Faculty Bibliography

BACKGROUND/UNASSIGNED:Coronary heart disease (CHD) is the leading cause of morbidity and mortality worldwide, yet current prediction tools do not fully capture sex differences in risk. Menopause further modifies women's risk of CHD, but underlying molecular mechanisms are not well understood. Proteomic profiling may provide new insights into these mechanisms. METHODS/UNASSIGNED:We analyzed 4,877 SomaScan™-based plasma proteins in 10,034 Atherosclerosis Risk in Communities (ARIC) participants. Using linear regression, we identified sex- and menopause-related differences in circulating protein concentrations. We performed pathway enrichment analyses to capture underlying biological mechanisms. To evaluate the associations between proteins and incident CHD and differences by sex or menopause status, we applied Cox regression. Finally, we used LASSO regression to identify proteins that improve CHD risk prediction beyond an established clinical model. RESULTS/UNASSIGNED:We observed significant differences in circulating proteins by sex and menopausal status, including early changes during the menopausal transition. We found protein associations with incident CHD differed markedly by sex and menopausal stage: eight proteins were associated with CHD in men, compared with 54 in women, and six and 17 proteins in peri‑ and postmenopausal women, respectively. In risk prediction analyses, adding sex-specific protein panels improved CHD prediction (ΔC-statistic=0.05 in men and 0.03 in women), with similar improvement across menopausal stages. CONCLUSIONS/UNASSIGNED:Proteomic profiles underlying CHD risk differ substantially by sex and menopausal stage. These findings suggest potential biological heterogeneity in CHD and support the study of sex- and menopause-related differences in underlying mechanisms.

BACKGROUND/UNASSIGNED:Long COVID (LC) is widespread; however, limited information has been reported on the likelihood that symptoms remit over time. OBJECTIVE/UNASSIGNED:To evaluate the likelihood of improvement among persons with likely LC. DESIGN/UNASSIGNED:Prospective, multisite cohort study (RECOVER-Adult [Researching COVID to Enhance Recovery]). SETTING/UNASSIGNED:83 U.S.-based sites across 33 states; Washington, DC; and Puerto Rico. PARTICIPANTS/UNASSIGNED:1019 persons in RECOVER-Adult with likely LC (LC Research Index [LCRI] ≥11) 12 months after first SARS-CoV-2 infection. MEASUREMENTS/UNASSIGNED:The primary outcome was time until 2 consecutive study visits with LCRI less than 11. Secondary outcomes were time until LCRI measure reduced 50% or more and quality of life was good or better, and LCRI decreased to 0. Unadjusted estimates of cumulative incidence and adjusted marginal cumulative incidence by age, sex, SARS-CoV-2 wave, and LC subtype were reported across all follow-up time points. RESULTS/UNASSIGNED:An estimated 36.2% (95% CI, 33.0% to 39.5%) met the primary outcome by 24 months after infection, and 50.1% (CI, 46.1% to 54.0%) met the primary outcome by 36 months. An estimated 56.4% (CI, 52.2% to 60.4%) and 26.9% (CI, 23.3% to 30.5%), respectively, met the 2 secondary outcomes by 36 months. Among persons who still reported likely LC at 18 months and 24 months after first infection, relative timing of subsequent symptom improvement was similar. LIMITATION/UNASSIGNED:Findings in this observational cohort are interpretable in a population with prevalent likely LC and do not address causal relationships between individual characteristics and symptom improvement. CONCLUSION/UNASSIGNED:Among persons with likely LC 12 months after initial SARS-CoV-2 infection, one half experience meaningful reductions in symptoms by 36 months, whereas a quarter experience complete remission of symptoms. These findings underscore both the potential for natural recovery and the urgent need for placebo-controlled therapeutic intervention trials. PRIMARY FUNDING SOURCE/UNASSIGNED:National Institutes of Health.

BACKGROUND:The food environment may influence neurodegeneration and mortality. This study examined associations of food deserts (FD) with brain health and survival using UK Biobank data. METHODS:). Cox, multistate survival, and mixed-effects models were used. Spatial clustering examined co-localization between FD and outcomes. Area-level FD was examined as the primary exposure, with FI evaluated mainly as a secondary effect modifier. RESULTS:decline. FI did not modify FD-ACM associations. CONCLUSIONS:Living in food deserts was linked to higher mortality and faster white matter decline, particularly among women. Findings highlight the role of area-level food environments in brain health and aging.

OBJECTIVES/OBJECTIVE:F]FES) positron emission tomography/computed tomography (PET/CT) in patients with estrogen receptor (ER)-positive breast cancer. MATERIALS AND METHODS/METHODS:F]FES PET/CT compared with conventional workup. Pooled proportions of management changes were calculated across the included studies, including subgroup and sensitivity analyses. RESULTS:F]FES PET/CT was beneficial in 39% (95% CI: 24-58%) by improving diagnostic certainty and supporting current treatment options. CONCLUSION/CONCLUSIONS:F]FES PET/CT impacted management in 38% of patients with ER-positive breast cancer. KEY POINTS/CONCLUSIONS:F]fluoroestradiol PET/CT had a substantial impact on the management of patients with ER-positive breast cancer.

PURPOSE OF REVIEW/OBJECTIVE:Elevated lipoprotein(a) [Lp(a)] is a common, causal risk factor for atherosclerotic cardiovascular disease (ASCVD). Clinicians continue to face questions regarding how overall risk should be refined once Lp(a) is identified. RECENT FINDINGS/RESULTS:International guidelines are beginning to universally recommend Lp(a) measurement at least once in adulthood, which will make the discovery of elevated Lp(a) a more common finding in routine practice. Despite this, Lp(a) remains absent from conventional risk equations. Additional stratification tools including assessment of subclinical atherosclerosis can be further applied to help distinguish inherited susceptibility from expressed disease. All of this together should support a more informed shared decision regarding the intensity of preventive therapy in these cases. We aim to provide a flexible framework that integrates Lp(a), contemporary risk equations, imaging, and selective genetics to produce actionable risk phenotypes which can guide the intensity of preventive decisions today.

Normotensive patients with pulmonary embolism (PE) experience highly variable outcomes. Despite advances in clinical prediction tools, echocardiography, and computed tomographic imaging, there is no universally agreed upon strategy to identify which normotensive patients with PE are at risk of decompensation. This article reviews the current state of evidence and recent advances in risk prediction tools, echocardiography, and imaging to predict clinical deterioration.

Pulmonary embolism is a life-threatening condition requiring prompt anticoagulation to prevent clot propagation and recurrence. Risk stratification guides therapy, with systemic thrombolysis reserved for high-risk patients and selected intermediate-high risk cases due to significant bleeding risk. Direct oral anticoagulants are preferred for most low and intermediate-low risk patients, while low-molecular-weight heparin and unfractionated heparin remain critical for higher- risk or procedurally complex cases. Emerging strategies including low-dose thrombolysis, catheter-directed therapies, and the future use of Factor XI inhibitors may improve safety without compromising efficacy. Management of bleeding complications necessitates rapid intervention, reversal when available, and coordinated multidisciplinary care.

BACKGROUND:Prior analyses of PALLAS (NCT02513394), a phase III trial that randomized patients with stage II-III hormone receptor-positive breast cancer to receive adjuvant palbociclib plus endocrine therapy (ET) or ET alone, did not show benefit of the combination. Separate data show extent of treatment-related neutropenia is associated with improved response to palbociclib and other cell cycle-specific therapies. We conducted an exploratory analysis to assess whether grade of treatment-related neutropenia could identify benefit from palbociclib in the adjuvant setting. METHODS:Patients receiving palbociclib were classified into those with treatment-emergent high-grade neutropenia (HGN) with maximum grade ≥3 (absolute neutrophil count <1000/mm3), or low-grade/no neutropenia (LGN) with maximum grade ≤2. These groups were compared to each other and to the ET-alone group for 5-year invasive disease-free survival (iDFS). RESULTS:5736 patients were included: 2840 in the palbociclib+ET arm and 2896 in the ET-alone arm. Patients receiving palbociclib+ET consisted of 1006 (35.4%) LGN and 1834 (64.6%) HGN. Lower body mass index (BMI), Asian race, prior chemotherapy, and mastectomy were associated with HGN (all p < 0.05). Patients receiving ET alone had inferior 5-year iDFS compared with patients who developed HGN by cycle 6 on palbociclib+ET (hazard ratio [HR] 1.19, 95% confidence interval [CI]:1.01-1.40; p = 0.04), an association that persisted after adjustment for prior chemotherapy, race, and BMI (HR 1.20, 95% CI:1.02-1.42; p = 0.03). CONCLUSION/CONCLUSIONS:In this exploratory analysis of the PALLAS trial, palbociclib+ET showed benefit over ET alone in patients who developed HGN in the first 6 treatment cycles. Neutropenia could be a useful biomarker for palbociclib efficacy. TRIAL REGISTRATION/BACKGROUND:clinicaltrials.gov, NCT02513394.

BACKGROUND:Magrolimab blocks CD47, a molecule that mediates cancer immune evasion from phagocytes. The ELEVATE TNBC study evaluated magrolimab plus standard-of-care therapies in advanced/metastatic triple-negative breast cancer (mTNBC). PATIENTS AND METHODS/METHODS:Two cohorts were enrolled in the safety run-in (SRI) and phase II portions. Phase II cohort 1 randomly assigned 28 patients with untreated, programmed death-ligand 1-negative mTNBC to receive nab-paclitaxel or paclitaxel with/without magrolimab. Phase II cohort 2 enrolled 43 patients with mTNBC (one to two prior lines of treatment in the metastatic setting) to receive magrolimab with sacituzumab govitecan. Primary endpoints were adverse event (AE) incidence (SRIs), investigator-assessed progression-free survival (PFS; phase II cohort 1), and objective response rate (ORR; phase II cohort 2). RESULTS:No dose-limiting toxicities occurred. In phase II cohort 1, median PFS was 13.9 and 10.0 months (hazard ratio 0.456, 95% confidence interval 0.147-1.409) and ORRs were 35.7% and 21.4% for magrolimab-taxane and taxane therapy, respectively. In phase II cohort 2, ORR was 38.1%, and median PFS was 5.5 months. Early study closure limited interpretation of efficacy; PFS/ORR values should be considered descriptive. AE rates were consistent with known profiles for each agent, with no new safety signals or fatal AEs. CONCLUSIONS:Magrolimab plus standard of care was manageable. Further studies are needed to determine the role of anti-CD47 therapies in mTNBC.

INTRODUCTION/BACKGROUND:Enrollment into clinical trials is challenging and has a major effect on the feasibility and the generalizability of a study. We used data from a previously completed hospital-based smoking cessation study to determine if enrollment rates varied by hospital admitting service, specifically comparing Medicine and Psychiatry departments. METHODS:We examined enrollment in the Financial Incentives for Smoking Cessation (FIESTA) study, which was conducted at the Veterans Affairs New York Harbor Healthcare System. FIESTA tested the effectiveness of financial incentives on smoking cessation among hospitalized patients. A total of 268 patients were eligible, with 182 enrolled in the original FIESTA study. In our secondary analysis, a LASSO approach was applied to the data set to create a model examining admitting service, age, sex, race and ethnicity, education, and number of cigarettes per day and their association with enrollment. RESULTS:The enrollment rates were higher for patients admitted to the Psychiatry service (80.2%) than to the Medicine and other services (59.9%). Patients with a high school education or less also had a higher enrollment rate (87.2%) than those with higher education (57.7%). Increasing age was associated with lower odds of enrollment (aOR = 0.97, 95% CI: 0.94, 0.99). Hispanic ethnicity appeared to associate with a higher odds of enrollment compared to non-Hispanic White (aOR = 2.52, 95% CI 1.11, 5.75). Higher odds of enrollment were observed among patients admitted to the Psychiatry service (aOR = 2.51, 95% CI: 1.23-5.12), while lower odds were observed among those with higher education (aOR = 0.17, 95% CI: 0.06-0.49). CONCLUSIONS:This research suggests that smoking cessation programs can effectively enroll a diverse patient population, including typically underrepresented groups such as those with lower education status and those with mental health diagnoses. Such enrollment efforts would enable studies to be more generalizable to the smoking population. Findings also emphasize the potential of urban hospital settings to support equitable enrollment efforts. The present work is a secondary analysis of the FIESTA RCT (NCT02506829). Future research should explore additional demographic factors, such as comorbidities and confidence in quitting, to better understand motivations for participation.