Faculty Bibliography

AIMS/OBJECTIVE:Treatment discontinuation is a common intercurrent event in randomized clinical trials (RCTs) that can bias treatment effect estimates, yet it remains under recognized and inconsistently addressed. Antithrombotic trials provide a relevant case, as bleeding-related discontinuation is common and more often occur in patients at increased risk also for ischaemic events. METHODS AND RESULTS/RESULTS:We reviewed large antithrombotic RCTs published in The New England Journal of Medicine (2020-2025) to assess reporting and analytic handling of treatment discontinuation. We also conducted simulations to examine how discontinuation patterns influence efficacy estimates under three scenarios: discontinuation only in the treatment arm, in both arms with similar patterns, and in both arms but outcome-associated only in the treatment arm. Treatment policy (intention-to-treat) and while-on-treatment strategies were compared within the ICH E9(R1) framework. Among fourteen reviewed antithrombotic RCTs, about one-third of patients discontinued treatment in trials with more than 6 months follow-up, with higher imbalance in open-label studies. Over half of discontinuations were safety-related, yet timing and temporary interruptions were rarely reported. Most reported both ITT and per-protocol (PP) analyses, with PP assuming non-informative censoring and yielding larger efficacy estimates. In simulations, treatment policy and while-on-treatment strategies were biased when discontinuation was outcome-associated, while Simon-Makuch curves helped identify prognostic discontinuation differing by treatment arm. CONCLUSION/CONCLUSIONS:Discontinuation is common, prognostically meaningful, and often oversimplified in analysis, threatening the validity of RCT findings. Explicitly addressing discontinuation as an intercurrent event within the estimand framework, along with stratified outcome curves, can improve interpretation and support more robust trial conclusions.

PURPOSE/UNASSIGNED:Vesicourethral anastomotic stenosis (VUAS) occurs after 1 to 3% of robotic-assisted radical prostatectomies (RARPs). Pelvic fascia-sparing techniques preserve more native anatomy and may reduce stenoses, but evidence is lacking. The aim of this study was to compare stenosis incidence, management, and outcomes after standard vs pelvic fascia-sparing RARP. MATERIALS AND METHODS/UNASSIGNED:We conducted a multi-institutional retrospective study of 910 standard, 409 Retzius-sparing, and 272 hood RARP during February 2012-September 2025. Standard and hood techniques used 18Fr urethral catheters, and the Retzius-sparing technique used 18Fr suprapubic catheters. The primary end point was cystoscopically confirmed VUAS requiring intervention within 12 months. Urinary continence was assessed using the validated Expanded Prostate Cancer Index Composite for Clinical Practice (EPIC-CP). Multivariable logistic regression assessed factors associated with VUAS. RESULTS/UNASSIGNED:= .046). CONCLUSIONS/UNASSIGNED:There were no VUAS after Retzius-sparing RARP, and Retzius-sparing vs standard approach was associated with lower odds of stenosis. Endoscopic management with structured self-catheterization achieved high success without worsening incontinence. Prospective studies are needed to validate our findings.

BACKGROUND/UNASSIGNED:Pyridostigmine bromide is a short-acting carbamate acetylcholinesterase inhibitor that has been shown to acutely augment parasympathetic signaling in cardiovascular disease populations. OBJECTIVE/UNASSIGNED:This study was undertaken to characterize pharmacodynamics, safety, and tolerability of pyridostigmine during repeated dosing in patients with heart failure. METHODS/UNASSIGNED:A prospective ascending-dose, forced titration, double-blind Phase II randomized clinical trial was conducted to compare the effects of pyridostigmine bromide (15, 30, and 60 mg TID over 8 weeks) versus matching placebo on red blood cell (RBC) acetylcholinesterase activity, cholinergic side effects, and physiologic measures of parasympathetic heart rate modulation and sympathovagal balance in ambulatory patients with chronic systolic heart failure. RESULTS/UNASSIGNED:< 0.001 vs placebo). Physiologic measures of parasympathetic heart rate modulation and sympathovagal balance did not differ between treatment groups. In the pyridostigmine bromide group, RBC acetylcholinesterase activity was not significantly associated with postexercise parasympathetic heart modulation. CONCLUSIONS/UNASSIGNED:Pyridostigmine bromide administered over 8 weeks was associated with a significant reduction of RBC acetylcholinesterase activity and relatively mild symptoms of cholinergic excess, but changes in parasympathetic signaling in the sinoatrial node previously reported after acute administration were not observed. Further investigations are needed to delineate pharmacodynamic and pathobiological factors contributing to these findings. ClinicalTrials.gov identifier: NCT01415921.

Plasmacytoid dendritic cells (pDCs) mount powerful antiviral type I interferon (IFN-I) responses, yet only a fraction of pDCs produces high levels of IFN-I. Here we report that peripheral pDCs in naive mice comprise three subsets (termed A, B and C) that represent progressive differentiation stages. This heterogeneity was generated by tonic IFN-I signaling elicited in part by the cGAS/STING and TLR9 DNA-sensing pathways. A small 'IFN-I-naive' subset (pDC-A) could give rise to other subsets; it was expanded in STING deficiency or after the IFN-I receptor blockade, but was abolished by exogenous IFN-I. In response to RNA viruses, pDC-A showed increased Bcl2-dependent survival and superior IFN-I responses, but was susceptible to virus infection. Conversely, the majority of pDCs comprised the 'IFN-I-primed' subsets (pDC-B/C) that showed lower IFN-I responses and poor survival, but did not support virus replication. Thus, tonic IFN-I signaling decreases the cytokine-producing capacity and survival of pDCs but increases their virus resistance, facilitating optimal antiviral responses.

BACKGROUND:Abdominal computed tomography (CT) is commonly performed in adults. Abdominal aortic calcification (AAC) can be visualized and quantified using artificial intelligence (AI) on CTs performed for other clinical purposes (opportunistic CT). We sought to investigate the value of AI-enabled AAC quantification as a predictor of coronary artery disease and its association with cardiovascular events. METHODS:A fully automated AI algorithm to quantify AAC from the diaphragm to aortic bifurcation using the Agatston score was retrospectively applied to a cohort of patient that underwent both non-contrast abdominal CT for routine clinical care and cardiac CT for coronary artery calcification (CAC) assessment. Subjects were followed for a median of 36 months for major adverse cardiovascular events (MACE, composite of death, myocardial infarction [MI], ischemic stroke, coronary revascularization) and major coronary events (MCE, MI or coronary revascularization). RESULTS:Our cohort included 3599 patients (median age 60 years, 62% male, 74% white) with an evaluable abdominal and cardiac CT. There was a positive correlation between presence and severity of AAC and CAC (r=0.56, P<0.001). AAC showed excellent discriminatory power for detecting or ruling out any CAC (AUC for PREVENT risk score 0.701 [0.683 to 0.718]; AUC for PREVENT plus AAC 0.782 [0.767 to 0.797]; P<0.001). There were 324 MACE, of which 246 were MCE. Following adjustment for the 10-year cardiovascular disease PREVENT score, the presence of AAC was associated with a significant risk of MACE (adjHR 2.26, 95% CI 1.67-3.07, P<0.001) and MCE (adjHR 2.58, 95% CI 1.80-3.71, P<0.001). A doubling of the AAC score resulted in an 11% increase in the risk of MACE and a 13% increase in the risk of MCE. CONCLUSIONS:Using opportunistic abdominal CTs, assessment of AAC using a fully automated AI algorithm, predicted CAC and was independently associated with cardiovascular events. These data support the use of opportunistic imaging for cardiovascular risk assessment. Future studies should investigate whether opportunistic imaging can help guide appropriate cardiovascular prevention strategies.

Although healthcare workers may be aware of the risks of physical inactivity, their levels of physical activity (PA) are similar to those of all US adults, with less than half engaging in sufficient PA. The purpose of this health promotion was to encourage daily PA among employees in a large academic healthcare system. We also tested whether individualized progress updates further influenced PA. This 10-week program was available to all employees of NYU Langone Health. Employees could sync their phone or accelerometer via app or web browser to count.it - the vendor chosen to monitor and manage step counts. Participants were asked to voluntarily provide basic information (age, sex, job role, work location) and complete the Physical Activity Vital Sign (minutes/week and intensity of PA) at enrollment and 10 weeks. For 10 weeks, participants were sent a message through their employee 'MyChart' portal with a link to information on the benefits of PA, and a reminder of that week's step-count challenge. Those meeting criteria for weekly challenges were included in gift card raffles. Participants were randomized 1:1 to receive the standard message ± additional emails detailing their progress. 3528 employees registered to participate (8% of all employees) although active users diminished over time (1225 at week 10). Average daily steps remained stable throughout (7319 + 4540 in week 1, 7229 + 5010 in week 10). Although there was no difference in any individual week, receipt of personalized feedback was associated with significantly higher average step counts throughout the 10-wk intervention as a whole (P = 0.01). Age and an urban work location were positively associated with steps, while female sex and a clerical job role were negatively associated with steps counts (all P < 0.005). Our findings provide important insight for workplace interventions to promote PA. They further suggest specific groups that may benefit from targeted efforts.

BACKGROUND/UNASSIGNED:Elevated perceived stress is associated with adverse outcomes following myocardial infarction (MI) and may account for poorer recovery among women vs men. OBJECTIVES/UNASSIGNED:This randomized controlled trial tested effects of a mindfulness-based intervention on stress levels among women with MI. METHODS/UNASSIGNED:Women with elevated stress (Perceived Stress Scale [PSS-4]≥6) at least 2 months after MI were enrolled from 12 hospitals in the United States and Canada and via community advertising. Participants were randomized to a remotely delivered mindfulness intervention (MBCT-Brief) or heart disease education, both 8 weeks long. Follow-up was 6 months. Changes in stress (PSS-10; primary outcome) and secondary outcomes (depressive symptoms, anxiety, quality of life, disease-specific health status, actigraphy-assessed sleep) were compared between groups. RESULTS/UNASSIGNED: = 0.036). CONCLUSIONS/UNASSIGNED:MBCT-Brief was associated with greater 6-month reductions in stress than an active control among adherent participants. More frequent mindfulness practice was associated with greater improvements in psychological outcomes. Strategies to engage women with MI in mindfulness training and support regular home practice may enhance these effects.

BACKGROUND:Lipoprotein(a) [Lp(a)] is a driver of residual cardiovascular risk. Proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) decrease Lp(a) with significant heterogeneity in response. We investigated contributors to the heterogeneous response. METHODS:CHOlesterol Reduction and Residual Risk in Diabetes (CHORD) was a prospective study examining lipid lowering in participants with a low-density lipoprotein cholesterol (LDL-C) >100 mg/dL with and without diabetes (DM) on lipid lowering therapy (LLT) for 30-days with evolocumab 140 mg every 14 days combined with either atorvastatin 80 mg or ezetimibe 10 mg daily. Lp(a) level was measured by immunoturbidometry, and the apolipoprotein (a) [apo(a)] isoform size was measured by denaturing agarose gel electrophoresis and western blotting. We examined the change in Lp(a) levels from baseline to 30 days. RESULTS:Among 150 participants (mean age 50 years, 58% female, 50% non-White, 17% Hispanic, 50% DM), median (interquartile range) Lp(a) was 27.5 (8-75) mg/dL at baseline and 23 (3-68) mg/dL at 30 days, leading to a 10% (0-36) median reduction (P < 0.001). Among 73 (49%) participants with Lp(a) ≥30 mg/dL at baseline, there was a 15% (3-25) median reduction in Lp(a) (P < 0.001). While baseline Lp(a) level was not correlated with change in Lp(a) (r = 0.04, P = 0.59), apo(a) size directly correlated with Lp(a) reduction (P < 0.001). After adjustment for age, sex, race/ethnicity, DM, and type of LLT, apo(a) size remained positively associated with a reduction in Lp(a) (Beta 0.95, 95% confidence interval, 0.93-0.97, P < 0.001). CONCLUSION/CONCLUSIONS:Our data demonstrate variation in Lp(a) reduction with potent LLT. Change in Lp(a) was strongly associated with apo(a) isoform size.

OBJECTIVES/OBJECTIVE:To describe the implementation of a workplace health promotion to address low levels of physical activity (PA). METHODS:Using the Exploration, Preparation, Implementation, Sustainment (EPIS) framework we implemented and evaluated a 10-week workplace step-count challenge to promote PA. All health system employees invited to participate. Data were collected on the exploration, preparation and implementation phases. RESULTS:During exploration, we recognized inadequate PA among employees. Meetings with key personnel were held to determine details of the health promotion and obtain support. We pursued a step-count PA intervention, capitalizing on employee ownership of smartphones with accelerometers. Vendors to host the intervention were evaluated. All employees were invited to participate. Participants received weekly messages about improving PA and notifications of weekly challenges. Exit interviews provided feedback and suggestions. CONCLUSION/CONCLUSIONS:A workplace health promotion focused on employee PA is feasible using EPIS.

OBJECTIVES/OBJECTIVE:We introduce a widely applicable model-based approach for estimating individual-level Social Determinants of Health (SDoH) and evaluate its effectiveness using the All of Us Research Program. MATERIALS AND METHODS/METHODS:Our approach utilizes aggregated SDoH datasets to estimate individual-level SDoH, demonstrated with examples of no high school diploma (NOHSDP) and no health insurance (UNINSUR) variables. Models are estimated using American Community Survey data and applied to derive individual-level estimates for All of Us participants. We assess concordance between model-based SDoH estimates and self-reported SDoHs in All of Us and examine associations with undiagnosed hypertension and diabetes. RESULTS:Compared to self-reported SDoHs, the area under the curve for NOHSDP is 0.727 (95% CI, 0.724-0.730) and for UNINSUR is 0.730 (95% CI, 0.727-0.733) among the 329 074 All of Us participants, both significantly higher than aggregated SDoHs. The association between model-based NOHSDP and undiagnosed hypertension is concordant with those estimated using self-reported NOHSDP, with a correlation coefficient of 0.649. Similarly, the association between model-based NOHSDP and undiagnosed diabetes is concordant with those estimated using self-reported NOHSDP, with a correlation coefficient of 0.900. DISCUSSION AND CONCLUSION/CONCLUSIONS:The model-based SDoH estimation method offers a scalable and easily standardized approach for estimating individual-level SDoHs. Using the All of Us dataset, we demonstrate reasonable concordance between model-based SDoH estimates and self-reported SDoHs, along with consistent associations with health outcomes. Our findings also underscore the critical role of geographic contexts in SDoH estimation and in evaluating the association between SDoHs and health outcomes.