Wang, Timothy C.

Abstract RATIONALE: Chronic lower respiratory diseases (CLRD) confer higher risks from respiratory viral infections, hence CLRD patients are prioritized for influenza, pneumococcal, and COVID-19 vaccination. Nonetheless, vaccine deferral and declination remain common. Given that COVID-19 vaccination is particularly polarizing, and attitudes toward it may differ from other vaccines, we assessed COVID-19 vaccination behaviors and attitudes in adults with versus without CLRD and/or smoking history, which is strongly associated with CLRD risk. METHODS: We pooled data from 10 cohorts participating in the Collaborative Cohort of Cohorts for COVID-19 Research (C4R) that collected pre-pandemic data on self-reported physician diagnosis of asthma or COPD. C4R assessed COVID-19 vaccination status through three waves of standardized questionnaires (2020-2022, 2021-2023, 2023-2024). Prompt COVID-19 vaccination was defined as self-report of receiving at least one COVID-19 vaccine by May 1, 2021. Cumulative COVID-19 vaccine count was self-reported on the Wave 3 Questionnaire. Vaccine attitudes and receipt of influenza and/or pneumococcal vaccines were self-reported on the Wave 1 or 2 Questionnaire. Age-adjusted Poisson regression was used to test associations of vaccination behaviors with CLRD and smoking status at the most recent pre-pandemic exam. RESULTS: Of 20,034 participants (pre-pandemic COPD, 9.3%; asthma, 11.7%; current smoking, 13.4%; former smoking, 36.3%), 64.2% reported prompt COVID-19 vaccination. Among the subset of 10,626 participants completing the Wave 3 Questionnaire in 2023-24, the median COVID-19 vaccine count was 3 (Q1:2, Q3:4). Compared to participants without CLRD, prompt vaccination was more likely in those with asthma (RR=1.04, 95%CI:1.01-1.07, p=0.008) and less likely with COPD (RR=0.94, 95%CI:0.91-0.98, p=0.001), but there were no differences in doses for asthma and COPD. Compared to never smokers, former smoking participants were more likely to receive prompt vaccination (RR=1.11, 95%CI:1.08-1.13, p<0.0001) and more vaccine doses (RR=1.03, 95%CI:1.01-1.05, p=0.015); conversely, current smoking was inversely associated with prompt vaccination (RR=0.94, 95%CI:0.91-0.97, p=0.001) and was associated with fewer doses (RR=0.93, 95%CI:0.89-0.96, p<0.0001). Participants with CLRD versus without CLRD were more likely to report receiving influenza and pneumococcal vaccines, but they were more likely to believe that vaccines are unsafe or ineffective (figure). CONCLUSIONS: COPD was associated with lower likelihood of prompt COVID-19 vaccination. Current smoking was associated with both lower likelihood of prompt COVID-19 vaccination and a lower number of COVID-19 vaccine doses by 2023-24. These associations may be partly attributed to negative vaccine attitudes and beliefs. How the COVID-19 pandemic may have influenced vaccine behaviors and attitudes merits additional study.

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.

Abstract Rationale: SARS-CoV-2 infection may be associated with new or worsening respiratory symptoms that, if persistent, may contribute to “Long COVID.” Research is needed on the prevalence and risk determinants of Long COVID and related respiratory symptoms in adults with and without pre-existing obstructive lung disease or smoking history. Methods: C4R is a prospective, observational study that collected information on SARS-CoV-2 infection using standardized methods across 14 NIH-funded cohorts. The third wave of C4R questionnaires, administered June 2023 to January 2025, assessed self-reported Long COVID via the question, “Do you think that you are experiencing, or have ever experienced, what has been called “long COVID,” or symptoms related to COVID at least a month after your infection?” Questionnaires also assessed the presence (vs absence) of 22 symptoms that have been linked to Long COVID, including cough, shortness of breath, and post-exertional malaise. Pre-pandemic obstructive lung disease (COPD or asthma) and smoking status (ever/never) were harmonized from self-reported data collected at the most recent pre-pandemic cohort exam. Poisson regression was used to assess prevalence ratios (PRs) adjusting for age, sex, BMI, education, and pre-pandemic hypertension, diabetes, cardiovascular disease, and depressive symptoms. PRs for respiratory symptoms were tested according to self-reported Long COVID and history of non-hospitalized or hospitalized infection; effect modification by pre-pandemic lung disease and smoking was assessed by multiplicative interaction terms and in fully stratified models. Results: Among 23,434 questionnaire respondents, 1,484 (6.3%) self-reported Long COVID, including 246/1,262 (19.5%) with pre-pandemic lung disease and 664/4,018 (16.5%) with smoking history. The adjusted PR for Long COVID was 1.17 (95%CI:0.99-1.39;P=0.06) comparing participants with/without lung disease and 1.17 (95%CI:1.04-1.32;P=0.01) comparing participants with/without smoking history. Respiratory symptoms were more prevalent in those with self-reported Long COVID, as well as in those with a history of hospitalized or non-hospitalized infection (Table). Associations were generally stronger in participants without pre-pandemic lung disease (p-interaction<0.05 for all comparisons). Respiratory symptoms were also more prevalent with a history of repeated, and pre-Omicron infections, and were less prevalent among participants vaccinated prior to their first infection; findings were similar even after excluding participants with self-reported Long COVID. Conclusions: Long COVID is common, particularly in adults with pre-existing COPD or asthma or smoking history. Long COVID and history of SARS-CoV-2 infection, including non-hospitalized infections, was associated with greater respiratory symptom burden. Whether SARS-CoV-2 infection or Long COVID are associated with development or progression of obstructive lung diseases warrants future studies.

INTRODUCTION: Reflux bile acids are believed to promote esophageal adenocarcinoma (EAC), but the role of systemic bile acids is unknown. This study aimed to assess associations between systemic bile acids and stages of Barrett's esophagus (BE) progression. METHODS: Subjects with and without BE were enrolled in this multicenter cross-sectional study. Targeted serum bile acid profiling was performed, and a subset of subjects completed a validated food frequency questionnaire. RNA sequencing was performed on BE or gastric cardia tissue to assess bile acid associations with gene expression. RESULTS: A total of 141 subjects were enrolled with serum bile acids profiled (49 non-BE; 92 BE: 44 no dysplasia, 25 indefinite/low grade dysplasia, 23 high-grade dysplasia/EAC). Lower Healthy Eating Index score, older age, higher body mass index, and no proton pump inhibitor use were associated with increased levels of multiple bile acids. Global bile acid pools were distinct between non-BE and stages of BE neoplasia ( P = 0.004). Increasing cholic acid was associated with high-grade dysplasia/EAC compared with non-BE, even after adjusting for EAC risk factors (adjusted odds ratio 2.03, 95% confidence interval 1.11–3.71) as was the combination of unconjugated primary bile acids (adjusted odds ratio 1.81, 95% confidence interval 1.04–3.13). High cholic acid levels were associated with tissue gene expression changes including increased DNA replication and reduced lymphocyte differentiation genes. DISCUSSION: Alterations in serum bile acids are independently associated with advanced neoplasia in BE and may contribute to neoplastic progression. Future studies should explore associated gut microbiome changes, proneoplastic effects of bile acids, and whether these bile acids, particularly cholic acid, represent potential biomarkers or viable therapeutic targets for advanced neoplasia in BE.

INTRODUCTION: Early neoplastic progression of Barrett's esophagus (BE) is often treated with endoscopic therapy. Although effective, some patients are refractory to therapy or recur after apparent eradication of the BE. The goal of this study was to determine whether genomic alterations within the treated BE may be associated with persistent or recurrent disease. METHODS: We performed DNA sequencing on pre-treatment esophageal samples from 45 patients who were successfully treated by endoscopic therapy and did not recur as well as pre-treatment and post-treatment samples from 40 patients who had persistent neoplasia and 21 patients who had recurrent neoplasia. The genomic alterations were compared between groups. RESULTS: The genomic landscape was similar between all groups. Patients with persistent disease were more likely to have pre-treatment alterations involving the receptor tyrosine kinase pathway ( P = 0.01), amplifications of oncogenes ( P = 0.01), and deletions of tumor suppressor genes ( P = 0.02). These associations were no longer significant after adjusting for patient age and BE length. More than half of patients with persistent (52.5%) or recurrent (57.2%) disease showed pre-treatment and post-treatment samples that shared at least 50% of their driver mutations. DISCUSSION: Pre-treatment samples were genomically similar between those who responded to endoscopic therapy and those who had persistent or recurrent disease, suggesting there is not a strong genomic component to treatment response. Although it was expected to find shared driver mutations in pre-treatment and post-treatment samples in patients with persistent disease, the finding that an equal number of patients with recurrent disease also showed this relation suggests that many recurrences represent undetected minimal residual disease.

Abstract Background Upadacitinib (UPA) is an oral Janus kinase inhibitor approved for the treatment of moderately to severely active Crohn’s disease (CD).1 The U-ENDURE (NCT03345823) maintenance study and long-term extension (LTE) evaluate the long-term efficacy and safety of UPA maintenance therapy. Here, we report the results of the U-ENDURE LTE. Methods Patients (pts) completing the U-ENDURE 52-week (wk) maintenance study were eligible to participate in the LTE and continue their previously assigned treatment (placebo [PBO], UPA 15 mg [UPA15] once daily [QD], or UPA 30 mg [UPA30] QD; blinded until the last pt completed maintenance wk52). Clinical response, clinical remission, endoscopic response, endoscopic remission, as well as high-sensitivity C-reactive protein (hs-CRP) and faecal calprotectin (FCP) were evaluated as-observed up to wk48 of the LTE among pts (PBO [N = 89], UPA15 [N = 107], UPA30 [N = 173]); excluding pts who received open-label UPA30 rescue therapy. Safety was assessed in all pts (PBO [N = 223], UPA15 [N = 221], UPA30 [N = 229]) from wk0 of the maintenance study up to LTE wk204 (cut-off date: 01 Aug 2023). Results At LTE wk0, the SF/APS clinical remission rates were 73.0%, 78.3%, and 80.3% for PBO, UPA15, and UPA30, respectively (Figure 1A). Similar rates were reported at LTE wk0 for CDAI clinical remission (PBO 75.3%, UPA15 81.3%, UPA30 80.9%; Figure 1B) and clinical response (CR-100: PBO 79.5%, UPA15 84.9%, UPA30 84.4%). Rates of clinical remission were stable through wk48 of the LTE. Endoscopic response (PBO 32.9%, UPA15 59.6%, UPA30 66.5%) and remission rates (PBO 27.8%, UPA15 42.4%, UPA30 47.3%) at LTE wk0 were sustained through wk48 with UPA while decreased with PBO (Figure 1C-D). At LTE wk0, the mean [95% CI] change from induction BL in hs-CRP was 1.8 [–0.4, 4.1], –13.2 [–17.9, –8.6], and –12.8 [–16.8, –8.9] for PBO, UPA15, and UPA30, respectively; sustained through wk48. Similar results were observed with FCP (mean [95% CI] change from induction BL: PBO 126 [–103, 356], UPA15 –2946 [–4121, –1772], UPA30 –1871 [–2577, –1165]). Severe adverse events (AEs) and serious AEs were lower with UPA treatment compared with PBO (Table 1). The rates of most AEs of special interest were similar between UPA and PBO; however, numerically higher rates of herpes zoster, adjudicated gastrointestinal perforations, neutropenia, lymphopenia, creatine phosphokinase elevation, and hepatic disorders were reported in pts treated with UPA vs PBO (Table 1). Conclusion In pts completing wk48 of the LTE, sustained efficacy was observed in clinical and endoscopic endpoints with over 2 years of UPA treatment, while maintaining an overall positive safety profile in pts with CD. Reference: 1. Loftus EV Jr, et al. N Engl J Med. 2023;388:1966–80