Citations

ABSTRACT Aims Opioid use disorder remains a major public health crisis in the United States, driven largely by rising overdose deaths from synthetic opioids, such as fentanyl. Emerging population‐level evidence suggests that GLP‐1 receptor agonists (GLP‐1RAs) may reduce overdose risk. However, their underlying molecular mechanisms are not well understood. We investigated the transcriptional effects of fentanyl and GLP‐1RAs using human induced pluripotent stem cell (iPSC)‐derived forebrain organoids and neurons. Methods Organoids were treated with fentanyl, liraglutide, or exenatide, followed by RNA sequencing. We extended these analyses to iPSC‐derived neurons exposed to additional therapeutic candidates, including the anticonvulsants topiramate and gabapentin, and the metabolic modulator β‐hydroxybutyrate. All compounds were tested at clinically relevant concentrations, and transcriptomic and functional genomic assays were performed. Results Across models and drug classes, we identified modulation of endoplasmic reticulum (ER) stress signaling as a shared molecular mechanism. Fentanyl and GLP‐1RAs consistently downregulated ER stress‐related genes, with TRIB3 as the most strongly suppressed target. We further identified CEBPB as a key upstream regulator and confirmed reduced CEBPB DNA‐binding activity in ER stress‐related genes. Conclusion These findings highlight ER stress modulation as a convergent pathway with potential therapeutic relevance for substance use disorders.

ABSTRACT Melanoma in skin of color (SOC), defined as Fitzpatrick skin tones IV‐VI, presents unique epidemiologic, diagnostic, and therapeutic challenges compared to non‐Hispanic White (NHW). Although SOC patients have a lower incidence of melanoma, they experience higher melanoma‐specific fatality rates, which may be attributable to later‐stage diagnoses, differences in the distribution patterns of melanoma subtypes, and systemic barriers to care. SOC patients, particularly non‐Hispanic Black individuals, have a higher proportion of acral lentiginous and mucosal melanomas, which arise in non‐sun‐exposed areas, carry lower mutational burdens, and respond less favorably to immunotherapy and BRAF/MEK‐targeted therapies. These anatomic and biological differences contribute to delayed recognition and reduced treatment efficacy. Concurrently, the rising incidence of melanoma in situ across racial and ethnic groups without corresponding decreases in invasive disease or similarly increased mortality rates raises concern for overdiagnosis. Artificial intelligence‐based diagnostic tools show promise in NHW populations but are limited by the underrepresentation of SOC in training datasets and diminished positive predictive value in low‐prevalence populations. The estimated number needed to screen to prevent one melanoma death in SOC populations ranges from approximately 46,000 to 201,000, underscoring the challenge of melanoma screening in this group. Suggested solutions and improvements include expanding healthcare access through patient navigators, developing culturally tailored education programs focused on identifying early invasive disease, diversifying AI training datasets to include acral and mucosal melanoma, biobanking rare melanoma subtypes, and decentralizing clinical trials into community settings. A multifaceted approach is essential to addressing overdiagnosis and improving melanoma outcomes in the SOC populations. image

ABSTRACT Background Primary sclerosing cholangitis (PSC) and primary biliary cholangitis (PBC) are rare, chronic cholestatic liver diseases with heterogeneous progression and limited biomarkers of disease biology. Epigenetic age acceleration has been demonstrated in PSC and PBC, suggesting accelerated biological aging. DNA methylation–derived telomere length (DNAmTL) reflects replicative aging and cellular turnover, but its role in PSC and PBC remains unclear. We aimed to evaluate DNAmTL in PSC and PBC and its association with disease severity. Methods We analysed and compared DNAmTL and age‐adjusted DNAmTL among patients with PSC ( n = 474) versus PSC controls ( n = 484) and patients with PBC ( n = 291) versus PBC controls ( n = 291). Associations with clinical outcomes were assessed using nonparametric tests and multivariable logistic regression models. Correlations with primary sclerosing cholangitis Risk Estimate Tool (PREsTO) score and epigenetic age acceleration (AgeAccelGrim) were evaluated using linear regression. Results Patients with PSC demonstrated significantly shorter age‐adjusted DNAmTL compared with controls (median −0.036 vs. 0.016, p < 0.001). Patients with PBC also exhibited reduced DNAmTL relative to controls (median 6.814 vs. 6.885, p < 0.001). Within PSC, shorter DNAmTL was associated with cirrhosis (OR 0.21, 95% CI 0.06–0.69, p = 0.013) and advanced disease (OR 0.20, 95% CI 0.06–0.67, p = 0.009). Shorter DNAmTL was also observed in hepatic decompensation and hepatobiliary malignancy, including cholangiocarcinoma. DNAmTL inversely correlated with PReSTO score ( p < 0.001). DNAmTL was strongly inversely correlated with AgeAccelGrim in both PSC and PBC ( p < 0.001). Conclusion Cholestatic liver diseases are associated with shortened DNAmTL, which independently correlates with disease severity in PSC. Together with epigenetic age acceleration, these findings support a model of accelerated biological aging in PSC and PBC characterized by converging signatures of accelerated biological aging that may contribute to progressive biliary injury and fibrosis.

Introduction Extracranial internal carotid artery (ICA) aneurysms are rare (<1% of arterial aneurysms) yet clinically significant due to risks of distal embolization, local compressive symptoms, and, less commonly, rupture. High-quality evidence is limited, and no consensus guidelines exist, management is therefore individualized to aneurysm morphology, cervical segment involvement, vessel tortuosity, and operator expertise. Flow diversion with Pipeline Embolization Device (PED) achieves aneurysm exclusion while reconstructing the parent artery and is especially useful in tortuous cervical segments. Clinical Summary A 60-year-old woman with incidentally discovered bilateral cervical ICA aneurysms (left 2.3 cm mid-ICA; right 0.5 cm) and a type III bovine arch underwent PED diversion of the lesion. Via femoral access, a long 6-F Fubuki sheath (Asahi Intecc, Irvine, USA) with Sofia catheter (Micro-Vention, Tustin, USA) support and systemic heparinization (ACT >250 s) enabled deployment of a 5.0 × 25 mm Pipeline Flex (Medtronic Neurovascular, Irvine, USA) across the aneurysm neck. Immediate angiography showed intra-aneurysmal stasis while preserving parent-artery flow . At 12 months, she is asymptomatic with a 70% reduction in the contrast-opacified aneurysm component to 7 mm, and the contralateral small aneurysm remains stable. Conclusion Flow diversion with a PED provided an effective, artery-preserving solution for a mid-cervical ICA aneurysm in tortuous anatomy, achieving immediate flow stasis with parent-artery patency. At 12 months, the patient is asymptomatic with a contrast-opacified component reduced to 7 mm. This case supports using flow diversion for extracranial ICA aneurysms when anatomy is favorable, alongside careful antiplatelet therapy and planned imaging follow-up.

Background: Operative decision-making in gastric gastrointestinal stromal tumor (GIST) surgery is strongly influenced by tumor anatomy. Although surgeons routinely consider anatomic features such as proximity to the gastroesophageal junction, posterior wall location, and endophytic growth during operative planning, their combined association with operative strategy has not been systematically evaluated. Methods: We evaluated whether commonly recognized anatomic features of gastric GISTs were associated with operative strategy in a contemporary minimally invasive surgical cohort. Tumors were characterized according to the presence of three predefined anatomic features: proximal location near the gastroesophageal junction, posterior wall involvement, and endophytic growth pattern. Cases were grouped as lower (0–1 features) or higher (2–3 features) complexity. The primary outcome was operative strategy, categorized as simple (wedge resection or enucleation) or complex (partial gastrectomy or transgastric resection). Associations between anatomic complexity and operative approach were evaluated. Results: A total of 83 patients were included, with 50 (60.2%) classified as lower complexity and 33 (39.8%) as higher complexity. Operative strategy varied significantly by complexity group. Tumors in the higher complexity group were more frequently managed with complex operative techniques, including partial gastrectomy and transgastric resection ( P = .002). This association remained significant after adjustment for tumor size (odds ratio 2.87, 95% CI: 1.12–7.65, P = .031). A graded relationship was observed, with increasing use of complex techniques as the number of anatomical features increased. The robotic platform was used more frequently in higher complexity cases ( P = .03). Perioperative outcomes were comparable between groups. Conclusions: Recognized anatomical features of gastric GISTs were associated with operative strategy and reflected real-world surgical decision-making. Systematically describing these features may facilitate preoperative assessment and improve consistency in reporting operative approaches.

Abstract INTRODUCTION Plasma phosphorylated tau 217 (p‑tau217) immunoassays are increasingly being used to assess Alzheimer's disease (AD) pathology despite limited data affirming test reliability over time. METHODS Clinical performance of the Fujirebio Lumipulse G p‑tau217 assay was assessed in 744 Mayo Clinic patients presenting for evaluation of cognitive impairment between July 2024 and December 2025. Cerebrospinal fluid p‑tau181/amyloid beta 42 or amyloid positron emission tomography, within 1 year of p‐tau217 testing, were used as reference. Analytical robustness was evaluated by tracking result frequencies over time, conducting quality control checks, performing 10 lot‑to‑lot comparisons, and comparing two versions of reagents. RESULTS Diagnostic accuracy for detection of AD pathology was 93% (95% confidence interval 91–95) with 23% intermediate results. Reduced estimated glomerular filtration rate was associated with increased intermediate results among amyloid‐negative individuals. Result frequencies remained stable, average imprecision was 8%, and analytical bias between lots and version changes were ≤ 11%. DISCUSSION The findings support plasma p‐tau217 reliability in clinical practice for evaluation of cognitively impaired individuals.

This Perspective discusses whether secondary genomic findings in the clinical context of diagnostic genomic sequencing tests should be sought and reported.

Abstract Skeletal muscle is a major determinant of functional status. The impact of advanced prostate cancer (aPC) systemic therapies on body composition is unknown. We identified aPC patients with serial PET-CTs receiving androgen deprivation therapy (ADT), androgen receptor pathway inhibitors (ARPI), chemotherapy, and/or Lutetium-177. An artificial intelligence algorithm quantified body composition changes from PET-CT images. Linear mixed effects models examined body composition changes over time by treatment type. The algorithm examined 2,342 PET-CTs from 468 patients. On multivariable analysis, ADT was associated with a 9% reduction in muscle density (-1.91 Hounsfield units), ARPIs an additional 6% (-1.4 Hounsfield units), and Lutetium-177 a subsequent 6% (-1.3 Hounsfield units), demonstrating progressive reduction in muscle density across later stages of systemic therapy. This large longitudinal analysis of body composition in aPC patients supports the use of an automated PET-CT algorithm to identify aPC patients on systemic therapy at risk for muscle wasting.