Faculty Bibliography

BACKGROUND:In the International Study of Comparative Health Effectiveness with Medical and Invasive Approaches (ISCHEMIA) trial, women had worse angina than men despite less severe coronary artery disease (CAD) and ischemia. We examined which patient and treatment factors might explain sex-based differences in angina. METHODS:ISCHEMIA randomized patients with moderate or severe ischemia to an initial invasive strategy of cardiac catheterization with complete revascularization plus guideline-directed medical therapy (GDMT), or an initial conservative strategy of GDMT alone with invasive management reserved for GDMT failure. Coronary CT angiography was performed in most participants. Angina-related health status was collected at baseline and 1-year using the Seattle Angina Questionnaire (SAQ). RESULTS:Of 4,617 ISCHEMIA participants with complete SAQ data, women averaged 6.5 points (95% CI 5.2-7.8) lower (worse) baseline SAQ summary scores (SS) than men. This difference was not reduced by adjustment for demographics and clinical characteristics. Women had lower unadjusted 1-year SAQ-SS than men (Invasive -3.8 points, Conservative -5.7 points). These sex-based differences were attenuated but not eliminated by adjustment for baseline SAQ-SS. Adjustment for post-randomization treatment (GDMT intensity, risk factor goal achievement and, in the invasive strategy, complete revascularization) did not narrow the sex difference. CONCLUSIONS:Women with chronic CAD in ISCHEMIA had worse angina-related health status than men at baseline and 1-year. Differences were not explained by demographic or clinical characteristics, intensity of GDMT, or completeness of revascularization. It is thus important to consider other factors that may mediate these results, including differences in nociception, coronary microvascular dysfunction and/or vasospasm.

OBJECTIVES/OBJECTIVE:Physician burnout is associated with both intention to leave practice and turnover. However, the individual dimensions of burnout-cynicism, exhaustion, and poor personal efficacy-have not been examined as predictors of physician intent to leave practice or departure. We sought to determine whether these individual dimensions of burnout are independent predictors of physician intent to leave practice or departure. DESIGN/METHODS:In a retrospective cohort study, we merged longitudinal survey data from all actively employed physicians at the Massachusetts General Physicians Organization (MGPO) from 2017, 2019, and 2021 with physician employment status two years after survey completion. SETTING/METHODS:Survey data were gathered from all actively employed physicians at the Massachusetts General Physicians Organization (MGPO), the largest physicians organization in New England and one of the largest in the USA. PARTICIPANTS/METHODS:There were 5976 survey responses from 2651 unique physicians over the three sequential survey years, with a survey response rate of > 90%. MAIN OUTCOMES AND MEASURES/METHODS:Rates of self-reported intention to leave and actual physician departure among physicians were analyzed by general burnout scores and scores on the three individual burnout subscales. RESULTS:Burnout was independently associated with both intention to leave (OR = 3.10, 95% CI 2.55-3.77) and physician departure (OR = 1.37, 95% CI 1.15-1.64). High scores on all three individual burnout subscales were associated with increased odds of intention to leave (exhaustion OR = 1.55, 95% CI 1.25-1.92; cynicism OR = 2.49, 95% CI 1.99-3.13; personal efficacy OR = 1.45, 95% CI 1.19-1.77). However, only high cynicism scores were associated with actual departure (cynicism OR = 1.37, 95% CI 1.12-1.68). Physicians who departed were significantly more likely to have previously expressed an intention to leave than those who remained (33.6% vs. 6.7%, p < 0.001). CONCLUSIONS:Physician cynicism is the only burnout dimension associated with departure, though multiple burnout dimensions are associated with intention to leave. Organizational efforts to combat cynicism may be especially effective in promoting physician retention.

Retinopathy of prematurity (ROP) is a leading cause of childhood blindness characterized by disrupted physiologic vascularization followed by pathologic neovascularization, classically organized around the insulin-like growth factor-1 (IGF-1)-vascular endothelial growth factor (VEGF) axis in the retina. Increasing evidence suggests that early-life gut dysbiosis may act as an upstream modifier of this biphasic process. In this review, we synthesize human cohort studies, multi-omics analyses, and experimental animal models examining associations between the neonatal gut microbiome and ROP. Preterm infants who develop severe ROP demonstrate enrichment of facultative anaerobes and reduced acquisition of obligate anaerobes, alongside altered predicted metabolic capacity. Microbiome-derived metabolites, including short-chain fatty acids, bile acid derivatives, and lipid mediators, have been shown in experimental systems to influence systemic IGF-1 production, hypoxia-inducible factor-1α stabilization, and VEGF signaling. Rodent oxygen-induced retinopathy models offer a translation framework to assess the functional link between microbial perturbation and retinal angiogenic responses. Collectively, these findings support a conceptual microbiome-IGF-1-VEGF-retina axis in which early intestinal dysbiosis may modulate inflammatory tone, metabolic signaling, and retinal vascular development. Although current evidence remains largely associative, integrating microbiome profiling with mechanistic and longitudinal studies may clarify potential causal pathways and identify novel biomarkers or preventive strategies for severe ROP.

OBJECTIVES/OBJECTIVE:Early screening is necessary to prevent increasing osteoporosis and fragility fractures. Though Dual-energy X-ray absorptiometry (DEXA) defines osteoporosis, it does not predict fragility-fractures well. Trabecular structure as seen on MRI may be more sensitive and specific for osteoporosis and distal radius trabecular structure may identify changes earlier. We aimed to compare distal-radius trabecular structure as seen on MRI in patients with normal risk for fragility-fracture to those with increased risk of fragility-fracture. METHODS:Ten low-risk and 9 high-risk subjects underwent ultra- short-echo-time (UTE) MRI sequence scanning of an uninjured distal radius. Structural components included: trabecular plate-width, plate-rod ratio, plate volume fraction, rod volume fraction, trabecular thickness, pore size, pore size variation and trabecular density. A T-test or Mann-Whitney U test was conducted to determine differences in trabecular structure between low- and high-risk groups. Specificity and sensitivity were calculated to assess wrist MRI as a screening tool. RESULTS:There were statistically significant differences between low- and risk-risk groups for all parameters except trabecular thickness (p < 0.05). CONCLUSION/CONCLUSIONS:This study supports the feasibility of wrist MRI as a screening tool for early osteoporosis. This could potentially enable early prevention. Further study including longitudinal follow-up to determine the ability of this tool to predict fragility fractures is needed. ADVANCES IN KNOWLEDGE/CONCLUSIONS:We compared trabecular structure in wrist-MRI of high-risk and low-risk for fragility fracture, finding significant differences with optimal sensitivity/specificity to predict osteoporosis. Wrist MRI may offer early and effective screening for osteoporosis.

Youth are presenting to Emergency Departments (EDs) following a suicide-related crisis at higher rates and younger ages. Clinicians lack tools to effectively discern suicide risk in younger patients. The present investigation examines how ED-based, suicidal pre-adolescents and adolescents conceptualize death. One hundred and sixty-seven suicidal pre-adolescents and adolescents (10-17 years; M = 12, SD = 1.4) presenting to a psychiatric ED with a suicide-related chief complaint completed assessments of suicidal ideation (SI; passive and active thoughts), suicide attempt (SA), depressive symptoms, and death conceptualizations (Death Avoidance, Escape Acceptance, Neutral Acceptance). Post-discharge SI and SA were assessed via survey emailed to participants 6 months later and via electronic medical record. At baseline, lower levels of Death Avoidance and higher levels of Escape Acceptance were most robustly associated with active SI. Pre-adolescents reported higher levels of Death Avoidance and lower levels of Escape Acceptance than adolescents at baseline. Death conceptualizations did not predict follow-up SI and SA. Youth who have recently experienced a suicide-related crisis are more likely to accept death as an escape from painand spend less time avoiding thoughts about death. This profile appears to be more representative of adolescents, relativeto pre-adolescents who display the opposite pattern.

BACKGROUND AND OBJECTIVE/OBJECTIVE:Most patients with high-risk localized prostate cancer (HRLPC) do not undergo stereotactic body radiotherapy (SBRT) in part because of the limited evidence of long-term outcomes. We report long-term efficacy and toxicity outcomes for men treated with SBRT for HRLPC. METHODS:Individual patient data from ten prospective clinical studies evaluating SBRT for HRLPC across nine institutions were pooled in the Stereotactic Body Radiotherapy for High-Risk Localized Carcinoma of the Prostate consortium. The Kaplan-Meier method was used to estimate 5-yr biochemical recurrence (BCR) and distant metastasis (DM), stratified by receipt of intensified treatment (≥12 mo of androgen deprivation therapy [ADT] with extremely dose-escalated [≥8 Gy/fraction] prostate-directed SBRT). The impact of intensified treatment on BCR-free survival and DM-free survival was evaluated using multivariable Cox proportional hazards models. Late Common Terminology Criteria for Adverse Events grade ≥2 gastrointestinal (GI) and genitourinary (GU) toxicity was analyzed using time-to-event models. KEY FINDINGS AND LIMITATIONS/UNASSIGNED:In 440 patients with a median follow-up time of 60.4 mo, 5-yr BCR and DM rates were 22% (95% confidence interval [CI] = 17-26%] and 9.2% (95% CI = 6.2-12%), respectively. In the 93 patients (21%) who received intensified treatment, 5-yr BCR and DM rates were 7.4% (95% CI = 1.7-13%) and 3.7% (95% CI = 0-7.9%), respectively. Receipt of intensified therapy was associated with a significant reduction in both BCR (hazard ratio [HR] = 0.38 [95% CI = 0.20-0.74], p = 0.005) and DM (HR = 0.43 [95% CI = 0.18-0.99], p = 0.049). For the overall cohort, 5-yr rates of grade ≥2 GU and GI toxicity were 23% (95% CI = 19-27%) and 10% (95% CI = 7-13%), respectively. Limitations include heterogeneous treatment techniques and the nonrandomized nature of the study. CONCLUSIONS AND CLINICAL IMPLICATIONS/CONCLUSIONS:The safety and efficacy profile of SBRT for HRLPC remains favorable at long-term follow-up, and SBRT should be integrated into shared decision-making for treatment of HRLPC.

OBJECTIVES/OBJECTIVE:Patients and experts agree that potentially inappropriate medications should be reconsidered after adverse drug events (ADEs), yet emergency providers are often hesitant to discuss deprescribing in deference to outpatient prescribers. We sought to explore patient communication preferences for deprescribing in the emergency department (ED) after an ADE. METHODS:We conducted a cross-sectional survey study of older adults aged 65 years and older presenting to a southeastern, academic ED from June 2024 to October 2024. While awaiting results, eligible participants completed a best-worst scaling survey comparing seven potential ED communication strategies for prompting deprescription of daily aspirin. The primary analysis tested whether an ED-initiated "therapeutic pause" ("Considering your bleeding, I would like you to hold your aspirin until you can discuss with your primary care provider") was preferred by > 50% of participants over a generic discharge referral to a primary care provider through a one-sided binomial test. Secondary analyses used conditional logistic regression to evaluate relative preference across all seven deprescribing phrases. RESULTS:In total, 102 patients completed the survey with a mean (SD) age of 75 years old (std dev 7). Among all respondents, 62% (95% CI, 52%-71%) preferred an ED-initiated 'therapeutic pause' of aspirin with primary care follow-up to the generic PCP deferral approach (p = 0.01). The least preferred statement was a strict deprescribing recommendation ("I do not think you need aspirin anymore"), which was selected as the least-favored communication approach in 65% of choice tasks. In conditional logistic regression, the therapeutic pause had greater odds of being selected as most preferred compared to the least preferred phrase (OR 9.3; 95% CI, 6.3-13.8). CONCLUSION/CONCLUSIONS:Our study suggests that ED physicians may take a proactive approach in addressing potential deprescribing in caring for patients with ADEs, such as initiating a therapeutic pause of aspirin after an episode of bleeding.

The identification of molecular subgroups of pediatric B-cell acute lymphocytic leukemia (B-ALL) has proven to be a powerful tool in understanding disease pathogenesis and treatment stratification. Studies have suggested aberrant transcription factor function and epigenetic regulation can explain differences between B-ALL subtypes, however, the impact of 3D genome re-organization remains unclear. Here we used in situ Hi-C and RNA-seq to profile the chromatin architectural landscape in healthy B-cell progenitors and B-ALL patient samples harboring prognostically relevant structural variations, including ETV6::RUNX1, KMT2A::AFF1, and BCR::ABL. We showed that B-ALLs undergo subtype-specific changes that, in part, reflect the differentiation stage of the disease, and that they acquire aberrant chromatin configurations that allow expression of oncogenic drivers. One such driver, ERG, displayed increased interactivity and expression in ETV6::RUNX1 B-ALL, and evidence suggests it plays a role in regulating survival and differentiation. Overall, these results underscore the essential role of 3D nuclear organization in acute leukemia.