Differentially co-expressed myofibre transcripts associated with abnormal myofibre proportion in chronic obstructive pulmonary disease.

BACKGROUND: Skeletal muscle dysfunction is a common extrapulmonary manifestation of chronic obstructive pulmonary disease (COPD). Alterations in skeletal muscle myosin heavy chain expression, with reduced type I and increased type II myosin heavy chain expression, are associated with COPD severity when studied in largely male cohorts. The objectives of this study were (1) to define an abnormal myofibre proportion phenotype in both males and females with COPD and (2) to identify transcripts and transcriptional networks associated with abnormal myofibre proportion in COPD. METHODS: Forty-six participants with COPD were assessed for body composition, strength, endurance and pulmonary function. Skeletal muscle biopsies from the vastus lateralis were assayed for fibre-type distribution and cross-sectional area via immunofluorescence microscopy and RNA-sequenced to generate transcriptome-wide gene expression data. Sex-stratified k-means clustering of type I and IIx/IIax fibre proportions was used to define abnormal myofibre proportion in participants with COPD and contrasted with previously defined criteria. Single transcripts and weighted co-expression network analysis modules were tested for correlation with the abnormal myofibre proportion phenotype. RESULTS: Abnormal myofibre proportion was defined in males with COPD (n = 29) as <18% type I and/or >22% type IIx/IIax fibres and in females with COPD (n = 17) as <36% type I and/or >12% type IIx/IIax fibres. Half of the participants with COPD were classified as having an abnormal myofibre proportion. Participants with COPD and an abnormal myofibre proportion had lower median handgrip strength (26.1 vs. 34.0 kg, P = 0.022), 6-min walk distance (300 vs. 353 m, P = 0.039) and forced expiratory volume in 1 s-to-forced vital capacity ratio (0.42 vs. 0.48, P = 0.041) compared with participants with COPD and normal myofibre proportions. Twenty-nine transcripts were associated with abnormal myofibre proportions in participants with COPD, with the upregulated NEB, TPM1 and TPM2 genes having the largest fold differences. Co-expression network analysis revealed that two transcript modules were significantly positively associated with the presence of abnormal myofibre proportions. One of these co-expression modules contained genes classically associated with muscle atrophy, as well as transcripts associated with both type I and type II myofibres, and was enriched for genetic loci associated with bone mineral density. CONCLUSIONS: Our findings indicate that there are significant transcriptional alterations associated with abnormal myofibre proportions in participants with COPD. Transcripts canonically associated with both type I and type IIa fibres were enriched in a co-expression network associated with abnormal myofibre proportion, suggesting altered transcriptional regulation across multiple fibre types.

Socio-demographic and comorbid risk factors for poor prognosis in patients hospitalized with community-acquired bacterial pneumonia in southeastern US.

BACKGROUND: How socio-demographic characteristics and comorbidities affect bacterial community-acquired pneumonia (CAP) prognosis during/after hospitalization is important in disease management. OBJECTIVES: To identify predictors of medical intensive care unit (MICU) admission, length of hospital stay (LOS), in-hospital mortality, and bacterial CAP readmission in patients hospitalized with bacterial CAP. METHODS: ICD-9/10 codes were used to query electronic medical records to identify a cohort of patients hospitalized for bacterial CAP at a tertiary hospital in Southeastern US between 01/01/2013-12/31/2019. Adjusted accelerated failure time and modified Poisson regression models were used to examine predictors of MICU admission, LOS, in-hospital mortality, and 1-year readmission. RESULTS: There were 1956 adults hospitalized with bacterial CAP. Median (interquartile range) LOS was 11 days (6-23), and there were 26 % (513) MICU admission, 14 % (266) in-hospital mortality, and 6 % (117) 1-year readmission with recurrent CAP. MICU admission was associated with heart failure (RR 1.38; 95 % CI 1.17-1.62) and obesity (RR 1.26; 95 % CI 1.04-1.52). Longer LOS was associated with heart failure (adjusted time ratio[TR] 1.27;95 %CI 1.12-1.43), stroke (TR 1.90;95 %CI 1.54,2.35), type 2 diabetes (TR 1.20;95 %CI 1.07-1.36), obesity (TR 1.50;95 %CI 1.31-1.72), Black race (TR 1.17;95 %CI 1.04-1.31), and males (TR 1.24;95 %CI 1.10-1.39). In-hospital mortality was associated with stroke (RR 1.45;95 %CI 1.03-2.04) and age ≥65 years (RR 1.34;95 %CI 1.06-1.68). 1-year readmission was associated with COPD (RR 1.55;95 %CI 1.05-2.27) and underweight BMI (RR 1.74;95 %CI 1.04-2.90). CONCLUSIONS: Comorbidities and socio-demographic characteristics have varying impacts on bacterial CAP in-hospital prognosis and readmission. More studies are warranted to confirm these findings to develop comprehensive care plans and inform public health interventions.

Anti-CELA1 antibody KF4 prevents emphysema by inhibiting stretch-mediated remodeling.

There are no therapies to prevent emphysema progression. Chymotrypsin-like elastase 1 (CELA1) is a serine protease that binds and cleaves lung elastin in a stretch-dependent manner and is required for emphysema in a murine antisense oligonucleotide model of α-1 antitrypsin (AAT) deficiency. This study tested whether CELA1 is important in strain-mediated lung matrix destruction in non-AAT-deficient emphysema and the efficacy of CELA1 neutralization. Airspace simplification was quantified after administration of tracheal porcine pancreatic elastase (PPE), after 8 months of cigarette smoke (CS) exposure, and in aging. In all 3 models, Cela1-/- mice had less emphysema and preserved lung elastin despite increased lung immune cells. A CELA1-neutralizing antibody was developed (KF4), and it inhibited stretch-inducible lung elastase in ex vivo mouse and human lung and immunoprecipitated CELA1 from human lung. In mice, systemically administered KF4 penetrated lung tissue in a dose-dependent manner and 5 mg/kg weekly prevented emphysema in the PPE model with both pre- and postinjury initiation and in the CS model. KF4 did not increase lung immune cells. CELA1-mediated lung matrix remodeling in response to strain is an important contributor to postnatal airspace simplification, and we believe that KF4 could be developed as a lung matrix-stabilizing therapy in emphysema.

Associations Between Coronary Artery Calcium Score and Exacerbation Risk in BLOCK-COPD.

Introduction: In 2019, the Beta-Blockers for the Prevention of Acute Exacerbations of Chronic Obstructive Pulmonary Disease study (BLOCK-COPD) evaluated the effect of metoprolol on exacerbation risk and mortality in a COPD population without indications for beta-blocker use. We hypothesized that an imaging metric of coronary artery disease (CAD), the coronary artery calcium (CAC) score, would predict exacerbation risk and identify a differential response to metoprolol treatment. Methods: The study population includes participants in the BLOCK-COPD study from multiple study sites. Participants underwent clinically indicated thoracic computed tomography (CT) scans ± 12 months from enrollment. The Weston scoring system quantified CAC. Adjusted Cox proportional hazards models evaluated for associations between CAC and time to exacerbation. Results: Data is included for 109 participants. The mean CAC score was 5.1±3.7, and 92 participants (84%) had CAC scores greater than 0. Over a median (interquartile range) follow-up time of 350 (280 to 352) days, there were 61 mild exacerbations and 19 severe/very severe exacerbations. No associations were found between exacerbations of any severity and CAC>0 or total CAC. Associations were observed between total CAC and CAC>0 in the left circumflex (LCx) and time to exacerbation of any severity (adjusted hazard ratio [aHR]=1.39, confidence interval [CI]: 1.08-1.79, p=0.01) and (aHR=1.96, 95% CI: 1.04-3.70, p=0.04), respectively. Conclusions: CAD is a prevalent comorbidity in COPD accounting for significant mortality. Our study confirms the high prevalence of CAD using the CAC score; however, we did not discover an association between CAC and exacerbation risk. We did find novel associations between CAC in the LCx and exacerbation risk which warrant further investigation in larger cohorts.

LC-MS/MS method for proline-glycine-proline and acetylated proline-glycine-proline in human plasma.

The extracellular cellular matrix (ECM) maintains tissue structure and regulates signaling functions by continuous degradation and remodeling. Inflammation or other disease conditions activate proteases including matrix metalloproteinases (MMPs) that degrade ECM proteins and in particular generate fragments of collagen and elastin, some of which are biologically active ECM peptides or matrikines. Stepwise degradation of collagen by MMP 8, 9 and prolyl endopeptidase release the matrikine proline-glycine-proline (PGP) and its product acetyl-PGP (AcPGP). These peptides are considered as potential biomarkers and therapeutic targets for many disease conditions such as chronic lung disease, heart disease, and cancer. However, there is no published, validated method for the measurement of PGP and AcPGP in plasma and therefore, we developed a sensitive, selective and reliable, isotope dilution LC-multiple reaction monitoring MS method for their determination in human plasma. The chromatographic separation of PGP and AcPGP was achieved in 3 min using Jupiter column with a gradient consisting of acidified acetonitrile and water at a flow rate of 0.5 ml/min. The limit of detection (LOD) for PGP and AcPGP was 0.01 ng/ml and the limit of quantification (LOQ) was 0.05 ng/ml and 0.1 ng/ml, respectively. Precision and accuracy values for all analytes were within 20 % except for the lowest QC of 0.01 ng/ml. The mean extraction recoveries of these analytes were > 90 % using a Phenomenex Phree cartridge and the matrix effect was < 15 % for all the QCs for PGP and AcPGP except the lowest QC. The stability of PGP and AcPGP was > 90 % in several tested conditions including autosampler use, storage at -80 °C, and after 6 times freeze-thaw cycles. Using this method, we successfully extracted and determined PGP levels in human plasma from healthy and COPD subjects. Therefore, this method is suitable for quantification of these peptides in the clinical setting.

Computed tomography measure of lung injury and future interstitial features: the CARDIA Lung Study.

Introduction: Visually normal areas of the lung with high attenuation on computed tomography (CT) imaging, termed CT lung injury, may represent injured but not yet remodelled lung parenchyma. This prospective cohort study examined if CT lung injury is associated with future interstitial features on CT and restrictive spirometry abnormality among participants from the Coronary Artery Risk Development in Young Adults (CARDIA) study. Methods: CARDIA is a population-based cohort study. CT scans obtained at two time points were assessed objectively for amount of lung tissue characterised as CT lung injury and interstitial features. Restrictive spirometry was defined as having a forced vital capacity (FVC) <80% predicted with forced expiratory volume in 1 s/FVC ratio >70%. Results: Among 2213 participants, the median percentage of lung tissue characterised as CT lung injury at a mean age of 40 years was 3.4% (interquartile range 0.8-18.0%). After adjustment for covariates, a 10% higher amount of CT lung injury at mean age 40 years was associated with a 4.37% (95% CI 3.99-4.74%) higher amount of lung tissue characterised as interstitial features at mean age 50 years. Compared to those with the lowest quartile of CT lung injury at mean age 40 years, there were higher odds of incident restrictive spirometry at mean age 55 years in quartile 2 (OR 2.05, 95% CI 1.20-3.48), quartile 3 (OR 2.80, 95% CI 1.66-4.72) and quartile 4 (OR 3.77, 95% CI 2.24-6.33). Conclusions: CT lung injury is an early objective measure that indicates risk of future lung impairment.

Causes of and Clinical Features Associated with Death in Tobacco Cigarette Users by Lung Function Impairment.

Rationale: Cigarette smoking contributes to the risk of death through different mechanisms. Objectives: To determine how causes of and clinical features associated with death vary in tobacco cigarette users by lung function impairment. Methods: We stratified current and former tobacco cigarette users enrolled in Genetic Epidemiology of Chronic Obstructive Pulmonary Disease (COPDGene) into normal spirometry, PRISm (Preserved Ratio Impaired Spirometry), Global Initiative for Chronic Obstructive Lung Disease (GOLD) 1-2 COPD, and GOLD 3-4 COPD. Deaths were identified via longitudinal follow-up and Social Security Death Index search. Causes of death were adjudicated after a review of death certificates, medical records, and next-of-kin interviews. We tested associations between baseline clinical variables and all-cause mortality using multivariable Cox proportional hazards models. Measurements and Main Results: Over a 10.1-year median follow-up, 2,200 deaths occurred among 10,132 participants (age 59.5 ± 9.0 yr; 46.6% women). Death from cardiovascular disease was most frequent in PRISm (31% of deaths). Lung cancer deaths were most frequent in GOLD 1-2 (18% of deaths vs. 9-11% in other groups). Respiratory deaths outpaced competing causes of death in GOLD 3-4, particularly when BODE index ⩾7. St. George's Respiratory Questionnaire score ⩾25 was associated with higher mortality in all groups: Hazard ratio (HR), 1.48 (1.20-1.84) normal spirometry; HR, 1.40 (1.05-1.87) PRISm; HR, 1.80 (1.49-2.17) GOLD 1-2; HR, 1.65 (1.26-2.17) GOLD 3-4. History of respiratory exacerbations was associated with higher mortality in GOLD 1-2 and GOLD 3-4, quantitative emphysema in GOLD 1-2, and airway wall thickness in PRISm and GOLD 3-4. Conclusions: Leading causes of death vary by lung function impairment in tobacco cigarette users. Worse respiratory-related quality of life is associated with all-cause mortality regardless of lung function.

A blood and bronchoalveolar lavage protein signature of rapid FEV1 decline in smoking-associated COPD.

Accelerated progression of chronic obstructive pulmonary disease (COPD) is associated with increased risks of hospitalization and death. Prognostic insights into mechanisms and markers of progression could facilitate development of disease-modifying therapies. Although individual biomarkers exhibit some predictive value, performance is modest and their univariate nature limits network-level insights. To overcome these limitations and gain insights into early pathways associated with rapid progression, we measured 1305 peripheral blood and 48 bronchoalveolar lavage proteins in individuals with COPD [n = 45, mean initial forced expiratory volume in one second (FEV1) 75.6 ± 17.4% predicted]. We applied a data-driven analysis pipeline, which enabled identification of protein signatures that predicted individuals at-risk for accelerated lung function decline (FEV1 decline ≥ 70 mL/year) ~ 6 years later, with high accuracy. Progression signatures suggested that early dysregulation in elements of the complement cascade is associated with accelerated decline. Our results propose potential biomarkers and early aberrant signaling mechanisms driving rapid progression in COPD.

Spatial transcriptomic profiling of coronary endothelial cells in SARS-CoV-2 myocarditis.

Objectives: Our objective was to examine coronary endothelial and myocardial programming in patients with severe COVID-19 utilizing digital spatial transcriptomics. Background: Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has well-established links to thrombotic and cardiovascular events. Endothelial cell infection was initially proposed to initiate vascular events; however, this paradigm has sparked growing controversy. The significance of myocardial infection also remains unclear. Methods: Autopsy-derived cardiac tissue from control (n = 4) and COVID-19 (n = 8) patients underwent spatial transcriptomic profiling to assess differential expression patterns in myocardial and coronary vascular tissue. Our approach enabled transcriptional profiling in situ with preserved anatomy and unaltered local SARS-CoV-2 expression. In so doing, we examined the paracrine effect of SARS-CoV-2 infection in cardiac tissue. Results: We observed heterogeneous myocardial infection that tended to colocalize with CD31 positive cells within coronary capillaries. Despite these differences, COVID-19 patients displayed a uniform and unique myocardial transcriptional profile independent of local viral burden. Segmentation of tissues directly infected with SARS-CoV-2 showed unique, pro-inflammatory expression profiles including upregulated mediators of viral antigen presentation and immune regulation. Infected cell types appeared to primarily be capillary endothelial cells as differentially expressed genes included endothelial cell markers. However, there was limited differential expression within the endothelium of larger coronary vessels. Conclusion: Our results highlight altered myocardial programming during severe COVID-19 that may in part be associated with capillary endothelial cells. However, similar patterns were not observed in larger vessels, diminishing endotheliitis, and endothelial activation as key drivers of cardiovascular events during COVID-19.

Electrocardiogram to Determine Mitral and Aortic Valve Opening and Closure.

PURPOSE: Knowledge of the timing of cardiac valve opening and closing is important in cardiac physiology. The relationship between valve motion and electrocardiogram (ECG) is often assumed, however is not clearly defined. Here we investigate the accuracy of cardiac valve timing estimated using only the ECG, compared to Doppler echocardiography (DE) flow imaging as the gold standard. METHODS: DE was obtained in 37 patients with simultaneous ECG recording. ECG was digitally processed and identifiable features (QRS, T, P waves) were examined as potential reference points to determine opening and closure of aortic and mitral valves, as compared to DE outflow and inflow measurement. Timing offset of the cardiac valves opening and closure between ECG features and DE was measured from derivation set (n = 19). The obtained mean offset in combination with the ECG features model was then evaluated on a validation set (n = 18). Using the same approach, additional measurement was also done for the right sided valves. RESULTS: From the derivation set, we found a fixed offset of 22 ± 9 ms, 2 ± 13 ms, 90 ± 26 ms, and - 2 ± - 27 ms when comparing S to aortic valve opening, Tend to aortic valve closure, Tend to mitral valve opening, and R to mitral valve closure respectively. Application of this model to the validation set showed good estimation of aortic and mitral valve opening and closure timing value, with low model absolute error (median of the mean absolute error of the four events = 19 ms compared to the gold standard DE measurement). For the right-sided (tricuspid and pulmonic) valves in our patient set, there was considerably higher median of the mean absolute error of 42 ms for the model. CONCLUSION: ECG features can be used to estimate aortic and mitral valve timings with good accuracy as compared to DE, allowing useful hemodynamic information to be derived from this easily available test.

Relationship Between Chronic Lung Disease Diagnosis and Susceptibility to E-Cigarette Use in Adults.

BACKGROUND: Electronic cigarettes (e-cigarettes) are known to cause adverse pulmonary effects, yet paradoxically, the prevalence of e-cigarette use has increased among individuals with chronic lung disease. We assessed the relationship between chronic lung disease and the susceptibility to e-cigarette use in adults and determined if specific behavioral, social, and environmental factors influence this relationship. METHODS: We enrolled adults age ≥ 18 y in Alabama with chronic lung disease from university medical clinics (n = 140) and individuals without chronic lung disease (n = 123, reference group) from January 2020-March 2021. A cross-sectional design was used where we administered questionnaires to collect sociodemographic information and assessed susceptibility to e-cigarette use, exposure to social and environmental factors (ie, advertisements, warning labels, special prices, others' e-cigarette vapors, use of an e-cigarette by others in the home, and visiting a web site or online discussion), and behavioral factors (ie, alcohol and cannabis use). Moderation analyses were conducted to determine if any of these factors would modify the association between chronic lung disease and susceptibility to e-cigarette use. RESULTS: Susceptibility to e-cigarette use was higher among adults without chronic lung disease than among those with chronic lung disease. Noticing e-cigarette warning labels and visiting a web site or online discussion about e-cigarettes were significantly associated with an increased likelihood of susceptibility to using e-cigarettes in both groups. Exposure to e-cigarette vapor from close contacts, special pricing, living with someone who uses e-cigarettes, and cannabis use were significantly associated with an increased likelihood of susceptibility to e-cigarette use in individuals without chronic lung disease. However, our analyses did not indicate a statistically significant interaction between chronic lung disease and any social, environmental, or behavioral factors on susceptibility to e-cigarette use. CONCLUSIONS: Individuals without chronic lung disease were more susceptible to e-cigarette use than those with chronic lung disease. Although the prevalence of some behavioral and environmental factors differed among individuals with and without chronic lung disease, these factors did not moderate the association between chronic lung disease and susceptibility to e-cigarette use. Longitudinal investigations are warranted to better test the temporal relationships between chronic lung disease, substance use, social and environmental factors, and the susceptibility to e-cigarette use among individuals with chronic lung disease to identify prevention strategies for this population.

Prolonged, physiologically relevant nicotine concentrations in the airways of smokers.

Nicotine from cigarette smoke is a biologically active molecule that has pleiotropic effects in the airway, which could play a role in smoking-induced lung disease. However, whether nicotine and its metabolites reach sustained, physiologically relevant concentrations on airway surfaces of smokers is not well defined. To address these issues, concentrations of nicotine, cotinine, and hydroxycotinine were measured by mass spectrometry (MS) in supernatants of induced sputum obtained from participants in the subpopulations and intermediate outcome measures in COPD study (SPIROMICS), an ongoing observational study that included never smokers, former smokers, and current smokers with and without chronic obstructive pulmonary disease (COPD). A total of 980 sputum supernatants were analyzed from 77 healthy never smokers, 494 former smokers (233 with COPD), and 396 active smokers (151 with COPD). Sputum nicotine, cotinine, and hydroxycotinine concentrations corresponded to self-reported smoking status and were strongly correlated to urine measures. A cutoff of ∼8-10 ng/mL of sputum cotinine distinguished never smokers from active smokers. Accounting for sample dilution during processing, active smokers had airway nicotine concentrations in the 70-850 ng/mL (∼0.5-5 µM) range, and concentrations remained elevated even in current smokers who had not smoked within 24 h. This study demonstrates that airway nicotine and its metabolites are readily measured in sputum supernatants and can serve as biological markers of smoke exposure. In current smokers, nicotine is present at physiologically relevant concentrations for prolonged periods, supporting a contribution to cigarette-induced airway disease.

Mortality Risk and Serious Cardiopulmonary Events in Moderate-to-Severe COPD: Post Hoc Analysis of the IMPACT Trial.

Background: In the InforMing the Pathway of COPD Treatment (IMPACT) trial, single-inhaler fluticasone furoate (FF) /umeclidinium (UMEC) /vilanterol (VI) significantly reduced severe exacerbation rates and all-cause mortality (ACM) risk versus UMEC/VI among patients with chronic obstructive pulmonary disease (COPD). This post hoc analysis aimed to define the risk of ACM during and following a moderate/severe exacerbation, and further determine the benefit-risk profile of FF/UMEC/VI versus FF/VI and UMEC/VI using a cardiopulmonary composite adverse event (AE) endpoint. Methods: The 52-week, double-blind IMPACT trial randomized patients with symptomatic COPD and ≥1 exacerbation in the prior year 2:2:1 to once-daily FF/UMEC/VI 100/62.5/25mcg, FF/VI 100/25mcg, or UMEC/VI 62.5/25mcg. Post hoc endpoints included the risk of ACM during, 1-90 and 91-365 days post moderate or severe exacerbation and time-to-first cardiopulmonary composite event. Results: Of the 10,355 patients included, 5034 (49%) experienced moderate/severe exacerbations. Risk of ACM was significantly increased during a severe exacerbation event compared with baseline (hazard ratio [HR]: 41.22 [95% confidence interval (CI) 26.49-64.15]; p<0.001) but not significantly different at 1-90 days post-severe exacerbation (HR: 2.13 [95% CI: 0.86-5.29]; p=0.102). Moderate exacerbations did not significantly increase the risk of ACM during or after an exacerbation. Cardiopulmonary composite events occurred in 647 (16%), 636 (15%), and 356 (17%) patients receiving FF/UMEC/VI, FF/VI, and UMEC/VI, respectively; FF/UMEC/VI significantly reduced cardiopulmonary composite event risk versus UMEC/VI by 16.5% (95% CI: 5.0-26.7; p=0.006). Conclusion: Results confirm a substantial mortality risk during severe exacerbations, and an underlying CV risk. FF/UMEC/VI significantly reduced the risk of a composite cardiopulmonary AE versus UMEC/VI.

Outcome expectancies and resistance self-efficacy mediate the relationship between asthma diagnosis and e-cigarette use among youth and young adults.

INTRODUCTION: The use of electronic cigarettes (e-cigarettes) may exacerbate pulmonary complications in youth and young adults with asthma. We sought to identify the cognitive mechanisms that might explain e-cigarette use in this population. We hypothesized that e-cigarette outcome expectancies and e-cigarette resistance self-efficacy would mediate the relationship between asthma diagnosis and e-cigarette use in youth and young adults. METHODS: We enrolled youth and young adults (15-25 years old) in Alabama with a clinical diagnosis of asthma (n = 130) or without a diagnosis of any chronic pulmonary disease (n = 115; reference group). Author-constructed and validated questionnaires (young adult e-cigarette use outcome expectancies and modified Self-efficacy Scale for Adolescent Smoking) were administered to collect demographic data and assess susceptibility to e-cigarette use as well as current use of e-cigarettes, e-cigarette outcome expectancies, and e-cigarette resistance self-efficacy. We then conducted structural equation modeling to test whether e-cigarette expectancies and e-cigarette resistance self-efficacy mediate the relationship between asthma and susceptibility to e-cigarette use as well as current e-cigarette use. RESULTS: The frequency of the susceptibility to e-cigarette use and current e-cigarette use was lower among those with clinically diagnosed asthma than among those without asthma (35.8% vs. 59.8% for susceptibility and 6.0% vs. 18.2% for current use). Individuals with asthma reported weaker expectancies that e-cigarettes would make them feel relaxed which, in turn, was a significant predictor of lower susceptibility to e-cigarette use and current e-cigarette use, suggesting mediation. Finally, individuals with asthma demonstrated greater e-cigarette resistance self-efficacy in the context of social opportunities and friends' influence to use e-cigarettes. This self-efficacy was associated with lower susceptibility to e-cigarette use as well as current e-cigarette use. CONCLUSION: Although longitudinal studies are needed to determine relationships prospectively, targeted interventions that reduce outcome expectancies and increase resistance self-efficacy to e-cigarette use may further reduce e-cigarette use among youth and young adults with asthma.

A Novel Provider Education Module to Enhance Detection of Alpha-1 Antitrypsin Deficiency.

Background: Alpha-1 antitrypsin deficiency (AATD) is the most common genetic risk factor for early-onset emphysema. However, AATD continues to be underrecognized and underdiagnosed. Provider awareness about AATD, concerns with testing costs, and limited understanding about therapeutic options contribute to its underdiagnosis. We hypothesized that provider education would improve awareness of AATD and improve screening. Objective: To evaluate the impact of a targeted provider education module on AATD screening. Methods: We developed a web-based education module to address barriers to screening for AATD, deployed the education module using the Medscape Education platform, assessed perceived healthcare provider confidence in AATD screening, and conducted a prospective pre and postintervention study of AATD testing practices at a high-volume academic outpatient subspecialty pulmonary clinic. Results: A total of 11,385 healthcare providers, including eight pulmonologists at our institution, completed the web-based education module. Confidence in identifying patients at high risk for AATD improved after completing the module ("not confident" in AATD screening was 7.7% postintervention compared with 19.4% preintervention). The rate of screening patients at high risk for AATD improved more than twofold (AATD screening rate 9.7% preintervention vs. 20.4% postintervention; P = 0.004). Among patients screened for AATD in our cohort, 27.2% had a genotype/phenotype or low alpha-1 antitrypsin concentration consistent with AATD. Conclusion: Targeted healthcare provider education can improve the confidence in testing for AATD. Improvements in provider confidence corresponded to improvements in AATD screening in a subspecialty pulmonary clinic. More than one-fourth of screening tests suggested AATD, underpinning the value of testing in high-risk individuals.

Spatial transcriptomic profiling of coronary endothelial cells in SARS-CoV-2 myocarditis.

Objectives: Our objective was to examine coronary endothelial and myocardial programming in patients with severe COVID-19 utilizing digital spatial transcriptomics. Background: Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has well-established links to thrombotic and cardiovascular events. Endothelial cell infection was initially proposed to initiate vascular events; however, this paradigm has sparked growing controversy. The significance of myocardial infection also remains unclear. Methods: Autopsy-derived cardiac tissue from control (n = 4) and COVID-19 (n = 8) patients underwent spatial transcriptomic profiling to assess differential expression patterns in myocardial and coronary vascular tissue. Our approach enabled transcriptional profiling in situ with preserved anatomy and unaltered local SARS-CoV-2 expression. In so doing, we examined the paracrine effect of SARS-CoV-2 infection in cardiac tissue. Results: We observed heterogeneous myocardial infection that tended to colocalize with CD31 positive cells within coronary capillaries. Despite these differences, COVID-19 patients displayed a uniform and unique myocardial transcriptional profile independent of local viral burden. Segmentation of tissues directly infected with SARS-CoV-2 showed unique, pro-inflammatory expression profiles including upregulated mediators of viral antigen presentation and immune regulation. Infected cell types appeared to primarily be capillary endothelial cells as differentially expressed genes included endothelial cell markers. However, there was limited differential expression within the endothelium of larger coronary vessels. Conclusions: Our results highlight altered myocardial programming during severe COVID-19 that may in part be associated with capillary endothelial cells. However, similar patterns were not observed in larger vessels, diminishing endotheliitis and endothelial activation as key drivers of cardiovascular events during COVID-19. Condensed Abstract: SARS-CoV-2 is linked to thrombotic and cardiovascular events; however, the mechanism remains uncertain. Our objective was to examine coronary endothelial and myocardial programming in patients with severe COVID-19 utilizing digital spatial transcriptomics. Autopsy-derived coronary arterial and cardiac tissues from control and COVID-19 patients underwent spatial transcriptomic profiling. Our approach enabled transcriptional profiling in situ with preserved anatomy and unaltered local SARS-CoV-2 expression. We observed unique, pro-inflammatory expression profiles among all COVID-19 patients. While heterogeneous viral expression was noted within the tissue, SARS-CoV-2 tended to colocalize with CD31 positive cells within coronary capillaries and was associated with unique expression profiles. Similar patterns were not observed in larger coronary vessels. Our results highlight altered myocardial programming during severe COVID-19 that may in part be associated with capillary endothelial cells. Such results diminish coronary arterial endotheliitis and endothelial activation as key drivers of cardiovascular events during COVID-19 infection. LIST OF HIGHLIGHTS: SARS-CoV-2 has variable expression patterns within the myocardium of COVID-19 patientsSARS-CoV-2 infection induces a unique myocardial transcriptional programming independent of local viral burdenSARS-CoV-2 myocarditis is predominantly associated with capillaritis, and tissues directly infected with SARS-CoV-2 have unique, pro-inflammatory expression profilesDiffuse endothelial activation of larger coronary vessels was absent, diminishing large artery endotheliitis as a significant contributor to cardiovascular events during COVID-19 infection.

Clinical risk factors for admission with Pseudomonas and multidrug-resistant Pseudomonas community-acquired pneumonia.

BACKGROUND: Microbial etiology for community-acquired pneumonia (CAP) is evolving with pathogens known for high CAP mortality e.g., Pseudomonas species. Chronic obstructive pulmonary disease (COPD) patients are at risk for hospitalization for CAP. Understanding regional patterns and risk factors for multidrug-resistant (MDR) Pseudomonas acquisition has implications for antimicrobial stewardship. OBJECTIVES: To evaluate the regional epidemiology of MDR Pseudomonas CAP and its association with COPD. METHODS: We queried the electronic medical records of the University of Alabama at Birmingham Healthcare System to identify patients hospitalized for CAP with Pseudomonas positive respiratory samples between 01/01/2013-12/31/2019. Log binomial regression models were used to examine associations between COPD diagnosis and risk of Pseudomonas/MDR Pseudomonas CAP. RESULTS: Cohort consisted of 913 culture positive CAP cases aged 59-year (IQR:48-68), 61% (560) male, 60% (547) white, 65% (580) current/past smokers, and 42% (384) COPD. Prevalence of Pseudomonas CAP in culture positive CAP was 18% (167), MDR Pseudomonas CAP in Pseudomonas CAP was 22% (36), and yearly incidence of MDR Pseudomonas CAP was stable (p = 0.169). COPD was associated with Pseudomonas CAP (RR 1.39; 95% CI 1.01, 1.91; p = 0.041) but not with MDR Pseudomonas CAP (0.71; 95% CI 0.35, 1.45; p = 0.349). Stroke (RR 2.64; 95% CI 1.51, 4.61; p = 0.0006) and use of supplemental oxygen (RR 2.31; 95% CI 1.30, 4.12; p = 0.005) were associated with MDR Pseudomonas CAP. CONCLUSION: Incidence of MDR Pseudomonas CAP was stable over time. COPD was associated with Pseudomonas CAP but not with MDR Pseudomonas CAP. Larger cohort studies are needed to confirm findings.