Citations

Abstract Rationale It is unknown whether air pollution is associated with radiographic features of interstitial lung disease in individuals with chronic obstructive pulmonary disease (COPD). Objectives To determine whether air pollution increases the prevalence of interstitial lung abnormalities (ILA) or percent high-attenuation areas (HAA) on computed tomography (CT) in individuals with a heavy smoking history and COPD. Methods We performed a cross-sectional study of SPIROMICS (Subpopulations and Intermediate Outcome Measures in COPD Study), focused on current or former smokers with COPD. Ten-year exposure to particulate matter ⩽2.5 μm in aerodynamic diameter (PM2.5), nitrogen oxides (NOx), nitrogen dioxide (NO2), and ozone before enrollment CT (completed between 2010 and 2015) were estimated with validated spatiotemporal models at residential addresses. We applied adjusted multivariable modified Poisson regression and linear regression to investigate associations between pollution exposure and relative risk (RR) of ILA or increased percent HAA (between −600 and −250 Hounsfield units), respectively. We assessed for effect modification by MUC5B-promoter polymorphism (variant allele carriers GT or TT vs. GG at rs3705950), smoking status, sex, and percent emphysema. Results Among 1,272 participants with COPD assessed for HAA, 424 were current smokers, and 249 were carriers of the variant MUC5B allele. A total of 519 participants were assessed for ILA. We found no association between pollution exposure and ILA or HAA. Associations between pollutant exposures and risk of ILA were modified by the presence of MUC5B polymorphism (P value interaction term for NOx = 0.04 and PM2.5 = 0.05) and smoking status (P value interaction term for NOx = 0.05; NO2 = 0.01; and ozone = 0.05). With higher exposure to NOx and PM2.5, MUC5B variant carriers had an increased risk of ILA (RR per 26 ppb NOx, 2.41; 95% confidence interval [CI], 0.97–6.0; and RR per 4 μg ⋅ m−3 PM2.5, 1.43; 95% CI, 0.93–2.2, respectively). With higher exposure to NO2, former smokers had an increased risk of ILA (RR per 10 ppb, 1.64; 95% CI, 1.0–2.7). Conclusions Exposure to ambient air pollution was not associated with interstitial features on CT in this population of heavy smokers with COPD. MUC5B modified the association between pollution and ILA, suggesting that gene–environment interactions may influence prevalence of interstitial lung features in COPD.

BACKGROUND AND OBJECTIVES: First pass effect (FPE) is a metric increasingly used to determine the success of mechanical thrombectomy (MT) procedures. However, few studies have investigated whether the duration of the procedure can modify the clinical benefit of FPE. We sought to determine whether FPE after MT for anterior circulation large vessel occlusion acute ischemic stroke is modified by procedural time (PT). METHODS: A multicenter, international data set was retrospectively analyzed for anterior circulation large vessel occlusion acute ischemic stroke treated by MT who achieved excellent reperfusion (thrombolysis in cerebral infarction 2c/3). The primary outcome was good functional outcome defined by 90-day modified Rankin scale scores of 0–2. The primary study exposure was first pass success (FPS, 1 pass vs ≥2 passes) and the secondary exposure was PT. We fit-adjusted logistic regression models and used marginal effects to assess the interaction between PT (≤30 vs >30 minutes) and FPS, adjusting for potential confounders including time from stroke presentation. RESULTS: A total of 1310 patients had excellent reperfusion. These patients were divided into 2 cohorts based on PT: ≤30 minutes (777 patients, 59.3%) and >30 minutes (533 patients, 40.7%). Good functional outcome was observed in 658 patients (50.2%). The interaction term between FPS and PT was significant ( P = .018). Individuals with FPS in ≤30 minutes had 11.5% higher adjusted predicted probability of good outcome compared with those who required ≥2 passes (58.2% vs 46.7%, P = .001). However, there was no significant difference in the adjusted predicted probability of good outcome in individuals with PT >30 minutes. This relationship appeared identical in models with PT treated as a continuous variable. CONCLUSION: FPE is modified by PT, with the added clinical benefit lost in longer procedures greater than 30 minutes. A comprehensive metric for MT procedures, namely, FPE 30 , may better represent the ideal of fast, complete reperfusion with a single pass of a thrombectomy device.

Abstract Metastatic castration-resistant prostate cancer (mCRPC) is an aggressive malignancy with poor outcomes. To investigate novel therapeutic strategies, we characterized three new metastatic prostate cancer patient derived-tumor xenograft (PDTX) models and developed 3D spheroids from each to investigate molecular targeted therapy combinations including CDK4/6 inhibitors (CDK4/6i) with AKT inhibitors (ATKi). Metastatic prostate cancer tissue was collected and three PDTX models were established and characterized using whole-exome sequencing. PDTX 3D spheroids were developed from these three PDTXs to show resistance patterns and test novel molecular-targeted therapies. CDK4/6i's were combined with AKTi's to assess synergistic antitumor response to prove our hypothesis that blockade of AKT overcomes drug resistance to CDK4/6i. This combination was evaluated in PDTX three-dimensional (3D) spheroids and in vivo experiments with responses measured by tumor volumes, PSA, and Ga-68 PSMA-11 PET-CT imaging. We demonstrated CDK4/6i's with AKTi's possess synergistic antitumor activity in three mCRPC PDTX models. These models have multiple unique pathogenic and deleterious genomic alterations with resistance to single-agent CDK4/6i's. Despite this, combination therapy with AKTi's was able to overcome resistance mechanisms. The IHC and Western blot analysis confirmed on target effects, whereas tumor volume, serum PSA ELISA, and radionuclide imaging demonstrated response to therapy with statistically significant SUV differences seen with Ga-68 PSMA-11 PET-CT. These preclinical data demonstrating antitumor synergy by overcoming single-agent CDK 4/6i as well as AKTi drug resistance provide the rational for a clinical trial combining a CDK4/6i with an AKTi in patients with mCRPC whose tumor expresses wild-type retinoblastoma 1.

Abstract The Infectious Diseases Society of America Training Program Directors Committee met in October 2022 and discussed an observed increase in clinical volume and acuity on infectious diseases (ID) services, and its impact on fellow education. Committee members sought to develop specific goals and strategies related to improving training program culture, preserving quality education on inpatient consult services and in the clinic, and negotiating change at the annual IDWeek Training Program Director meeting. This paper outlines a presentation of ideas brought forth at the meeting and is meant to serve as a reference document for infectious diseases training program directors seeking guidance in this area.

PURPOSE Oncology advanced practice providers (APPs), including nurse practitioners, clinical nurse specialists, physician assistants, and clinical pharmacists, contribute significantly to quality cancer care. Understanding the research-related roles of APPs in the National Cancer Institute's (NCI) Community Oncology Research Program (NCORP) could lead to enhanced protocol development, trial conduct, and accrual. METHODS The 2022 NCORP Landscape Assessment Survey asked two questions about the utilization and roles of APPs in the NCORP. RESULTS A total of 271 practice groups completed the 2022 survey, with a response rate of 90%. Of the 259 nonpediatric exclusive practice groups analyzed in this study, 92% used APPs for clinical care activities and 73% used APPs for research activities. APPs most often provided clinical care for patients enrolled in trials (97%), followed by assistance with coordination (65%), presenting/explaining clinical trials (59%), screening patients (49%), ordering investigational drugs (37%), and consenting participants (24%). Some groups reported APPs as an enrolling investigator (18%) and/or participating in institutional oversight/selection of trials (15%). Only 5% of NCORP sites reported APPs as a site primary investigator for trials, and very few (3%) reported APPs participating in protocol development. CONCLUSION Practice groups report involving APPs in clinical research within the NCORP network; however, opportunities for growth exists. As team-based care has enhanced clinical practice in oncology, this same approach can be used to enhance successful research. Suggested strategies include supporting APP research-related time, recognition, and education. The findings of this survey and subsequent recommendations may be applied to all adult oncology practices that participate in clinical research.

Background Socioeconomic status (SES) is associated with cardiovascular health (CVH). Potential differences by sex in this association remain incompletely understood in Black Americans, where SES disparities are posited to be partially responsible for cardiovascular inequities. The association of SES measures (income, education, occupation, and insurance) with CVH scores was examined in the Jackson Heart Study. Methods and Results American Heart Association CVH components (non–high‐density‐lipoprotein cholesterol, blood pressure, diet, tobacco use, physical activity, sleep, glycemia, and body mass index) were scored cross‐sectionally at baseline (scale: 0–100). Differences in CVH and 95% CIs (Estimate, 95% CI) were calculated using linear regression, adjusting for age, sex, and discrimination. Heterogeneity by sex was assessed. Participants had a mean age of 54.8 years (SD 12.6 years), and 65% were women. Lower income, education, occupation (non‐management/professional versus management/professional occupations), and insurance status (uninsured, Medicaid, Veterans Affairs, or Medicare versus private insurance) were associated with lower CVH scores (all P <0.01). There was heterogeneity by sex, with greater magnitude of associations of SES measures with CVH in women versus men. The lowest education level (<high school) versus highest (>high school) was associated with 8.8‐point lower (95% CI: −10.2 to −7.3) and 5.4‐point lower (95% CI: −7.2 to −3.6) CVH scores in women and men, respectively (interaction P =0.003). The lowest (<25 000) versus highest level of income (≥$75 000) was associated with a greater reduction in CVH scores in women than men (interaction P =0.1142). Conclusions Among Black Americans, measures of SES were associated with CVH, with a greater magnitude in women compared with men for education and income. Interventions aimed to address CVH through SES should consider the role of sex.

BACKGROUND: Patients with heart failure (HF) with preserved ejection fraction (HFpEF) and obesity experience a high burden of symptoms and functional impairment, and a poor quality of life. In the STEP-HFpEF trial (Research Study to Investigate How Well Semaglutide Works in People Living With Heart Failure and Obesity), once-weekly semaglutide 2.4 mg improved symptoms, physical limitations, and exercise function, and reduced inflammation and body weight. This prespecified analysis investigated the effects of semaglutide on the primary and confirmatory secondary end points across the range of the Kansas City Cardiomyopathy Questionnaire (KCCQ) scores at baseline and on all key summary and individual KCCQ domains. METHODS: STEP-HFpEF randomly assigned 529 participants with symptomatic HF, an ejection fraction of ≥45%, and a body mass index of ≥30 kg/m 2 to once-weekly semaglutide 2.4 mg or placebo for 52 weeks. Dual primary end points change in KCCQ-Clinical Summary Score (CSS) and body weight. Confirmatory secondary end points included change in 6-minute walk distance, a hierarchical composite end point (death, HF events, and change in KCCQ-CSS and 6-minute walk distance) and change in C-reactive protein. Patients were stratified by KCCQ-CSS tertiles at baseline. Semaglutide effects on the primary, confirmatory secondary, and select exploratory end points (N-terminal pro-brain natriuretic peptide) were examined across these subgroups. Semaglutide effects on additional KCCQ domains (Total Symptom Score [including symptom burden and frequency], Physical Limitations Score, Social Limitations Score, Quality of Life Score, and Overall Summary Score) were also evaluated. RESULTS: Baseline median KCCQ-CSS across tertiles was 37, 59, and 77 points, respectively. Semaglutide consistently improved primary end points across KCCQ tertiles 1 to 3 (estimated treatment differences [95% CI]: for KCCQ-CSS, 10.7 [5.4 to 16.1], 8.1 [2.7 to 13.4], and 4.6 [–0.6 to 9.9] points; for body weight, –11 [–13.2 to –8.8], –9.4 [–11.5 to –7.2], and –11.8 [–14.0 to –9.6], respectively; P interaction =0.28 and 0.29, respectively); the same was observed for confirmatory secondary and exploratory end points ( P interaction >0.1 for all). Semaglutide-treated patients experienced improvements in all key KCCQ domains (estimated treatment differences, 6.7–9.6 points across domains; P ≤0.001 for all). Greater proportion of semaglutide-treated versus placebo-treated patients experienced at least 5-, 10-, 15-, and 20-point improvements in all KCCQ domains (odds ratios, 1.6–2.9 across domains; P <0.05 for all). CONCLUSIONS: In patients with HFpEF and obesity, semaglutide produced large improvements in HF-related symptoms, physical limitations, exercise function, inflammation, body weight, and N-terminal pro-brain natriuretic peptide, regardless of baseline health status. The benefits of semaglutide extended to all key KCCQ domains. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT04788511.