Faculty Bibliography

PURPOSE/OBJECTIVE:Mobile health cardiac rehabilitation may improve access to care among older adults with ischemic heart disease, but engagement remains poorly understood. We analyzed weekly engagement data from the RESILIENT (Rehabilitation Using Mobile Health for Older Adults with Ischemic Heart Disease in the Home Setting) trial, a large, randomized trial of mobile health cardiac rehabilitation in older adults conducted in the United States. METHODS:Data from 298 intervention participants were analyzed. Weekly engagement was scored from 0 to 11 based on exercise entry (7 points), communication with exercise therapist (2 points), video viewing (1 point), and blood pressure measurement (1 point). Latent class analysis identified digital engagement phenotypes. Participant characteristics were compared, and multivariable logistic regression identified factors associated with phenotype membership. RESULTS:Median age was 71.0 years, 28% were women, 23% were non-White, and 62% were enrolled after elective percutaneous coronary intervention. Latent class analysis identified 3 phenotypes: persistently low (n = 81), intermediate declining (n = 93), and persistently high (n = 124). Participants with persistently low engagement were more likely to be non-White (48% vs 12% vs 15%, P < .001), Medicaid enrolled (22% vs 8% vs 7%, P = .001), have less than high school education (16% vs 4% vs 3%, P < .001), have frailty phenotype (28% vs 10% vs 7%, P < .001), and have a greater mean number of comorbidities (3.1 vs 3.0 vs 2.6; P = .012). After adjustment, non-White race and frailty remained independently associated with low engagement. Improvement in 6-minute walk test distance varied: 20.8 m (low), 29.7 m (intermediate), and 54.5 m (high) (P = .003). CONCLUSIONS:Three distinct digital engagement phenotypes emerged. Persistently low engagement was more common among non-White and frail participants, underscoring ongoing disparities despite efforts to overcome the digital divide.

PURPOSE/OBJECTIVE:Obesity is increasingly encountered among patients requiring extracorporeal membrane oxygenation (ECMO) for severe respiratory or cardiac failure. It alters respiratory and cardiovascular physiology and drug pharmacokinetics and introduces technical and logistical challenges that may complicate patient selection, ECMO initiation, cannulation, anticoagulation, and monitoring. This review summarizes current evidence regarding the epidemiology, physiological implications, outcomes, and management of obesity in patients supported with veno-venous (VV) or veno-arterial (VA) ECMO. RESULTS:Available evidence, largely retrospective and based on body mass index classifications, suggests that obesity should not be considered a contraindication to VV-ECMO, with outcomes comparable to or potentially better than those of patients without obesity. However, obesity-related respiratory mechanics may exaggerate the apparent severity of lung injury, emphasizing the need for optimized conventional ARDS management, including appropriate ventilatory strategies and prone positioning, before ECMO initiation. In contrast, outcomes during VA-ECMO are more heterogeneous, particularly in extracorporeal cardiopulmonary resuscitation (ECPR), and may be influenced by patient selection, comorbidities, and timing of support. Obesity also creates important technical challenges requiring individualized cannulation, anticoagulation, and perfusion strategies. CONCLUSION/CONCLUSIONS:Obesity alone should not preclude access to ECMO, particularly VV-ECMO. Successful management requires anticipation of obesity-related challenges, appropriate infrastructure, and structured multidisciplinary protocols. Further prospective studies are needed to clarify obesity-specific risks, optimize management strategies, and evaluate long-term outcomes.

From 2014 to 2025, accelerated 3-year MD programs (A3YP) have expanded significantly, such that 20% of allopathic medical schools offer a program to earn the MD degree in three years. While maintaining rigorous and comparable educational standards as traditional 4-year programs, A3YPs aim to address physician workforce shortages, reduce student debt, and provide individualized education pathways into specific specialties. Among the thirty-two A3YPs in existence, twenty-two medical schools have graduated 1141 students to date, with numbers increasing annually. Nineteen programs are linked to a residency program, though six of these programs consistently match students outside their linked program. As more medical schools implement A3YPs and an increasing number of graduates enter the National Residency Matching Program (NRMP), residency program directors will encounter A3YP applicants more frequently. The proliferation of A3YPs presents both challenges and opportunities for residency program directors in evaluating applicants. Despite the differences in their applications, including limited extracurricular activities and time for visiting rotations, these applicants have been found to perform similarly in standardized testing and residency milestones, and have similar well-being and satisfaction as traditional students. This perspective outlines key considerations for PDs and provides a foundation for contextually evaluating the increasing numbers of these applicants graduating from A3YPs.

BACKGROUND/UNASSIGNED:Cardiac stress testing is a cornerstone of risk stratification and management in patients with chronic coronary disease, yet the consistency and accuracy of its interpretation remain poorly defined. This analysis evaluated variation in the interpretation of myocardial ischemia between enrollment sites and core laboratories in the ISCHEMIA trial (International Study of Comparative Health Effectiveness With Medical and Invasive Approaches). METHODS/UNASSIGNED:ISCHEMIA was a global (37 countries, 2012-2018) randomized trial of an initial invasive versus conservative strategy in patients with chronic coronary disease and moderate or severe ischemia. This analysis included participants with site-interpreted qualifying stress tests-nuclear, echocardiography (echo), cardiac magnetic resonance, or exercise tolerance test-and independent core laboratory adjudication. Core laboratories, serving as the reference standard, reinterpreted tests blinded to site results. A trinary outcome variable (site underestimation, concordance, or overestimation) was defined by comparing site-determined ischemia levels to standardized core lab assessments. Adjusted mixed-effects logistic regression models with random site intercepts assessed variability. RESULTS/UNASSIGNED:Among 6971 participants (mean age, 62.8 years; 73% men), site interpretations showed 0% no/mild (by design), 43% moderate, and 57% severe ischemia. Core labs reclassified these as 8% none, 11% mild, 30% moderate, and 51% severe ischemia. For the imaging modalities, median site-core lab agreement rates were ≈55%; nearly 25% of site-classified moderate/severe cases were downgraded to no or mild ischemia by core labs. Adjusted median odds ratios for site overestimation were 2.36 (95% CI, 2.02-2.82; nuclear), 1.98 (95% CI, 1.62-2.60; echo), 1.89 (95% CI, 1.0-5.41; cardiac magnetic resonance), and 2.15 (95% CI, 1.76-2.79; exercise tolerance test). Adjusted median odds ratios for underestimation ranged from 1.25 to 1.77. CONCLUSIONS/UNASSIGNED:In ISCHEMIA, enrollment sites frequently overestimated or underestimated the severity of myocardial ischemia compared with core laboratory assessments, highlighting the need for strategies to improve the consistency and accuracy of stress testing interpretation in patients with chronic coronary disease. REGISTRATION/UNASSIGNED:URL: https://www.clinicaltrials.gov; Unique identifier: NCT01471522.

BACKGROUND:Patients with diabetes frequently have multivessel disease and are at increased risk of adverse outcomes. The outcomes with a new-generation ultra-thin strut sirolimus-eluting stent (SES) vs everolimus-eluting stent (EES) is unclear as stent-to-stent comparison trials have routinely excluded these patients or included a small proportion of such patients. OBJECTIVES/OBJECTIVE:The purpose of this study was to compare the clinical outcomes of ultra-thin biodegradable polymer (BP) SES vs durable polymer (DP) EES when combined with contemporary optimal medical therapy in patients with diabetes and multivessel disease. METHODS:The TUXEDO-2 is an investigator-initiated prospective, open-label, multicenter, 2 × 2 factorial, randomized (1:1) controlled trial. Patients undergoing percutaneous coronary intervention were randomized to receive either a Supraflex Cruz SES or Xience EES. The participants were also randomized to Ticagrelor or Prasugrel. The primary endpoint was target lesion failure, a composite of cardiac death, target vessel myocardial infarction or ischemia-driven target lesion revascularization at 1-year follow up. The trial was designed to test noninferiority of BP-SES vs DP-EES, with a noninferiority margin of 4.5% (1-sided upper 97.5% confidence bound). RESULTS:= 0.005). There were no significant differences in cardiac death (3.6% vs 3.4%), target vessel myocardial infarction (6.61% vs 7.54%), and ischemia-driven target lesion revascularization (0.8% vs 1.0%) between the 2 groups. Nonfatal myocardial infarction (4.7% vs 6.4%) and stent thrombosis was similar (1.0 % vs 0.7%) between the 2 groups. CONCLUSIONS:In patients with diabetes and multivessel disease undergoing percutaneous coronary intervention, ultra-thin biodegradable polymer SES was noninferior to durable polymer EES at 1 year follow-up. (Trial Registration Number CTRI/2019/11/022088).

BACKGROUND AND OBJECTIVES/OBJECTIVE:Compartmentalized CNS inflammation involving B cells is implicated in gray matter injury and disease progression in multiple sclerosis (MS). Products secreted by B cells of patients with MS can kill oligodendrocytes and neurons, a cytotoxicity conferred by their exosome-enriched extracellular vesicle (Ex En) fraction. METHODS:To explore the potential molecular mediators of this cytotoxicity, we profiled proteomic and transcriptomic cargo of Ex En isolated from B cells of patients with treatment-naive MS and matched healthy controls. RESULTS:MS B-cell-derived Ex En appeared enriched in cell-death-associated proteins (including fibrinogen, complement C9, APP, and SPARC) and deficient in cell-survival-associated proteins (such as galectin-3). Abnormal enrichment for cell-death proteins was supported by gene set enrichment analysis. Protein pathway analysis revealed densely connected prodeath modules in the MS B-cell-derived Ex En, contrasting with homeostatic signatures in controls. Transcriptomic analysis further revealed that Ex En of MS B cells appeared to carry reduced levels of miRNAs (miR-182, miR-212, and miR-1270) known to inhibit apoptosis. DISCUSSION/CONCLUSIONS:Our findings indicate that B-cell-derived Ex En of patients with MS, previously shown to impair neuronal and glial survival, harbor an abnormal cytotoxic molecular profile that may contribute to CNS-compartmentalized injury and progressive MS biology.

The September 11, 2001, terrorist attacks on the World Trade Center (9/11) exposed both disaster responders and community members to a complex mixture of environmental contaminants, resulting in long-term health consequences. While clinical and research efforts have characterized health effects among adult survivors (community members) and responders, less is known about individuals who were exposed in utero, during childhood, adolescence, or young adulthood. Recognizing this gap, Congress amended the Public Health Service Act (42 U.S.C. § 300mm-51(c)) to establish a Research Cohort for Emerging Health Impacts on Youth to promote research on those individuals who were 21 years of age or younger at the time of exposure. This Commentary reviews the historical development of post-9/11 monitoring, treatment, and research programs, and discusses the unique challenges of conducting research in such a youth cohort 25 years after the event. A central coordinating center supported by community-based field sites offers a promising approach to promoting research among this cohort and addressing critical gaps in understanding the lifelong impacts of 9/11 exposures.

Acute myeloid leukemia (AML) is a blood cancer with poor survival outcomes. Acute respiratory failure frequently occurs due to leukemia infiltration of the lungs. Underlying mechanisms remain unexplored and therapeutic interventions remain empiric. Here we map the AML lung microenvironment at spatial and single-cell resolution. We show that extensive remodeling is coupled with inflammation and impaired tissue integrity and function. Steroid treatment significantly reduces AML burden and lung infiltration, improving oxygenation and pulmonary function. As a mechanistic correlate, the S-type lectin Lgals9 is triggered by inflammation and mediates cell-cell interactions within infiltrated lungs. Also, the alarmin IL-33 and its receptor (IL-1RL1) are involved in cell-cell interactions within the leukemic lung microenvironment. Targeting either the Lgals9 or IL-33 axis significantly decreases overall AML burden and lung infiltration through effects on both the immune microenvironment and AML cells. Our studies delineate pulmonary infiltration phenotypes in acute leukemia, enabling new treatment strategies.

IMPORTANCE:The relative efficacy and safety of oral P2Y purinergic receptor 12 (P2Y12) inhibitors (clopidogrel, ticagrelor, or prasugrel) after percutaneous coronary intervention (PCI) are not well defined. OBJECTIVE:To assess the efficacy and safety of oral P2Y12 inhibitors in patients who underwent PCI. DATA SOURCES AND STUDY SELECTION:PubMed and Embase were searched until November 15, 2025, for randomized clinical trials comparing at least 2 of the 3 agents. DATA EXTRACTION AND SYNTHESIS:Data were abstracted by 2 independent authors according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting guidelines. Random-effects odds ratios (ORs) and 95% confidence intervals were calculated. Data were analyzed in December 2025. MAIN OUTCOMES AND MEASURES:The primary efficacy outcome was major adverse cardiovascular events (MACE), while the primary safety outcome was major bleeding. The primary analysis compared prasugrel and ticagrelor in reference to clopidogrel using a mixed treatment comparison meta-analysis. RESULTS:Data were analyzed from 15 randomized clinical trials that included 48 904 patients (mean [SD] age, 63.2 [4.21] years; 13 330 female patients [27.3%]). Compared with clopidogrel, there was a lower risk of MACE (OR, 0.80; 95% CI, 0.69-0.93) driven by lower myocardial infarction (OR, 0.71; 95% CI, 0.62-0.82) and stent thrombosis (OR, 0.48; 95% CI, 0.37-0.62) with prasugrel. MACE was not reduced with ticagrelor compared with clopidogrel, although there was lower stent thrombosis (OR, 0.73; 95% CI, 0.59-0.91). Furthermore, there was lower risk of MACE with prasugrel compared to ticagrelor (OR, 0.83; 95% CI, 0.70-0.98) driven by lower myocardial infarction (OR, 0.78; 95% CI, 0.65-0.94) and stent thrombosis (OR, 0.66; 95% CI, 0.49-0.88). There was a higher risk of major bleeding with ticagrelor vs clopidogrel (OR, 1.24; 95% CI, 1.01-1.52) driven by higher intracranial hemorrhage (OR, 1.89; 95% CI, 1.08-3.33). Prasugrel ranked first, followed by ticagrelor and clopidogrel, for MACE, myocardial infarction, and stent thrombosis. CONCLUSIONS AND RELEVANCE:In this systematic review and meta-analysis of 15 randomized clinical trials in patients who underwent PCI, prasugrel provided the optimal balance between efficacy and safety compared with ticagrelor and clopidogrel.

PURPOSE/OBJECTIVE:To investigate intravitreal anti-VEGF drug use among Medicare Fee-For-Service (FFS) and Medicare Advantage (MA) beneficiaries. DESIGN/METHODS:Retrospective, cross-sectional analysis of de-identified healthcare data from the American Academy of Ophthalmology's IRIS® Registry (Intelligent Research in Sight) for patient encounters between January 2017 to December 2022. PARTICIPANTS/METHODS:Medicare beneficiaries 65 years and older with FFS or MA coverage with continuous insurance enrollment for at least12 months. METHODS:Unique FFS and MA beneficiaries receiving intravitreal anti-VEGF were included. Patients were considered to be treated with a particular drug if more than 50% of their injections for at least 12 months were with that drug. For each anti-VEGF drug, we compared proportions of patients treated (more than 50% of their injections) with that drug between FFS and MA and calculated the difference in use between the two Medicare health care programs. MAIN OUTCOME MEASURES/METHODS:Differences in anti-VEGF drug utilization between FFS and MA. RESULTS:930,411 beneficiaries underwent 12,942,057 intravitreal injections. In the FFS group, aflibercept 2mg was used most frequently (43.8%; n = 4,271,050), followed by bevacizumab (34.7%; n = 3,382,439), ranibizumab (20.6%; n = 2,008,791), brolucizumab (0.6%; n = 56,728) and faricimab (0.4%; n = 40,729). In the MA group, bevacizumab was used most frequently (45.1%; n = 1,436,151), followed by aflibercept 2mg (37.8%; n = 1,201,311), ranibizumab (6.5%; n = 524,758), brolucizumab (0.4%; n = 13,406), and faricimab (0.2%; n = 6,694). Repackaged bevacizumab (lower cost) was more common in the MA group compared with the FFS group (60.0% vs. 47.0%; difference (diff) = 13.0%, 95% CI:12.8, 13.3%; P<.001). Higher cost drugs were used significantly less often among persons with MA compared with FFS, respectively (aflibercept 2mg (28.9 vs. 36.6%; diff = -7.7%; 95% CI -7.9%, -7.4%; P<.001), ranibizumab (11.9% vs. 16.8%; diff = -4.9%; 95% CI -5.03%, -4.7%; P<.001), faricimab (0.06% vs. 0.24%; diff = -0.18%; 95% CI -0.19%, -0.16%); P<.001, and brolucizumab (0.12% vs. 0.19%; diff = -0.07%; 95% CI -0.09%, -0.05%; P<.001). CONCLUSIONS:Beneficiaries enrolled in MA were less likely to receive higher cost, anti-VEGF drugs, raising concerns about reduced beneficiary access to newer more expensive anti-VEGF drugs in MA.