Citations

ABSTRACT Bipolar disorder’s (BD) clinical heterogeneity has an unresolved genetic basis. We meta-analyzed genome-wide association studies (GWAS) of 16 BD subphenotypes in 226,032 individuals from 57 cohorts (38,022 cases); 10 advanced to multivariate and multi-trait analyses. Four factors (compulsive, psychotic, dysregulated, internalizing) explained 82.8% of shared genetic variance. BD1 and BD2 loaded on distinct factors despite a high genetic correlation; 87.0% of common-factor loci were significant in neither subtype. Unipolar mania aligned with psychosis over internalizing, and was distinguishable from BD1, and rapid cycling showed heritable cross-domain liability. We identified 356 risk loci, 158 novel, including the first univariate-GWAS associations for psychosis, unipolar mania, rapid cycling and schizoaffective disorder—and 249 credible genes (89 high-confidence), 12 with approved-drug or clinical-phase annotations. Cell-type association showed a midbrain dopaminergic–GABAergic gradient along the psychotic factor. BD’s genetic architecture appears hierarchical—a general liability resolving into dimensions of course and comorbidity beyond diagnostic subtypes.

Background The Midclavicle Block achieves balanced methylene blue spread across both anterosuperior and posteroinferior periosteal surfaces in cadavers with intact clavicles. Objective To evaluate the anatomical distribution pattern of the Midclavicle Block in cadaveric specimens with midshaft clavicle fractures, with a focus on periosteal coverage and involvement of the fracture site. Methods An anatomical study was conducted on 10 cadavers (20 clavicular regions). A midshaft clavicle fracture model was created, and the Midclavicle Block technique was applied under ultrasound guidance. A methylene blue solution was injected, and dissections were performed to evaluate dye spread primarily in the deep muscular and the clavicular plane, including the fracture site. Probabilistic maps of dye distribution were generated. Results The anatomical dissection in the deep muscular plane revealed consistent staining of the fracture site in all specimens, along with the subclavius muscle and the clavipectoral fascia, while the pectoralis minor muscle remained unaffected in every case. As the dissection progressed toward the infraclavicular brachial plexus plane, no staining of the plexus was observed, with dye spread restricted to the subclavius muscle and adjacent clavipectoral fascia. The mean staining of the anterosuperior and posteroinferior periosteal surfaces was 55.5% (95% CI: 50.6% to 60.4%) and 53.8% (95% CI: 49.5% to 58.1%), respectively. The highest dye concentration was observed in the middle third of the clavicle, corresponding to the fracture zone. Conclusion The Midclavicle Block resulted in effective periosteal coverage and targeted fracture site staining. Clinical studies are needed to confirm its in vivo efficacy, given the limitations inherent to cadaveric specimens.

ABSTRACT Background Membranous nephropathy (MN) associated with phospholipase A2 receptor (PLA2R) antibodies is the most common cause of nephrotic syndrome in non-diabetic adult patients. This study investigated the relationship between clinical phenotypes and renal outcomes in this population, emphasizing the potential for phenotype-based treatment stratification. Methods We conducted a retrospective, multi-center cohort study of PLA2R-positive MN. Unsupervised cluster analysis grouped patients based on clinicopathological characteristics. Primary outcomes included complete or partial remission within 2 years of biopsy and end-stage kidney disease (ESKD) or death during follow-up. Results Among 178 patients, three distinct clusters emerged (n = 89, 70, and 19). Within 2 years of biopsy, 102 patients (57%) achieved complete or partial remission. Cluster 1, characterized by the mildest disease markers, including the lowest body mass index, serum anti-PLA2R titer, serum creatinine, proteinuria, and triglycerides, had the highest remission rate of 72%, compared with 50% in cluster 2 and 54% in cluster 3. Cluster 2 had significantly lower remission compared to cluster 1 (HR 0.64, 95% CI 0.42–0.96, P = .03); results were similar in cluster 3, albeit not statistically significant (HR 0.50, 95% CI 0.23–1.09, P = .08). Elevated anti-PLA2R levels (>100 U/ml) and proteinuria (>8 g/24-hour) predicted reduced remission (HR 0.56, 95% CI 0.36–0.88, P = .01; HR 0.43, 95% CI 0.26–0.73, P = .002, respectively), while high high-density lipoprotein levels were protective (HR 1.01, 95% CI 1.00–1.02, P = .048). Overall, 21 patients (12%) developed ESKD or died. ESKD-free survival differed significantly across clusters (log-rank test P = .04). Conclusions Unsupervised clustering identified distinct clinical phenotypes in PLA2R-positive MN, each associated with different renal prognoses. Phenotype-based risk stratification could enhance treatment precision, improve patient outcomes, and potentially reduce treatment-related adverse effects.

Background: Despite the association of insulin resistance (IR) in the pathophysiology of Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD), few studies have evaluated the utility of acanthosis nigricans (AN) as a clinical predictor for this condition. Thus, we aimed to determine the role of AN as a risk factor and clinical predictor of MASLD. Methods: This cross-sectional study conducted a comprehensive clinical history and physical examination. The presence of acanthosis nigricans was assessed in the neck, elbows, axillae, and knuckles. Liver biochemical parameters were measured, hepatic fat was analyzed using the controlled attenuation parameter (CAP), while hepatic stiffness was evaluated in kilopascals (kPA) with the FibrosScan 530 Compact and Smart Exam software. Multiple analyses were performed to determine the relationship between acanthosis nigricans and MASLD. Results: We recruited 251 adult participants. The mean BMI was 29.9 ± 7.3 kg/m 2 , including 40.2% of participants with obesity and 63.7% with AN. Transient elastography evaluation resulted in 65.7% and 6% participants with hepatic steatosis (S3, 48.6%) and fibrosis, respectively. A non-adjusted (OR 2.63, 95% CI 1.57-4.52) and adjusted model (OR 1.97, 95% CI 0.95-4.12) were determined for AN as a risk factor for liver steatosis. Furthermore, the presence of AN in knuckles resulted in an association to predict liver steatosis (OR 2.09, 95% CI 1.01-4.35), while a multivariate analysis indicated that AN predicts a higher steatosis grade (S2 OR = 6.58, CI 95% 1.18-36.53; S3 OR = 2.36, CI 95% 1.04-5.3). Conclusions: Acanthosis nigricans demonstrated to predict a higher steatosis grade in adults with overweight and obesity. Our study supports the clinical applicability of AN as a screening tool for MASLD to identify high-risk subjects in resource-limited settings. Additional studies are needed to define alternative diagnostic tools for the early identification of metabolic risk factors in populations with specific clinical or demographic characteristics.

Objective: We aimed to estimate the prevalence of cardiovascular diseases (CVDs) and cardiometabolic diseases (CMB) in Brazil, and their relationship with a healthy lifestyle score based on the six pillars of lifestyle medicine proposed by the American College of Lifestyle Medicine. Methods: Data were derived from the 2019 Brazilian National Health Survey, a nationwide cross-sectional study. The prevalence of CVDs/CMB was based on medical-endorsed, self-reported diagnoses and weighted for sample strata. A healthy lifestyle score (0-14 points; the higher the score, the better) incorporates physical activity, diet, sleep, mental health, risky substance use, and social connections. Results: Among 88,531 adults included in the analysis (mean age: 47.1 years; 52.9% female), the weighted prevalence of CVDs/CMB ranged from 1.9% (stroke) to 25.9% (hypertension). Weighted Poisson regression models, adjusted for age, sex, socioeconomic status, and geographic disparities, showed an inverse linear relationship between lifestyle score and CVDs/CMB prevalence. Participants in the highest lifestyle score quartile exhibited lower prevalence for heart diseases [0.48 (95% CI: 0.43, 0.53)], stroke [0.35 (95% CI: 0.29, 0.43)], hypertension [0.85 (95% CI: 0.80, 0.90)], diabetes [0.80 (95% CI: 0.70, 0.91)], dyslipidemia [0.73 (95% CI: 0.66, 0.80)], and obesity [0.81 (95% CI: 0.74, 0.88)], compared to the lowest quartile ( P < 0.001 for all). Conclusions: Higher scores on the six pillars of lifestyle medicine are associated with a lower prevalence of major CVDs/CMB in Brazil.

Key Points Preexisting CKD, elevated serum creatinine, and severe interstitial fibrosis and tubular atrophy were linked to poor renal prognosis in renal sarcoidosis. Steroid therapy was strongly associated with renal recovery and improved long-term outcomes in renal sarcoidosis. Early detection and management of renal involvement in sarcoidosis are critical to preventing irreversible kidney damage. Background Renal sarcoidosis (RS) is a rare but potentially severe manifestation of sarcoidosis, primarily affecting the kidneys through granulomatous interstitial nephritis and calcium metabolic disturbances. This study evaluates the clinicopathologic features and renal outcomes of biopsy-proven RS, focusing on identifying predictors of renal recovery and disease progression. Methods This retrospective study included 43 biopsy-proven RS at Mayo Clinic (2012–2024). Demographic, clinical, laboratory, and histopathologic data were analyzed. Renal recovery within 6 months was classified as complete, partial, or no recovery based on serum creatinine (sCr) changes. Long-term adverse composite outcomes included the CKD onset, CKD progression, ESKD, dialysis initiation, or death. Logistic regression and Cox proportional hazards regression were used to assess predictors of renal outcomes. Results Among the cohort, 84% exhibited interstitial nephritis, with granulomatous interstitial nephritis in 33%. Calcium phosphate deposits were found in 58% of cases. Hypercalciuria (90%) was more common than hypercalcemia (74%). Within 6 months, 86% achieved recovery (74% complete, 12% partial), while 40% experienced long-term adverse composite outcomes. Higher sCr at biopsy (≥2.4 mg/dl) and moderate-to-severe interstitial fibrosis and tubular atrophy were associated with reduced complete recovery and worse long-term outcomes, while preexisting CKD significantly increased the risk of adverse long-term outcomes. Steroid therapy significantly increased the likelihood of complete recovery and reduced the risk of adverse long-term outcomes. Conclusions Preexisting CKD, elevated sCr at biopsy, interstitial fibrosis and tubular atrophy, and steroid therapy are key predictors of renal outcomes in RS. Early diagnosis and intervention are crucial to preventing irreversible kidney damage.

PURPOSE Tumor treating fields (TTFields) use alternating electric fields to disrupt cancer cell proliferation. Feasibility of TTFields therapy with gemcitabine/nab-paclitaxel was previously demonstrated in patients with advanced pancreatic adenocarcinoma. PANOVA-3 was designed to confirm safety and efficacy of TTFields in patients with unresectable locally advanced pancreatic adenocarcinoma (LA-PAC). METHODS In this global phase III trial, 571 patients with newly diagnosed LA-PAC were randomly assigned to receive gemcitabine 1,000 mg/m 2 and nab-paclitaxel 125 mg/m 2 by intravenous infusion once a day on days 1, 8, and 15 of a 28-day cycle with or without TTFields. The primary end point was overall survival (OS). Secondary end points included progression-free survival (PFS), local PFS, pain-free survival, and overall response rate (ORR). Distant PFS was analyzed post hoc. RESULTS OS was significantly prolonged using TTFields with gemcitabine/nab-paclitaxel versus gemcitabine/nab-paclitaxel (median, 16.2 months [95% CI, 15.0 to 18.0] v 14.2 months [95% CI, 12.8 to 15.4]; hazard ratio [HR], 0.82 [95% CI, 0.68 to 0.99]; P = .039). PFS, local PFS, and ORR were not improved. Pain-free survival was significantly prolonged with TTFields with gemcitabine/nab-paclitaxel (median, 15.2 months [95% CI, 10.3 to 22.8] v 9.1 months [95% CI, 7.4 to 12.7]; HR, 0.74 [95% CI, 0.56 to 0.97]; P = .027), as was distant PFS (median, 13.9 months [95% CI, 12.2 to 16.8] v 11.5 months [95% CI, 10.4 to 12.9]; HR, 0.74 [95% CI, 0.57 to 0.96]; P = .022). Device-related skin adverse events (AEs) were experienced by 76.3% of patients. Most device-related skin AEs were mild to moderate, with 7.7% of patients reporting a grade 3 AE. CONCLUSION This study demonstrated significant OS, pain-free survival, and distant PFS benefits for TTFields with gemcitabine/nab-paclitaxel versus gemcitabine/nab-paclitaxel in patients with unresectable LA-PAC, with no additive systemic toxicity.