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Abstract Introduction Resilient smokers, who maintain respiratory health despite smoking, remain poorly characterized. Airway epithelial cell gene expression in resilient smokers can provide insight into mechanisms and pathways that may protect smokers from developing smoking-related lung disease. The objective of this study is to identify genes and potential pathways associated with lung-related resilience. Methods Resilient smokers were defined based on a previously published multi-dimensional definition which includes the absence of: 1) spirometric airflow limitation, 2) symptoms (cough/sputum, dyspnea), 3) radiographic (HRCT) abnormalities, 4) exacerbations, and 5) an accelerated FEV1 decline. “Non-resilient” smokers had preserved spirometry but showed abnormalities in at least one domain of resilience. We analyzed airway epithelial brush samples from 21 resilient and 34 non-resilient smokers from SPIROMICS. Differential gene expression was performed using DESeq2 package in R, which estimates differential expression using generalized linear models. We adjusted for sequencing batch, age (continuous), race, gender, and current smoking status. While controlling for these covariates we evaluated differential gene expression between resilient and non-resilient smokers, the interaction between resilience and smoking status, and in each sub-category of resilient (absence of symptoms, radiographic abnormalities, exacerbations, and accelerated decline in FEV1). Results We identified 98 genes that were differentially expressed (FDR ≤0.1) when comparing resilient to non-resilient smokers, 20 of those genes were up regulated in resilient smokers (Figure 1). Notable genes included cadherin-12 (CDH12), aspartate beta-hydroxylase (ASPH), and protein kinase AMP-activated alpha 2 (PRKAA2). CDH12 is involved in cell adhesion and epithelial integrity. ASPH influences cell adhesion and signaling. PRKAA2 plays role in cellular homeostasis and stress response, which may be altered in non-resilient smokers, affecting cellular metabolism and inflammation. BPI folding containing family A member (BPIFA1) was significantly associated with smoking status in the interaction analysis, suggesting its role in modulating the impact of smoking on resilience. BPIFA1 has anti-microbial properties, regulates immune responses, and contributes mucosal surface protection. Sub-category analysis identified 17 genes associated with resilience to symptoms and 2 genes related to physiologic resilience (FEV1 decline), though no significant genes were associated with radiographic or exacerbation resilience. Conclusion Differential gene expression of airway epithelial cells identified distinct expression patterns between resilient and non-resilient smokers. Specifically, genes associated with epithelial cell adhesion, signaling, and cellular homeostasis were up regulated in resilient smokers. These findings suggest that resilient smokers may have transcriptomic profiles and potential mechanisms that mitigate the effects of cigarette smoke.

Abstract Rationale: Fibrotic interstitial lung diseases (f-ILDs) often lead to increased dyspnea and decreased physical activity, negatively impacting patient quality of life. While center-based pulmonary rehabilitation (PR) provides known benefits, access and adherence may be limited. This study investigates the implementation of a home-based pulmonary rehabilitation program with telephonic health coaching to improve physical activity and respiratory-related quality of life (RR-QOL) over 12 weeks. Methods: This prospective, single-center, non-randomized study enrolled patients with various f-ILD subtypes and severities over two years. Participants engaged in video-based exercises (25 minutes/day, 6 days per week) with weekly telephonic health coaching. Primary outcomes included changes in average daily steps, dyspnea (modified Medical Research Council (mMRC)), and self-reported RR-QOL (Chronic Respiratory Questionnaire (CRQ)- Physical and Emotional Summary domain scores). Minimal Clinically Important Differences (MCID) for study endpoints were defined as ≥600 steps per day, 1-point change in mMRC, and 0.5-point change in CRQ Physical and Emotional Summary scores, used to stratify patient responses to intervention as improved, stable, or worsened. Pre- and post-intervention summary results were compared using paired two-sample t-tests. The percentage of patients reaching MCID thresholds for improvement in primary endpoints was also reported. Results: 88 patients completed the program (mean age 70.2 years, 54% male, and mean FVC 66.9%). Mean CRQ Physical Summary scores improved from baseline 4.09 to 4.35 (mean improvement of 0.26 with 95% CI [0.06, 0.46]). 35% of patients achieved MCID change in the CRQ Physical Summary score, 34% in the CRQ Emotional score, and 22% in mMRC. Although 24% of patients increased their daily steps by 600 or more, average daily steps declined from 7,594 to 7,103 (mean decrease of 492 with 95% CI [101, 883]). When stratified by outcome responses to intervention (improved, stable, or worsened), lower baseline DLCO% was associated with decreased CRQ Physical Summary Scores and daily steps. Conclusion: Home-based PR may improve self-reported quality of life in f-ILD patients, as evidenced by improved CRQ Physical Summary scores. DLCO% may be associated with poorer response to PR intervention, as lower values were associated with declines in CRQ Physical Summary scores and daily steps. These findings support the potential utility of home-based rehabilitation and customizing individual strategies according to baseline characteristics and background disease progression.

Abstract Introduction Persistent dyspnea increases the risk of disability and impairs quality of life in older patients with bronchiectasis. The impact of dyspnea and fatigue on patients with bronchiectasis in long term follow-up has not been adequately established. We sought to determine if fatigue and higher-grade dyspnea are associated with worse clinical outcomes in 5-years of longitudinal follow-up. Methods We analyzed data collected from a prospective cohort of adult patients with bronchiectasis enrolled in the US Bronchiectasis and Nontuberculous Mycobacteria Research Registry. Patients with a modified Medical Research Council (mMRC) dyspnea score collected at baseline and during 3-5 years of follow-up were included and stratified as mMRC<2 versus mMRC ≥2. Kruskal-Wallis, independent sample t-tests and chi-square tests were used to test the differences in medians and means for continuous variables and associations between categorical variables, respectively, between the baseline mMRC groups and bronchiectasis severity index (BSI) components at follow-up. A multivariable logistic regression analysis was performed to determine the association between dyspnea and clinical outcomes (exacerbations and hospitalizations) at follow-up. Results 1185 adult patients with bronchiectasis met the inclusion criteria. The median age (interquartile range) was 76 (68 to 83) years. At baseline, patients with mMRC ≥2 had a higher proportion of co-existing diagnoses such as asthma, chronic obstructive pulmonary disease (COPD), otitis/rhinosinusitis, rheumatologic disease, and pneumonia compared to patients with mMRC <2 (all p<0.05, data not shown). Furthermore, patients with mMRC > 2 compared to patients with mMRC <2 had higher prevalence of fatigue, acute exacerbations and pulmonary related hospitalizations, and lower mean percentage predicted forced expiratory volume in one second (FEV1) at follow-up (all p< 0.05) (Table 1). Interestingly, body mass index was slightly higher among those with baseline mMRC ≥2 compared to mMRC <2 (p=0.02). Among those with mMRC ≥2 at both baseline and follow-up (n=67, 42%), the odds of having ≥1 exacerbation was 2.4 times higher (odds ratio [OR] 2.45, 95% confidence interval [CI] 1.45-4.1) and 2.8 times higher for ≥1 hospitalization (OR 2.8, 95% CI 1.45-5.2) during follow-up after adjusting for fatigue. Conclusion Elevated dyspnea was associated with a greater proportion of patients with bronchiectasis exhibiting acute exacerbations and pulmonary related hospitalizations and lower lung function during follow-up. Research is still needed to understand the causes (drivers) of dyspnea to implement better treatment strategies and reduce adverse outcomes in bronchiectasis patients.

Abstract RATIONALE: The American Thoracic Society (ATS) recently recommended using “race-neutral” GLI-Global prediction equations to interpret spirometry results. However, the unintended consequences for workers have not been fully evaluated. METHODS: We analyzed the impact of adopting GLI-Global on 24 hypothetical subjects, using on-line calculators to examine the effects on 1) larger vs. smaller predicted values; 2) Black, Southeast Asian, Northeast Asian, and White races; and 3) 80%, 100%, and 120% of race-specific predicted forced vital capacity (FVC). RESULTS: Race-specific predicted FVCs decline by group: White > NE Asian > SE Asian > Black, with a difference of 0.84 L between Blacks and Whites. GLI-Global Predicteds are midway between Blacks’ and Whites’. Workers at 80% of race-specific Predicted change the most when GLI-Global is employed: Blacks and SE Asians show declining %Predicted values and Z-scores and an increase in FVCs<LLN, while Whites and NE Asians show increasing %Predicted and Z-scores and a decrease in FVCs<LLN. CONCLUSIONS: Choice of prediction equation for use in occupational health practice differentially affects individuals in several groups: a) When fixed criteria are used for job placement and retention decisions, Black and SE Asian persons may be particularly adversely affected, while Whites and NE Asians will more likely exceed the fixed criteria; b) When fixed criteria are used for disability decisions, Black and SE Asian persons may look increasingly disabled, while White and NE Asian persons may now fail to qualify for disability; and c) Disparate effects are most prominent for persons with lung function measures in the lower portion of the normal range. Since occupational criteria are unlikely to change quickly, clinicians and policymakers should consider the real-world implications of mandating or recommending specific equations.

Abstract Rationale: The Deterioration Index (DTI) may serve as a crucial tool for predicting adverse patient outcomes; however, there is a paucity of literature attempting to externally validate this tool in specific clinical scenarios. In this study, we analyzed the relationship between DTI scores during rapid response team (RRT) activations and subsequent ICU transfer, initiation of goals of care (GOC) conversations, and 90-day mortality. Methods: This was a retrospective single-center review of adult patients who had an RRT activation while hospitalized between January 1, 2023 and December 31, 2023. This study was approved by our hospital institutional review board. Deterioration scores (0-100) were recorded every 15 minutes during the RRT event, and the highest score of each encounter was selected for analysis. The primary outcome was transfer to the ICU as a direct result of the RRT activation. Secondary outcomes included GOC discussions following RRT activation and 90-day mortality. GOC discussions, defined as physician-led conversations that specifically addressed code status, treatment priorities, or broader goals of care, met criteria only if initiated within 72 hours of the analyzed RRT activation. Logistic regression was used to assess the relationship between DTI scores during RRT activations and the aforementioned variables. Results: A total of 1643 patients were included in the analysis. For every 1-point increase in the deterioration score, the odds of ICU transfer increased by 2.7% (OR: 1.027, CI: 1.021-1.034, p<0.0001), the odds of a goals of care discussion within 72 hours increased by 3.3% (OR: 1.033, CI: 1.025-1.040, p<0.0001), and the likelihood of mortality within 90 days increased by 2.6% (OR: 1.026, CI: 1.019-1.033, p<0.0001). Conclusion: Our findings contribute to external validation of DTI predictive value during RRT events. DTI scores were associated with key clinical outcomes, including ICU transfer and 90-day mortality. There was also an association between DTI scores and the likelihood of physician-led GOC discussions, suggesting that DTI may demonstrate predictive value not only of patient outcomes, but also the likelihood of specific non-medical physician actions. Further validation of these scores in prospective studies, specifically in the context of acute decompensation events, could help facilitate the integration of DTI-based RRT interventions into routine hospital practice.

Abstract Rationale: Propofol can increase the risk of hypertriglyceridemia and subsequent pancreatitis in critically ill patients. It is unclear whether modifying or continuing sedation regimens in patients experiencing hypertriglyceridemia while on propofol infusion influences the development of adverse events such as acute pancreatitis. This study compared the clinical outcomes of patients receiving invasive mechanical ventilation (IMV) who had their propofol regimen modified versus continued following the detection of hypertriglyceridemia. Methods: A targeted trial emulation was conducted using retrospective data from 5 Mayo Clinic hospitals between 05/05/2018 and 06/30/2023. Inclusion criteria included: 1) receiving IMV and continuous propofol infusion for >24 hours, 2) experiencing triglyceride level >400 mg/dL while on propofol, and 3) still requiring IMV at 24-hours after hypertriglyceridemia onset. Patients were then categorized based on whether they had their propofol regimen modified (i.e., dose reduction by ≥50% or any reduction with alternative sedatives started) versus continued (no reduction or <50% reduction without alternative sedative initiation). Outcomes included 30-day ventilator-free days, successful extubation, acute pancreatitis (determined by chart review, in-duplicate), ICU and hospital length of stay, 30- and 90-days alive and at home, as well as all-cause mortality. Analyses were conducted using stabilized inverse probability of treatment weights with adjustments for covariates selected a priori. Sensitivity analyses, where only benzodiazepines or benzodiazepines and ketamine were considered to be eligible alternative sedatives, were done. Results: During the study period, 728 patients were included, of whom 422 had their propofol regimen modified (Image). The two groups had similar demographics, comorbidities, and illness severity. We identified 14 cases of acute pancreatitis possibly attributable to propofol, with 9 cases in the modified and 5 cases in the continued regimen group (2.1% versus 1.6%; P=0.63). Following adjustment for covariates, there were no significant differences in any outcomes of interest. After censoring for mortality, there was no significant difference in the 30-day cumulative incidence of successful extubation when comparing those with their regimen modified versus continued (Hazard ratio [HR] 0.95; 95% confidence intervals [CI] 0.77 to 1.18; P=0.70). There was also no significant difference in the 90-day survival rate between the two groups (HR 0.89; 95% CI 0.71 to 1.11; P=0.34). These findings remained consistent upon sensitivity analyses. Conclusion: There were no differences in outcomes among patients who had their propofol regimens modified versus continued following the detection of hypertriglyceridemia. Further prospective investigations are needed to identify the optimal strategy for managing sedative regimens in this patient population.

Abstract Rationale: While survival of premature infants has improved with NICU interventions, prematurity remains a risk for developing chronic lung diseases. Oxygen supplementation in the NICU is unfortunately necessary, and clinical practice has shifted towards use of moderate hyperoxia (<60% O2) to minimize detrimental effects of very high O2 concentration (80-90%) such as bronchopulmonary dysplasia. However, even moderate hyperoxia increases the risk of bronchial airway diseases and wheezing/asthma with airway hyperreactivity and remodeling. We previously found that moderate hyperoxia induces cellular senescence in human fetal airway smooth muscle cells (fASM) and fibroblasts. However, the mechanisms by which hyperoxia enhances cellular senescence in fASM are not known. We investigated the role of endoplasmic reticulum (ER) stress and mitochondrial dysfunction, using fASM cells exposed to 21% (normoxia) vs. 50% O2 (hyperoxia). Methods: fASM isolated from lungs of 18-20 week aborted fetuses (Mayo IRB exempt; period of rapid bronchial airway growth) were exposed to normoxia, hyperoxia or etoposide (10 µM; positive control for senescence induction). Cells and lysates were harvested at days 2, 3 or 7 to assess markers of senescence markers, ER stress and mitochondrial morphology, and levels of cytosolic and mitochondrial ROS, using real-time fluorescence imaging, Western blotting, immunofluorescence, and a novel immuno-FISH staining of telomere associated foci (TAF). Mitochondria-specific antioxidant MitoQ [100 nM], ER stress inhibitor Salubrinal [12.5 µM] or mitochondrial fission inhibitor Mdivi-1 [10 µM] were used to assess their effects on senescence markers and interactions between ER stress and mitochondria in inducing senescence. Results: Hyperoxia enhanced cellular senescence via upregulation of p21, PAI-1, and Cav-1; downregulation of LMNB1 and Ki-67, with increased γH2A.X- and TAF-positive cells. Hyperoxia increased cytosolic and mitochondrial ROS, and markers of the three ER stress pathways (ATF6, IRE1α, XBP1s, PDI, GADD34). Hyperoxia altered mitochondrial morphology with increased fission protein Drp1 and fusion proteins Mfn1/2. Inhibition of Drp1 with Mdivi-1 blocked mitochondrial fragmentation, but not senescence. However, hyperoxia-induced p21 was reduced by the PERK pathway inhibitor Salubrinal and MitoQ. Conclusions: Hyperoxia induces senescence in fASM via mitochondrial ROS and ER stress: pathways that offer new opportunities to blunt detrimental effects of oxygen in developing lung via mitochondrial targeted antioxidants and/or ER stress inhibition.

Abstract Introduction Sex-based differences in morbidity and mortality for pulmonary hypertension (PH) are insufficiently addressed in current research. However, recognizing these differences is crucial for optimal clinical management and improving outcomes. This study assesses the effect of sex on survival among PH patients, while accounting for disease severity, comorbidities, treatment, and race. Methods We analyzed data from the PVRI GoDeep meta-registry, including all incident patients with complete hemodynamic profiles. Survival was evaluated using Kaplan-Meier and Cox proportional hazards models, adjusted for various confounders. Analyses included both PAH and non-PAH groups and risk assessment by the ESC/ERS 2022, REVEAL lite 2, and COMPERA 4-strata scores. All analyses were performed using R (The R Foundation). Results A total of 19,663 incident PH patients were included in the analysis, with 5,581 patients (28%) diagnosed with Group 1 PH and a median age of 64 years [IQR: 52-73]. Among these, male patients (8,704, 44%) had a significantly higher mortality risk than female patients across the entire cohort and within all PH subtypes. The adjusted hazard ratio for mortality in male versus female patients was 1.391 [95% CI: 1.260-1.536] in the overall population and 1.404 [95% CI: 1.264-1.561] for those with PAH. This survival difference was consistent across various severity levels, age groups, and in the presence of comorbidities such as obesity and cardiovascular diseases, as well as among those receiving PAH-specific therapies as well as patients who remained without treatment during the observation period. Notably, male disadvantage in survival was observed in low, intermediate, and high-risk categories for ESC/ERS 2022, REVEAL lite 2, and COMPERA scores but not within REVEAL 2.0, which includes male sex as a non-modifiable risk factor. Racial analysis revealed a greater mortality risk for males among White patients, with no significant differences noted in Black or Asian populations. Conclusion Our PVRI GoDeep meta-registry analysis demonstrates that male PH patients face higher mortality risk across both PAH and non-PAH groups, independent of disease etiology, age, severity, comorbidities, and treatment factors, with this risk amplified in White patients. These findings suggest that male sex should be further considered as a risk factor to refine predictive models for survival in PH.

Abstract Rationale: The US prison population carries a high burden of chronic disease and disability, with older adults constituting the fastest growing subpopulation. When medical needs exceed a prison's healthcare service capabilities, incarcerated patients are transported to clinics and hospitals in surrounding communities. The influence of prison policies on off-site medical care of incarcerated patients is poorly understood. This study aims to identify and classify correctional policies regulating the care of incarcerated patients in community hospitals. Methods: Between 6/2024-10/2024 we searched the Internet for policies from states’ Departments of Corrections (DOC) pertaining to healthcare of incarcerated patients. We compiled, reconciled and organized those policies according to date, jurisdiction and relevance to hospital care. We then developed a preliminary thematic coding scheme and, using mixed inductive and deductive content analysis, two coders independently applied our codebook to each policy. Any coding discrepancies were resolved by consensus, and when necessary, with adjudication by a third team member. Results: Forty-eight state DOCs and the District of Columbia (totaling 49 “states”) have publicly available policies pertaining to healthcare. Among these, 20/49 (41%) have policies pertaining to the protection of bodily privacy during healthcare encounters. Separately, 31 (63%) have policies regarding the confidentiality of incarcerated patients’ medical encounters and records. Thirty-four (69%) maintain policies regarding incarcerated individuals’ right to select and consent to treatment. Thirty-three (67%) include language about the right to refuse treatment. Twenty-six states (53%) direct that incarcerated individuals be informed of their right to access healthcare either in writing (22/49; 45%), verbally (20/49; 41%), or through posted signage (5/49; 10%). Twenty-one states (43%) address shackling during off-site medical care, but only 15 (31%) address responding to requests from off-site clinicians to minimize or remove patients’ restraints. Just 4/49 states (8%) use person-centered language (avoiding terms like “offender” and “inmate”). Policy excerpts addressing key domains are depicted in the Table. Conclusions: Correctional policies regarding the care of incarcerated patients in community hospitals vary significantly in scope and content across states. While incarcerated people have a Constitutionally protected right to accept or refuse healthcare, including making their own treatment decisions, many state policies do not explicitly mandate how these disclosures must be communicated to patients or their healthcare providers. These silences, when combined with security measures like shackling and the ubiquitous presence of officers, countermand person-centered care and undermine the ability of hospital healthcare professionals to uphold the rights and dignity of incarcerated patients.

Abstract RATIONALE: Deferral and declination of the COVID-19 vaccine is correlated with many factors, including different health guidelines and difficulties accessing the vaccine. In the US, COVID-19 vaccines were made available in tranches of clinical risk starting in December 2020 and were available to all adults on April 19, 2021. In the post-pandemic period, repeating COVID-19 vaccination with updated formulations is broadly recommended. Given that the public health impact of vaccine allocation strategies depends on public acceptance of vaccination, we aimed to evaluate demographic, clinical and social correlates of (1) receiving at least one COVID-19 vaccine by May 1, 2021 (prompt vaccination) and (2) the total number of vaccine doses received (vaccine count) through 2023-2024. METHODS: The Collaborative Cohort of Cohorts for COVID-19 Research (C4R) is a prospective observational meta-cohort study comprising 14 extant NIH-funded population-based cohorts. C4R assessed COVID-19 vaccination using three waves of standardized questionnaires (2020-2021, 2021-2023, 2023-2024). Prompt vaccination was defined by participant self-report of vaccination before May 1, 2021; participants vaccinated after May1, 2021 were classified as non-prompt; participants with missing vaccination information were excluded. Vaccine count was defined by self-report on the 2023-2024 wave Questionnaire. Demographic, clinical and social factors were classified by self-report and/or objective measures from the most recent pre-pandemic cohort exam. Poisson models regressed either prompt vaccination or vaccine count on pre-pandemic factors. RESULTS: Of 17,866 participants (mean age, 6713 years; 60.1% female; 42.1% non-Hispanic White, 22.0% Black, 28.9% Hispanic/Latino, 3.4% American Indian, 2.3% South Asian, 1.4% East Asian), 11,481 (64.3%) reported prompt vaccination. Of the subset of 14,529 participants completing the Wave 3 questionnaire, the median vaccine count in 2023-24 was 3 (Q1, 2; Q3 4). Likelihood of prompt vaccination was higher with greater age, income, and education and with history of diabetes and hypertension; prompt vaccination was less likely with male sex, current smoking, and non-White race and ethnicity (table). Similar associations were observed with respect to vaccine count (table). CONCLUSIONS: In a diverse C4R cohort community-based sample, earlier and greater COVID-19 vaccination was associated with older age and several clinical comorbidities; in contrast, later and lesser vaccine uptake was observed among historically marginalized groups. Whether disparities in COVID-19 vaccination could contribute to disparities in post-COVID-19 conditions merits further investigation.