Faculty Bibliography

The rs6923761 (Gly168Ser) missense variant in the glucagon-like peptide-1 receptor (GLP-1R) has been associated with favorable anthropometric and metabolic parameters in individuals with obesity but decreased responsiveness to incretin-based therapies. Here, we performed a pre-specified analysis of a randomized-controlled trial in individuals with obesity and pre-diabetes comparing treatment with the GLP-1R agonist liraglutide, the dipeptidyl peptidase 4 inhibitor sitagliptin or hypocaloric diet, and evaluated the effects of the rs6923761 variant on outcomes. We found significantly greater weight loss to liraglutide with each copy of the variant allele present, indicating a gene dose effect. In addition, individuals with the variant allele exhibited a significant reduction in the pro-thrombotic and pro-inflammatory factor plasminogen activator inhibitor-1 after liraglutide treatment. There was no effect of genotype on fasting glucose after liraglutide treatment, yet individuals with the variant allele exhibited decreased responsiveness to liraglutide and hypocaloric diet in measurements of fasting insulin, C-peptide, glucagon, and HOMA-IR. In conclusion, we found that the GLP-1R rs6923761 variant exerts a dual impact on liraglutide efficacy-enhancing weight loss while diminishing metabolic benefits. The observed associations could be consistent with the constitutive activation of the GLP-1R in the presence of this variant with reduced activation/signaling in response to pharmacologic agents, a pattern that has been observed with the rs10305492 variant in animal models. Future studies are needed to investigate the molecular mechanisms of associations with the rs6923761 variant.

IMPORTANCE/UNASSIGNED:Despite evidence of clinical benefits and guidelines recommending first-line treatment intensification (TI) for metastatic castration-sensitive prostate cancer (mCSPC), the majority of patients do not receive it. OBJECTIVE/UNASSIGNED:To identify barriers to and facilitators of first-line TI. DESIGN, SETTING, AND PARTICIPANTS/UNASSIGNED:The IMPLEMENT study (December 2022 to August 2024) comprised 3 phases and used a mixed-methods, qualitative and quantitative approach. US-based urologists and oncologists who were primary treaters for 1 or more patients with mCSPC in the past 6 months, had been practicing for 2 to 35 years, spent 50% or more of their time in direct patient care, and were able to provide informed consent were included. EXPOSURE/UNASSIGNED:Phase 1 consisted of semistructured interviews based on the Theoretical Domains Framework. Phase 2 consisted of a discrete choice experiment to identify priority barriers and helpful resources. Phase 3 consisted of cocreation sessions to ideate potential solutions to underutilization based on the findings of the previous phases. MAIN OUTCOMES AND MEASURES/UNASSIGNED:The primary outcome in phase 1 was barriers to and facilitators of first-line TI, as identified through thematic analysis. The primary outcome of phase 2 was perceived helpfulness of potential resources for first-line TI decisions, measured with a coefficient of helpfulness [CoH] for each resource. The primary outcome of phase 3 was potential solutions to increase TI uptake, as cocreated and ranked by urologists and oncologists. RESULTS/UNASSIGNED:In total, 352 participants were included in IMPLEMENT, with 36 in phase 1 (33 men [92%]; mean [range] years in practice, 19 [5-34]), 302 in phase 2 (253 men [84%]; mean [range] years in practice, 18 [4-35]), and 14 in phase 3 (12 men [86%]; mean [range], years in practice, 20 [8-35]). In each phase, one-half of participants were oncologists and one-half were urologists (18 urologists and 18 oncologists in phase 1, 151 urologists and 151 oncologists in phase 2, and 7 urologists and 7 oncologists in phase 3). In phase 1, 5 domains had the greatest perceived influence on intensification: memory, attention, and decision processes; environmental context and resources; knowledge; beliefs about consequences; and social or professional role. Urologists more commonly reported barriers to intensification, while oncologists more commonly reported facilitators. In phase 2, urologists found decision-support tools most helpful (CoH, 3.27; 95% CI, 2.90-3.65), while oncologists preferred databases of posttreatment options (CoH, 2.58; 95% CI, 2.29-2.89) and clinical trial summaries (CoH, 2.41; 95% CI, 2.14-2.69). In phase 3, cross-specialty tumor boards were ranked by both specialties as the best solution to address TI underutilization. CONCLUSIONS AND RELEVANCE/UNASSIGNED:This study using a mixed-methods approach with quantitative and qualitative components found that the issues underlying TI underutilization were numerous and multifactorial; the barriers encountered by physicians and the resources to help address them varied by specialty. These findings offer insights into physician-supported strategies that could help improve rates of first-line TI for mCSPC in the US.

IMPORTANCE/UNASSIGNED:The emergency department (ED) is a critical point of contact within the health care system and an opportunity to initiate nonpharmacologic migraine treatment. OBJECTIVE/UNASSIGNED:To examine whether progressive muscle relaxation (PMR) smartphone-based migraine self-management improved patient-reported outcomes for migraine compared with enhanced usual care. DESIGN, SETTING, AND PARTICIPANTS/UNASSIGNED:A randomized clinical trial of the smartphone application RELAXaHEAD with and without PMR. Patients aged 18 to 65 years visiting New York University Langone Health EDs for headache who met migraine criteria and self reported 4 or more migraine days per month were recruited from June 2019 to October 2021 with follow-up at 3 months. Data were analyzed from June 2022 to June 2025. INTERVENTION/UNASSIGNED:Participants in the intervention group were asked to listen to the app-based PMR for 60 days. Participants in the control group were asked to use the app as a symptom diary. MAIN OUTCOMES AND MEASURES/UNASSIGNED:Primary outcome was change in migraine-related disability (MIDAS). Secondary outcomes were change in migraine-specific quality of life (MSQv2) and monthly headache days (MHDs). Adherence (number of days of diary use, PMR use and total minutes of PMR use over 90-day period) was measured using back-end analytics. RESULTS/UNASSIGNED:Of the 94 patients (median [IQR] age, 33 [26-45] years; 57 [82.6%] female) randomized (48 control patients and 46 PMR patients), 69 of 94 (73%) had 1 or more follow-up MIDAS scores and constituted the modified intent-to-treat population (35 control patients and 34 PMR patients). The mean (SD) change in MIDAS scores from baseline to 3 months (last observation carried forward [LOCF] used if missing 3-month follow-up data) differed between groups (PMR, 25.09 [29.64] vs control, 6.86 [59.61]; P = .01). PMR had nearly double the number of respondents improving by 5 or more MIDAS points (28 of 34 [82.4%] vs 16 of 35 [45.7%] respondents; P = .002). There was no difference in MSQv2 domains from baseline to LOCF between PMR and control (mean [SD] role function preventive domain for PMR, 16.9 [24.5] vs control, 11.3 [25.9]); emotional function domain (mean [SD] for PMR, 26.5 [26.9] vs control, 19.8 [38.5]); and role function restrictive domain (mean [SD] for PMR, 18.1 [22.7] vs control, 18.7 [26.8]). Mean (SD) change in MHDs (baseline to 3 months) did not differ between groups (PMR, 2.9 [8.0]; 23 days vs control, -1.6 [6.5]; 25 days). CONCLUSION AND RELEVANCE/UNASSIGNED:A PMR-based self-management program offered to patients with migraine after ED discharge yielded clinically significant reductions in migraine-related disability. TRIAL REGISTRATION/UNASSIGNED:ClinicalTrials.gov Identifier: NCT04281030.

BACKGROUND:To encourage high-quality, reduced-cost care for total joint arthroplasty (TJA), the Centers of Medicare & Medicaid Services mandated a pay-for-performance model, the Comprehensive Care for Joint Replacement (CJR), as part of the Patient Protection and Affordable Care Act (PPACA). The CJR incentivizes cost containment, and it was anticipated that its implementation would reduce access to TJA for high-cost populations. Patients with end-stage kidney disease (ESKD) undergoing kidney replacement therapy (dialysis and kidney transplant) are costly compared with healthier patients, but it was unknown whether this population lost access to hip and knee replacement because of CJR implementation. This population allows study of whether TJA is accessible for medically complex patients whose risk of surgical complications has been mitigated, as kidney transplantation improves outcomes compared with dialysis, allowing evaluation as to whether access improved when patients crossed over from dialysis to transplantation. Because all patients with ESKD are included in a mandated national registry, we can quantify whether access changed for patients who underwent dialysis and transplantation. QUESTIONS/PURPOSES/OBJECTIVE:(1) How did the rate of TJA change amid the shift to bundled payments for patients with ESKD receiving dialysis? (2) How did the rate of TJA change amid the shift to bundled payments for patients with ESKD after kidney transplant? METHODS:This was an observational cohort study from 2008 to 2018 using the United States Renal Data System, a mandatory national registry that allows for the opportunity to study all individuals with ESKD. During the study period, we identified 1,324,614 adults undergoing routine dialysis and 187,212 adult kidney transplant recipients; after exclusion for non-Medicare primary insurance (n = 785,224 for dialysis and 78,011 for transplant), patients who were 100 years or older (n = 79 and 0, respectively), those who resided outside of 50 US states and Puerto Rico (n = 781 and 87, respectively), missing dialysis status for the dialysis cohort (n = 8658), and multiorgan transplant recipients for the transplant cohort (n = 2442), our study population was 40% (529,872) of patients who underwent routine dialysis and 57% (106,672) of adult kidney transplant recipients, respectively. TJA was ascertained using Medicare Severity Diagnosis Related Groups and ICD-9 and ICD-10 codes. We divided the study period by PPACA (January 1, 2014, to March 31, 2016) and CJR (April 1, 2016, to December 31, 2018) implementation and compared the incidence of TJA by era using mixed-effects Poisson regression adjusting for calendar time and clinical and demographic variables. RESULTS:After adjustment for linear temporal trend and patient case mix, there was no evidence of association between policy implementation and the incidence of TJA. In the dialysis cohort, the adjusted incidence rate ratio (IRR) for TJA was 1.06 (95% confidence interval [CI] 0.98 to 1.14; p = 0.2) comparing PPACA with the previous period and 1.02 (95% CI 0.96 to 1.08; p = 0.6) comparing CJR with the previous periods. Similarly, in the transplant cohort, the adjusted IRR for TJA was 0.82 (95% CI 0.67 to 1.02; p = 0.07) comparing PPACA with the previous period and 1.10 (95% CI 0.94 to 1.28; p = 0.9) comparing CJR with the previous periods. CONCLUSION/CONCLUSIONS:There was no loss in access to TJA for medically complex patients receiving kidney replacement therapy. The increase in TJA incidence for patients after kidney transplant and decrease for patients receiving dialysis suggest that surgeons continued to provide care for higher risk patients whose risk of morbidity or mortality with total joint replacement has been maximally improved after transplantation. LEVEL OF EVIDENCE/METHODS:Level III, prognostic study.

OBJECTIVES/OBJECTIVE:We aimed to describe pediatric firearm incidents treated at 6 New York City public trauma hospitals over a 5-year period. METHODS:We conducted a retrospective, multi-institutional, descriptive study of firearm-related incidents among patients below 18 years treated at 6 municipal trauma centers in New York City from July 1, 2016, to June 30, 2021. We used trauma registries, electronic health records (EHR), and geospatial analysis, supplemented with Gun Violence Archive (GVA) and New York Police Department data to characterize and map incidents, excluding missing data. RESULTS:Of n=176 patients, data on injury intent and circumstances were unavailable for 13% (n=22) and 22% (n=38), respectively. Most were male (n=161, 91%), Black (n=133, 76%), and adolescents (median 16 y, IQR: 15, 17) who sustained nonfatal (n=166, 94%) assaults (n=151, 98%). Limited available data suggests that identified assailants were unknown to the unintentional victims of community violence. Incidents largely occurred on weekdays (n=133, 76%); between 15:00 and 20:59 (n=72, 42%); and outside a residential home (n=149, 93%), including sidewalk/street (n=85, 53%) and playground/park/basketball court (n=25, 16%). The most common circumstances were running/jogging/walking outside (n=54, 39%), altercation involvement (n=32, 23%), and drive-by (n=27, 20%). Fifty-four percent (n=72) of incidents occurred within 0.2 miles of public housing in 3 primary geospatial clusters. GVA and New York Police Department databases suggest between 39% and 46% capture of relevant incidents. CONCLUSIONS:Regional gun violence data suffers from a lack of standardization and missingness across sources. Nonetheless, triangulating available data from trauma registries, EHR, GVA, and geospatial analysis, we found that most pediatric patients were Black, adolescent, unintended victims who sustained assaults on weekdays, outside a home, and within 0.2 miles of public housing in 3 primary clusters. These results may inform hospital data surveillance and ongoing evidence-based prevention strategies.

BACKGROUND:Plasma proteomic data can be used to discover breast cancer risk biomarkers beyond established risk factors. Discovery using a large-scale platform in a diverse population is needed. METHODS:We investigated 4,712 plasma proteins and breast cancer risk among post-menopausal women in a prospective cohort analysis in the Atherosclerosis Risk in Communities study. Proteins were measured by SomaScan® 5K Assay. Incident cases were ascertained primarily from state cancer registries. We estimated hazard ratios (HRs) and 95% confidence intervals (CIs) using Cox regression adjusting for risk factors, and applied the Benjamini-Hochberg method to control false discovery. We determined whether the statistically significant proteins were confirmed in a case-cohort study within the European Prospective Investigation into Cancer and Nutrition (EPIC). RESULTS:After median follow-up of 23.3 years, 340 of 4,403 women had an incident breast cancer. Two proteins were statistically significantly associated after p-value adjustmentper doubling, the HR of breast cancer was 1.45 (95% CI: 1.23-1.70, p = 7.47*10-6, padjusted=0.0370) for protein LEG1 homolog and 2.52 (95% CI: 1.66-3.83, p = 1.50*10-5, padjusted=0.0371) for ADP-dependent glucokinase. Results were consistent in a lagged analysis and among both Black (28.1%) and White women. In EPIC, both associations were confirmed (protein LEG1 homolog, HR = 1.24, 95% CI 1.14-1.35, p = 9.79*10-7, ADP-dependent glucokinase, HR = 1.13, 95% CI 1.03-1.23, p = .01). CONCLUSION/CONCLUSIONS:We identified two plasma proteins associated with increased breast cancer risk over the longer-term in post-menopausal women; both were confirmed in an independent cohort. If further validated, these plasma protein biomarkers could be considered for utility in current risk stratification tools.

INTRODUCTION/BACKGROUND:Esophageal adenocarcinoma (EAC) develops through histopathological stages, including Barrett's esophagus (BE). We analyzed the associations between plasma levels of one-carbon metabolism factors and risks of long-segment BE or EAC. METHODS:Plasma levels were measured from an Irish population-based case-control study [Factors INfluencing the Barrett's Adenocarcinoma Relationship (FINBAR) study; 204 long-segment BE cases, 211 EAC cases, and 251 controls]. A "methyl replete score" was derived by assigning a score of 0 (< median) or 1 (> median) to the levels of three dietary methyl donors (methionine, choline, and betaine) and summing across the metabolites. Multinomial logistic regression models were used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for the associations between EAC or BE and sex-specific quartiles or score using the lowest level as the reference category and adjusted for potential confounders. RESULTS:Highest methionine, betaine, vitamin B6 (PLP), and choline levels were all associated with 62-82% reduced risks of EAC (ptrends <0.001). Conversely, S-adenosylmethionine (SAM), the SAM/S-adenosylhomocysteine (SAH) ratio, total homocysteine (tHcy), and cystathionine were associated with a greater than two-fold increased EAC risk. A higher methyl replete score was associated with reduced EAC risk (OR 0·33; 95%CI: 0·16-0·66). The highest versus lowest plasma methionine levels were borderline statistically significantly associated long-segment BE (OR 0·55; 95%CI: 0·28-1·07), but all other associations were null. CONCLUSIONS:Several biomarkers of one-carbon metabolism are associated with EAC risk, particularly markers of dietary methyl group donors. Future studies to replicate and prospectively evaluate these markers are warranted.

Cardiovascular disease (CVD) and cancer remain the leading causes of mortality in the United States, where poor diet has surpassed smoking as the leading risk factor for death, and life expectancy has hit a plateau as CVD mortality has stagnated over the past decade. Although the pathophysiology of CVD and cancer is complex and multifactorial, lifestyle factors including diet often contribute significantly to their pathogenesis. There is a wealth of observational data as well as emerging trial data supporting the benefits of a predominantly whole-food plant-based diet in the prevention of CVD and cancer. However, there is a need for implementation science to effectuate existing knowledge. Given the shortcomings of the standard American diet, characterized by excessive intake of red meat and ultraprocessed foods, while deficient in fiber and phytonutrients, it will be necessary to shift default patterns of eating to make healthy choices the path of least resistance.

BACKGROUND:Glucagon-like peptide-1 receptor agonists (GLP1RA) provide survival benefits in people with diabetes, including kidney transplant (KT) recipients with pre-existing diabetes. Post-transplant diabetes mellitus (PTDM) is common, but the benefits of GLP1RAs remain undefined in this population. We aim to describe current usage practices and outcomes in PTDM. METHODS:We used USRDS and Medicare claims data (2013-2022) to conduct a drug utilization profile of GLP1RA among 7681 first-time adult KT recipients with PTDM. We used survival analysis to estimate GLP1RA initiation incidence and associated patient, graft, and safety outcomes. RESULTS:A total of 430 adult KT recipients with PTDM were prescribed GLP1RA. Dulaglutide was the most commonly prescribed medication (46.1%). The 5-year cumulative incidence of GLP-1 receptor agonists prescription was 9.8%. Median (interquartile range) time from PTDM diagnosis to first prescription was 1.7 (0.6, 3.4) years. GLP1RA use was not associated with a difference in the risk of mortality or graft failure but was associated with a 1.80-fold (95% confidence interval [CI]: 1.11-2.91) increased risk of diabetic retinopathy. No increased risk of pancreatitis, biliary complications, or medullary thyroid cancer were identified. CONCLUSIONS:GLP1RA use in KT recipients with PTDM was not associated with graft or patient survival, though longer follow-up is necessary. GLP1RA use was associated with an increased risk of diabetic retinopathy, and care should be taken when initiating these agents.