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BACKGROUND: The optimal antithrombotic treatment after transcatheter left atrial appendage closure (LAAC) remains to be determined. The objective of this trial was to compare anticoagulation and antiplatelet therapy for preventing device-related thrombosis (DRT) after LAAC. METHODS: This was a prospective multicenter international randomized trial comparing 2 different antithrombotic strategies for preventing DRT after LAAC in patients with nonvalvular atrial fibrillation. Patients were randomized (1:1) to receive direct oral anticoagulants (DOACs) or dual antiplatelet therapy (DAPT; aspirin+clopidogrel) for 60 days. Patients underwent transesophageal echocardiography at 60 days, and the images were analyzed in a central echocardiography laboratory by experienced echocardiographers blinded to the allocated treatment. The primary outcome was DRT as determined by transesophageal echocardiography 60 days after LAAC in patients receiving the allocated treatment at the time of transesophageal echocardiography (per-protocol analysis). The safety outcome included all-cause mortality, stroke, bleeding, or site-reported DRT within 60 days after LAAC in all randomized patients (intention-to-treat analysis). RESULTS: A total of 510 patients (mean age 77±9 years, 35% women) were included between October 2018 and May 2025, and 253 and 257 patients were randomized to the DOAC and DAPT groups, respectively. Of these, 399 patients underwent transesophageal echocardiography and were receiving the allocated treatment at 60 days after LAAC. The primary outcome occurred in 3 patients (1.5%) in the DOAC group compared with 8 patients (4.1%) in the DAPT group (difference, −2.7% [95% CI, −6.0% to 0.6%]; P =0.110). The safety outcome occurred in 52 patients (22.5%) in the DOAC group compared with 82 patients (34.9%) in the DAPT group (difference, −12.4% [95% CI, −20.6% to −4.2%]; P =0.003), and differences were mainly driven by a lower rate of bleeding events in the DOAC group (44 patients [17.4%] versus 64 patients [24.9%]; difference, −7.5% [95% CI, −14.6% to −0.4%]; P =0.038). CONCLUSIONS: The use of DOACs after LAAC failed to reduce DRT compared with DAPT, but it was associated with an improved safety profile. The results of this study should be interpreted with caution because of statistical power issues related to the narrower-than-expected between-group differences and will need confirmation in future larger studies. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT03568890.

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: R.J. Auchus: Has been involved in contracted research with companies such as Neurocrine Biosciences/Neurocrine UK, LTD, Spruce Biosciences, Corcept Therapeutics, Crinetics Pharmaceuticals, Recordati Rare Diseases, Adrenas Therapeutics, and Mineralys Pharmaceuticals, Served as consultant for organizations like Quest Diagnostics, Corcept Therapeutics, Xeris Pharmaceuticals, Crinetics Pharmaceuticals, Novo Nordisk, Neurocrine Biosciences/Neurocrine UK, LTD, Recordati Rare Diseases, H Lundbeck A/S, Sparrow Pharmaceuticals, Astellas Pharmaceuticals, and Acerand Therapeutics. O. Hamidi: Advisory board member for Neurocrine Biosciences, Corcept Therapeutics, Recordati Rare Diseases, Crinetics Pharmaceuticals, Inc, Camurus, Xeris Pharmaceuticals, Inc, Educational speaking engagement with Recordati Rare Diseases. I. Bancos: None. K. Saag: Recieved grants or contracts from Amgen, Arthrosi, Horizon, LG Pharma, Radius, and Olatec, Received consulting fees from Amgen, Anthrosi, Atom Bioscience, Horizon, LG Pharma, Angitia, and Gruenthal. H. Falhammar: None. U. Srirangalingam: Consulting fees from Crinetics Pharmaceuticals, Diurnal Ltd and H Lundbeck A/S. M. Calanchini: None. E. Jen: Full-time employee of Neurocrine Biosciences, Inc. V.H. Lin: Full-time employee of Neurocrine Biosciences, Inc. J. Sturgeon: Full-time employee of Neurocrine Biosciences, Inc. J.L. Chan: Full-time employee of Neurocrine Biosciences, Inc. Background: Crinecerfont, a corticotropin releasing factor type 1 receptor (CRF1) antagonist, is a first-in-class medication that is FDA-approved for adjunctive treatment to glucocorticoid (GC) replacement to control androgens in patients with classic congenital adrenal hyperplasia (CAH). In the Phase 3 CAHtalyst™ Adult study (NCT04490915), crinecerfont (100 mg BID) significantly reduced adrenal androgens, enabling substantial GC dose reductions from Day 1 baseline (BL) at the end of double-blind placebo-controlled (DBPC) treatment at Week 24, with a least-squares (LS) mean percent change of -27.3% vs. -10.3% for placebo (LS mean difference [LSMD] -17.0%, P<0.0001). At the end of open-label (OL) treatment at Month 12, mean percent decreases from BL in GC dose were -24.6% in participants who continued on crinecerfont (CFT/CFT) and -29.7% in those who switched from placebo (PBO/CFT). Objective: To evaluate clinical outcomes in adults with CAH who received up to 1 year of crinecerfont, in the context of substantial GC dose reductions. Methods: Outcomes related to excess adrenocorticotropic hormone (ACTH)/androgens (e.g., hirsutism in female participants) and GC exposure (e.g., body mass index [BMI], insulin resistance, hyperlipidemia) were analyzed at the end of DBPC treatment (Week 24) and the end of OL treatment (Month 12). DBPC outcomes with P-values are presented as LS mean changes with LSMD. Results: In female participants, mean hirsutism visual analog scale scores (out of 0 [no symptoms] to 100 [very severe symptoms]) were 40.6 (crinecerfont) and 37.4 (placebo) at BL. Changes from BL at end of DBPC (Week 24) and OL (Month 12) were: Week 24 (-9.8 for crinecerfont [n=58] vs -2.8 placebo [n=27], LSMD -7.0, P=0.1564); Month 12 (-11.5 CFT/CFT [n=56], -12.9 PBO/CFT [n=27]). Mean BMI at BL was 30.1 kg/m2 (crinecerfont) and 29.0 kg/m2 (placebo). Changes from BL were: at Week 24 (-0.4 vs. -0.02 for crinecerfont [n=118] vs. placebo [n=57], LSMD -0.40, P=0.1068); at Month 12 (-0.8 CFT/CFT [n=114], -0.4 PBO/CFT [n=56]). Mean homeostatic model assessment of insulin resistance values were high at BL (crinecerfont 3.2, placebo 3.0). Changes from BL were: at Week 24 (-0.6 vs. -0.4 for crinecerfont [n=61] vs placebo [n=29], LSMD -0.29, P=0.3454); at Month 12 (-0.5 CFT/CFT [n=107], -0.9 PBO/CFT [n=54]). Mean values for cholesterol (total, LDL, and HDL) and triglycerides were within normal range or near optimal at BL and remained stable. Conclusion: Adults with CAH who received up to 1 year of crinecerfont continued to show improvements in BMI and insulin resistance, as expected with lower GC doses. Moreover, despite substantial GC dose reductions, hirsutism in female participants improved with crinecerfont. Given the known adverse effects of ACTH/androgen excess and chronic supraphysiologic GC exposure, these results represent a promising therapeutic advancement in CAH. Presentation: Sunday, July 13, 2025

Abstract Disclosure: S.R. Chacko: None. C.A. Villavicencio Torres: None. K. Yu: None. S.G. Waguespack: None. L. Lu: None. Z. Belaya: None. T. Bandgar: None. A. Sada: None. O. Ragnarsson: None. B. Altieri: None. A. Newman: None. P. Vibhatavata: None. M. Tóth: None. E.V. Varlamov: None. C. Badiu: None. A. Paissan: None. M. St-Jean: None. H. Falhammar: None. N. Imamudeen: None. L. Haberbosch: None. M. Bobrowicz: None. A. Tabarin: None. R. Shah: None. M.R. Gadelha: None. A. Peersen: None. W.F. Young: None. J. Kaplan: None. J. Varghese: None. M.A. Habra: None. O. Golounina: None. G.A. Melnichenko: None. A.R. Lila: None. C. Yamichannaiah: None. I. Bancos: None. Context: Cushing syndrome (CS) due to ectopic ACTH secretion (EAS) is a rare condition, associated with severe hypercortisolism and consequent morbidity and mortality. Its varied and often emergent presentation make diagnosis and treatment challenging. Objectives: 1.Characterize clinical and biochemical presentation of EAS. 2.Describe the scope of hypercortisolism-related complications, overall and CS-specific mortality. 3.Identify factors associated with CS-specific mortality. Methods: We conducted a multicenter retrospective cohort study in patients with EAS at 37 centers. Outcomes were clinical/biochemical severity scores, complications, overall and CS-specific mortality. Results: In 1053 patients [median age at diagnosis 52 years (IQR 37-64), 57% women], metastatic disease was present at diagnosis in 585 (56%). The most common sources of EAS were bronchial neuroendocrine neoplasm (NEN) (304, 29%), pancreatic NEN (114, 11%) and small cell lung carcinoma (114, 11%), with the source of EAS being occult in 192 (18%). Clinical and biochemical severity scores were severe in 475 (45%) and 873 patients (92%) respectively. Hypokalemia was present in 819 patients (78%) in the year prior to diagnosis. Of 342 patients (32%) who had IPSS, 301 (88%) suggested an ectopic source, 7 (2%) a pituitary source, and 23 (7%) were non-diagnostic. Of 595 patients who had both functional and cross-sectional imaging, discordant findings were seen in 122 (21%), concordant lesion was seen on both in 326 (55%), and no lesion in 147 (25%). Of those with discordant results, cross-sectional imaging was accurate in 66 (54%) and functional imaging in 56 (46%).Management included medical therapy alone in 237 (23%), surgical excision of the source of EAS in 158 (15%), bilateral adrenalectomy in 77 (7%) and multimodal therapies in 498 patients (47%). Complications within 5 years after diagnosis included hospitalization related to CS or its therapy in 351 (33%), infection in 337 (32%), thromboembolic event in 102 (10%), cardiovascular event in 83 (8%) and cerebrovascular event in 27 (3%). During a median follow-up of 35 months (IQR 20-122) from CS diagnosis, death occurred in 462 patients (44%), with the cause of death related to CS in 149 (14%). CS-specific mortality was higher in metastatic compared with non-metastatic disease (19% vs. 7%, P<0.001). On multivariable analysis of age, sex, clinical and biochemical severity, older age (HR 1.03, 95% CI: 1.02-1.04) and lower clinical severity score (HR 0.97, 95% CI: 0.94-0.99), were associated with higher CS-specific mortality. Conclusion: Our interim analysis, the largest worldwide, found that most patients with EAS had severe hypercortisolism and hypokalemia. Metastatic disease was present in 56%, and the source of EAS was occult in 18%. CS-related death occurred in 14%, emphasizing the need for urgent management. Presentation: Monday, July 14, 2025

Abstract Disclosure: I. Bancos: None. H. Falhammar: None. J. Young: None. R. Pivonello: Received research funding from Corcept Therapeutics, Neurocrine Biosciences, Recordati AG, Spruce Bioscience and Xeris Pharmaceuticals (Strongbridge Biopharma), Consultant for Corcept Therapeutics, Crinetics Pharmaceuticals, HLundbeck A/S and Recordati Rare Diseases.. G. Russo: None. M.R. Stancampiano: None. V.H. Lin: Full-time employee of Neurocrine Biosciences, Inc. J. Sturgeon: Full-time employee of Neurocrine Biosciences, Inc. J.L. Chan: Full-time employee of Neurocrine Biosciences, Inc. Background: In patients with classic congenital adrenal hyperplasia (CAH), chronic glucocorticoid (GC) treatment, especially at supraphysiologic doses, can lead to weight gain or obesity. Crinecerfont, a corticotropin releasing factor type 1 receptor (CRF1) antagonist, is a first-in-class medication that is FDA-approved for adjunctive treatment to GC replacement to control androgens in patients with CAH. In CAHtalyst™ Adult (NCT04490915), least-squares mean (LSM) percent changes in GC dose at Week 24 (end of double-blind placebo-controlled [DBPC] period) indicated a significant reduction with crinecerfont (-27.3% vs 10.3% for placebo; LSM difference [LSMD] -17.0%; P<0.0001) while androstenedione was maintained or improved relative to Day 1 baseline (BL). At Month 12 (end of open-label [OL] period), mean percent decreases from BL were -24.6% in participants continuing crinecerfont (CFT/CFT) and -29.7% in those switched from placebo (PBO/CFT). Objective: To evaluate weight-related outcomes in adults with CAH who received up to 1 year of crinecerfont. Methods: Mean change from Day 1 BL in body mass index (BMI) and mean percentage change from BL in weight were analyzed at Week 24 and Month 12. Achievement of >5% reduction in weight was also analyzed, with results presented as % (n/N: n=number meeting response threshold, N=number who were overweight/obese [BMI ≥25 kg/m2]) at BL and had available data at assessment [Week 24 and Month 12]). For predefined endpoints in the DBPC period, results are presented as LSM changes with LSMD and P-value. Results: Mean BMI at BL was 30.1 kg/m2 (crinecerfont) and 29.0 kg/m2 (placebo), and >70% of participants were overweight or obese (74.6% [91/122] crinecerfont; 63.3% [38/60] placebo). At Week 24, LSM changes from BL for crinecerfont vs placebo were as follows: BMI (-0.42 vs -0.02; LSMD: 0.40, P=0.1068); percent change in weight (1.45% vs -0.07%; LSMD: 1.38%, P=0.0856). At Month 12, further mean reductions from BL were observed with crinecerfont in BMI (-0.81 kg/m2 CFT/CFT, -0.44 kg/m2 PBO/CFT) and weight (-2.72% CFT/CFT, -1.37% PBO/CFT). Among participants who were overweight or obese at BL, a higher percentage achieved >5% reduction in weight at Week 24 with crinecerfont 18.4% (16/87) versus placebo 13.5% (5/37). At Month 12, 27.4% (23/84) and 38.9% (14/36) achieved this threshold in the CFT/CFT and PBO/CFT groups, respectively. Conclusion: Adults with CAH who received up to 1 year of crinecerfont showed reductions in BMI and weight. Among participants who were overweight or obese at BL, 30.8% achieved a >5% reduction in weight at Month 12. These analyses indicate that the substantial GC dose reductions enabled by crinecerfont can allow for improvements in the weight-related effects associated with chronic supraphysiologic GC exposure. Presentation: Sunday, July 13, 2025

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.

Abstract Aims Endogenous endophthalmitis (EE) is a rarely reported complication of infective endocarditis (IE). In an international series, we sought to determine the clinical and microbiological profile, treatment, and outcome of patients presenting with IE-related EE. Methods and results Cases recorded from 2014 to 2023 in nine centres in Europe and the United States were collected. Results were compared to a matched control group. Conclusion Sixty-six patients with EE were reported, mean age of 65.2 ± 14.9 years, 71% (n = 47) male. Blood cultures were positive in 97% (64 cases) of patients, with a predominance of streptococci (46%, n = 30). As compared with the control group (n = 264), the EE group presented with more frequent diabetes (35% vs. 21%, P = 0.02), history of cirrhosis (9% vs. 3%, P = 0.04), glomerulonephritis (15% vs. 0.4%, P < 0.001), embolism before admission (92% vs. 55%, P < 0.001), and Janeway lesions (9% vs. 1%, P = 0.002). Streptococcal infection (46% vs. 26%, P = 0.001) was more frequent and Enterococcal infection (0% vs. 18%, P < 0.001) less frequent in the EE group. The main ocular symptoms were a decrease in visual acuity (96%), red eye (55%), and ocular pain (55%). Treatment of EE consisted of intravitreal antibiotic injection in 55 (83%) patients and vitrectomy in 17 (26%). Improvement of visual acuity was observed in 36 (55%) patients. Conclusion EE is a serious complication of IE with severe residual vision impairment. Patients with IE should be evaluated for ocular complications, since early detection of EE is crucial to prevent delays in management and to preserve visual function.

The clinical courses of 51 patients with postherpetic pain who were referred to the Pain Clinic were reviewed. Twenty-three patients were treated on a trial basis with an intensive series of sensory and sympathetic blocks, whereas 28 control patients, who were seen before the initiation of this study, were treated with other modalities. Fifteen control patients (54%) were disabled by postherpetic neuralgia, as compared with four patients (17%) in the trial group.

Abstract Background Insulin resistance leads to changes in lipid and lipoprotein metabolism prior to developing prediabetes, including an increase in the concentration of large very-low-density lipoprotein particles (LVLDL-p), the mean size of VLDL (VLDL-s), and the concentration of small low-density lipoprotein particles (sLDL-p). Conversely, there is a decrease in the concentration of large high-density lipoprotein particles (LHDL-p), mean size of HDL (HDL-s), and mean size of LDL (LDL-s). Clinically validated studies show that proton nuclear magnetic resonance (NMR) can measure these six parameters and derive a lipoprotein insulin resistance (LP-IR) score, ranging from 0 to 100, with higher scores indicating greater risk for insulin resistance. The reference method for calculating LP-IR relies on a proprietary NMR spectrometer, spectral deconvolution method, and algorithm. This study seeks to determine if lipoprotein subfraction parameters measured from a commercially available NMR system can produce LP-IR scores comparable to the reference method. Methods Serum lipoprotein NMR spectra were collected using a Bruker Ascend 600 MHz magnet, Bruker Avance NEO 500 spectrometer, and the Numares AXINON lipoFIT System to report the six LP-IR score parameters between January 2023 and January 2025 (Cohort A, n = 2,474). During the same period, LP-IR score and parameters were collected using the Vantera Clinical Analyzer (400 MHz) with the LipoProfile LP4 method (Cohort B, n = 2,959). Linear regression of decile-matched data for each parameter yielded adjustment equations to align lipoFIT values with the LipoProfile method. LP-IR scores were then calculated for both adjusted and unadjusted values using a previously published LP-IR scoring algorithm. Finally, LP-IR scores were compared for sera with measures from both instruments was (Cohort C, n = 108). Results The median concentrations of sLDL-p, LDL-s, VLDL-s, HDL-S matched between Cohort A and B (<1% difference). Significant differences were noted for LVLDL-p and LHDL-p, with percent differences of 21.5% and 23.5%, respectively. Despite closely matching medians, the distributions varied greatly, with a mean interquartile range (IQR) percent difference across measures of 31.2% (Table 1). After distribution matching, all parameter median and mean IQR percent differences fell to <5% and <10%, respectively, between Cohort A and Cohort B. In Cohort C the LP-IR score matched well (y=1.1x-15, r=0.92; 95%CI 0.88, 0.94). Following distribution matching adjustment of lipoFIT values for Cohort C, new calculated LP-IR scores matched with reduced bias (y=0.94x-1.2) while correlation was slightly reduced (r=0.88 [0.83, 0.92]). By comparison, adjustments made via scaling lipoFIT values proportionally by the ratio of the medians between Cohort A and Cohort B yielded calculated LP-IR scores in Cohort C that maintained a similar bias prior to adjustments (y=1.2x-21), highlighting the ability of distribution matching to reduce bias. Conclusion Adjustments to measured lipoprotein parameters from a commercially available NMR spectrometer can be achieved via distribution matching. These adjustments greatly reduce the bias between a commercially available method and algorithm compared to the reference method, allowing for wider adoption of LP-IR score reporting.