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Rationale: Individuals with chronic obstructive pulmonary disease (COPD) have airflow obstruction and maldistribution of ventilation. For those living at high altitude, any gas exchange abnormality is compounded by reduced partial pressures of inspired oxygen. Objectives: Does residence at higher altitude exposure affect COPD outcomes, including lung function, imaging characteristics, symptoms, health status, functional exercise capacity, exacerbations, and mortality? Methods: From the SPIROMICS (Subpopulation and Intermediate Outcome Measures in COPD Study) cohort, we identified individuals with COPD living below 1,000 ft (305 m) elevation ( n  = 1,367) versus above 4,000 ft (1,219 m) elevation ( n  = 288). Multivariable regression models were used to evaluate associations of exposure to high altitude with COPD-related outcomes. Measurements and Main Results: Living at higher altitude was associated with reduced functional exercise capacity as defined by 6-minute-walk distance (-32.3 m [95% confidence interval, -49.8 to -14.8 m]). There were no differences in patient-reported outcomes as defined by symptoms (COPD Assessment Test and modified Medical Research Council dyspnea scale), or health status (St. George's Respiratory Questionnaire). Higher altitude was not associated with a different rate of FEV 1 decline. Higher altitude was associated with lower odds of severe exacerbations (incidence rate ratio, 0.65 [95% confidence interval, 0.46 to 0.90]). There were no differences in small airway disease, air trapping, or emphysema. In longitudinal analyses, higher altitude was associated with increased mortality (hazard ratio, 1.25 [95% confidence interval, 1.0 to 1.55]); however, this association was no longer significant when accounting for air pollution. Conclusions: Long-term altitude exposure is associated with reduced functional exercise capacity in individuals with COPD, but this did not translate into differences in symptoms or health status. In addition, long-term high-altitude exposure did not affect progression of disease as defined by longitudinal changes in spirometry. Clinical trial registered with www.clinicaltrials.gov (NCT01969344).

Background: Pulmonary microvasculature alterations are implicated in emphysema pathogenesis, but the association between pulmonary microvascular blood volume (PMBV) and emphysema has not been directly assessed at scale, and prior studies have used non-specific measures of emphysema., Methods: The Multi-Ethnic Study of Atherosclerosis Lung Study invited participants recruited from the community without renal impairment to undergo contrast-enhanced dual-energy CT. Pulmonary blood volume was calculated by material decomposition; PMBV was defined as blood volume in the peripheral 2 cm of the lung. Non-contrast CT was acquired to assess per cent emphysema and novel CT emphysema subtypes, which include the diffuse emphysema subtype and small-airways-related combined bronchitic-apical emphysema subtype. Generalised linear regression models included age, sex, race/ethnicity, body size, smoking, total lung volume and small airway count., Results: Among 495 participants, 53% were never-smokers and the race/ethnic distribution was 35% white, 31% black, 15% Hispanic and 18% Asian. Mean PMBV was 352±120 mL; mean per cent emphysema was 4.95±4.75%. Lower PMBV was associated with greater per cent emphysema (-0.90% per 100 mL PMBV, 95% CI: -1.29 to -0.51). The association was of larger magnitude in participants with 10 or more pack-years smoking and airflow obstruction, but present among participants with no smoking history or airflow limitation, and was specific to the diffuse CT emphysema subtype (-1.48% per 100 mL PMBV, 95% CI: -2.31 to -0.55)., Conclusion: In this community-based study, lower PMBV was associated with greater per cent emphysema, including in participants without a smoking history or airflow limitation, and was specific to the diffuse CT emphysema subtype., Competing Interests: Competing interests: EAHo is a founder and shareholder of VIDA Diagnostics, which makes the software used for secondary per cent emphysema measures in this article. YS and NA report receiving grants from the NIH. JG is a shareholder of VIDA Diagnostics and reports receiving grants from the NIH. DWK acknowledges grant support from the US Department of Defense and ZOLL Medical Corporation for work unrelated to this study, is a co-founder and shareholder of OscillaVent, and is listed as a co-inventor on US and European patents related to multi-frequency oscillatory ventilation. Unrelated to this work, EDM reports consulting fees paid by Amgen, AstraZeneca, Boehringer Ingelheim, Edwards Lifescience, Esperion, Medtronic, Merck, Novo Nordisk, Novartis, New Amsterdam and Pfizer. Unrelated to this work, PN reports receiving grant funding from GE Healthcare, consulting fees from Cannon, honoraria from the Society of Cardiovascular CT and American Society of Nuclear Cardiology, as well as owning stock in Moderna. BS reports receiving grants from the NIH, Canadian Institutes of Health Research, Fonds de la recherche en santé du Québec and the Research Institute of the McGill University Health Centre. RGB reports receiving grants from the COPD Foundation, the US Environmental Protection Agency, the American Lung Association and the NIH., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Forty to fifty percent of women and 13%-22% of men experience an osteoporosis-related fragility fracture in their lifetimes. After the age of 50 years, the risk of hip fracture doubles in every 10 years. x-Ray based DXA is currently clinically used to diagnose osteoporosis and predict fracture risk. However, it provides only 2-D representation of bone and is associated with other technical limitations. Thus, alternative methods are needed., Purpose: To develop and evaluate an ultra-low dose (ULD) hip CT-based automated method for assessment of volumetric bone mineral density (vBMD) at proximal femoral subregions., Methods: An automated method was developed to segment the proximal femur in ULD hip CT images and delineate femoral subregions. The computational pipeline consists of deep learning (DL)-based computation of femur likelihood map followed by shape model-based femur segmentation and finite element analysis-based warping of a reference subregion labeling onto individual femur shapes. Finally, vBMD is computed over each subregion in the target image using a calibration phantom scan. A total of 100 participants (50 females) were recruited from the Genetic Epidemiology of COPD (COPDGene) study, and ULD hip CT imaging, equivalent to 18 days of background radiation received by U.S. residents, was performed on each participant. Additional hip CT imaging using a clinical protocol was performed on 12 participants and repeat ULD hip CT was acquired on another five participants. ULD CT images from 80 participants were used to train the DL network; ULD CT images of the remaining 20 participants as well as clinical and repeat ULD CT images were used to evaluate the accuracy, generalizability, and reproducibility of segmentation of femoral subregions. Finally, clinical CT and repeat ULD CT images were used to evaluate accuracy and reproducibility of ULD CT-based automated measurements of femoral vBMD., Results: Dice scores of accuracy (n = 20), reproducibility (n = 5), and generalizability (n = 12) of ULD CT-based automated subregion segmentation were 0.990, 0.982, and 0.977, respectively, for the femoral head and 0.941, 0.970, and 0.960, respectively, for the femoral neck. ULD CT-based regional vBMD showed Pearson and concordance correlation coefficients of 0.994 and 0.977, respectively, and a root-mean-square coefficient of variation (RMSCV) (%) of 1.39% with the clinical CT-derived reference measure. After 3-digit approximation, each of Pearson and concordance correlation coefficients as well as intraclass correlation coefficient (ICC) between baseline and repeat scans were 0.996 with RMSCV of 0.72%. Results of ULD CT-based bone analysis on 100 participants (age (mean ± SD) 73.6 ± 6.6 years) show that males have significantly greater (p < 0.01) vBMD at the femoral head and trochanteric regions than females, while females have moderately greater vBMD (p = 0.05) at the medial half of the femoral neck than males., Conclusion: Deep learning, combined with shape model and finite element analysis, offers an accurate, reproducible, and generalizable algorithm for automated segmentation of the proximal femur and anatomic femoral subregions using ULD hip CT images. ULD CT-based regional measures of femoral vBMD are accurate and reproducible and demonstrate regional differences between males and females., (© 2024 The Author(s). Medical Physics published by Wiley Periodicals LLC on behalf of American Association of Physicists in Medicine.)

Rationale: Rheumatoid arthritis (RA) has been implicated in interstitial lung disease (ILD) as majority of studies have been comprised of patients with known RA. However, it remains unclear whether an underlying risk for RA in combination with genetic risk for pulmonary fibrosis is associated with radiological markers of early lung injury and fibrosis in broader population samples., Objective: Determine whether genetic and serological biomarkers of RA risk in combination with the MUC5B (rs35705950) risk allele (T) are associated with interstitial lung abnormalities (ILA) on computed tomography (CT) scans., Methods: Associations of RA-risk HLA-DRB1 alleles ( *04:01, *04:08, *04:05, *04:04, *10:01 ) and serum RA autoantibodies with ILA in the Multi-Ethnic Study of Atherosclerosis (MESA, n=4,018) and COPDGene (n=5,963) cohorts were modeled using logistic regression and adjusted for age, sex, self-reported race and ethnicity, smoking history, body mass index, and principal components of genetic ancestry., Results: The prevalence of an RA risk HLA-DRB1 allele was 16.5% and 21.9% in MESA and COPDGene, respectively. ILA was present in 3.9% and 11% in MESA and COPDGene, respectively. An RA risk HLA-DRB1 allele was not significantly associated with ILA in MESA and COPDGene. In MESA, higher serum levels of IgA rheumatoid factor (RF) and anti-cyclic citrullinated peptide were associated with an odds ratio (OR) for ILA of 1.20 (95% CI 1.07-1.35) and 1.19 (95% CI 1.04-1.37), respectively. Among smokers without baseline ILA, per doubling of IgM RF was associated with an OR for ILA 10 years later of 1.25 (95% CI 1.08-1.43). Associations were not significantly different by MUC5B risk allele status., Conclusions: RA-related HLA-DRB1 alleles were not associated with ILA, whereas higher serum levels of IgM RF among smokers without baseline ILA were associated with subsequent ILA.

Background: Exposure to metals, a newly recognized risk factor for cardiovascular disease (CVD), could be related to atherosclerosis progression., Objectives: The authors hypothesized that higher urinary levels of nonessential (cadmium, tungsten, uranium) and essential (cobalt, copper, zinc) metals previously associated with CVD would be associated with baseline and rate of change of coronary artery calcium (CAC) progression, a subclinical marker of CVD in MESA (Multi-Ethnic Study of Atherosclerosis)., Methods: We analyzed data from 6,418 MESA participants with spot urinary metal levels at baseline (2000-2002) and 1 to 4 repeated, continuous measures of CAC over a 10-year period. We used linear mixed-effect models to assess the association of baseline urinary metal levels with baseline CAC and cumulative change in CAC over a 10-year period. Urinary metals (μg/g creatinine) and CAC were log transformed. Models were adjusted for baseline sociodemographic factors, estimated glomerular filtration rate, lifestyle factors, and clinical factors., Results: At baseline, the median CAC was 6.3 (Q1-Q3: 0.7-58.2). Comparing the highest to lowest quartile of urinary cadmium, CAC levels were 51% (95% CI: 32%, 74%) higher at baseline and 75% (95% CI: 47%, 107%) higher over the 10-year period. For urinary tungsten, uranium, and cobalt, the corresponding CAC levels over the 10-year period were 45% (95% CI: 23%, 71%), 39% (95% CI: 17%, 64%), and 47% (95% CI: 25%, 74%) higher, respectively, with no difference for models with and without adjustment for clinical factors. For copper and zinc, the corresponding estimates dropped from 55% to 33% and from 85% to 57%, respectively, after adjustment for clinical factors. The associations of metals with CAC were comparable in magnitude to those for classical CVD risk factors., Conclusions: Exposure to metals was generally associated with extent of coronary calcification at baseline and follow-up. These findings support that metals are associated with the progression of atherosclerosis, potentially providing a novel strategy for the prevention and treatment of atherosclerosis progression., Competing Interests: Funding Support and Author Disclosures The Multi-Ethnic Study of Atherosclerosis (MESA) is supported by contracts 75N92020D00001, HHSN268201500003I, N01-HC-95159, 75N92020D00005, N01-HC-95160, 75N92020D00002, N01-HC-95161, 75N92020D00003, N01-HC-95162, 75N92020D00006, N01-HC-95163, 75N92020D00004, N01-HC-95164, 75N92020D00007, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168, and N01-HC-95169 from the National Heart, Lung, and Blood Institute; and by grants UL1-TR-000040, UL1-TR-001079, and UL1-TR-001420 from the National Center for Advancing Translational Sciences (NCATS). This publication was developed under the Science to Achieve Results (STAR) research assistance agreements, No. RD831697 (MESA Air) and RD-83830001 (MESA Air Next Stage), awarded by the U.S. Environmental Protection Agency (EPA). It has not been formally reviewed by the EPA. The views expressed in this document are solely those of the authors and the EPA does not endorse any products or commercial services mentioned in this publication. Work in the authors’ laboratories is also supported in part by NIH grants P42ES023716, P42ES010349, P42ES033719, P30ES009089, T32ES007322, R01ES029967, R01HL155576, R01ES029967, and R01ES028758. The authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Valid, high-resolution estimates of population-level exposure to air pollutants are necessary for accurate estimation of the association between air pollution and the occurrence or exacerbation of adverse health outcomes such as Chronic Obstructive Pulmonary Disease (COPD)., Objectives: We produced fine-scale individual-level estimates of ambient concentrations of multiple air pollutants (fine particulate matter [PM 2.5 ], NO X , NO 2 , and O 3 ) at residences of participants in the Subpopulations and Intermediate Outcomes in COPD Air Pollution (SPIROMICS Air) study, located in seven regions in the US. For PM 2.5 , we additionally integrated modeled estimates of particulate infiltration based on home characteristics and measured total indoor concentrations to provide comprehensive estimates of exposure levels., Methods: To estimate ambient concentrations, we used a hierarchical high-resolution spatiotemporal model that integrates hundreds of geographic covariates and pollutant measurements from regulatory and study-specific monitors, including ones located at participant residences. We modeled infiltration efficiency based on data on house characteristics, home heating and cooling practices, indoor smoke and combustion sources, meteorological factors, and paired indoor-outdoor pollutant measurements, among other indicators., Results: Cross-validated prediction accuracy (R 2 ) for models of ambient concentrations was above 0.80 for most regions and pollutants. Particulate matter infiltration efficiency varied by region, from 0.51 in Winston-Salem to 0.72 in Los Angeles, and ambient-source particles constituted a substantial fraction of total indoor PM 2.5 ., Conclusion: Leveraging well-validated fine-scale approaches for estimating outdoor, ambient-source indoor, and total indoor pollutant concentrations, we can provide comprehensive estimates of short and long-term exposure levels for cohorts undergoing follow-up in multiple different regions., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Prescott G Woodruff reports a relationship with AstraZeneca, Sanofi, Regeneron, Roche that includes: consulting or advisory. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Lung structure and cardiac structure and function are associated cross-sectionally. The classic literature suggests relationships of airways disease to cor pulmonale and emphysema to reduced cardiac output (CO) but longitudinal data are lacking., Methods: The Multi-Ethnic Study of Atherosclerosis Chronic Obstructive Pulmonary Disease (COPD) Study was a multi-center longitudinal COPD case-control study of participants 50-79 years with ≥10 pack-years smoking without clinical cardiovascular disease. Segmental airway wall area (WA) and percent emphysema were measured on computed tomography. Right and left ventricle (RV, LV) parameters were assessed on magnetic resonance imaging (MRI) in exams six years apart. Longitudinal and period cross-sectional associations were evaluated with mixed models adjusted for demographics, body size, and smoking., Results: The 187 participants with repeated MRI were 67±7 years old; 42% had COPD; 22% currently smoked; and the race/ethnicity distribution was 54% white, 30% Black, 14% Hispanic, and 3% Asian. Greater WA at enrollment was associated with longitudinal increase in RV mass (3.5 g per 10mm 2 WA, 95% CI: 1.1, 5.9). Greater percent emphysema was associated with stably lower LV end diastolic volume (-7.8 mL per 5% emphysema, 95% CI: -10.3, -3.0) and CO (-0.2 L·min -1 per 5% emphysema, 95% CI: -0.4, -0.1)., Conclusion: Cardiac associations varied by lung structure over six years in this multi-ethnic study. Greater WA at enrollment was associated with longitudinal increases in RV mass; whereas greater percent emphysema was associated with stable decrements in LV filling and CO., (Copyright ©The authors 2024. For reproduction rights and permissions contact permissions@ersnet.org.)

Background The extent of liver steatosis can be assessed using US attenuation coefficient (AC) algorithms currently implemented in several US systems. However, little is known about intersystem and interoperator variability in measurements. Purpose To assess intersystem and interoperator agreement in US AC measurements for fat quantification in individuals with varying degrees of liver steatosis and to assess the correlation of each manufacturer's AC algorithm results with MRI proton density fat fraction (PDFF). Materials and Methods This prospective study was conducted at Southwoods Imaging, Youngstown, Ohio, September 30-October 1, 2023. Two operators independently obtained AC measurements using eight US systems equipped with an AC algorithm from different manufacturers. On the same day, MRI PDFF measurement was performed by a different operator. Correlation between US AC and MRI PDFF was assessed using a mixed-effects model. Agreement between systems and operators was evaluated using the intraclass correlation coefficient (ICC). Results Twenty-six individuals (mean age, 55.4 years ± 10.7 [SD]; 16 female participants) were evaluated. The correlation of US AC with MRI PDFF was high for five AC algorithms ( r range, 0.70-0.86), moderate for two ( r = 0.62 for both), and poor for one ( r = 0.47). In pairwise comparisons, none of the pairs of systems achieved excellent agreement (overall ICC = 0.33 [95% CI: 0.15, 0.52]). One pair showed good agreement (ICC = 0.79 [95% CI: 0.66, 0.87]), eight pairs showed moderate agreement (ICC range, 0.50 [95% CI: 0.22, 0.69] to 0.73 [95% CI: 0.49, 0.85]), and 19 pairs showed poor agreement (ICC range, 0.11 [95% CI: -0.06, 0.37] to 0.48 [95% CI: 0.20, 0.67]). Interoperator agreement on AC value was excellent for the Samsung Medison algorithm (ICC = 0.90 [95% CI: 0.80, 0.96]), good for the Siemens Healthineers (ICC = 0.76 [95% CI: 0.54, 0.89]) and Canon Medical Systems (ICC = 0.76 [95% CI: 0.16, 0.92]) algorithms, and moderate for the remaining algorithms (ICC range, 0.50 [95% CI: 0.16, 0.73] to 0.74 [95% CI: 0.51, 0.88]). The mean AC value obtained by the two operators did not differ for any system except the system from Canon Medical Systems. Conclusion There was substantial variability in AC values obtained with different US systems, precluding interchangeability between systems for liver steatosis diagnosis and follow-up imaging. Interoperator agreement ranged from moderate to excellent. © RSNA, 2024 Supplemental material is available for this article. See also the editorial by Han in this issue.

Background/objectives: Algorithms for quantifying liver fat content based on the ultrasound attenuation coefficient (AC) are currently available; however, little is known about whether their accuracy increases by applying quality criteria such as the interquartile range-to-median ratio (IQR/M) or whether the median or average AC value should be used., Methods: AC measurements were performed with the Aplio i800 ultrasound system using the attenuation imaging (ATI) algorithm (Canon Medical Systems, Otawara, Tochigi, Japan). Magnetic resonance imaging proton density fat fraction (MRI-PDFF) was the reference standard. The diagnostic performance of the AC median value of 5 measurements (AC-M) was compared to that of AC average value (AC-A) of 5 or 3 acquisitions and different levels of IQR/M for median values or standard deviation/average (SD/A) for average values were also analyzed. Concordance between AC-5M, AC-5A, and AC3A was evaluated with concordance correlation coefficient (CCC)., Results: A total of 182 individuals (94 females; mean age, 51.2y [SD: 15]) were evaluated. A total of 77 (42.3%) individuals had S0 steatosis (MRI-PDFF < 6%), 75 (41.2%) S1 (MRI-PDFF 6-17%), 10 (5.5%) S2 (MRI-PDFF 17.1-22%), and 20 (11%) S3 (MRI-PDFF ≥ 22.1%). Concordance of AC-5A and AC-3A with AC-5M was excellent (CCC: 0.99 and 0.96, respectively). The correlation with MRI-PDFF was almost perfect. Diagnostic accuracy of AC-5M, AC-5A, and AC3A was not significantly affected by different levels of IQR/M or SD/A., Conclusions: The accuracy of AC in quantifying liver fat content was not affected by reducing the number of acquisitions (from five to three), by using the mean instead of the median, or by reducing the IQR/M or SD/A to ≤5%.

Background: The biological mechanisms leading some tobacco-exposed individuals to develop early-stage chronic obstructive pulmonary disease (COPD) are poorly understood. This knowledge gap hampers development of disease-modifying agents for this prevalent condition., Objectives: Accordingly, with National Heart, Lung and Blood Institute support, we initiated the SubPopulations and InteRmediate Outcome Measures In COPD Study (SPIROMICS) Study of Early COPD Progression (SOURCE), a multicenter observational cohort study of younger individuals with a history of cigarette smoking and thus at-risk for, or with, early-stage COPD. Our overall objectives are to identify those who will develop COPD earlier in life, characterize them thoroughly, and by contrasting them to those not developing COPD, define mechanisms of disease progression., Methods/discussion: SOURCE utilizes the established SPIROMICS clinical network. Its goal is to enroll n=649 participants, ages 30-55 years, all races/ethnicities, with ≥10 pack-years cigarette smoking, in either Global initiative for chronic Obstructive Lung Disease (GOLD) groups 0-2 or with preserved ratio-impaired spirometry; and an additional n=40 never-smoker controls. Participants undergo baseline and 3-year follow-up visits, each including high-resolution computed tomography, respiratory oscillometry and spirometry (pre- and postbronchodilator administration), exhaled breath condensate (baseline only), and extensive biospecimen collection, including sputum induction. Symptoms, interim health care utilization, and exacerbations are captured every 6 months via follow-up phone calls. An embedded bronchoscopy substudy involving n=100 participants (including all never-smokers) will allow collection of lower airway samples for genetic, epigenetic, genomic, immunological, microbiome, mucin analyses, and basal cell culture., Conclusion: SOURCE should provide novel insights into the natural history of lung disease in younger individuals with a smoking history, and its biological basis., (JCOPDF © 2024.)

Chronic liver disease is a world-wide epidemic. Any etiology that causes inflammation in the liver will lead to chronic liver disease. Presently, the most common inciting factor worldwide is steatotic liver disease. Recent advances in ultrasound imaging provide a multiparametric ultrasound methodology of diagnosing, staging, and monitoring treatment of chronic liver disease. Elastography has become a standard of care technique for the evaluation of liver fibrosis. Quantitative ultrasound allows for determination of the degree of fatty infiltration of the liver. Portal hypertension is the most important factor in determination of liver decompensation. B-mode findings combined with Doppler, and elastography techniques provide qualitative and quantitative methods of determining clinically significant portal hypertension. A newer method using contrast enhanced ultrasound may allow for a non-invasive quantitative estimation of the portal pressures. This paper reviews the use of multiparametric ultrasound in the evaluation of chronic liver disease including conventional B-mode ultrasound, Doppler, elastography and quantitative ultrasound for estimation of liver fat. The recent guidelines are presented and advised protocols reviewed., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Individuals with chronic obstructive pulmonary disease (COPD) are often at risk for or have comorbid cardiovascular disease and are likely to die of cardiovascular-related causes. Objectives: To prioritize a list of research topics related to the diagnosis and management of patients with COPD and comorbid cardiovascular diseases (heart failure, atherosclerotic vascular disease, and atrial fibrillation) by summarizing existing evidence and using consensus-based methods. Methods: A literature search was performed. References were reviewed by committee co-chairs. An international, multidisciplinary committee, including a patient advocate, met virtually to review evidence and identify research topics. A modified Delphi approach was used to prioritize topics in real time on the basis of their potential for advancing the field. Results: Gaps spanned the translational science spectrum from basic science to implementation: 1 ) disease mechanisms; 2 ) epidemiology; 3 ) subphenotyping; 4 ) diagnosis and management; 5 ) clinical trials; 6 ) care delivery; 7 ) medication access, adherence, and side effects; 8 ) risk factor mitigation; 9 ) cardiac and pulmonary rehabilitation; and 10 ) health equity. Seventeen experts participated, and quorum was achieved for all votes (>80%). Of 17 topics, ≥70% agreement was achieved for 12 topics after two rounds of voting. The range of summative Likert scores was -15 to 25. The highest priority was "Conduct pragmatic clinical trials with patient-centered outcomes that collect both pulmonary and cardiac data elements." Health equity was identified as an important topic that should be embedded within all research. Conclusions: We propose a prioritized research agenda with the purpose of stimulating high-impact research that will hopefully improve outcomes among people with COPD and cardiovascular disease.

Background: Exposure to metals has been associated with cardiovascular disease (CVD) end points and mortality, yet prospective evidence is limited beyond arsenic, cadmium, and lead. In this study, we assessed the prospective association of urinary metals with incident CVD and all-cause mortality in a racially diverse population of US adults from MESA (the Multi-Ethnic Study of Atherosclerosis)., Methods: We included 6599 participants (mean [SD] age, 62.1 [10.2] years; 53% female) with urinary metals available at baseline (2000 to 2001) and followed through December 2019. We used Cox proportional hazards models to estimate the adjusted hazard ratio and 95% CI of CVD and all-cause mortality by baseline urinary levels of cadmium, tungsten, and uranium (nonessential metals), and cobalt, copper, and zinc (essential metals). The joint association of the 6 metals as a mixture and the corresponding 10-year survival probability was calculated using Cox Elastic-Net., Results: During follow-up, 1162 participants developed CVD, and 1844 participants died. In models adjusted by behavioral and clinical indicators, the hazard ratios (95% CI) for incident CVD and all-cause mortality comparing the highest with the lowest quartile were, respectively: 1.25 (1.03, 1.53) and 1.68 (1.43, 1.96) for cadmium; 1.20 (1.01, 1.42) and 1.16 (1.01, 1.33) for tungsten; 1.32 (1.08, 1.62) and 1.32 (1.12, 1.56) for uranium; 1.24 (1.03, 1.48) and 1.37 (1.19, 1.58) for cobalt; 1.42 (1.18, 1.70) and 1.50 (1.29, 1.74) for copper; and 1.21 (1.01, 1.45) and 1.38 (1.20, 1.59) for zinc. A positive linear dose-response was identified for cadmium and copper with both end points. The adjusted hazard ratios (95% CI) for an interquartile range (IQR) increase in the mixture of these 6 urinary metals and the corresponding 10-year survival probability difference (95% CI) were 1.29 (1.11, 1.56) and -1.1% (-2.0, -0.05) for incident CVD and 1.66 (1.47, 1.91) and -2.0% (-2.6, -1.5) for all-cause mortality., Conclusions: This epidemiological study in US adults indicates that urinary metal levels are associated with increased CVD risk and mortality. These findings can inform the development of novel preventive strategies to improve cardiovascular health., Competing Interests: None.

Rationale: It is unknown whether air pollution is associated with radiographic features of interstitial lung disease in individuals with chronic obstructive pulmonary disease (COPD). Objectives: To determine whether air pollution increases the prevalence of interstitial lung abnormalities (ILA) or percent high-attenuation areas (HAA) on computed tomography (CT) in individuals with a heavy smoking history and COPD. Methods: We performed a cross-sectional study of SPIROMICS (Subpopulations and Intermediate Outcome Measures in COPD Study), focused on current or former smokers with COPD. Ten-year exposure to particulate matter ⩽2.5 μm in aerodynamic diameter (PM 2.5 ), nitrogen oxides (NO x ), nitrogen dioxide (NO 2 ), and ozone before enrollment CT (completed between 2010 and 2015) were estimated with validated spatiotemporal models at residential addresses. We applied adjusted multivariable modified Poisson regression and linear regression to investigate associations between pollution exposure and relative risk (RR) of ILA or increased percent HAA (between -600 and -250 Hounsfield units), respectively. We assessed for effect modification by MUC5B -promoter polymorphism (variant allele carriers GT or TT vs. GG at rs3705950), smoking status, sex, and percent emphysema. Results: Among 1,272 participants with COPD assessed for HAA, 424 were current smokers, and 249 were carriers of the variant MUC5B allele. A total of 519 participants were assessed for ILA. We found no association between pollution exposure and ILA or HAA. Associations between pollutant exposures and risk of ILA were modified by the presence of MUC5B polymorphism ( P value interaction term for NO x  = 0.04 and PM 2.5  = 0.05) and smoking status ( P value interaction term for NO x  = 0.05; NO 2  = 0.01; and ozone = 0.05). With higher exposure to NO x and PM 2.5 , MUC5B variant carriers had an increased risk of ILA (RR per 26 ppb NO x , 2.41; 95% confidence interval [CI], 0.97-6.0; and RR per 4 μg ⋅ m -3 PM 2.5 , 1.43; 95% CI, 0.93-2.2, respectively). With higher exposure to NO 2 , former smokers had an increased risk of ILA (RR per 10 ppb, 1.64; 95% CI, 1.0-2.7). Conclusions: Exposure to ambient air pollution was not associated with interstitial features on CT in this population of heavy smokers with COPD. MUC5B modified the association between pollution and ILA, suggesting that gene-environment interactions may influence prevalence of interstitial lung features in COPD.

Diffuse liver disease is a substantial world-wide problem. With the combination of conventional ultrasound of the abdomen, fat quantification and elastography, appropriate staging of the patient can be assessed. This information allows for the diagnosis of steatosis and detection of fibrosis as well as prognosis, surveillance, and prioritization for treatment. With the potential for reversibility with appropriate treatment accurate assessment for the stage of chronic liver disease is critical., Competing Interests: Disclosure R.G. Barr has received a speaker honorarium from Canon Medical systems, Philips Ultrasound, Siemen Healthineers, Mindray, Samsung Ultrasound, Hologic Ultrasound. He has received research grants from Philips Ultrasound, Canon Ultrasound, Canon MRI, Samsung, South Korea, Siemens Healthineers, Germany, Hologic, United States, Mindray and equipment grants from Canon Medical Systems, United States, Philips Ultrasound, and Siemens Healthineers. He receives royalties from Thieme Publishers and Elsevier Publisher. He is on the advisory panels of Bracco Diagnostics and Lantheus., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Rationale: Identification and validation of circulating biomarkers for lung function decline in COPD remains an unmet need., Objective: Identify prognostic and dynamic plasma protein biomarkers of COPD progression., Methods: We measured plasma proteins using SomaScan from two COPD-enriched cohorts, the Subpopulations and Intermediate Outcomes Measures in COPD Study (SPIROMICS) and Genetic Epidemiology of COPD (COPDGene), and one population-based cohort, Multi-Ethnic Study of Atherosclerosis (MESA) Lung. Using SPIROMICS as a discovery cohort, linear mixed models identified baseline proteins that predicted future change in FEV 1 (prognostic model) and proteins whose expression changed with change in lung function (dynamic model). Findings were replicated in COPDGene and MESA-Lung. Using the COPD-enriched cohorts, Gene Set Enrichment Analysis (GSEA) identified proteins shared between COPDGene and SPIROMICS. Metascape identified significant associated pathways., Measurements and Main Results: The prognostic model found 7 significant proteins in common (p < 0.05) among all 3 cohorts. After applying false discovery rate (adjusted p < 0.2), leptin remained significant in all three cohorts and growth hormone receptor remained significant in the two COPD cohorts. Elevated baseline levels of leptin and growth hormone receptor were associated with slower rate of decline in FEV 1 . Twelve proteins were nominally but not FDR significant in the dynamic model and all were distinct from the prognostic model. Metascape identified several immune related pathways unique to prognostic and dynamic proteins., Conclusion: We identified leptin as the most reproducible COPD progression biomarker. The difference between prognostic and dynamic proteins suggests disease activity signatures may be different from prognosis signatures.

Purpose: It has been reported that the estimate of ultrasound attenuation coefficient (AC) is affected by depth of measurement, with linear decrease of values with depth. It is unknown whether backscatter coefficient (BSC) has similar behavior., Methods: This retrospective study was performed with Sequoia US system equipped with ultrasound derived fat fraction (UDFF) algorithm (Siemens Healthineers, Issaquah, WA, USA) that combines BSC with AC. UDFF was obtained positioning upper edge of the region of interest at 1.5,2,3,4,5 cm below liver capsule. BSC data were extracted from UDFF offline. A fractional polynomial regression, which selects the best model considering the polynomial development of the variables of interest, was used. Covariates included were age, sex, skin-to-liver-capsule distance, stiffness. Distance was included as linear factor or with a power ranging from - 2 to 3, and the best fitting model was chosen according to partial F test. Body mass index (BMI) was not included because of collinearity with skin-to-liver capsule distance., Results: 104 individuals (56 females; age: 57.9 ± 13.0 years; BMI: 29.0 ± 6.5 kg/m 2 ; skin-to-liver-capsule distance: 2.3 ± 0.7 cm; liver stiffness: 7.5 ± 5.5 kiloPascal) were studied. Best fitting model for BSC included a combination of depth as linear factor and square root. BSC showed a decrease of - 13.98 dB/cm-steradian for each logarithmic increase of 1 cm depth (coefficient: - 13.98; 95% CI: - 21.016; - 5.379; p = .001). Skin-to-liver-capsule distance and stiffness also were independent predictors of BSC., Conclusions: The estimation of the BSC in the liver exhibits a depth dependence that significantly affects results. A standardized acquisition protocol is needed to compare results and reliably assess changes over time., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

The World Federation for Ultrasound in Medicine and Biology (WFUMB) has promoted the development of this document on multiparametric ultrasound. Part 2 is a guidance on the use of the available tools for the quantification of liver fat content with ultrasound. These are attenuation coefficient, backscatter coefficient, and speed of sound. All of them use the raw data of the ultrasound beam to estimate liver fat content. This guidance has the aim of helping the reader in understanding how they work and interpret the results. Confounding factors are discussed and a standardized protocol for measurement acquisition is suggested to mitigate them. The recommendations were based on published studies and experts' opinion but were not formally graded because the body of evidence remained low at the time of drafting this document., Competing Interests: Conflict of interest G.F. has received a speaker honorarium from Canon Medical Systems, Fujifilm Healthcare, Mindray Medical Imaging, Philips Ultrasound, Siemens Healthineers. She has served on advisory boards for Philips Healthcare and Siemens Healthineers and her university has received ultrasound equipment grants and unrestricted research grants from Canon Medical Systems, Esaote SpA, Fujifilm Medical Systems, Philips Ultrasound. She receives royalties from Elsevier Publisher. R.G.B. has received a speaker honorarium from Canon Medical systems, Philips Ultrasound, Siemens Healthineers, Mindray, Samsung Ultrasound, Hologic Ultrasound. He has received research grants from Philips Ultrasound, Canon Ultrasound, Canon MRI, Samsung, Siemens Healthineers, Hologic, Mindray and equipment grants from Canon Medical Systems, Philips Ultrasound, Mindray, Samsung Ultrasound and Siemens Healthineers. He is on the advisory board of Lantheus Medical. He receives royalties from Thieme Publishers and Elsevier Publisher. A.B. is consultant for Boehringer-Ingelheim and has received speaker honoraria from GE Healthcare and Hologic Ultrasound. She has received research ultrasound equipment support from GE Healthcare. I.S. has received speaker fees from Siemens Healthineers, General Electric, Samsung Ultrasound, Canon Medical Systems. V.W.W. served as a consultant or advisory board member for AbbVie, Boehringer Ingelheim, Echosens, Gilead Sciences, Intercept, Inventiva, Novo Nordisk, Pfizer, Sagimet Biosciences, TARGET PharmaSolutions, and Visirna; and a speaker for Abbott, AbbVie, Gilead Sciences, Novo Nordisk, Unilab. He has received a research grant from Gilead Sciences and is a co-founder of Illuminatio Medical Technology. T.R. received grant support from Abbvie, Boehringer Ingelheim, Gilead, Intercept/Advanz Pharma, MSD, Myr Pharmaceuticals, Philips Healthcare, Pliant, Siemens and W. L. Gore & Associates; speaking honoraria from Abbvie, Gilead, Intercept/Advanz Pharma, Roche, MSD, W. L. Gore & Associates; consulting/advisory board fee from Abbvie, Astra Zeneca, Bayer, Boehringer Ingelheim, Gilead, Intercept/Advanz Pharma, MSD, Resolution Therapeutics, Siemens; and travel support from Abbvie, Boehringer Ingelheim, Dr. Falk Pharma, Gilead and Roche. T.K. has received speaker honoraria from Echosens, Falk Foundation and Jazz Pharmaceuticals. He has served on advisory boards for Echosens and his university has received ultrasound equipment and unrestricted research grants from Canon Medical Systems and Echosens. M.T. has received a speaker honorarium from Siemens Healthcare, Echosens, Norgine, Madrigal, Takeda, and Tillotts Pharma. Advisory fee from Boehringer Ingelheim, AstraZeneca, GSK. Co-founder and board member of Evido. Board member for Alcohol & Society (non-governmental organisation). A.C.C. has received speaker honorarium from Novo Nordisk. O.T.A. has served as a consultant or adviser to Novo Nordisk, Resonance Health, Norgine and Sun Pharma. He has received research ultrasound equipment support from Canon Medical Systems. L.C. has served as a consultant for Boston Pharmaceuticals, Echosens, GSK, Madrigal, MSD, Novo Nordisk, Pfizer, Sagimet and Siemens Healthineers; and lecture fees from Echosens, Gilead, Inventiva, Madrigal and Novo Nordisk. C.F.D. has received speaker honorarium from AbbVie, Bracco, Falk Foundation, Fujifilm Healthcare, GE Healthcare, Janssen, Mindray Medical Imaging, Olympus, Pentax, Siemens Healthcare, Sonoscape. H.I. has received research grants from Canon Medical Systems and GE Healthcare. She has received research ultrasound equipment support from Canon Medical Systems. D.H.L. has received research grants and speaker honorarium from Canon Medical Systems. W.K. has received speaker honorarium from Novo Nordisk, Eaisi, Roche. C.P.O. has been a consultant or participant in clinical trials for NovoNordisk, Pfizer, Inventiva, Astra-Zeneca, Boehringer Ingelheim. S.K.S. declares no conflict of interest., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Objectives: To assess whether meal or water intake may affect the measurement of the ultrasound (US) attenuation coefficient (AC) imaging, a parameter that is directly related to liver fat content., Methods: The study was performed in two centers (Italy and USA). AC was obtained using the ATI algorithm implemented in the Aplio i-series US systems (Canon Medical Systems, Japan) by one operator at each center. Measurements were performed at baseline and 5, 15, 30, 45 minutes after drinking 500 mL of water (group 1), or 30, 45, 60, 90, 120 minutes after eating a meal of about 600 kcal (group 2). Multilevel generalized estimating equations for repeated measures were used for the statistical analysis to consider the clustered nature of the data., Results: Twenty-six individuals were enrolled: 11 (10 females; age, 43.7 ± 12.5 years) in Italy and 15 (10 females; age, 60.7 ± 6.3 years) in USA. At B-mode US, 10 (38.5%) had liver steatosis. The baseline AC values, in decibel/centimeter/megahertz, were 0.64 (0.12) in group 1 and 0.66 (0.13) in group 2. There was not any significant difference in AC values at every time-point after water or meal intake either in group 1 or group 2. This result did not change including sex, age, and skin-to-liver capsule into the models., Conclusions: The measurement of the AC, which is a biomarker of liver steatosis, does not require a fasting state and drinking water does not affect the result., (© 2024 American Institute of Ultrasound in Medicine.)

The World Federation for Ultrasound in Medicine and Biology (WFUMB) endorsed the development of this document on multiparametric ultrasound. Part 1 is an update to the WFUMB Liver Elastography Guidelines Update released in 2018 and provides new evidence on the role of ultrasound elastography in chronic liver disease. The recommendations in this update were made and graded using the Oxford classification, including level of evidence (LoE), grade of recommendation (GoR) and proportion of agreement (Oxford Centre for Evidence-Based Medicine [OCEBM] 2009). The guidelines are clinically oriented, and the role of shear wave elastography in both fibrosis staging and prognostication in different etiologies of liver disease is discussed, highlighting advantages and limitations. A comprehensive section is devoted to the assessment of portal hypertension, with specific recommendations for the interpretation of liver and spleen stiffness measurements in this setting., Competing Interests: Conflict of interest G.F. has received a speaker honorarium from Canon Medical Systems, Fujifilm Healthcare, Mindray Medical Imaging, Philips Ultrasound and Siemens Healthineers. She has served on advisory boards for Philips Healthcare and Siemens Healthineers, and her university has received ultrasound equipment grants and unrestricted research grants from Canon Medical Systems, Esaote SpA, Fujifilm Medical Systems and Philips Ultrasound. She receives royalties from Elsevier. R.G.B. has received a speaker honorarium from Canon Medical systems, Philips Ultrasound, Siemens Healthineers, Mindray, Samsung Ultrasound and Hologic Ultrasound. He has received research grants from Philips Ultrasound, Canon Ultrasound, Canon MRI, Samsung, Siemens Healthineers, Hologic and Mindray, and equipment grants from Canon Medical Systems, Philips Ultrasound, Mindray, Samsung Ultrasound and Siemens Healthineers. He is on the advisory board of Lantheus Medical. He receives royalties from Thieme and Elsevier. A.B. is consultant for Boehringer–Ingelheim and has received speaker honoraria from GE Healthcare and Hologic Ultrasound. She has received research ultrasound equipment support from GE Healthcare. I.S. has received speaker fees from Siemens Healthineers, General Electric, Samsung Ultrasound and Canon Medical Systems. V.W.S.W. served as a consultant or advisory board member for AbbVie, Boehringer Ingelheim, Echosens, Gilead Sciences, Intercept, Inventiva, Novo Nordisk, Pfizer, Sagimet Biosciences, TARGET PharmaSolutions and Visirna, and as a speaker for Abbott, AbbVie, Gilead Sciences, Novo Nordisk and Unilab. He has received a research grant from Gilead Sciences and is a co-founder of Illuminatio Medical Technology. T.R. received grant support from Abbvie, Boehringer Ingelheim, Gilead, Intercept/Advanz Pharma, MSD, Myr Pharmaceuticals, Philips Healthcare, Pliant, Siemens and W. L. Gore & Associates; speaking honoraria from Abbvie, Gilead, Intercept/Advanz Pharma, Roche, MSD and W. L. Gore & Associates; a consulting/advisory board fee from Abbvie, Astra Zeneca, Bayer, Boehringer Ingelheim, Gilead, Intercept/Advanz Pharma, MSD, Resolution Therapeutics and Siemens; and travel support from Abbvie, Boehringer Ingelheim, Dr. Falk Pharma, Gilead and Roche. T.K. has received speaker honoraria from Echosens, Falk Foundation and Jazz Pharmaceuticals, and has served on advisory boards for Echosens and his university has received ultrasound equipment and unrestricted research grants from Canon Medical Systems and Echosens. M.T. has received a speaker honorarium from Siemens Healthcare, Echosens, Norgine, Madrigal, Takeda and Tillotts Pharma and an advisory fee from Boehringer Ingelheim, AstraZeneca and GSK; she is a co-founder and board member of Evido and is a board member for Alcohol & Society (non-governmental organization). ACC has received speaker honorarium from Novo Nordisk. O.T.A. has served as a consultant or adviser to Novo Nordisk, Resonance Health, Norgine and Sun Pharma; he has received research ultrasound equipment support from Canon Medical Systems. L.C. has received consulting fees from Boston Pharmaceutical, Echosens, Gilead, GSK, Madrigal, MSD, Novo Nordisk, Pfizer, Sagimet and Siemens Healthineers, and speaker fees from Echosens, Gilead, Inventiva, Madrigal and Novo Nordisk. C.F.D. has received a speaker honorarium from AbbVie, Bracco, Falk Foundation, Fujifilm Healthcare, GE Healthcare, Janssen, Mindray Medical Imaging, Olympus, Pentax, Siemens Healthcare and Sonoscape. H.I. has received research grants from Canon Medical Systems and GE Healthcare and research ultrasound equipment support from Canon Medical Systems. D.H.L. has received research grants and a speaker honorarium from Canon Medical Systems. W.K. has received a speaker honorarium from Novo Nordisk, Eaisi and Roche. C.P.O. has been a consultant or participant in clinical trials for NovoNordisk, Pfizer, Inventiva, Astra-Zeneca and Boehringer Ingelheim. S.K.S. declares no conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background Attenuation coefficient (AC) and shear-wave speed (SWS) are established US markers for assessing patients with metabolic dysfunction-associated steatotic liver disease (MASLD), while shear-wave dispersion slope (DS) is not. Purpose To assess the relationship between the multiparametric US imaging markers DS, AC, and SWS and liver histopathologic necroinflammation in patients with MASLD. Materials and Methods This international multicenter prospective study enrolled consecutive patients with biopsy-proven MASLD between June 2019 and March 2023. Before biopsy, all participants underwent multiparametric US, and measurements of DS, AC, and SWS were obtained. Multivariable linear regression analyses were performed to assess the association of clinical variables and imaging markers with pathologic findings. The diagnostic performance of imaging markers for determining inflammation grade, steatosis grade, and fibrosis stage was assessed using the area under the receiver operating characteristic curve (AUC). Results A total of 124 participants (mean age, 53 years ± 15 [SD]; 62 males) were evaluated. In multivariable regression, lobular inflammation was associated with DS (regression coefficient, 0.06; P = .02), alanine aminotransferase level (regression coefficient, 0.002; P = .002), and Hispanic or Latino ethnicity (regression coefficient, -0.68; P = .047), while steatosis was associated with AC (regression coefficient, 3.66; P < .001) and fibrosis was associated with SWS (regression coefficient, 2.02; P < .001) and body mass index (regression coefficient, 0.05; P = .02). DS achieved an AUC of 0.72 (95% CI: 0.63, 0.82) for identifying participants with inflammation grade A2 or higher (moderate to severe inflammation). AC showed excellent performance for identifying participants with grade S1 (mild) or higher steatosis (AUC, 0.92 [95% CI: 0.87, 0.97]), while SWS showed excellent performance for identifying participants with fibrosis stage F2 or higher (clinically significant fibrosis) (AUC, 0.91 [95% CI: 0.86, 0.96]). Of the three US markers, SWS showed the highest AUC (0.81 [95% CI: 0.74, 0.89]) for the diagnosis of metabolic dysfunction-associated steatohepatitis. Conclusion Of the three US imaging markers (DS, AC, and SWS), DS was most associated with lobular inflammation grade at histologic examination and demonstrated fair diagnostic performance in distinguishing moderate to severe lobular inflammation. ClinicalTrials.gov Identifier: NCT04012242 Published under a CC BY 4.0 license. Supplemental material is available for this article. See also the editorial by Yin in this issue.

Rationale: The airway microbiome has the potential to shape chronic obstructive pulmonary disease (COPD) pathogenesis, but its relationship to outcomes in milder disease is unestablished. Objectives: To identify sputum microbiome characteristics associated with markers of COPD in participants of the Subpopulations and Intermediate Outcome Measures of COPD Study (SPIROMICS). Methods: Sputum DNA from 877 participants was analyzed using 16S ribosomal RNA gene sequencing. Relationships between baseline airway microbiota composition and clinical, radiographic, and mucoinflammatory markers, including longitudinal lung function trajectory, were examined. Measurements and Main Results: Participant data represented predominantly milder disease (Global Initiative for Chronic Obstructive Lung Disease stage 0-2 obstruction in 732 of 877 participants). Phylogenetic diversity (i.e., range of different species within a sample) correlated positively with baseline lung function, decreased with higher Global Initiative for Chronic Obstructive Lung Disease stage, and correlated negatively with symptom burden, radiographic markers of airway disease, and total mucin concentrations ( P  < 0.001). In covariate-adjusted regression models, organisms robustly associated with better lung function included Alloprevotella , Oribacterium , and Veillonella species. Conversely, lower lung function, greater symptoms, and radiographic measures of small airway disease were associated with enrichment in members of Streptococcus , Actinobacillus , Actinomyces , and other genera. Baseline sputum microbiota features were also associated with lung function trajectory during SPIROMICS follow-up (stable/improved, decline, or rapid decline groups). The stable/improved group (slope of FEV 1 regression ⩾66th percentile) had greater bacterial diversity at baseline associated with enrichment in Prevotella , Leptotrichia , and Neisseria species. In contrast, the rapid decline group (FEV 1 slope ⩽33rd percentile) had significantly lower baseline diversity associated with enrichment in Streptococcus species. Conclusions: In SPIROMICS, baseline airway microbiota features demonstrate divergent associations with better or worse COPD-related outcomes.

Rationale: Rates of emphysema progression vary in chronic obstructive pulmonary disease (COPD), and the relationships with vascular and airway pathophysiology remain unclear. Objectives: We sought to determine if indices of peripheral (segmental and beyond) pulmonary arterial dilation measured on computed tomography (CT) are associated with a 1-year index of emphysema (EI; percentage of voxels <-950 Hounsfield units) progression. Methods: Five hundred ninety-nine former and never-smokers (Global Initiative for Chronic Obstructive Lung Disease stages 0-3) were evaluated from the SPIROMICS (Subpopulations and Intermediate Outcome Measures in COPD Study) cohort: rapid emphysema progressors (RPs; n  = 188, 1-year ΔEI > 1%), nonprogressors ( n  = 301, 1-year ΔEI ± 0.5%), and never-smokers ( n  = 110). Segmental pulmonary arterial cross-sectional areas were standardized to associated airway luminal areas (segmental pulmonary artery-to-airway ratio [PAAR seg ]). Full-inspiratory CT scan-derived total (arteries and veins) pulmonary vascular volume (TPVV) was compared with small vessel volume (radius smaller than 0.75 mm). Ratios of airway to lung volume (an index of dysanapsis and COPD risk) were compared with ratios of TPVV to lung volume. Results: Compared with nonprogressors, RPs exhibited significantly larger PAAR seg (0.73 ± 0.29 vs. 0.67 ± 0.23; P  = 0.001), lower ratios of TPVV to lung volume (3.21 ± 0.42% vs. 3.48 ± 0.38%; P  = 5.0 × 10 -12 ), lower ratios of airway to lung volume (0.031 ± 0.003 vs. 0.034 ± 0.004; P  = 6.1 × 10 -13 ), and larger ratios of small vessel volume to TPVV (37.91 ± 4.26% vs. 35.53 ± 4.89%; P  = 1.9 × 10 -7 ). In adjusted analyses, an increment of 1 standard deviation in PAAR seg was associated with a 98.4% higher rate of severe exacerbations (95% confidence interval, 29-206%; P  = 0.002) and 79.3% higher odds of being in the RP group (95% confidence interval, 24-157%; P  = 0.001). At 2-year follow-up, the CT-defined RP group demonstrated a significant decline in postbronchodilator percentage predicted forced expiratory volume in 1 second. Conclusions: Rapid one-year progression of emphysema was associated with indices indicative of higher peripheral pulmonary vascular resistance and a possible role played by pulmonary vascular-airway dysanapsis.

Rationale Dysanapsis refers to a mismatch between airway tree caliber and lung size arising early in life. Dysanapsis assessed by computed tomography (CT) is evident by early adulthood and associated with chronic obstructive pulmonary disease (COPD) risk later in life. Objective By examining the genetic factors associated with CT-assessed dysanapsis, we aimed to elucidate its molecular underpinnings and physiological significance across the lifespan. Methods We performed a genome-wide association study (GWAS) of CT-assessed dysanapsis in 11,951 adults, including individuals from two population-based and two COPD-enriched studies. We applied colocalization analysis to integrate GWAS and gene expression data from whole blood and lung. Genetic variants associated with dysanapsis were combined into a genetic risk score that was applied to examine association with lung function in children from a population-based birth cohort (n=1,278) and adults from the UK Biobank (n=369,157). Measurements and Main Results CT-assessed dysanapsis was associated with genetic variants from 21 independent signals in 19 gene regions, implicating HHIP , DSP , and NPNT as potential molecular targets based on colocalization of their expression. Higher dysanapsis genetic risk score was associated with obstructive spirometry among 5 year old children and among adults in the 5th, 6th and 7th decades of life. Conclusions CT-assessed dysanapsis is associated with variation in genes previously implicated in lung development and dysanapsis genetic risk is associated with obstructive lung function from early life through older adulthood. Dysanapsis may represent an endo-phenotype link between the genetic variations associated with lung function and COPD.

Rational: Ground glass opacities (GGO) in the absence of interstitial lung disease are understudied., Objective: To assess the association of GGO with white blood cells (WBCs) and progression of quantified chest CT emphysema., Methods: We analyzed data of participants in the Subpopulations and Intermediate Outcome Measures In COPD Study (SPIROMICS). Chest radiologists and pulmonologists labeled regions of the lung as GGO and adaptive multiple feature method (AMFM) trained the computer to assign those labels to image voxels and quantify the volume of the lung with GGO (%GGO AMFM ). We used multivariable linear regression, zero-inflated negative binomial, and proportional hazards regression models to assess the association of %GGO AMFM with WBC, changes in %emphysema, and clinical outcomes., Measurements and Main Results: Among 2,714 participants, 1,680 had COPD and 1,034 had normal spirometry. Among COPD participants, based on the multivariable analysis, current smoking and chronic productive cough was associated with higher %GGO AMFM . Higher %GGO AMFM was cross-sectionally associated with higher WBCs and neutrophils levels. Higher %GGO AMFM per interquartile range at visit 1 (baseline) was associated with an increase in emphysema at one-year follow visit by 11.7% (Relative increase; 95%CI 7.5-16.1%;P<0.001). We found no association between %GGO AMFM and one-year FEV 1 decline but %GGO AMFM was associated with exacerbations and all-cause mortality during a median follow-up time of 1,544 days (Interquartile Interval=1,118-2,059). Among normal spirometry participants, we found similar results except that %GGO AMFM was associated with progression to COPD at one-year follow-up., Conclusions: Our findings suggest that GGO AMFM is associated with increased systemic inflammation and emphysema progression.

Rationale: Airway tree morphology varies in the general population and may modify the distribution and uptake of inhaled pollutants. Objectives: We hypothesized that smaller airway caliber would be associated with emphysema progression and would increase susceptibility to air pollutant-associated emphysema progression. Methods: MESA (Multi-Ethnic Study of Atherosclerosis) is a general population cohort of adults 45-84 years old from six U.S. communities. Airway tree caliber was quantified as the mean of airway lumen diameters measured from baseline cardiac computed tomography (CT) (2000-2002). Percentage emphysema, defined as percentage of lung pixels below -950 Hounsfield units, was assessed up to five times per participant via cardiac CT scan (2000-2007) and equivalent regions on lung CT scan (2010-2018). Long-term outdoor air pollutant concentrations (particulate matter with an aerodynamic diameter ⩽2.5 μm, oxides of nitrogen, and ozone) were estimated at the residential address with validated spatiotemporal models. Linear mixed models estimated the association between airway tree caliber and emphysema progression; modification of pollutant-associated emphysema progression was assessed using multiplicative interaction terms. Measurements and Main Results: Among 6,793 participants (mean ± SD age, 62 ± 10 yr), baseline airway tree caliber was 3.95 ± 1.1 mm and median (interquartile range) of percentage emphysema was 2.88 (1.21-5.68). In adjusted analyses, 10-year emphysema progression rate was 0.75 percentage points (95% confidence interval, 0.54-0.96%) higher in the smallest compared with largest airway tree caliber quartile. Airway tree caliber also modified air pollutant-associated emphysema progression. Conclusions: Smaller airway tree caliber was associated with accelerated emphysema progression and modified air pollutant-associated emphysema progression. A better understanding of the mechanisms of airway-alveolar homeostasis and air pollutant deposition is needed.

Background: Pneumonia-related hospitalization may be associated with advanced skeletal muscle loss due to aging (i.e., sarcopenia) or chronic illnesses (i.e., cachexia). Early detection of muscle loss may now be feasible using deep-learning algorithms applied on conventional chest CT., Objectives: To implement a fully automated deep-learning algorithm for pectoralis muscle measures from conventional chest CT and investigate longitudinal associations between these measures and incident pneumonia hospitalization according to Chronic Obstructive Pulmonary Disease (COPD) status., Materials and Methods: This analysis from the Multi-Ethnic Study of Atherosclerosis included participants with available chest CT examinations between 2010 and 2012. We implemented pectoralis muscle composition measures from a fully automated deep-learning algorithm (Mask R-CNN, built on the Faster Region Proposal Network (R-) Convolutional Neural Network (CNN) with an extension for mask identification) for two-dimensional segmentation. Associations between CT-derived measures and incident pneumonia hospitalizations were evaluated using Cox proportional hazards models adjusted for multiple confounders which include but are not limited to age, sex, race, smoking, BMI, physical activity, and forced-expiratory-volume-at-1 s-to-functional-vital-capacity ratio. Stratification analyses were conducted based on baseline COPD status., Results: This study included 2595 participants (51% female; median age: 68 (IQR: 61, 76)) CT examinations for whom we implemented deep learning-derived measures for longitudinal analyses. Eighty-six incident pneumonia hospitalizations occurred during a median 6.67-year follow-up. Overall, pectoralis muscle composition measures did not predict incident pneumonia. However, in fully-adjusted models, only among participants with COPD (N = 507), CT measures like extramyocellular fat index (hazard ratio: 1.98, 95% CI: 1.22, 3.21, p value: 0.02), were independently associated with incident pneumonia., Conclusion: Reliable deep learning-derived pectoralis muscle measures could predict incident pneumonia hospitalization only among participants with known COPD., Clinical Relevance Statement: Pectoralis muscle measures obtainable at zero additional cost or radiation exposure from any chest CT may have independent predictive value for clinical outcomes in chronic obstructive pulmonary disease patients., Key Points: •Identification of independent and modifiable risk factors of pneumonia can have important clinical impact on patients with chronic obstructive pulmonary disease. •Opportunistic CT measures of adipose tissue within pectoralis muscles using deep-learning algorithms can be quickly obtainable at zero additional cost or radiation exposure. •Deep learning-derived pectoralis muscle measurements of intermuscular fat and its subcomponents are independently associated with subsequent incident pneumonia hospitalization., (© 2023. The Author(s), under exclusive licence to European Society of Radiology.)

Rationale: Chronic obstructive pulmonary disease (COPD) and emphysema are associated with endothelial damage and altered pulmonary microvascular perfusion. The molecular mechanisms underlying these changes are poorly understood in patients, in part because of the inaccessibility of the pulmonary vasculature. Peripheral blood mononuclear cells (PBMCs) interact with the pulmonary endothelium. Objectives: To test the association between gene expression in PBMCs and pulmonary microvascular perfusion in COPD. Methods: The Multi-Ethnic Study of Atherosclerosis (MESA) COPD Study recruited two independent samples of COPD cases and controls with ⩾10 pack-years of smoking history. In both samples, pulmonary microvascular blood flow, pulmonary microvascular blood volume, and mean transit time were assessed on contrast-enhanced magnetic resonance imaging, and PBMC gene expression was assessed by microarray. Additional replication was performed in a third sample with pulmonary microvascular blood volume measures on contrast-enhanced dual-energy computed tomography. Differential expression analyses were adjusted for age, gender, race/ethnicity, educational attainment, height, weight, smoking status, and pack-years of smoking. Results: The 79 participants in the discovery sample had a mean age of 69 ± 6 years, 44% were female, 25% were non-White, 34% were current smokers, and 66% had COPD. There were large PBMC gene expression signatures associated with pulmonary microvascular perfusion traits, with several replicated in the replication sets with magnetic resonance imaging ( n  = 47) or dual-energy contrast-enhanced computed tomography ( n  = 157) measures. Many of the identified genes are involved in inflammatory processes, including nuclear factor-κB and chemokine signaling pathways. Conclusions: PBMC gene expression in nuclear factor-κB, inflammatory, and chemokine signaling pathways was associated with pulmonary microvascular perfusion in COPD, potentially offering new targetable candidates for novel therapies.

High-resolution full lung CT scans now enable the detailed segmentation of airway trees up to the 6th branching generation. The airway binary masks display very complex tree structures that may encode biological information relevant to disease risk and yet remain challenging to exploit via traditional methods such as meshing or skeletonization. Recent clinical studies suggest that some variations in shape patterns and caliber of the human airway tree are highly associated with adverse health outcomes, including all-cause mortality and incident COPD. However, quantitative characterization of variations observed on CT segmented airway tree remain incomplete, as does our understanding of the clinical and developmental implications of such. In this work, we present an unsupervised deep-learning pipeline for feature extraction and clustering of human airway trees, learned directly from projections of 3D airway segmentations. We identify four reproducible and clinically distinct airway sub-types in the MESA Lung CT cohort.

Robust quantification of pulmonary emphysema on computed tomography (CT) remains challenging for large-scale research studies that involve scans from different scanner types and for translation to clinical scans. Although the domain shifts in different CT scanners are subtle compared to shifts existing in other modalities (e.g., MRI) or cross-modality, emphysema is highly sensitive to it. Such subtle difference limits the application of general domain adaptation methods, such as image translation-based methods, as the contrast difference is too subtle to be distinguished. Existing studies have explored several directions to tackle this challenge, including density correction, noise filtering, regression, hidden Markov measure field (HMMF) model-based segmentation, and volume-adjusted lung density. Despite some promising results, previous studies either required a tedious workflow or eliminated opportunities for downstream emphysema subtyping, limiting efficient adaptation on a large-scale study. To alleviate this dilemma, we developed an end-to-end deep learning framework based on an existing HMMF segmentation framework. We first demonstrate that a regular UNet cannot replicate the existing HMMF results because of the lack of scanner priors. We then design a novel domain attention block, a simple yet efficient cross-modal block to fuse image visual features with quantitative scanner priors (a sequence), which significantly improves the results.

In this cross-sectional study performed in Canada, we evaluated the frustration levels of prepartum and postpartum mother and father couple-pairs. Our goal was to determine if there were differences in frustration levels between mothers and fathers while listening to prolonged infant crying, and further, how frustration levels might differ between prepartum and postpartum samples. Using two discrete groups, prepartum (Sample 1; N = 48) and postpartum (Sample 2; N = 44) mother and father couple-pairs completed 600 s of listening to audio-recorded infant cry sounds. Participants continuously reported their subjective frustration using a computerized Continuous Visual Analog Scale (CVAS). There was no significant difference in frustration responses between mothers and fathers across both prepartum and postpartum samples. Postpartum mothers and fathers experienced greater frustration than their prepartum counterparts, and frustration increased faster in postpartum couples compared to prepartum couples. Informing first-time parents of the universal experiences of frustration to prolonged crying bouts that are characteristic of their infant's early weeks of life may lead to greater understanding towards their infant, and perhaps decreased instances of harmful responses., (© 2024 Michigan Association for Infant Mental Health.)

Smaller mean airway tree caliber is associated with airflow obstruction and chronic obstructive pulmonary disease (COPD). We investigated whether airway tree caliber heterogeneity was associated with airflow obstruction and COPD. Two community-based cohorts (MESA Lung, CanCOLD) and a longitudinal case-control study of COPD (SPIROMICS) performed spirometry and computed tomography measurements of airway lumen diameters at standard anatomical locations (trachea-to-subsegments) and total lung volume. Percent-predicted airway lumen diameters were calculated using sex-specific reference equations accounting for age, height, and lung volume. The association of airway tree caliber heterogeneity, quantified as the standard deviation (SD) of percent-predicted airway lumen diameters, with baseline forced expired volume in 1-second (FEV 1 ), FEV 1 /forced vital capacity (FEV 1 /FVC) and COPD, as well as longitudinal spirometry, were assessed using regression models adjusted for age, sex, height, race-ethnicity, and mean airway tree caliber. Among 2,505 MESA Lung participants (means ± SD age: 69 ± 9 yr; 53% female, mean airway tree caliber: 99 ± 10% predicted, airway tree caliber heterogeneity: 14 ± 5%; median follow-up: 6.1 yr), participants in the highest quartile of airway tree caliber heterogeneity exhibited lower FEV 1 (adjusted mean difference: -125 mL, 95%CI: -171,-79), lower FEV 1 /FVC (adjusted mean difference: -0.01, 95%CI: -0.02,-0.01), and higher odds of COPD (adjusted odds ratio: 1.42, 95%CI: 1.01-2.02) when compared with the lowest quartile, whereas longitudinal changes in FEV 1 and FEV 1 /FVC did not differ significantly. Observations in CanCOLD and SPIROMICS were consistent. Among older adults, airway tree caliber heterogeneity was associated with airflow obstruction and COPD at baseline but was not associated with longitudinal changes in spirometry. NEW & NOTEWORTHY In this study, by leveraging two community-based samples and a case-control study of heavy smokers, we show that among older adults, airway tree caliber heterogeneity quantified by CT is associated with airflow obstruction and COPD independent of age, sex, height, race-ethnicity, and dysanapsis. These observations suggest that airway tree caliber heterogeneity is a structural trait associated with low baseline lung function and normal decline trajectory that is relevant to COPD.

Background: Higher 25-hydroxyvitamin D (25(OH)D) concentrations in serum has a positive association with pulmonary function. Investigating genome-wide interactions with 25(OH)D may reveal new biological insights into pulmonary function., Objectives: We aimed to identify novel genetic variants associated with pulmonary function by accounting for 25(OH)D interactions., Methods: We included 211,264 participants from the observational United Kingdom Biobank study with pulmonary function tests (PFTs), genome-wide genotypes, and 25(OH)D concentrations from 4 ancestral backgrounds-European, African, East Asian, and South Asian. Among PFTs, we focused on forced expiratory volume in the first second (FEV 1 ) and forced vital capacity (FVC) because both were previously associated with 25(OH)D. We performed genome-wide association study (GWAS) analyses that accounted for variant×25(OH)D interaction using the joint 2 degree-of-freedom (2df) method, stratified by participants' smoking history and ancestry, and meta-analyzed results. We evaluated interaction effects to determine how variant-PFT associations were modified by 25(OH)D concentrations and conducted pathway enrichment analysis to examine the biological relevance of our findings., Results: Our GWAS meta-analyses, accounting for interaction with 25(OH)D, revealed 30 genetic variants significantly associated with FEV 1 or FVC (P 2df <5.00×10 -8 ) that were not previously reported for PFT-related traits. These novel variant signals were enriched in lung function-relevant pathways, including the p38 MAPK pathway. Among variants with genome-wide-significant 2df results, smoking-stratified meta-analyses identified 5 variants with 25(OH)D interactions that influenced FEV 1 in both smoking groups (never smokers P 1df interaction <2.65×10 -4 ; ever smokers P 1df interaction <1.71×10 -5 ); rs3130553, rs2894186, rs79277477, and rs3130929 associations were only evident in never smokers, and the rs4678408 association was only found in ever smokers., Conclusion: Genetic variant associations with lung function can be modified by 25(OH)D, and smoking history can further modify variant×25(OH)D interactions. These results expand the known genetic architecture of pulmonary function and add evidence that gene-environment interactions, including with 25(OH)D and smoking, influence lung function., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Due to the steatosis epidemic, noninvasive quantification of liver fat content is of great interest. Magnetic resonance (MR) techniques, including proton MR spectroscopy (MRS) and MR chemical shift imaging can quantify liver fat by measuring, directly or indirectly (the latter), the proton density fat fraction (PDFF). They have shown excellent diagnostic accuracy and are currently the reference standard for the noninvasive assessment of liver steatosis and are used in clinical trials for evaluating the change in liver fat over time. Using ultrasound (US), three different quantitative parameters can be obtained to estimate liver fat: attenuation coefficient, backscatter coefficient, and speed of sound. Controlled attenuation parameter (CAP), which estimates the attenuation of the US beam, was the first algorithm available and is performed with a non-imaging system. Currently, several other algorithms are available on B-mode imaging ultrasound systems, and they have shown an accuracy similar to or higher than the CAP. This article reports the current knowledge about their application in patients with metabolic dysfunction-associated steatotic liver disease.

Objective: The aim of this study is to describe a comprehensive contrast-enhanced ultrasound (CEUS) imaging protocol and analysis method to implement CEUS LI-RADS (Liver Imaging Reporting and Data System) in a quantifiable manner. The methods that are validated with a prospective single-center study aim to simplify CEUS LI-RADS evaluation, remove observer bias, and potentially improve the sensitivity of CEUS LI-RADS., Materials and Methods: This prospective single-center study enrolled patients with hepatocellular carcinoma (April 2021-June 2022; N = 31; mean age ± SD, 67 ± 6 years; 24 men/7 women). For each patient, at least 2 CEUS loops spanning over 5 minutes were collected for different lesion scan planes using an articulated arm to hold the transducer. Automatic respiratory gating and motion compensation algorithms removed errors due to breathing motion. The long axis of the lesion was measured in the contrast and fundamental images to capture nodule size. Parametric processing of time-intensity curve analysis on linearized data provided quantifiable information of the wash-in and washout dynamics via rise time ( RT ) and degree of washout ( DW ) parameters extracted from the time-intensity curve, respectively. A Welch t test was performed between lesion and parenchyma RT for each lesion to confirm statistically significant differences. P values for bootstrapped 95% confidence intervals of the relative degree of washout ( rDW ), ratio of DW between the lesion and surrounding parenchyma, were computed to quantify lesion washout. Coefficient of variation (COV) of RT , DW , and rDW was calculated for each patient between injections for both the lesion and surrounding parenchyma to gauge reproducibility of these metrics. Spearman rank correlation tests were performed among size, RT , DW , and rDW values to evaluate statistical dependence between the variables., Results: The mean ± SD lesion diameter was 23 ± 8 mm. The RT for all lesions, capturing arterial phase hyperenhancement, was shorter than that of surrounding liver parenchyma ( P < 0.05). All lesions also demonstrated significant ( P < 0.05) but variable levels of washout at both 2-minute and 5-minute time points, quantified in rDW . The COV of RT for the lesion and surrounding parenchyma were both 11%, and the COV of DW and rDW at 2 and 5 minutes ranged from 22% to 31%. Statistically significant relationships between lesion and parenchyma RT and between lesion RT and lesion DW at the 2- and 5-minute time points were found ( P < 0.05)., Conclusions: The imaging protocol and analysis method presented provide robust, quantitative metrics that describe the dynamic vascular patterns of LI-RADS 5 lesions classified as hepatocellular carcinomas. The RT of the bolus transit quantifies the arterial phase hyperenhancement, and the DW and rDW parameters quantify the washout from linearized CEUS intensity data. This unique methodology is able to implement the CEUS-LIRADS scheme in a quantifiable manner for the first time and remove its existing issues of currently being qualitative and suffering from subjective evaluations., Competing Interests: Conflicts of interest and sources of funding: R.G.B. has received research grants from Philips Ultrasound, Siemens Healthineers, Canon Medical Systems, Mindray, Samsung Ultrasound, and Hologic. R.G.B. is also on the speaker's bureau for Philips Ultrasound, Siemens Ultrasound, Canon Medical Systems, Mindray, Bracco Diagnostics, and Hologic. R.G.B. participates in advisory panels for Lantheus Medical and Hologic, and received royalties from Thieme and Elsevier Publishers. M.D. has received research grants from Philips Ultrasound and GE Healthcare, is also on the speaker's bureau and advisory panel for Philips Ultrasound, and received royalties from Elsevier Publishers. Y.K. has received research grants from Bracco and Canon Medical Systems., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Rationale: The SubPopulations and InteRmediate Outcome Measures in COPD Study (SPIROMICS) is a prospective cohort study that enrolled 2981 participants with the goal of identifying new chronic obstructive pulmonary disease (COPD) subgroups and intermediate markers of disease progression. Individuals with COPD and obstructive sleep apnea (OSA) experience impaired quality of life and more frequent exacerbations. COPD severity also associates with computed tomography scan-based emphysema and alterations in airway dimensions., Objectives: The objective was to determine whether the combination of lung function and structure influences the risk of OSA among current and former smokers., Methods: Using 2 OSA risk scores, the Berlin Sleep Questionnaire (BSQ), and the DOISNORE50 (Diseases, Observed apnea, Insomnia, Snoring, Neck circumference > 18 inches, Obesity with body mass index [BMI] > 32, R = are you male, Excessive daytime sleepiness, 50 = age ≥ 50) (DIS), 1767 current and former smokers were evaluated for an association of lung structure and function with OSA risk., Measurements and Main Results: The study cohort's mean age was 63 years, BMI was 28 kg/m2, and forced expiratory volume in 1 second (FEV1) was 74.8% predicted. The majority were male (55%), White (77%), former smokers (59%), and had COPD (63%). A high-risk OSA score was reported in 36% and 61% using DIS and BSQ respectively. There was a 9% increased odds of a high-risk DIS score (odds ratio [OR]=1.09, 95% confidence interval [CI]:1.03-1.14) and nominally increased odds of a high-risk BSQ score for every 10% decrease in FEV1 %predicted (OR=1.04, 95%CI: 0.998-1.09). Lung function-OSA risk associations persisted after additionally adjusting for lung structure measurements (%emphysema, %air trapping, parametric response mapping for functional small airways disease, , mean segmental wall area, tracheal %wall area, dysanapsis) for DIS (OR=1.12, 95%CI:1.03-1.22) and BSQ (OR=1.09, 95%CI:1.01-1.18)., Conclusions: Lower lung function independently associates with having high risk for OSA in current and former smokers. Lung structural elements, especially dysanapsis, functional small airways disease, and tracheal %wall area strengthened the effects on OSA risk., (JCOPDF © 2024.)

Bulk-tissue molecular quantitative trait loci (QTLs) have been the starting point for interpreting disease-associated variants, and context-specific QTLs show particular relevance for disease. Here, we present the results of mapping interaction QTLs (iQTLs) for cell type, age, and other phenotypic variables in multi-omic, longitudinal data from the blood of individuals of diverse ancestries. By modeling the interaction between genotype and estimated cell-type proportions, we demonstrate that cell-type iQTLs could be considered as proxies for cell-type-specific QTL effects, particularly for the most abundant cell type in the tissue. The interpretation of age iQTLs, however, warrants caution because the moderation effect of age on the genotype and molecular phenotype association could be mediated by changes in cell-type composition. Finally, we show that cell-type iQTLs contribute to cell-type-specific enrichment of diseases that, in combination with additional functional data, could guide future functional studies. Overall, this study highlights the use of iQTLs to gain insights into the context specificity of regulatory effects., Competing Interests: Declaration of interests F.A. is an employee of Illumina, Inc. and an inventor on a patent application related to TensorQTL. T.L. advises Variant Bio, Goldfinch Bio, GlaxoSmithKline, and Pfizer and has equity in Variant Bio., (Copyright © 2023 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

Background: Preserved Ratio Impaired Spirometry (PRISm) is defined as FEV 1 <80% predicted, FEV 1 /FVC ≥0.70. PRISm is associated with respiratory symptoms and co-morbidities. Our objective was to discover novel genetic signals for PRISm and see if they provide insight into the pathogenesis of PRISm and associated co-morbidities., Methods: We undertook a genome-wide association study (GWAS) of PRISm in UK Biobank participants (Stage 1), and selected SNPs reaching genome-wide significance for replication in 13 cohorts (Stage 2). A combined meta-analysis of Stage 1 and Stage 2 was done to determine top SNPs. We used cross-trait Linkage Disequilibrium score regression to estimate genome-wide genetic correlation between PRISM and pulmonary and extra-pulmonary traits. Phenome-wide association studies of top SNPs was performed., Results: 22 signals reached significance in the joint meta-analysis, including four signals novel for lung function. A strong genome-wide genetic correlation (r g ) between PRISm and spirometric COPD (r g =0.62, p-value <0.001) was observed, and genetic correlation with type II diabetes (r g =0.12, p-value 0.007). PheWAS showed that 18 of 22 signals were associated with diabetic traits and 7 with blood pressure traits., Discussion: This is the first GWAS to successfully identify SNPs associated with PRISm. Four of the signals; rs7652391 (nearest gene MECOM ), rs9431040 ( HLX ), rs62018863 ( TMEM114 ) and rs185937162 ( HLA-B ) have not been described in association with lung function before, demonstrating the utility of using different lung function phenotypes in GWAS. Genetic factors associated with PRISm are strongly correlated with risk of both other lung diseases and extra-pulmonary co-morbidity., (Copyright ©The authors 2023.)

Rationale: Indoor pollutants have been associated with chronic obstructive pulmonary disease morbidity, but it is unclear whether they contribute to disease progression. Objectives: We aimed to determine whether indoor particulate matter (PM) and nitrogen dioxide (NO 2 ) are associated with lung function decline among current and former smokers. Methods: Of the 2,382 subjects with a history of smoking in SPIROMICS AIR, 1,208 participants had complete information to estimate indoor PM and NO 2 , using individual-based prediction models, in relation to measured spirometry at two or more clinic visits. We used a three-way interaction model between time, pollutant, and smoking status and assessed the indoor pollutant-associated difference in FEV 1 decline separately using a generalized linear mixed model. Measurements and Main Results: Participants had an average rate of FEV 1 decline of 60.3 ml/yr for those currently smoking compared with 35.2 ml/yr for those who quit. The association of indoor PM with FEV 1 decline differed by smoking status. Among former smokers, every 10 μg/m 3 increase in estimated indoor PM was associated with an additional 10 ml/yr decline in FEV 1 ( P  = 0.044). Among current smokers, FEV 1 decline did not differ by indoor PM. The results of indoor NO 2 suggest trends similar to those for PM ⩽2.5 μm in aerodynamic diameter. Conclusions: Former smokers with chronic obstructive pulmonary disease who live in homes with high estimated PM have accelerated lung function loss, and those in homes with low PM have lung function loss similar to normal aging. In-home PM exposure may contribute to variability in lung function decline in people who quit smoking and may be a modifiable exposure.

Background: Treatment and preventative advances for chronic obstructive pulmonary disease (COPD) have been slow due, in part, to limited subphenotypes. We tested if unsupervised machine learning on CT images would discover CT emphysema subtypes with distinct characteristics, prognoses and genetic associations., Methods: New CT emphysema subtypes were identified by unsupervised machine learning on only the texture and location of emphysematous regions on CT scans from 2853 participants in the Subpopulations and Intermediate Outcome Measures in COPD Study (SPIROMICS), a COPD case-control study, followed by data reduction. Subtypes were compared with symptoms and physiology among 2949 participants in the population-based Multi-Ethnic Study of Atherosclerosis (MESA) Lung Study and with prognosis among 6658 MESA participants. Associations with genome-wide single-nucleotide-polymorphisms were examined., Results: The algorithm discovered six reproducible (interlearner intraclass correlation coefficient, 0.91-1.00) CT emphysema subtypes. The most common subtype in SPIROMICS, the combined bronchitis-apical subtype, was associated with chronic bronchitis, accelerated lung function decline, hospitalisations, deaths, incident airflow limitation and a gene variant near DRD1 , which is implicated in mucin hypersecretion (p=1.1 ×10 -8 ). The second, the diffuse subtype was associated with lower weight, respiratory hospitalisations and deaths, and incident airflow limitation. The third was associated with age only. The fourth and fifth visually resembled combined pulmonary fibrosis emphysema and had distinct symptoms, physiology, prognosis and genetic associations. The sixth visually resembled vanishing lung syndrome., Conclusion: Large-scale unsupervised machine learning on CT scans defined six reproducible, familiar CT emphysema subtypes that suggest paths to specific diagnosis and personalised therapies in COPD and pre-COPD., Competing Interests: Competing interests: EDA, PPB, AM, YS, WS, JHMA, MHC, DC, EH, DRJ, SK, JDK, TL, JL, ECO, WP, MRP, SSR, EKS, KEW and AFL reports receiving grants from the National Institutes of Health (NIH). JY performed the work at Columbia University but is now an employee of Google. EAH reports receiving grants from the NIH; being a founder and shareholder of VIDA Diagnostics; and holding patents for an apparatus for analysing CT images to determine the presence of pulmonary tissue pathology, an apparatus for image display and analysis, and a method for multiscale meshing of branching biological structures. EBA reports receiving grants from the American Heart Association and the NIH. CBC reports receiving personal fees from GlaxoSmithKline. MTD reports receiving a grant from the NHLBI and personal fees from AstraZeneca, GlaxoSmithKline, Pulmonx, PneumRx/BTG and Quark. MKH reports consulting for GlaxoSmithKline, AstraZeneca and Boehringer Ingelheim receiving research support from Novartis and Sunovion. NNH reports receiving grants from the NIH, Boehringer Ingelheim, and the COPD Foundation. JDK reports receiving grants from US Environmental Protection Agency and the NIH. FJM reports serving on COPD advisory boards for AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Sunovion and Teva; serving as a consultant for ProterixBio and Verona; serving on the steering committees of studies sponsored by the NHLBI, AstraZeneca, and GlaxoSmithKline; having served on data safety and monitoring boards of COPD studies supported by Genentech and GlaxoSmithKline. BMS reports receiving grants from the NIH, Canadian Institutes of Health Research (CIHR), Fonds de la recherche en santé du Québec (FRQS), the Research Institute of the McGill University Health Centre, the Quebec Lung Association and AstraZeneca. PGW reports receiving personal fees for consultancy from Theravance, AstraZeneca, Regeneron, Sanofi, Genentech, Roche and Janssen. RGB reports receiving grants from the COPD Foundation, the US Environmental Protection Agency (EPA), the American Lung Association and the NIH., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

The consequences of returning infectious pathogen test results identified incidentally in research studies have not been well-studied. Concerns include identification of an important health issue for individuals, accuracy of research test results, public health impact, potential emotional distress for participants, and need for IRB permissions. Blood RNA-sequencing analysis for non-human RNA in 3984 participants from the COPDGene study identified 228 participants with evidence suggestive for hepatitis C virus (HCV) infection. We hypothesized that incidentally discovered HCV results could be effectively returned to COPDGene participants with attention to the identified concerns. In conjunction with a COPDGene Participant Advisory Panel, we developed and obtained IRB approval for a process of returning HCV research results and an HCV Follow-Up Study questionnaire to capture information about previous HCV diagnosis and treatment information and participant reactions to return of HCV results. During phone calls following the initial HCV notification letter, 84 of 124 participants who could be contacted (67.7%) volunteered that they had been previously diagnosed with HCV infection. Thirty-one of these 124 COPDGene participants were enrolled in the HCV Follow-Up Study. Five of the 31 HCV Follow-Up Study participants did not report a previous diagnosis of HCV. For four of these participants, subsequent clinical HCV testing confirmed HCV infection. Thus, 30/31 Follow-Up Study participants had confirmed HCV diagnoses, supporting the accuracy of the HCV research test results. However, the limited number of participants in the Follow-Up Study precludes an accurate assessment of the false-positive and false-negative rates of the research RNA sequencing evidence for HCV. Most HCV Follow-Up Study participants (29/31) were supportive of returning HCV research results, and most participants found the process for returning HCV results to be informative and not upsetting. Newly diagnosed participants were more likely to be pleased to learn about a potentially curable infection (p = 0.027) and showed a trend toward being more frightened by the potential health risks of HCV (p = 0.11). We conclude that HCV results identified incidentally during transcriptomic research studies can be successfully returned to research study participants with a carefully designed process., (© 2023. The Author(s).)