Michigan Medicine

To examine the cross-sectional relationship between dietary intake and epigenetic age acceleration, as well as the prospective relationship between epigenetic age acceleration and cardiometabolic parameters measured two years later. In 526 adolescents aged 7-18 years (average age 14.50) residing in Mexico City, dietary intake was assessed using a semi-quantitative food frequency questionnaire. Adherence to three dietary patterns was derived from principal component analysis. Blood leukocyte DNA methylation was measured with the Illumina Infinium MethylationEPIC BeadChip, from which epigenetic age acceleration was calculated for six epigenetic clocks: Horvath, Skin-Blood, PhenoAge, GrimAge, Pediatric-Buccal-Epigenetic (PedBE), and Wu. Nine cardiometabolic parameters were assessed two years after assessment of diet and epigenetic age acceleration. Linear regression models for sex-stratified associations were examined. Among males, the Meat & Starchy foods pattern was positively associated with Wu epigenetic age acceleration, showing a 0.096-year increase, while folate intake in females was associated with a 0.004-year decelerated GrimAge. Prospective analysis showed positive associations between epigenetic age acceleration and fat distribution and insulin resistance, particularly in males. In females, only GrimAge acceleration was associated in the expected manner with increased waist circumference (β=0.62cm), BMI (β=0.25kg/m2), fasting insulin (β=0.86 μIU/mL), and insulin resistance (β=0.21). Skin-Blood acceleration was associated with decreased HDL in males, and PedBE acceleration was associated with triglycerides in both sexes, though in opposing directions. Adolescent diet was not strongly associated with baseline epigenetic age acceleration. However, epigenetic age acceleration was associated prospectively with fat distribution and insulin resistance.

Left ventricular (LV) dysfunction is a potential cardioembolic source of ischemic stroke, but its role in recurrent stroke risk and treatment response remains unclear. We explore whether LV injury associates with the risk of recurrent stroke and modifies the association between anticoagulation and stroke recurrence using real-world data. We performed a multicenter, retrospective study of Cardiac Abnormalities in Stroke Prevention and Recurrence cohort across 27 US sites. Patients with LV ejection fraction ≥20% were included. LV injury, defined as LV ejection fraction 20% to 40% and wall motion abnormality, was the primary exposure and treatment effect modifier. The treatment of interest was anticoagulant versus antiplatelet therapy. The composite outcome included recurrent stroke, major bleeding, or death. Outcomes were evaluated using unadjusted and inverse probability weighting adjusted Cox proportional hazards models, with treatment effect modification tested by LV injury status. Among 2685 patients enrolled, 2328 with complete data were analyzed (median age, 65 years; 49.8% female; median follow-up, 1.6 years). LV injury was present in 310 patients (13.3%). Overall, 535 events occurred: 258 recurrent ischemic strokes, 28 hemorrhagic strokes, 67 major hemorrhages, and 256 deaths. LV injury was associated with a higher unadjusted risk of the primary outcome (hazard ratio [HR], 1.51 [95% CI, 1.21-1.87]), though nonsignificant after inverse probability weighting adjustment (adjusted HR, 1.29 [95% CI, 0.97-1.70]). In the LV injury subgroup, anticoagulation versus antiplatelet therapy was associated with a lower risk of the primary outcome (adjusted HR, 0.24 [95% CI, 0.10-0.59]), relative to the non-LV injury subgroup (adjusted HR, 1.28 [95% CI, 0.83-1.95]; p[LV-interaction], 0.001). Similar interactions were seen for EF 20% to 40% (versus >40%; adjusted HR, 0.19 [95% CI, 0.04-0.86]; p[LV-interaction], 0.001) and wall motion abnormality (versus no wall motion abnormality; adjusted HR, 0.33 [95% CI, 0.15-0.73]). After cryptogenic stroke, anticoagulation in those with LV injury was associated with lower rates of recurrent stroke, major bleeding, and death. These findings warrant confirmation in a dedicated randomized controlled trial. URL: https://www.clinicaltrials.gov; Unique identifier: NCT06398366.

RET fusions appear in 1%-2% of non-small cell lung cancers (NSCLCs). The results from the ARROW study (ClinicalTrials.gov identifier: NCT03037385) supported US Food and Drug Administration approval of pralsetinib, an oral selective RET inhibitor, for metastatic RET-altered NSCLC and RET fusion-positive thyroid cancers. ARROW was a phase I/II open-label study of pralsetinib 400 mg once daily in RET fusion-positive NSCLCs. Coprimary end points were overall response rate (ORR) and safety. Key secondary end points included duration of response, progression-free survival, and overall survival (OS). At data lock (May 20, 2024), 281 patients initiated pralsetinib (median treatment duration, 15.0 months). ORR (measurable disease patients; n = 259) was 78% (95% CI, 69 to 86) for treatment-naïve patients and 63% (95% CI, 54 to 71) for prior platinum-based chemotherapy patients. Median OS was 44.3 months (95% CI, 30.9 to 53.1), 50.1 months (95% CI, 28.3 to not reached) in treatment-naïve patients, and 39.7 months (95% CI, 27.8 to 53.2) in prior platinum patients. Common grade ≥3 treatment-related adverse events were anemia (21%), hypertension (15%), and decreased neutrophils (13%). Three treatment-related deaths occurred (pneumonia, n = 2; interstitial lung disease and rhabdomyolysis, n = 1 each). Safety was consistent with previous ARROW reports; no hypersensitivity was reported in patients receiving prior immunotherapies. Pralsetinib produced robust, durable responses with manageable safety in treatment-naïve and previously treated patients with RET fusion-positive NSCLCs, confirming previous findings with longer follow-up.

Buprenorphine, despite effectiveness as a medication for opioid use disorder (MOUD), remains underutilized in emergency departments (EDs), with few scalable, statewide programs to improve prescribing. This study evaluated whether a tailored, emergency medicine-specific training offered by the Overdose Prevention Engagement Network (OPEN) across Michigan increased buprenorphine prescribing. This pre-post cohort study compared 9-month periods before vs. after training using IQVIA dispensing data linked by National Provider Identifier (NPI) to participating clinicians. Eligible participants were ED clinicians attending a single, expert-led, incentivized OPEN training session (2020-2023). Clinician-level outcomes of buprenorphine prescription fills (primary), unique patients treated, and new patient initiations were analyzed using adjusted mixed model regression. Fills among non-participating ED clinicians were descriptively examined. Among 203 ED clinicians, buprenorphine fills increased after training from 531 to 963 fills or from 2.6 to 4.7 fills/clinician (adjusted difference+2.1 fills/clinician, 95% CI 0.9 to 3.3). Unique patients dispensed buprenorphine increased from 162 to 457 (adjusted difference+1.5 patients/clinician, 95% CI 1.1 to 1.9), and new initiations increased from 53 to 222 (adjusted difference/clinician +0.8, 95% CI 0.6 to 1.0). Non-participants had 2.2 and 2.4 fills/clinician in pre- and post-training periods, respectively. A tailored training session for MOUD prescribing for ED clinicians was associated with increased buprenorphine prescription fills, patients treated, and new initiations. These findings suggest that this scalable, low-resource approach to enhance prescriber skills in emergency care settings may inform state and national strategies to expand buprenorphine access as part of efforts to address the opioid crisis.