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Background: Prenatal exposure to cannabis may influence childhood cognition and behavior, but the epidemiologic evidence is mixed. Even less is known about the potential impact of secondhand exposure to cannabis during early childhood. Objective: This study sought to assess whether prenatal and/or postnatal exposure to cannabis was associated with childhood cognition and behavior. Study design: This sub-study included a convenience sample of 81 mother–child pairs from a Colorado-based cohort. Seven common cannabinoids (including delta 9-tetrahydrocannabinol (Δ9-THC) and cannabidiol (CBD)) and their metabolites were measured in maternal urine collected mid-gestation and child urine collected at age 5 years. Prenatal and postnatal exposure to cannabis was dichotomized as exposed (detection of any cannabinoid) and not exposed. Generalized linear models examined the associations between prenatal or postnatal exposure to cannabis with the NIH Toolbox and Child Behavior Checklist T-scores at age 5 years. Results: In this study, 7% (n = 6) of the children had prenatal exposure to cannabis and 12% (n = 10) had postnatal exposure to cannabis, with two children experiencing this exposure at both time points. The most common cannabinoid detected in pregnancy was Δ9-THC, whereas the most common cannabinoid detected in childhood was CBD. Postnatal exposure to cannabis was associated with more aggressive behavior (β: 3.2; 95% CI: 0.5, 5.9), attention deficit/hyperactivity problems (β: 8.0; 95% CI: 2.2, 13.7), and oppositional/defiant behaviors (β: 3.2; 95% CI: 0.2, 6.3), as well as less cognitive flexibility (β: −15.6; 95% CI: −30.0, −1.2) and weaker receptive language (β: −9.7; 95% CI: −19.2, −0.3). By contrast, prenatal exposure to cannabis was associated with fewer internalizing behaviors (mean difference: −10.2; 95% CI: −20.3, −0.2) and fewer somatic complaints (mean difference: −5.2, 95% CI: −9.8, −0.6). Conclusions: Our study suggests that postnatal exposure to cannabis is associated with more behavioral and cognitive problems among 5-year-old children, independent of prenatal and postnatal exposure to tobacco. The potential risks of cannabis use (including smoking and vaping) during pregnancy and around young children should be more widely communicated to parents.

Objective To assess the impact of fetal exposure to cannabis on adiposity and glucose-insulin traits in early life. Research Design and Methods We leveraged a subsample of 103 mother-child pairs from Healthy Start, an ethnically diverse Colorado-based cohort. Twelve cannabinoids/metabolites of cannabis (including Δ9-tetrahydrocannabinol and cannabidiol) were measured in maternal urine collected at ~27 weeks’ gestation. Fetal exposure to cannabis was dichotomized as exposed (any cannabinoid > limit of detection [LOD]) and not exposed (all cannabinoids < LOD). Fat mass and fat-free mass were measured via air displacement plethysmography at follow-up (mean age: 4.7 years). Glucose and insulin were obtained after an overnight fast. Generalized linear models estimated the associations between fetal exposure to cannabis with adiposity measures (fat mass [kg], fat-free mass [kg], adiposity [fat mass percentage], body mass index [BMI], and BMI z-scores) and metabolic measures (glucose [mg/dL], insulin [uIU/mL], and homeostatic model assessment of insulin resistance [HOMA-IR]). Results Approximately 15% of the women had detectable levels of any cannabinoid, indicating fetal exposure to cannabis. Exposed offspring had higher fat mass (1.0 kg; 95% CI, 0.3-1.7), fat-free mass (1.2 kg; 95% CI, 0.4-2.0), adiposity (2.6%; 95% CI, 0.1-5.2), and fasting glucose (5.6 mg/dL; 95% CI, 0.8-10.3) compared with nonexposed offspring. No associations were found with fasting insulin (in the fully adjusted model), HOMA-IR, BMI, or BMI z-scores. Conclusions We provide novel evidence to suggest an association between fetal exposure to cannabis with increased adiposity and fasting glucose in childhood, a finding that should be validated in other cohorts.

The Collaborative Cohort of Cohorts for COVID-19 Research (C4R) is a national prospective study of adults at risk for coronavirus disease 2019 (COVID-19) comprising 14 established United States (US) prospective cohort studies. For decades, C4R cohorts have collected extensive data on clinical and subclinical diseases and their risk factors, including behavior, cognition, biomarkers, and social determinants of health. C4R will link this pre-COVID phenotyping to information on SARS-CoV-2 infection and acute and post-acute COVID-related illness. C4R is largely population-based, has an age range of 18-108 years, and broadly reflects the racial, ethnic, socioeconomic, and geographic diversity of the US. C4R is ascertaining severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and COVID-19 illness using standardized questionnaires, ascertainment of COVID-related hospitalizations and deaths, and a SARS-CoV-2 serosurvey via dried blood spots. Master protocols leverage existing robust retention rates for telephone and in-person examinations, and high-quality events surveillance. Extensive pre-pandemic data minimize referral, survival, and recall bias. Data are being harmonized with research-quality phenotyping unmatched by clinical and survey-based studies; these will be pooled and shared widely to expedite collaboration and scientific findings. This unique resource will allow evaluation of risk and resilience factors for COVID-19 severity and outcomes, including post-acute sequelae, and assessment of the social and behavioral impact of the pandemic on long-term trajectories of health and aging.

RATIONALE: The course of lung function, respiratory symptoms, and functional status over time in people who smoke cigarettes is still incompletely understood. The COPDGene (Genetic Epidemiology of Chronic Obstructive Pulmonary Disease [COPD]) study provides a unique cohort to examine these trajectories, and now 10-year follow-up data are available. OBJECTIVES: This study aims to provide insight into the progression of spirometric parameters, respiratory symptoms, and functional capacity over 10 years in current and former cigarette smokers. METHODS: We analyzed available longitudinal data for COPDGene participants who did not change smoking status over three visits spanning approximately 10 years of follow-up. Change in postbronchodilator forced expiratory volume in 1 second (FEV(1)), St. George’s Respiratory Questionnaire (SGRQ), and 6-minute walk distance (6MWD) from Phase 1 to Phase 3 were examined using linear mixed models. Terms were included in the models to estimate mean progression separately for current and former cigarette smokers. Models were stratified by baseline Global Initiative for Chronic Obstructive Lung Disease (GOLD) spirometry stages as well as by new 2019 COPDGene classification. RESULTS: The mean age at enrollment of the 9,103 participants in this analysis was 59.8 years (SD = 9.2 yr); 46.4% were women, and 32.6% were African American. In all GOLD COPD groups, including participants with normal spirometry, and all groups categorized by 2019 COPDGene classification, FEV(1) decreased, SGRQ increased (indicating higher symptom burden), and 6MWD decreased over the 10-year follow-up period. Current smokers exhibited a greater mean loss of FEV(1) over the study period than former smokers for all groups except those with preserved ratio impaired spirometry. For both SGRQ and 6MWD, rates of progression tended to be similar for former and current smokers except for 6MWD in the highest severity groups, in which former smokers had greater progression. However, this could be impacted by some current smokers with faster progression who had quit smoking and were dropped from analyses. CONCLUSIONS: Progression in FEV(1), SGRQ, and 6MWD overall appears to be slow, and the change over time in groups traditionally characterized as not having disease closely mirrors that of the groups with COPD at all GOLD stages. Current cigarette smokers had greater loss of FEV(1) than former smokers, whereas SGRQ and 6MWD changes were more similar between current and former cigarette smokers.

ObjectivesInvestigate the prevalence and mortality impact of interstitial lung abnormalities (ILA) in rheumatoid arthritis (RA) and non-RA comparators.MethodsWe analyzed associations between ILA, RA, and mortality in COPDGene, a multicenter prospective cohort study of current or former smokers, excluding known interstitial lung disease (ILD) or bronchiectasis. All participants had research chest high-resolution computed tomography (HRCT) reviewed by a sequential reading method to classify ILA as present, indeterminate, or absent as well as fibrotic or nonfibrotic ILA subtype. RA cases were identified by self-report RA and DMARD use; non-RA comparators had neither an RA diagnosis nor used DMARDs. We examined the association and mortality risk of RA and ILA using multivariable logistic regression and Cox regression.ResultsWe identified 83 RA cases and 8725 non-RA comparators with HRCT performed for research purposes. ILA prevalence was 16.9% in RA cases and 5.0% in non-RA comparators. After adjusting for potential confounders including genetics, smoking, and other lifestyle factors, ILA were more common among those with RA compared to non-RA (OR 4.76 95%CI 2.54 to 8.92). RA with ILA or indeterminate for ILA was associated with higher mortality compared to non-RA without ILA (HR 3.16, 95%CI 2.11 to 4.74) and RA cases without ILA (HR 3.02, 95%CI 1.36 to 6.75).ConclusionsRA was associated with ILA and this persisted after adjustment for smoking and genetic/lifestyle risk factors. RA with ILA in chronic heavy smokers had 3-fold increased mortality, emphasizing the importance of further screening and treatment strategies for subclinical ILD in RA.KEY MESSAGESWhat is already known on this topicUp to a third of patients with rheumatoid arthritis (RA) may have evidence of subclinical interstitial lung abnormalities on computed tomography (CT) scans of the chest.Cigarette smoking and theMUC5Bpromoter variant are known risk factors for RA-associated interstitial lung disease.What this study addsWe found that 17% of RA patients had subclinical interstitial lung abnormalities. RA had 4-fold higher odds of interstitial lung abnormalities than non-RA comparators, adjusted for smoking, theMUC5Bpromoter variant, and other factors.Participants with RA and no interstitial lung abnormalities were not at increased mortality risk while those with interstitial lung abnormalities or indeterminate for ILA had a three-fold increased risk of mortality compared to RA and non-RA patients without interstitial lung abnormalities.How this study might affect research, practice or policyThe presence of subclinical interstitial lung abnormalities confers significant mortality risk in RA and emphasizes the need to establish the clinical utility of screening, prevention, and treatment strategies targeting subclinical lung disease.

Background CT is the standard method used to assess bronchiectasis. A higher airway-to-artery diameter ratio (AAR) is typically used to identify enlarged bronchi and bronchiectasis; however, current imaging methods are limited in assessing the extent of this metric in CT scans. Purpose To determine the extent of AARs using an artificial intelligence-based chest CT and assess the association of AARs with exacerbations over time. Materials and Methods In a secondary analysis of ever-smokers from the prospective, observational, multicenter COPDGene study, AARs were quantified using an artificial intelligence tool. The percentage of airways with AAR greater than 1 (a measure of airway dilatation) in each participant on chest CT scans was determined. Pulmonary exacerbations were prospectively determined through biannual follow-up (from July 2009 to September 2021). Multivariable zero-inflated regression models were used to assess the association between the percentage of airways with AAR greater than 1 and the total number of pulmonary exacerbations over follow-up. Covariates included demographics, lung function, and conventional CT parameters. Results Among 4192 participants (median age, 59 years; IQR, 52-67 years; 1878 men [45%]), 1834 had chronic obstructive pulmonary disease (COPD). During a 10-year follow-up and in adjusted models, the percentage of airways with AARs greater than 1 (quartile 4 vs 1) was associated with a higher total number of exacerbations (risk ratio [RR], 1.08; 95% CI: 1.02, 1.15

BACKGROUND: Smokers manifest varied phenotypes of pulmonary impairment. RESEARCH QUESTION: Which pulmonary phenotypes are associated with coronary artery disease (CAD) in smokers? STUDY DESIGN AND METHODS: We analyzed data from the University of Pittsburgh COPD Specialized Center for Clinically Oriented Research (SCCOR) cohort (n = 481) and the Genetic Epidemiology of COPD (COPDGene) cohort (n = 2,580). Participants were current and former smokers with > 10 pack-years of tobacco exposure. Data from the two cohorts were analyzed separately because of methodologic differences. Lung hyperinflation was assessed by plethysmography in the SCCOR cohort and by inspiratory and expiratory CT scan lung volumes in the COPDGene cohort. Subclinical CAD was assessed as the coronary artery calcium score, whereas clinical CAD was defined as a self-reported history of CAD or myocardial infarction (MI). Analyses were performed in all smokers and then repeated in those with airflow obstruction (FEV(1) to FVC ratio, < 0.70). RESULTS: Pulmonary phenotypes, including airflow limitation, emphysema, lung hyperinflation, diffusion capacity, and radiographic measures of airway remodeling, showed weak to moderate correlations (r < 0.7) with each other. In multivariate models adjusted for pulmonary phenotypes and CAD risk factors, lung hyperinflation was the only phenotype associated with calcium score, history of clinical CAD, or history of MI (per 0.2 higher expiratory and inspiratory CT scan lung volume; coronary calcium: OR, 1.2; 95% CI, 1.1-1.5; P = .02; clinical CAD: OR, 1.6; 95% CI, 1.1-2.3; P = .01; and MI in COPDGene: OR, 1.7; 95% CI, 1.0-2.8; P = .05). FEV(1) and emphysema were associated with increased risk of CAD (P < .05) in models adjusted for CAD risk factors; however, these associations were attenuated on adjusting for lung hyperinflation. Results were the same in those with airflow obstruction and were present in both cohorts. INTERPRETATION: Lung hyperinflation is associated strongly with clinical and subclinical CAD in smokers, including those with airflow obstruction. After lung hyperinflation was accounted for, FEV(1) and emphysema no longer were associated with CAD. Subsequent studies should consider measuring lung hyperinflation and examining its mechanistic role in CAD in current and former smokers.

Rationale: Type 2 Diabetes (T2D) is one of the leading chronic diseases among smokers. Chronic obstructive pulmonary disease (COPD) is common among people with diabetes, with the lung posited as an additional target organ of diabetes. Previous literature suggests that some medications treating comorbidities of COPD patients may also benefit lung function. Objectives: We used a novel statistical method to identify comorbidity medications associated with pulmonary function progression and assess potential effects using an adjusted mixed effect model among smokers with and without COPD. Methods: Participants from the COPDGene cohort who completed initial visit (P1) , and 5-year follow up (P2) from 20through 2017 with complete demographics, clinical information, and medication history were included in the study. A least absolute shrinkage and selection operator (LASSO) model with false discovery rate control by a knockoff filter was used to identify medication classes associated with COPD progression in participants with and without T2D treatment. An adjusted linear mixed model was then used to confirm the association between selected medication and the change in percent emphysema and other lung function variables from P1 to P2. Results: A total of 3,786 out of 10,198 smokers with complete information from P1 and P2 were included. Overall, 359 out of 3,786 smokers reported having T2D at P1, 2out of 359 patients were treated with the class of biguanides (metformin) at P1. The LASSO selection identified metformin as strongly associated with percent emphysema change. Adjusted linear mixed models confirmed that metformin use is associated with the reduction of emphysema in smokers (p Conclusions: Our study identified and confirmed an association between metformin and reduced emphysema progression among smokers with and without COPD. Metformin, a common treatment for diabetes, may also have protective effect on lung function. Disclosure Y.Li: Employee; Vertex Pharmaceuticals Incorporated. R.B.Conway: None. K.Young: None. K.A.Pratte: None. D.Foer: Research Support; IBM Watson Health. S.Rennard: Advisory Panel; GlaxoSmithKline plc., Sanofi, Verona, Verona, Consultant; Bergenbio, Boehringer Ingelheim International GmbH, NovoVentures. E.Austin: None. Y.Gwon: None. G.L.Kinney: None. Funding U01HL089897U01HL089856

The recent COVID-19 pandemic, which saw an increased risk of subsequent diabetes among persons with COVID-19 as well as greater casualties among persons with diabetes, has brought renewed attention to the role of lung function in diabetes. We tested the relationship of lung function and chronic obstructive pulmonary disease (COPD) with diabetes in a population of current and former smokers. Using data from the COPD Genetic Epidemiology (COPDGene) cohort, we conducted a diabetes follow-up (2012-2018) of a cohort of Black and White current and former smokers with (n=2442) and w/out (n=2214) COPD, aged 39-85 years and w/out diabetes at cohort entry. Lung function was modeled using Forced Expiratory Volume at 1 second % predicted (FEV1%P) . COPD was defined as the ratio of FEV1% to FVC% The incidence of diabetes was 8% over the five years of follow-up, representing a 43% increase in prevalence. After controlling for age, sex, and race, COPD at baseline was a significant risk factor for diabetes (OR=1.51, 1.21-1.88) . Significant interaction existed between baseline COPD and baseline Fev1%p (p-interaction=0.01) , such that Fev1%p only predicted diabetes among those w/out (OR=0.98, 0.96-0.99) but not among those with COPD at baseline (OR=0.99, 0.99-1.00) . Upon stratification by race, Fev1%p was a significant predictor among Blacks but not Whites, but effect modification by race was not observed. Blacks were at twice the risk of diabetes overall (OR=2.04, 1.59-2.60) and were at 3 times the risk among those w/out COPD (OR=2.91, 1.98-4.27) . BMI increased risk in both races regardless of COPD status; however, a higher BMI was a stronger risk factor for diabetes among Whites than Blacks, particularly for those with baseline COPD (race*BMI interaction p=0.06) . In this large population of current and former smokers, our data suggest that lower lung function prior to the development of COPD is a risk factor for diabetes, particularly among Blacks. BMI is an important risk factor in both races, but appears to play a stronger role among Whites. Disclosure R. B. Conway: None. K. Young: None. Y. Li: Employee; Vertex Pharmaceuticals Incorporated. E. Austin: None. G. L. Kinney: None. Funding National Institutes of Health (U01HL089897)

Yisha Li,1 Ran Dai,2 Yeongjin Gwon,2 Stephen I Rennard,3 Barry J Make,4 Dinah Foer,5 Matthew J Strand,4 Erin Austin,6 Kendra A Young,1 John E Hokanson,1 Katherine A Pratte,7 Rebecca Conway,1 Gregory L Kinney1 On behalf of COPDGene investigators1Department of Epidemiology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA; 2Department of Biostatistics, School of Public Health, University of Nebraska Medical Center, Omaha, NE, USA; 3Division of Pulmonary, Critical Care and Sleep Medicine, University of Nebraska Medical Center, Omaha, NE, USA; 4Department of Medicine, National Jewish Health, Denver, CO, USA; 5Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA; 6Mathematical and Statistical Sciences, University of Colorado Denver, Denver, CO, USA; 7Department of Biostatistics, National Jewish Health, Denver, CO, USACorrespondence: Gregory L Kinney, Department of Epidemiology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA, Tel +1 303-724-4437, Email GREG.KINNEY@CUANSCHUTZ.EDU

Purpose Medication patterns include all medications in an individual's clinical profile. We aimed to identify chronic co-morbidity treatment patterns through medication use among COPDGene participants and determine whether these patterns were associated with mortality, acute exacerbations of chronic obstructive pulmonary disease (AECOPD) and quality of life. Materials and methods Participants analyzed here completed Phase 1 (P1) and/or Phase 2 (P2) of COPDGene. Latent class analysis (LCA) was used to identify medication patterns and assign individuals into unobserved LCA classes. Mortality, AECOPD, and the St. George's Respiratory Questionnaire (SGRQ) health status were compared in different LCA classes through survival analysis, logistic regression, and Kruskal-Wallis test, respectively. Results LCA identified 8 medication patterns from 32 classes of chronic comorbid medications. A total of 8110 out of 10,127 participants with complete covariate information were included. Survival analysis adjusted for covariates showed, compared to a low medication use class, mortality was highest in participants with hypertension+diabetes+statin+antiplatelet medication group. Participants in hypertension+SSRI+statin medication group had the highest odds of AECOPD and the highest SGRQ score at both P1 and P2. Conclusion Medication pattern can serve as a good indicator of an individual's comorbidities profile and improves models predicting clinical outcomes.

COPD is a heterogeneous syndrome. Many COPD subtypes have been proposed, but there is not yet consensus on how many COPD subtypes there are and how they should be defined. The COPD Genetic Epidemiology Study (COPDGene), which has generated 10-year longitudinal chest imaging, spirometry, and molecular data, is a rich resource for relating COPD phenotypes to underlying genetic and molecular mechanisms. In this article, we place COPDGene clustering studies in context with other highly cited COPD clustering studies, and summarize the main COPD subtype findings from COPDGene. First, most manifestations of COPD occur along a continuum, which explains why continuous aspects of COPD or disease axes may be more accurate and reproducible than subtypes identified through clustering methods. Second, continuous COPD-related measures can be used to create subgroups through the use of predictive models to define cut-points, and we review COPDGene research on blood eosinophil count thresholds as a specific example. Third, COPD phenotypes identified or prioritized through machine learning methods have led to novel biological discoveries, including novel emphysema genetic risk variants and systemic inflammatory subtypes of COPD. Fourth, trajectory-based COPD subtyping captures differences in the longitudinal evolution of COPD, addressing a major limitation of clustering analyses that are confounded by disease severity. Ongoing longitudinal characterization of subjects in COPDGene will provide useful insights about the relationship between lung imaging parameters, molecular markers, and COPD progression that will enable the identification of subtypes based on underlying disease processes and distinct patterns of disease progression, with the potential to improve the clinical relevance and reproducibility of COPD subtypes.

Studies have shown that chronic obstructive pulmonary disease (COPD) and smoking are associated with increased suicide risk. To date there are no prospective studies examining suicide risk among smokers along a spectrum of pulmonary disease ranging from completely normal spirometry to severe COPD.Which clinical variables predict death by suicide or overdose of indeterminate intent in a large cohort of heavy smokers within the COPDGene study?We studied data from 9,930 participants involved in COPDGene, a multisite, prospective cohort study of current and former smokers. Primary cause of adjudicated deaths was identified using death certificates, family reports, and medical records. We examined time to death by suicide/overdose as the primary outcome in Cox regression adjusted for age, sex, race, BMI, pack-years, current smoking status, airflow limitation (%predicted FEVThe cohort was 47% female, 33% Black (67% White), had a mean (SD) age of 59.6 (9.0) years, and mean FEVIn this well-characterized cohort of current and former smokers with and without COPD, we identified risk factors for suicide/overdose that emphasize the subjective experience of illness over objective assessments of lung function.

Individuals with Chronic Obstructive Pulmonary Disease (COPD) often develop anxiety and depression, which worsen illness management and prognosis. Physical and psychological symptoms, contextual and illness-related factors display complex reciprocal interactions, which give rise to heterogeneous presentations. Examining the patterns of association between specific physical and psychological symptoms in patients with COPD may help to focus on the precision of the patient-centred care.We used network analyses to examine the links between symptoms of COPD, depression and anxiety.Data from 1587 individuals with COPD from the COPDGene study were included. We estimated a Bayesian Gaussian Graphical Model to highlight the unique associations between symptoms of COPD (assessed with the COPD Assessment Test), depression and anxiety (assessed with the Hospital Anxiety and Depression Scale (HADS), while examining the role of sociodemographic characteristics, lung function tests, and health status.Unique Variable Analysis reduced 14 HADS items to Tension/worry (chronic anxiety), Fear/panic (acute anxiety), Restlessness, Anhedonia, Sadness and Slowing. In network analyses, chest-tightness was related to acute anxiety, while cough and weakness were connected with core depressive symptoms (sadness and lack of pleasure). Chronic anxiety was linked with acute anxiety and depressive symptoms. Findings were confirmed accounting for the role of confounders, including lung function, sex, ethnicity and lifestyle factors. A simulation based on our model yielded distinct predictions about anxiety and depression in two participants with similar COPD severity, but different symptom profiles.Network analyses highlighted specific associations between symptoms of COPD, depression and anxiety. Accounting for symptom-level interactions may help to promote personalized treatment approaches.

OBJECTIVE To differentiate diabetic ketoacidosis (DKA) from hyperglycemic ketosis due to cannabis hyperemesis syndrome (HK-CHS) in adults with type 1 diabetes. RESEARCH DESIGN AND METHODS Of 295 adults with type 1 diabetes who were seen with DKA-related ICD-10 codes, 68 patients with 172 DKA events meeting the inclusion criteria were analyzed. Cannabis use was defined as a positive urine test result for cannabis. Linear mixed models were used to define HK-CHS (pH ≥7.4 with bicarbonate ≥15 mmol/L [mEq/L]), and sensitivity and specificity were calculated using the receiver operating characteristic (ROC) curve. RESULTS Cannabis users had significantly higher pH (7.42 ± 0.01 vs. 7.09 ± 0.02) and bicarbonate (19.2 ± 0.61 vs. 9.1 ± 0.71 mmol/L) (P < 0.0001) compared with nonusers. The area under the ROC curve for a positive cannabis urine test result predicting HK-CHS was 0.9892. CONCLUSIONS In patients who present with DKA and higher pH, especially pH ≥7.4, cannabis use should be considered in the differential diagnosis.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) and bronchiectasis can overlap and share pathologic features, such as small airway disease (SAD). Whether the presence of SAD and emphysema in smokers with CT-derived bronchiectasis is associated with exacerbations is unknown. PURPOSE: To assess whether SAD and emphysema in smokers with CT-derived bronchiectasis are associated with future exacerbations. MATERIALS AND METHODS: SAD and emphysema were quantified using the parametric response map method in former and current heavy smokers with and without bronchiectasis at CT from the COPDGene Study (from July 2009 to July 2018). Exacerbations were prospectively assessed through biannual follow-up. An exacerbation was defined as an increase in or new onset of respiratory symptoms treated with antibiotics and/or corticosteroids. Severe exacerbations were defined as those that required hospitalization. The association of a high burden of SAD (≥15.6%) and high burden of emphysema (≥5%) at CT with exacerbations was assessed with generalized linear mixed models. RESULTS: Of 737 participants, 387 (median age, 64 years [interquartile range, 58–71 years]; 223 women) had CT-derived bronchiectasis. During a 9-year follow-up, after adjustment for age, sex, race, body mass index, current smoking status, pack-years, exacerbations before study entry, forced expiratory volume in 1 second, or FEV(1), and bronchiectasis severity CT score, high burden of SAD and high burden of emphysema were associated with a higher number of exacerbations per year (relative risk [RR], 1.89 [95% CI: 1.54, 2.33] and 1.37 [95% CI: 1.13, 1.66], respectively; P ≤ .001 for both). Results were comparable among participants with bronchiectasis meeting criteria for COPD (n = 197) (RR, 1.67 [95% CI: 1.23, 2.27] for high burden of SAD and 1.51 [95% CI: 1.20, 1.91] for high burden of emphysema; P ≤ .001 for both). CONCLUSION: In smokers with CT-derived bronchiectasis and chronic obstructive pulmonary disease, structural damage to lung parenchyma and small airways was associated with a higher number of exacerbations per year. Clinical trial registration no. NCT00608764 © RSNA, 2021

In the general population, chronic obstructive pulmonary disease (COPD) and Preserved Ratio Impaired Spirometry (PRISm) have been shown to increase mortality risk. While increased respiratory disease risk has been observed in type 1 diabetes (T1D), data on PRISm and COPD, especially in middle-age, are scarce in T1D. We thus assessed correlates of COPD and PRISm among individuals with childhood-onset T1D. Data were from the 30-year visit of the EDC study (n=162, median age/T1D duration, 56/47 years). Pulmonary function was assessed with the NDD EasyOne™ Spirometer using NHANES reference values for the predicted values. COPD was defined as Forced Expiratory Volume in 1 Second (FEV1)/Forced Vital Capacity (FVC) 1.3) was associated with greater odds of COPD (OR=4.64, 95% CI: 1.42-15.13, p=0.01) and BMI with PRISm (OR=1.10, 95% CI: 1.01-1.21, p=0.03). No other risk factor was associated with COPD or PRISm. In conclusion, high ABI and BMI appear to be independently associated with greater odds of COPD and PRISm, respectively, in T1D. Disclosure J. Ju: None. G. L. Kinney: None. R. G. Miller: None. T. J. Orchard: None. T. Costacou: None. Funding National Institutes of Health (DK34818)

Cannabis use is known to increase DKA risk in adults with T1D. We evaluated diabetes self-management, glycemic control, and its relationship with DKA risk in T1D by cannabis use. Adults with T1D followed at the Barbara Davis Center were invited for a survey between September and October of 2020. Information on demographics, cannabis use (CUDIT-R), self-reported DKA in the past year, self-reported A1c, and diabetes self-management (DSMQ) were collected using validated questionnaires. Of 905 respondents, 238 reported using cannabis (26.2%). Cannabis users were younger (mean±SD 31±12 vs. 37 ±15 y, p Disclosure D. Giese: None. G. L. Kinney: None. C. Geno rasmussen: None. J. K. Snell-bergeon: Stock/Shareholder; Self; GlaxoSmithKline plc. V. Shah: Advisory Panel; Self; Medscape, Sanofi, Research Support; Self; Dexcom, Inc., Eli Lilly and Company, Insulet Corporation, Novo Nordisk, Sanofi, vTv Therapeutics.

Type 1 diabetes mellitus (T1DM) increases the risk of atherosclerotic cardiovascular disease (CVD) in humans by poorly understood mechanisms. Using mouse models of T1DM-accelerated atherosclerosis, we found that relative insulin deficiency rather than hyperglycemia elevated levels of apolipoprotein C3 (APOC3), an apolipoprotein that prevents clearance of triglyceride-rich lipoproteins (TRLs) and their remnants. We then showed that serum APOC3 levels predict incident CVD events in subjects with T1DM in the Coronary Artery Calcification in Type 1 Diabetes (CACTI) study. To explore underlying mechanisms, we investigated the impact of Apoc3 antisense oligonucleotides (ASOs) on lipoprotein metabolism and atherosclerosis in a mouse model of T1DM. Apoc3 ASO treatment abolished the increased hepatic Apoc3 expression in diabetic mice - resulting in lower levels of TRLs - without improving glycemic control. APOC3 suppression also prevented arterial accumulation of APOC3-containing lipoprotein particles, macrophage foam cell formation, and the accelerated atherosclerosis in diabetic mice. Our observations demonstrate that relative insulin deficiency increases APOC3 and that this results in elevated levels of TRLs and accelerated atherosclerosis in a mouse model of T1DM. Because serum levels of APOC3 predicted incident CVD events in the CACTI study, inhibiting APOC3 might reduce CVD risk in T1DM patients.

Rationale: Cor pulmonale (right ventricular [RV] dilation) and cor pulmonale parvus (RV shrinkage) are both described in chronic obstructive pulmonary disease (COPD). The identification of emphysema as a shared risk factor suggests that additional disease characterization is needed to understand these widely divergent cardiac processes. Objectives: To explore the relationship between computed tomography measures of emphysema and distal pulmonary arterial morphology with RV volume, and their association with exercise capacity and mortality in ever-smokers with COPD enrolled in the COPDGene Study. Methods: Epicardial (myocardium and chamber) RV volume (RV(EV)), distal pulmonary arterial blood vessel volume (arterial BV5: vessels

The Genetic Epidemiology of COPD (COPDGene) study is a noninterventional, multicenter, longitudinal analysis of > 10,000 subjects, including smokers with a ≥ 10 pack-year history with and without COPD and healthy never smokers. The goal was to characterize disease-related phenotypes and explore associations with susceptibility genes. The subjects were extensively phenotyped with the use of comprehensive symptom and comorbidity questionnaires, spirometry, CT scans of the chest, and genetic and biomarker profiling. The objective of this review was to summarize the major advances in the clinical epidemiology of COPD from the first 10 years of the COPDGene study. We highlight the influence of age, sex, and race on the natural history of COPD, and the impact of comorbid conditions, chronic bronchitis, exacerbations, and asthma/COPD overlap.

Objectives To compare the frequency of anxiety/depressive symptoms and use of anxiolytic-hypnotics/antidepressants in smokers with and without COPD and to identify characteristics associated with having unmedicated symptoms. Methods Cross-sectional analysis of ambulatory, current/former smokers ≥10 pack years enrolled in the COPDGene study. We measured anxiety/depressive symptoms using the Hospital Anxiety and Depression Scale (subscales ≥8), recorded anxiolytic-hypnotic/antidepressant use, and defined unmedicated symptoms as elevated anxiety/depressive symptoms and not on medications. Regression analysis identified characteristics associated with having unmedicated symptoms. Key results Of 5331 current/former smokers (45% with and 55% without COPD), 1332 (25.0%) had anxiety/depressive symptoms. Anxiety symptoms were similar in frequency in smokers with and without COPD (19.7% overall), while depressive symptoms were most frequent in severe-very severe COPD at 20.7% (13.1% overall). In the entire cohort, 1135 (21.2%) were on medications. Anxiolytic-hypnotic use was highest in severe-very severe COPD (range 7.6%–12.0%), while antidepressant use showed no significant variation in smokers with and without COPD (range 14.7%–17.1%). Overall, 881 (66% of those with symptoms) had unmedicated symptoms, which was associated with African American race (adjusted OR 2.95, 95% CI 2.25–3.87), male gender (adjusted OR 1.93, 95% CI 1.57–2.36), no health insurance (adjusted OR 2.38, 95% CI 1.30–4.35), severe-very severe COPD (adjusted OR 1.48, 95% CI 1.04–2.11), and higher respiratory symptoms/exacerbation history (adjusted OR 2.21, 95% CI 1.62–3.02). Conclusions Significant unmet mental health care needs exist in current and former smokers with and without COPD. One in five have unmedicated symptoms, identified by key demographic and clinical characteristics. Primary funding source National Institutes of Health and The COPD Foundation .

Author(s): Regan, Elizabeth A; Lowe, Katherine E; Make, Barry J; Lynch, David A; Kinney, Gregory L; Budoff, Matthew J; Mao, Song Shou; Dyer, Debra; Curtis, Jeffrey L; Bowler, Russell P; Han, MeiLan K; Beaty, Terri H; Hokanson, John E; Kern, Elizabeth; Humphries, Stephen; Curran-Everett, Douglas; van Beek, Edwin JR; Silverman, Edwin K; Crapo, James D; Finigan, James H; COPDGene® Investigators | Abstract: BackgroundLung cancer screening (LCS) via chest computed tomography (CT) scans can save lives by identifying early-stage tumors. However, most smokers die of comorbid smoking-related diseases. LCS scans contain information about smoking-related conditions that is not currently systematically assessed. Identifying these common comorbid diseases on CT could increase the value of screening with minimal impact on LCS programs. We determined the prevalence of 3 comorbid diseases from LCS eligible scans and quantified related adverse outcomes.MethodsWe studied COPD Genetic Epidemiology study (COPDGene®) participants (n=4078) who met criteria for LCS screening at enrollment (age g 55 years, and l 80 years, g 30 pack years smoking, current smoker or former smoker within 15 years of smoking cessation). CT scans were assessed for coronary artery calcification (CAC), emphysema, and vertebral bone density. We tracked the following clinically significant events: myocardial infarctions (MIs), strokes, pneumonia, respiratory exacerbations, and hip and vertebral fractures.ResultsOverall, 77% of eligible CT scans had one or more of these diagnoses identified. CAC (g 100 mg) was identified in 51% of scans, emphysema in 44%, and osteoporosis in 54%. Adverse events related to the underlying smoking-related diseases were common, with 50% of participants reporting at least one. New diagnoses of cardiovascular disease, emphysema and osteoporosis were made in 25%, 7% and 46%, of participants respectively. New diagnosis of disease was associated with significantly more adverse events than in participants who did not have CT diagnoses for both osteoporosis and cardiovascular risk.ConclusionsExpanded analysis of LCS CT scans identified individuals with evidence of previously undiagnosed cardiovascular disease, emphysema or osteoporosis that corresponded with adverse events. LCS CT scans can potentially facilitate diagnoses of these smoking-related diseases and provide an opportunity for treatment or prevention.

Background: Chronic inflammation contributes to aging and organ dysfunction in the general population, and is a particularly important determinant of morbidity and mortality among people with HIV (PWH). The effect of cannabis use on chronic inflammation is not well understood among PWH, who use cannabis more frequently than the general population. Materials and Methods: We evaluated participants in the Multicenter AIDS Cohort Study (MACS) beginning in 2004 with available data on cannabis use and inflammatory biomarkers. Associations of current cannabis use with plasma concentrations of inflammatory markers were adjusted for hepatitis C, tobacco smoking, and comorbidities. Markers were analyzed individually and in exploratory factor analysis (EFA). Results: We included 1352 men within the MACS. Twenty-seven percent of HIV-negative men, 41% of HIV viremic men, and 35% of virologically suppressed men reported cannabis use at baseline. Among cannabis users, 20-25% in all groups defined by HIV serostatus were daily users, and the same proportion reported weekly use. The remaining ∼50% of users in all groups reported monthly or less frequent use. Four biomarker groupings were identified by EFA: Factor 1: immune activation markers; Factor 2: proinflammatory cytokines; Factor 3: Th1- and Th2-promoting cytokines; and Factor 4: inflammatory chemokines. In EFA, daily users had 30% higher levels of Factor 2 biomarkers than nonusers (p=0.03); this was the only statistically significant difference by cannabis use status. Among individual markers, concentrations of IL-1β, IL-2, IL-6, and IL-8 (Factor 2); IL-10 (Factor 3); and BAFF (Factor 1) were higher (p

BACKGROUND AND AIMS: To estimate during pregnancy correlations between frequency of self-reported use of marijuana, and quantified marijuana metabolite in biospecimens including urine, sera, and umbilical cord homogenate. DESIGN: Prospective cohort SETTING: Two urban hospitals in Colorado with legal recreational and medicinal marijuana PARTICIPANTS: Pregnant women (5ng/mL) of 11-nor-9-carboxy-delta-9-tetrahydrocannabinol (THC-COOH). Liquid chromatography tandem mass spectrometry quantified THC-COOH in umbilical cord homogenate (ng/g). Last marijuana use by any measure was recorded to evaluate the time frame over which THC-COOH remains detectable (>0.10 ng/g) in cord. FINDINGS: From December 2017 through May 2019, 51 pregnant women enrolled, and 46 were included in analyses (2 withdrew and 3 had a spontaneous abortion). The majority were normal weight, White or Black race, and insured by Medicaid. At the time of enrollment between seven to 15 weeks’ gestation, 87% had ongoing use by self-report, or positive urine or serum. The majority (33 [66%]) stopped using prior to delivery. Sera and urine results were strongly correlated with self-reported use frequency (Spearman correlation coefficient (r) range 0.70-0.87 across visits, p

In COPD, anaemia is associated with increased morbidity, but the relationship between haemoglobin over its entire observed range and morbidity is poorly understood. Such an understanding could guide future therapeutic targeting of haemoglobin in COPD management. Leveraging the COPDGene study, we conducted a cross-sectional analysis of haemoglobin from COPD participants, examining symptoms, quality of life, functional performance, and acute exacerbations of COPD (AECOPD). Haemoglobin was analysed both as a continuous variable and categorised into anaemia, normal haemoglobin, and polycythaemia groups. Fractional polynomial modelling was used for continuous analyses; categorical models were multivariable linear or negative binomial regressions. Covariates included demographics, comorbidities, emphysema, diffusing capacity, and airflow obstruction. From 2539 participants, 366 (14%) were identified as anaemic and 125 (5%) as polycythaemic. Compared with normal haemoglobin, anaemia was significantly associated with increased symptoms (COPD Assessment Test score: p=0.006, modified Medical Research Council (mMRC) Dyspnoea Score: p=0.001); worse quality of life (St. George's Respiratory Questionnaire (SGRQ) score: p, Haemoglobin is nonlinearly associated with clinical outcomes in COPD, with increased morbidity at either extreme of the observed range, suggesting that therapeutic correction of anaemia might be most beneficial if targeting normal haemoglobin values https://bit.ly/3ovl7Lt

Background Metformin is associated with improved respiratory outcomes in asthma; however, metformin in COPD and asthma-COPD overlap (ACO) remains unexplored. Objective To determine the association between metformin use and respiratory outcomes in COPD and ACO. Study design and methods Participants with COPD (FEV1/FVC Results Among participants with ACO, metformin use was associated with lower rate of total (adjusted incidence rate ratio [aIRR] 0.3; 95% confidence interval [95%CI] 0.11, 0.77) and severe exacerbations (aIRR 0.29; 95%CI 0.10, 0.89). Among participants with COPD alone, there was no association between metformin use with total (aIRR 0.98; 95%CI 0.62, 1.5) or severe exacerbations (aIRR 1.3; 95% CI 0.68, 2.4) (p-interaction Conclusions Metformin use was associated with fewer respiratory exacerbations and improved quality of life among individuals with ACO but not COPD alone. Results suggest a potential role for metformin in ACO which requires further prospective study. Trial Registry: NCT00608764

Background Attenuation of transforming growth factor β by blocking angiotensin II has been shown to reduce emphysema in a murine model. General population studies have demonstrated that the use of angiotensin converting enzyme inhibitors (ACEis) and angiotensin-receptor blockers (ARBs) is associated with reduction of emphysema progression in former smokers and that the use of ACEis is associated with reduction of FEV1 progression in current smokers. Research Question Is use of ACEi and ARB associated with less progression of emphysema and FEV1 decline among individuals with COPD or baseline emphysema? Methods Former and current smokers from the Genetic Epidemiology of COPD Study who attended baseline and 5-year follow-up visits, did not change smoking status, and underwent chest CT imaging were included. Adjusted linear mixed models were used to evaluate progression of adjusted lung density (ALD), percent emphysema (%total lung volume Results Over 5 years of follow-up, compared with nonusers, ACEi and ARB users with COPD showed slower ALD progression (adjusted mean difference [aMD], 1.6; 95% CI, 0.34-2.9). Slowed lung function decline was not observed based on phase 1 medication (aMD of FEV1 % predicted, 0.83; 95% CI, –0.62 to 2.3), but was when analysis was limited to consistent ACEi and ARB users (aMD of FEV1 % predicted, 1.9; 95% CI, 0.14-3.6). No effect modification by smoking status was found for radiographic outcomes, and the lung function effect was more pronounced in former smokers. Results were similar among participants with baseline emphysema. Interpretation Among participants with spirometry-confirmed COPD or baseline emphysema, ACEi and ARB use was associated with slower progression of emphysema and lung function decline. Trial Registry ClinicalTrials.gov ; No.: NCT00608764; URL: www.clinicaltrials.gov

Type 2 diabetes is increasing in all ancestry groups1. Part of its genetic basis may reside among the rare (minor allele frequency 2. We analyzed high-coverage (mean depth 38.2x) whole genome sequencing from 9,639 individuals with T2D and 34,994 controls in the NHLBI’s Trans-Omics for Precision Medicine (TOPMed) program2 to show that rare, non-coding variants that are poorly captured by genotyping arrays or imputation panels contribute h2=53% (P=4.2×10−5) to the genetic component of risk in the largest (European) ancestry subset. We coupled sequence variation with islet epigenomic signatures3 to annotate and group rare variants with respect to gene expression4, chromatin state5 and three-dimensional chromatin architecture6, and show that pancreatic islet regulatory elements contribute to T2D genetic risk (h2=8%, P=2.4×10−3). We used islet annotation to create a non-coding framework for rare variant aggregation testing. This approach identified five loci containing rare alleles in islet regulatory elements that suggest novel biological mechanisms readily linked to hypotheses about variant-to-function. Large scale whole genome sequence analysis reveals the substantial contribution of rare, non-coding variation to the genetic architecture of T2D and highlights the value of tissue-specific regulatory annotation for variant-to-function discovery.