Citations

Abstract M.D.-Ph.D. programs in the United States have traditionally followed a “2- n -2” curricular model, with the graduate phase occurring between the pre-clerkship and clerkship portions of medical training. While well established, this format can limit trainee autonomy in shaping their physician-scientist training trajectories. In response, some programs have introduced a “3- n -1” model, allowing students to complete clerkships before beginning Ph.D. training. Our institution implemented multiple flexible curricula in 2017. Understanding why trainees choose one pathway is important as programs consider implementing more adaptable training structures. To investigate these factors, we surveyed M.D.-Ph.D. students at our institution, which offers multiple flexible curricular alternatives, about contributions to their curricular decisions. Responses supported that trainees weigh considerations across medical education, scientific development, and integrated physician-scientist training domains. Although the traditional pathway was a popular option, most students pursued one of the flexible pathways. Our findings suggest that introducing flexibility in the timing of undergraduate medical education and graduate training can support diverse educational, logistical, and personal priorities while maintaining the rigor of physician-scientist training. Offering multiple pathways empowers trainees to design trajectories that best fit their needs. Continued longitudinal studies are needed to assess the long-term impacts of flexible curricula on physician-scientist career outcomes.

Chylous effusion is a complication most frequently seen in the iatrogenic setting secondary to thoracic surgery or other intervention. Management of this complication includes conservative measures, surgical exploration/ligation, and percutaneous thoracic duct embolization. This case presents a medically complex patient with persistent chylous effusions after thoracoscopic resection of a fluorodeoxyglucose (FDG) and Cu 64 DOTATATE-avid retrocrural lymph node. Initial conventional fluoroscopic lymphangiogram and thoracic duct embolization were unsuccessful. Subsequent magnetic resonance lymphangiography (MRL) more accurately localized the leak which was then marked with computed tomography-guided needle placement before conversion to fluoroscopically guided embolization. This case demonstrates the utility of MRL as a problem-solving tool for localizing hard-to-treat lymphatic leaks. MRL localized embolization is a safe and effective treatment for lymphatic leaks.

Staphylococcus aureus is a well-known pathogen responsible for a wide range of diseases with life-threatening consequences. Its public health burden continues to be significant due to pervasive colonization and growing antimicrobial-resistance (i.e., methicillin-resistant S. aureus, MRSA). In the present study we found that exposure of human bronchial epithelial (hBE) cells to spent culture supernatants of the MRSA strain USA300 induced an increase in mitochondrial ROS production and ATP release that was inhibited by pretreatment with the ROS scavenger glutathione (GSH). ATP secretion involved activation of probenecid-sensitive pannexin 1 channels and bafilomycin A1-dependent exocytosis. ATP exocytosis was inhibited by an antagonist peptide targeting the Receptor for Advanced Glycation End (RAGE) products suggesting that RAGE activation was involved in regulating vesicular ATP release. ATP secretion produced a sustained increase in intracellular Ca 2+ concentration which was dependent upon Ca 2+ uptake from the extracellular solution. Moreover, the sustained JE2-induced Ca 2+ response was not observed in spent supernatants from the less virulent S. aureus agrA mutants used to stimulate hBE cells whereas media from fadX and codY mutants produced responses similar to JE2. Furthermore, wildtype, fadX and codY supernatants evoked secretion of the type-2 inflammatory cytokine IL-33, whereas no response was elicited by media from the less virulent argA mutant. These findings indicate that exposure to secreted virulence factors from S. aureus induces oxidative stress in hBE cells that leads to ATP secretion, sustained Ca 2+ uptake and IL-33 secretion, which has been previously shown to induce type-2 inflammation in airways. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.

Cancer-induced muscle wasting affects many people with cancer, reducing treatment tolerance and survival. We identified a natural dietary compound, ursolic acid, that attenuates muscle atrophy across five preclinical cancer models spanning pancreatic, colon, and lung cancer. Ursolic acid inhibits cancer-induced changes in muscle mRNA expression, preserves muscle strength, and remains protective during chemotherapy, without affecting food intake or tumor burden. These results identify ursolic acid as a promising, translatable dietary supplement for supportive cancer care.

BACKGROUND: Free fibula flaps have been widely used for bony reconstruction in pediatric patients. While donor site complications have been well studied in adults, data in the pediatric population remains limited. This study exclusively reports donor-site morbidity following fibula flap harvests in the pediatric and adolescent population. METHODS: We reviewed all patients younger than 18 years with open physes who underwent fibula flap harvests at a single academic institution from 1997 to 2024. Demographics, clinical and surgical characteristics, and donor-site complications were recorded. RESULTS: Fifty-seven free fibula flaps were harvested from 55 pediatric patients (mean age 12 years; 29 female) with a mean follow-up of 6 years. Flaps were most commonly used for lower extremity reconstruction (52%) and following tumor resection (74%). Osteoarticular flaps (n=8) were associated with transient deep peroneal nerve palsy in four cases, all of which recovered antigravity dorsiflexion by 6 months. In standard segmental harvests (n=49), donor-site complications occurred in 38%, most frequently valgus ankle deformity (9%) and neuropathic pain (6%). Valgus deformity was more likely in patients with shorter distal residual fibula and an age–residual fibula index (A-RFI) <16. CONCLUSIONS: Vascularized fibula flaps are safe and versatile for pediatric skeletal reconstruction. Donor-site complications are common but generally manageable, with full recovery of nerve function. Osteoarticular harvests carry the highest risk of peroneal nerve injury, and valgus ankle deformity may occur, particularly with an age–residual fibula index <16. Careful planning and age-adjusted fibular preservation are essential to optimize outcomes.

Abstract Background The Global Bipolar Cohort (GBC) was established to identify existing bipolar disorder (BD) cohorts worldwide and foster collaborations focused on descriptive and analytic outcomes relevant to BD. A distributed analytic framework has been implemented to engage multiple sites without the need for central data pooling. This report describes the GBC endeavor and global functional impairment patterns. Cross-cohort comparisons of functional correlates are limited by heterogeneous measures and data-sharing constraints. Large, culturally diverse comparisons are needed to distinguish broadly reproducible correlates from cohort-specific effects. Participating sites completed a 28-item descriptive survey covering diagnostic methods, cognition, genetics, treatment, functioning, and follow-up strategies. We implemented a harmonized local logistic regression model of dichotomized functional outcome and shared summary statistics only. Results We identified 69 cohorts across five continents. Thirty-seven cohorts contributed functional outcome analyses from 17,130 participants. Outcome measures included clinician-rated disability scales and social indicators such as employment and marital status. The proportion classified with poor functioning ranged from 16% to 77% (mean 50%). In 32 of 37 cohorts, the overall regression model significantly explained variance in functioning. Current depressive symptoms were the most robust and reproducible correlate of poor functional outcome: they were assessed in 29 cohorts, significant in 22 (75.8%), ranked among the top three correlates in 22, and were the top-ranked correlates in 19. Associations between depressive burden and poor functioning were observed across clinician-rated disability scales and work or social indicators, and across geographically diverse cohorts. Comorbid substance use disorder and medication-related variables were associated with poorer functioning in subsets of cohorts, whereas sex, ancestry, bipolar subtype, psychosis history, and premorbid IQ showed weak or inconsistent associations. Cognitive measures, available in a minority of regression models, showed modest and non-uniform effects. Conclusions Across heterogeneous international cohorts, current depressive symptom burden emerged as the most consistent correlate of poor functioning in bipolar disorder. These findings replicate earlier multisite work at a larger scale, show that protocol-based distributed analyses can identify reproducible clinical signals without sharing individual-level data, and support prioritizing detection and treatment of depressive symptoms when aiming to improve real-world functioning. Future work should expand longitudinal harmonization and representation of under-studied populations.

BACKGROUND: Transthyretin amyloidosis with cardiomyopathy is a progressive, fatal disease characterized by deposition of extracellular misfolded transthyretin (TTR) in the myocardium. Eplontersen is an N-acetylgalactosamine ligand–conjugated antisense oligonucleotide targeting hepatocyte TTR messenger RNA to reduce the production of circulating TTR. METHODS: CARDIO-TTRansform is a Phase 3, randomized, double-blind, placebo-controlled trial to assess the efficacy and safety of eplontersen in transthyretin amyloidosis with cardiomyopathy. Key inclusion criteria include histological evidence of amyloid deposits or grade 2 to 3 cardiac uptake on cardiac scintigraphy in the absence of plasma cell dyscrasia, New York Heart Association class I–III, and end-diastolic interventricular septum thickness >12 millimeters. Participants were randomized 1:1 to receive eplontersen 45 mg or placebo, administered subcutaneously every 4 weeks for up to 140 weeks, followed by a 20-week post-treatment evaluation period or open-label extension. Participants received locally available standard of care, including unrestricted use of TTR stabilizers. The primary end point is a composite of cardiovascular mortality and recurrent clinical cardiovascular events through 140 weeks. Secondary end points, in order of testing hierarchy, include changes from baseline in 6-minute walk distance and Kansas City Cardiomyopathy Questionnaire overall summary score, recurrent cardiovascular events, all-cause mortality, the primary end point in the patient subgroup receiving stabilizers at baseline, and cardiovascular mortality. Echocardiography was performed in all participants, with cardiovascular magnetic resonance imaging and technetium scintigraphy in a subset. CONCLUSIONS: CARDIO-TTRansform is fully enrolled, with 1432 randomized participants who were dosed with study drug or placebo. As the largest transthyretin amyloidosis with cardiomyopathy study to date, it will evaluate whether eplontersen improves cardiovascular outcomes in patients receiving locally available standard of care, including TTR stabilizers. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT04136171. URL: http://ClinicalTrialsRegister.eu ; Unique identifier: EudraCT number 2019-002835-27.

Abstract Introduction The relationship between sleep and brain metabolism remains unclear. This study aimed to examine whether overnight sleep features, using a home sleep apnea system based on peripheral arterial tonometry, are associated with regional FDG-PET changes in older adults. Methods We analyzed cognitively unimpaired adults (≥60 years) from the Mayo Clinic Study of Aging (MCSA) cohort who were not receiving sleep apnea treatment. Participants underwent overnight sleep assessment with the WatchPAT system, followed by FDG-PET imaging the next morning. FDG-PET data were co-registered to 3T MRI and automatically segmented into 122 anatomical regions. PET signal was referenced to the pons (SUVR). We computed voxel-weighted median FDG signal across 47 bilateral cortical and subcortical regions of interest (ROIs), excluding brainstem and cerebellum. Associations between sleep architecture and sleep apnea/hypoxemia burden and regional metabolism were assessed using partial Spearman’s rank correlation, adjusting for age. Results Thirty-seven participants were included (70.3% female; median [IQR] age: 72.0 [68.0–78.0] years). Wake after sleep onset (WASO) showed widespread negative associations with FDG uptake in cortical regions (p&lt; 0.05), particularly the ventromedial/ventrolateral (rs=–0.47 to –0.33) prefrontal cortex, lateral temporal (rs=–0.38 to –0.33), and occipital (rs=–0.47 to –0.37) cortices. Total sleep time (TST) was positively associated with medial structures (p&lt; 0.05), including the posterior cingulate (rs=0.39), retrosplenial cortex (rs=0.48), hippocampus/parahippocampal (rs=0.34 to 0.36), calcarine cortex (ρ=0.38), thalamus (rs=0.37), and caudate (rs=0.43). Hypoxic burden was positively associated with medial occipital regions (rs=0.35 to 0.39) and AHI-4% with cuneus (rs=0.33). Regional gray matter volume did not mediate these associations. WASO correlated with Insomnia Severity Index (rs=0.43, p=0.008) and self-reported refreshing sleep (rs=0.046). Conclusion Overnight sleep macrostructure features (WASO and TST) and hypoxic burden are significantly associated with brain metabolism, potentially underlying symptoms of sleep disturbance and cognitive aging. Support (if any) Mayo Clinic Alzheimer’s Disease Research Center Development Award (P30 AG062677), R01 AG056366, U01 AG006786, R01 AG056366, R01 AG034676, R37 AG011378, R01 AG041851, R01 NS097495, R01 AG068206, P30 AG062677, R01 HL065176. CLARA project work with funding from the European Union’s HORIZON EUROPE research and innovation programme (No 101136607).

Abstract Introduction The remedē System® Therapy Study (reST) is a real world evaluation using transvenous phrenic nerve stimulation (TPNS) to treat adults with moderate-to-severe central sleep apnea (CSA). Based on previous clinical trials, it was expected that most patients with CSA would have heart failure (HF). However, recent CSA prevalence publications demonstrated the opposite. We present the baseline characteristics of patients with CSA treated with TPNS. Methods Adult subjects determined eligible for a commercial TPNS device implant by routine clinical PSGs were consented to participate in the trial. Baseline assessments were performed and medical history collected. Patients will be followed for ≥1 year following therapy activation; follow-up is ongoing. This report describes the baseline characteristics of the patient population. Results Twenty-nine sites enrolled a total of 197 subjects (171 United States & 26 the Netherlands) between July 2019 and March 2025. Median [Q1-Q3] age was 70 [61-76] years, 82% were male, and 97% white race. Body mass index was 28.7 [25.8-31.6] kg/m2, with neck size 41 [28-44] cm. Patients had moderate-to-severe CSA with site-reported apnea-hypopnea index of 46/hour [30-64], including central apnea index of 24/hour [13-38]. Despite a range of comorbidities among patients, HF was documented in just 23%. Other cardiovascular conditions were more prevalent, including hypertension (70%), hyperlipidemia (65%), coronary artery disease (37%), atrial fibrillation (34%), and prior stroke (14%). Non-cardiac issues such as depression (27%), diabetes (26%), and renal disease (18%) were also present. Additionally, 22% of patients used narcotics, and 89% had previously failed another CSA therapy, most often CPAP (79%), Bi-PAP (39%), or ASV (32%). Lastly, almost 20% were from high altitude locations (&gt;5,000 feet). Conclusion Patients implanted with TPNS had significant co-morbidities. However, HF was much less common than anticipated. This finding could be due to CSA being present in clinical practice with a wider range of underlying causes beyond HF, or undiagnosed early-stage HF. Alternatively, it may reflect referral bias for this specific therapy, with patients selected because of prior treatment failures or other comorbidities. These possibilities highlight the importance of recognizing CSA in a diverse patient population and underscore the need for multidisciplinary team management. Support (if any) ZOLL Respicardia, Inc.