Citations

ABSTRACT Suicidality contributes substantially to global morbidity and mortality, yet despite its heritability, its biological etiology remains largely elusive. We conducted multi-ancestry genome-wide association study meta-analyses of suicidal ideation (259,747 cases), suicide attempt (64,993 cases), suicide death (9,197 cases), and suicidal behavior (suicide attempt/ death, 75,300 cases), across 54 cohorts (e.g., the Psychiatric Genomics Consortium, Million Veteran Program, UK Biobank). We identified 77 significant loci across meta-analyses, including 59 previously unreported for suicidality. SNP-based heritability ranged from 2.0-6.7% and there were strong, yet incomplete, genetic correlations between suicidality phenotypes (0.70-0.88). Fine-mapping prioritized putative causal SNPs and 20 credible genes. Enrichment analyses implicated synaptic pathways and neuronal populations predominantly in subcortical brain regions (e.g., amygdala excitatory, medium spiny, hippocampal CA1-3). Together, these findings establish suicidality as a polygenic set of traits with both shared and distinct genetic influences, providing a foundation for future studies of suicide biology and etiology.

Abstract Disclosure: I. Bancos: AstraZeneca. A. Ben-Shlomo: AstraZeneca. O. Hamidi: Recordati Rare Diseases, Neurocrine Biosciences, Corcept Therapeutics, Crinetics, Camurus, Xeris. A. Hamrahian: AstraZeneca. W. Huang: None. L.S. Kirschner: Corcept Therapeutics, AstraZeneca, Crinetics, Sparrow Pharma, Spruce Biosciences. R. Sam: AstraZeneca. A.F. Turcu: AstraZeneca. A. Lihn: AstraZeneca. A. Mallappa: AstraZeneca. S. Perl: AstraZeneca. B. Tuyishimire: AstraZeneca. M.J. Brown: GlaxoSmithKline, Pfizer, Inc., Bristol-Myers Squibb, AstraZeneca. Introduction: Mineralocorticoid receptor antagonist (MRA) treatment for primary aldosteronism (PA) has limited efficacy in some patients. Highly selective, competitive aldosterone synthase inhibitors (ASIs) offer an alternative therapeutic approach. SPARK (NCT04605549) was a Phase 2, open-label, multicenter trial of the ASI baxdrostat in patients with PA. Methods: Eligibility entailed: aged ≥18 years; diagnosis of PA; willingness to discontinue MRA up to 4 weeks before baxdrostat initiation; and systolic blood pressure (SBP) rise ≥20 mmHg or SBP ≥160 mmHg after discontinuation of MRA, or SBP ≥150 mmHg for patients with newly diagnosed PA who had not taken MRAs in the past 12 weeks. Patients entered a 12-week treatment period (Part 1) of once daily baxdrostat 2 mg, up-titrated to 4 mg or 8 mg at week (W) 4 or W8, respectively, if there was no significant risk of hypotension. Baxdrostat could be down-titrated to 2 mg or continued at 4 mg as needed. After W12, patients could continue baxdrostat up to W72 (Part 2) with doses at investigators’ discretion. Primary endpoints were safety, tolerability and change from baseline in mean seated SBP at W12. Results: Fifteen patients enrolled and completed Part 1; 14 patients continued to Part 2. Median (range) age was 54 (32, 75) years, 67% of patients were male, 47% were White, and median (range) body mass index was 32.0 (24.4, 41.4) kg/m2. At baseline, plasma renin activity (PRA) was <1 ng/mL/h in 12/15 (80%) patients, and 8/15 (53%) patients had hypokalemia (serum potassium <3.5 mmol/L). Mean (range) baseline SBP was 151.5 (130, 174) mmHg; diastolic BP (DBP) was 90.3 (74, 103) mmHg. At W12, mean (range) SBP change from baseline was –29.5 (–47, –12), –24.4 (–31, –17), and –23.9 (–47, –8) mmHg for patients on baxdrostat 2 mg (n=2), 4 mg (n=5), and 8 mg (n=7), respectively; DBP change was –8.0 (–14, –2), –10.4 (–20, 0), and –11.6 (–25, 7) mmHg, respectively. Overall, 11/15 (73%) patients achieved BP <140/90 mmHg and 6/15 (40%) achieved BP <130/80 mmHg at W12; reduced BP persisted in Part 2. No deaths were reported. Nine out of 15 (60%) patients had a treatment-emergent adverse event (TEAE) during W4–W12 of Part 1 (all mild/moderate), including 1/15 (7%) patient with hyperkalemia; no serious TEAEs were reported. In Part 2, 14/14 (100%) patients had a TEAE (most mild/moderate), including 5/14 (36%) patients with hyperkalemia; one serious TEAE of hyperkalemia was reported. Mean (standard deviation, SD) serum potassium levels increased from 3.9 (0.6) mEq/L at baseline to 4.7 (0.5) mEq/L at W12. Mean (SD) 24-h urine aldosterone excretion at baseline and W12 were 30.3 (17.5) and 3.2 (2.7) µg/day, respectively. At W12, 7/15 (47%) patients had achieved unsuppressed PRA (≥1.0 ng/mL/h). Conclusions: Baxdrostat, an ASI, was well tolerated and led to reduced BP and unsuppressed renin in patients with PA. Inhibiting aldosterone synthase may be an alternative to MRAs for treating PA. Presentation: Sunday, July 13, 2025

Importance Contemporary guidelines recommend sentinel lymph node biopsy (SLNB) for patients with melanoma with predicted risk of SLN metastasis greater than 10% and consideration of SLNB when the risk is 5% to 10%. A gene expression profile (GEP)–based test that can accurately identify patients with a low risk of SLN metastasis would refine selection for SLNB. Objective To establish the predictive capability of the combined clinicopathological factors and GEP (CP-GEP) test to identify patients with primary cutaneous melanoma who can safely forgo SLNB and to investigate the prognostic value of CP-GEP regarding the outcome in patients with cutaneous melanoma after a negative SLNB (not reported herein). Design, Setting, and Participants This prognostic study was conducted from September 2021 to June 2024 at 9 academic medical centers with experienced melanoma surgeons. Included were patients with biopsy-proven invasive cutaneous melanoma with T1 to T3 tumors and clinically negative regional LNs. All patients were deemed candidates for SLNB using standard clinical criteria. GEP was performed on formalin-fixed, paraffin-embedded tissue from the primary melanoma biopsy. Analyses were performed from December 2024 to August 2025. Intervention CP-GEP testing to determine risk of having a positive SLNB in patients with T1 to T3 cutaneous melanoma who were considered appropriate candidates for the procedure based on standard clinical parameters. Main Outcomes and Measures CP-GEP results were reported as low risk or high risk; the primary outcome measure was negative predictive value (NPV) in low-risk cases. Analyses included NPV assessment by tumor (T) subcategory, primary site, and age. Results A total of 1761 patients (median [IQR] age, 64 [53-72] years; 997 male [56.6%]) underwent SLNB (310 [17.6%] SLN positive) and had a successful CP-GEP test; GEP was successful in 97.7% of samples. A total of 651 patients (37.0%) were considered low risk by CP-GEP. Among low-risk cases, 46 (7.1%) were SLN positive, and NPV was 92.9% (95% CI, 90.7%-94.8%). High-risk cases had a 23.8% (264 of 1110) SLN-positive rate. The percentage of cases with low-risk CP-GEP declined with increasing T category (T1 = 346 of 507 [68.2%]; T2 = 295 of 897 [32.9%]; T3 = 10 of 357 [2.8%]). CP-GEP results were consistent in discriminating SLN-positive rates across primary sites, histologic subtypes, and mitotic count categories. In 2 large subsets, clinical stage IB (n = 1187) and patients 65 years and older (n = 832), 6.5% (95% CI, 4.6%-8.8%) of low-risk clinical stage IB cases and 6.6% (95% CI, 4.2%-9.7%) of all low-risk cases in patients 65 years and older were SLN positive vs 18.3% (95% CI, 15.3%-21.6%) and 20.3% (95% CI, 16.8%-24.2%) for high-risk cases, respectively. Conclusions and Relevance In this multicenter, prospective, blinded, prognostic study, the CP-GEP test reliably identified patients with melanoma with less than 10% SLN metastasis risk. SLN metastasis rates were approximately 3-fold greater for high-risk vs low-risk CP-GEP cases. In appropriately selected patients, the CP-GEP test may add value for shared patient-surgeon decision-making.

Abstract The diagnosis of T‐cell neoplasms remains one of the most challenging areas in hematopathology due to the immunophenotypic heterogeneity and subtle aberrancies often present in these entities. This “Best Practice” manuscript provides a practical framework for laboratories to design, validate, and interpret immunophenotyping studies of immature and mature T‐cell neoplasms. We outline the utility of key antigens in the screening and classification of T‐cell lymphomas/leukemia including TRBC1 and TRBC2. Analytical strategies using the “difference from normal” method and template‐based gating are discussed, along with validation considerations aligned with CLSI H62 guidelines. By integrating these principles into laboratory workflows, this manuscript aims to standardize and improve the assessment of T‐cell neoplasms across diverse clinical settings.

Background: Massive weight loss after bariatric surgery (BS) often results in excess skin, leading to physical discomfort and impaired quality of life (QoL). Body contouring surgery (BCS) addresses these issues by restoring body image, improving function, and enhancing overall QoL, but its added value on patient-reported outcome measures (PROMs) remains underexplored. Methods: A systematic search of PubMed, Scopus, Embase, Web of Science, and Cochrane databases was conducted from inception to March of 2025. Studies comparing PROMs between patients undergoing BS alone and those undergoing BS + BCS were included. Retrieved studies were assessed using the Risk of Bias in Nonrandomized Studies of Interventions (ROBINS-I) tool. Outcomes were pooled using random effects models. Results: Fifteen non-randomized studies involving 7339 patients were included (BS, 4339 [59.1%]; BS + BCS, 3000 [40.9%]). Patients undergoing BS + BCS had a significantly greater percentage of total weight loss (mean difference [MD], 4.40% [95% CI, 1.69, 7.10]; P < 0.01). BODY-Q improvements favored the BS + BCS group in body image, physical, psychological, sexual, and social function (MD, 16.07 [95% CI, 12.14, 20.0]; P < 0.01). Among patients receiving only BS, those desiring BCS reported lower body satisfaction (MD, −0.40 [95% CI, −0.70, −0.10]; P < 0.01) and lower appraisal of excess skin scores (standardized MD, −1.09 [95% CI, −1.83, −0.36]; P = 0.02) than those without desire for BCS. Conclusions: BCS after BS yields substantial improvements in overall QoL. These findings highlight the importance of BCS as a fundamental element of comprehensive postbariatric care that significantly enhances long-term patient satisfaction and drives durable multidimensional recovery.

Importance The effect of cornea donor diabetes on endothelial cell density (ECD) and morphometry after Descemet membrane endothelial keratoplasty (DMEK) is not known. Objective To determine whether endothelial cell loss (ECL) and morphometric changes 1 year after successful DMEK are related to cornea donor’s diabetes status. Design, Setting, and Participants This was a multicenter, double-masked, randomized clinical trial conducted from February 2022 to July 2024 at 28 US clinical sites (46 surgeons) and 13 eye banks. Included in the trial were the eyes of recipients (some of whom received tissue from donors without diabetes and others who received tissue from donors with diabetes) who underwent successful DMEK, primarily for Fuchs endothelial corneal dystrophy, and had at least 1 analyzable postoperative endothelial image. Intervention DMEK performed with a cornea from a donor without or with diabetes, assigned using a minimization procedure to achieve an approximate 2:1 distribution. Main Outcomes and Measures ECD, ECL, coefficient of variation in cell area (CV), and percentage of hexagonal cells (HEX) at 1 year from eye bank and postoperative specular central endothelial images. Results A total 1274 eyes of 982 recipients (mean [SD] age, 70 [8] years; 569 female [57.9%]; 816 [64.1%] with tissue from donors without diabetes and 458 [35.9%] with tissue from donors with diabetes) were included in the study. Preoperatively, mean (SD) central ECD in tissue from donors without diabetes and with diabetes were 2676 (290) cells/mm 2 and 2671 (286) cells/mm 2 , respectively. At 1 year, mean (SD) ECL was 28.3% (16.1%) and 28.0% (17.0%), in the donor groups without and with diabetes, respectively (adjusted mean difference = −0.4%; 95% CI, −2.3% to 1.4%), resulting in a mean (SD) 1-year ECD of 1927 (498) cells/mm 2 and 1920 (496) cells/mm 2 , respectively (adjusted mean difference = 10 cells/mm 2 ; 95% CI, −36 to 56; P = .95). No difference in ECD at 1 year associated with diabetes severity was noted ( P = .97). Mean (SD) CV did not differ at 1 year between the 2 groups of eyes (31.5% [4.1%] vs 31.4% [4.1%]; adjusted mean difference = −0.4%; 95% CI, −0.9% to 0.1%; P = .51), and mean (SD) HEX did not differ at 1 year between the 2 groups of eyes (57.7% [5.8%] vs 57.2% [5.8%]; adjusted mean difference = 0.1%, 95% CI, −0.8% to 0.9%; P = .33). Conclusions and Relevance This randomized clinical trial found that ECL and morphometry 1 year after DMEK were not affected by cornea donor diabetes status. With comparable 1-year graft success with tissue from donors with and without diabetes demonstrated in this trial, these findings support the use of corneas from donors with diabetes for endothelial keratoplasty procedures. Trial Registration ClinicalTrials.gov Identifier: NCT05134480

Importance If the success of Descemet membrane endothelial keratoplasty (DMEK) is not affected by whether the donor has diabetes, then the donor pool should expand. Objective To determine whether the 1-year DMEK success rate is affected by the presence of diabetes in the donor. Design, Setting, and Participants This was a multicenter, double-masked, randomized clinical trial conducted from February 2022 to July 2025 at 28 clinical sites (46 surgeons), with donor corneas provided by 13 eye banks in the US. Included in the study were individuals undergoing low to moderate risk DMEK (95% for Fuchs endothelial corneal dystrophy). Study data were analyzed from April to September 2025. Intervention DMEK performed with a cornea from a donor without or with diabetes, assigned using a minimization procedure (comparable with randomization) to achieve an approximate 2:1 distribution, respectively. Main Outcomes and Measures Graft success at 1 year Results A total of 1097 individuals (1421 study eyes; median [IQR] age, 71 [66-76] years; 631 female [57.5%]) were included in the study. The 1-year cumulative probability of graft success was 96.3% (95% CI, 95.0%-97.5%) among 912 study eyes (64.2%) receiving tissue from donors without diabetes and 97.1% (95% CI, 95.5%-98.4%) among 509 study eyes (35.8%) receiving tissue from donors with diabetes (difference between groups = 0.7 percentage points; 95% CI, −1.2 to 2.6; P = .63). The 1-year cumulative probability of graft success was 96.5% (95% CI, 93.6%-98.9%) in the mild donor diabetes severity subgroup (n = 173) and 97.3% (95% CI, 95.4%-98.8%) in the moderate to severe donor diabetes severity subgroup (n = 336), using a diabetes severity rating scale based on medical history. The rates of primary donor failure, early failure related to surgical complications, and subsequent failure were as follows: 2.5% (23 of 912), 0.7% (6 of 912), and 0.3% (3 of 912), respectively, in recipients of tissue from a donor without diabetes, and 2.6% (13 of 509), 0.4% (2 of 509), and 0%, respectively, among recipients of tissue from a donor with diabetes. There were no failures due to graft rejection. Conclusions and Relevance The 1-year success rate in eyes undergoing DMEK with successfully prepared tissue was very high regardless of donor diabetes status. These results, supported by the separately reported finding that endothelial cell loss and cornea morphometry after 1 year were not affected by donor diabetes status, provide strong support for having no restrictions on the use of tissue from donors with diabetes for DMEK. Trial Registration ClinicalTrials.gov Identifier: NCT05134480

Abstract Rehabilitation after musculoskeletal trauma is globally acknowledged as essential for restoring function and improving quality of life; however, significant variation exists in rehabilitation frameworks and services worldwide. Although certain principles—such as early intervention, structured care pathways, and multidisciplinary approaches—are universally recognized as important determinants of outcomes in trauma patients, their implementation and effectiveness vary considerably due to differences in health care infrastructure, economic resources, policy frameworks, and cultural contexts. Drawing on comparative analyses of rehabilitation frameworks across regions, including North America, Latin America, Europe, Asia-Pacific, and Africa, this paper identifies structural variations, systemic challenges, and innovations that can inform global rehabilitation efforts. Strategic international collaboration focusing on shared learning, standardized protocols, technology integration, and targeted investments is key to creating equitable and sustainable rehabilitation models, especially in resource-limited settings and aging populations.

Abstract The da Vinci Single-Port (SP) system is a robotic surgery platform that allows access into the abdominal cavity through a single short surgical incision. The omentum is an attractive donor site for vascularized omental lymph node transfer (VOLT) in the treatment of lymphedema. We hypothesize that SP robotic VOLT will allow for improvement in perioperative outcomes as compared to open laparotomy for omental flap harvest. A retrospective cohort study was performed, comprised of a study sample of patients with a diagnosis of lymphedema who presented to our institution for VOLT using either an open or SP robotic technique between May 2020 and February 2023. The primary outcome was length of hospital stay. The secondary outcomes included intraoperative complication rate, postoperative complication rate, and length of surgery. Fifteen patients underwent da Vinci SP omental flap harvest, and 14 patients underwent open harvest. There was no significant difference in average age, BMI, sex, or lymphedema etiology between the two groups. Average length of stay was 2.2 ± 1.7 days in the SP group and 2.3 ± 2.1 days in the open group (p = 0.91). There were no significant differences in terms of intraoperative or postoperative complications between the two groups. Ninety-three percent of SP robotic and 86% of open patients reported at least partial subjective improvement following VOLT (p = 0.50). Our findings suggest that SP robotic omental harvest for VOLT is feasible. Perioperative outcomes show comparable results in terms of length of hospital stay, complications, and subjective postoperative improvement when comparing the open to the SP approach.