondrial amidoxime-reducing component 1 (MARC1), microsomal triglyceride transfer protein large subunit (MTTP), alcohol dehydrogenase 1B (ADH1B), transmembrane channel like 4 (TMC4)/membrane-bound O-acyltransferase domain containing 7 (MBOAT7) and receptor-type tyrosine-protein phosphatase δ (PTPRD). Implicated genes highlight mitochondrial, cholesterol and de novo lipogenesis as causally contributing to NAFLD predisposition. Phenome-wide association study (PheWAS) analyses suggest at least seven subtypes of NAFLD. Individuals in the top 10% and 1% of genetic risk have a 2.5-fold to 6-fold increased risk of NAFLD, cirrhosis and hepatocellular carcinoma. These genetic variants identify subtypes of NAFLD, improve estimates of disease risk and can guide the development of targeted therapeutics., (© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Background: Key to the success of any prospective cohort study is the effective recruitment and retention of participants, but the specific factors that influence younger adults of the Millennial generation to participate in research are not well-understood. The objective of this qualitative study was to identify factors that motivated participation and engagement in longitudinal research studies focused on respiratory health among a diverse group of young adults., Methods: We conducted qualitative, semi-structured interviews with 50 younger adult participants (aged 25-35 years) regarding factors influencing their participation in longitudinal research studies. Thematic analysis was used to develop, organize, and tabulate the frequency of key themes. In exploratory analyses, we examined for patterns in the distribution of key themes across racial, ethnic, or socioeconomic groups., Results: Participants identified several key themes that affected their willingness to participate in longitudinal studies. These included the health-related benefits generated by research (both to the individual and to society at-large), factors related to the institution and study team conducting the research, concerns regarding unethical and/or unrepresentative study design, and barriers to participation in research. Certain factors may be more impactful to underrepresented groups, including concerns regarding data privacy and confidentiality., Conclusions: In this diverse group of younger adults, we identified specific factors that motivated participation and predicted high engagement in longitudinal research studies focused on respiratory health. Implementing and integrating these factors into study protocols may improve recruitment and retention, including among participants who are historically underrepresented in research., (© 2023. BioMed Central Ltd., part of Springer Nature.)

The factors associated with persistent hypoxemia after pulmonary embolus (PE) are not well understood. Predicting the need for oxygen post discharge at the time of diagnosis using available CT imaging will enable better discharge planning. To examine the relationship between CT derived imaging markers (automated computation of arterial small vessel fraction, pulmonary artery diameter to aortic diameter ratio (PA:A), right to left ventricular diameter ratio (RV:LV) and new oxygen requirement at the time of discharge in patients diagnosed with acute intermediate-risk PE. CT measurements were obtained in a retrospective cohort of patients with acute-intermediate risk PE admitted to Brigham and Women's Hospital between 2009 and 2017. Twenty one patients without a history of lung disease requiring home oxygen and 682 patients without discharge oxygen requirements were identified. There was an increased median PA:A ratio (0.98 vs. 0.92, p = 0.02) and arterial small vessel fraction (0.32 vs. 0.39, p = 0.001) in the oxygen-requiring group], but no difference in the median RV:LV ratio (1.20 vs. 1.20, p = 0.74). Being in the upper quantile for the arterial small vessel fraction was associated with decreased odds of oxygen requirement (OR 0.30 [0.10-0.78], p = 0.02). Loss of arterial small vessel volume as measured by arterial small vessel fraction and an increase in the PA:A ratio at the time of diagnosis were associated with the presence of persistent hypoxemia on discharge in acute intermediate-risk PE., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)