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Importance Treatment for cognitive dysfunction due to postacute sequelae of long COVID (ie, symptoms of fatigue, malaise, weakness, confusion that persist beyond 12 weeks after an initial COVID infection) remains a significant unmet need. Objective To test evidence-based rehabilitation strategies for improving cognitive symptoms in persons with long COVID. Design, Setting, and Participants This was a 5-arm, multicenter, randomized clinical trial of 3 remotely delivered interventions conducted between August 17, 2023, and June 10, 2024. The study took place at 22 trial sites and included the screening of individuals with cognitive long COVID. Interventions Participants were randomized to 1 of 5 arms: adaptive computerized cognitive training (BrainHQ [Posit Science]), cognitive-behavioral rehabilitation involving both group and individual counseling sessions (PASC-Cognitive Recovery [PASC-CoRE]) paired with BrainHQ, and transcranial direct current stimulation (tDCS) paired with BrainHQ. Two comparator arms were included as follows: unstructured computer puzzles and games (active comparator) and sham tDCS paired with BrainHQ. The interventions occurred 5 times per week over 10 weeks. Main Outcomes and Measures Cognitive and behavioral in-person assessments were performed at baseline, midintervention, at the end of intervention, and 3 months after the end of the intervention. The primary outcome measure was the modified Everyday Cognition Scale 2 (ECog2) completed at the end of the intervention compared to the baseline visit based on participant self-report looking back over the prior 7 days. Results A total of 378 individuals were screened, from which there were 328 participants (median [IQR] age, 48.0 [37.0-58.0] years; 241 female [73.5%]; race: 15 Asian [4.6%], 47 Black [14.3%], and 235 White [71.6%]; ethnicity: 52 Hispanic [15.9%]). None of the 3 active interventions demonstrated benefits on the modified ECog2 in the intention-to-treat population by the end of the intervention period. The adjusted differences in mean change were 0.0 (95% CI, −0.2 to 0.2) for BrainHQ vs active comparator, 0.1 (95% CI, −0.1 to 0.3) for PASC-CoRE + BrainHQ vs active comparator, 0.0 (95% CI, −0.2 to 0.2) for tDCS-active + BrainHQ vs tDCS-sham + BrainHQ, and 0.1 (95% CI, −0.1 to 0.3) for PASC-CoRE + BrainHQ vs BrainHQ alone. Secondary participant-reported outcomes and neuropsychological tests showed no differential benefits for any treatment arm. All 5 arms demonstrated some improvements over time on the modified ECog2 and on secondary outcomes. There were no serious adverse events attributable to the interventions. Conclusions and Relevance This phase 2 randomized clinical trial failed to demonstrate differential benefits for online cognitive training, a structured cognitive rehabilitation program, and tDCS for cognitive long COVID. Trial Registration ClinicalTrials.gov Identifier: NCT05965739 .

Background: Transvenous lead extraction (TLE) is the standard of care for cardiac implantable electronic device (CIED) infections. Data regarding the optimal timing of CIED reimplantation after TLE are not well established. Objective: This study aims to assess the 5-year outcomes of early (≤7 days) versus non-early (>7 days) CIED reimplantation following TLE for CIED infection using a multi-national database. Methods: Using the TriNetX Analytics Research Network, we included patients aged ≥18 years who underwent TLE for CIED infection between 1/1/2014 and 1/1/2020. Patients were further categorized into two groups: early CIED reimplantation (≤7 days from TLE) and non-early CIED reimplantation. Propensity score matching (PSM) was performed by including patient demographics, LVEF, cardiac comorbidities and medications. The study outcomes included all-cause mortality and cardiac adverse events during a 5-year study period. Results: A total of 1668 patients in the early CIED reimplantation group and 1550 in the non-early group were identified. After PSM, 1327 patients in each group were analyzed. Compared to non-early group, early CIED reimplantation group was associated with significantly higher odds of all-cause hospitalization (odds ratio [OR]: 1.837, 95% confidence interval [CI]: 1.532-2.203) and repeated device infection (OR: 1.569, 95% CI: 1.314-1.873) at 5-year follow-up. However, no significant differences were observed in all-cause mortality (OR: 0.927, 95% CI: 0.778-1.104), HF exacerbation (OR: 1.021, 95% CI: 0.855-1.218), cardiac arrest (OR:0.924, 95% CI: 0.739-1.157), stroke (OR: 1.169, 95% CI: 0.915-1.494), cardiac thrombus (OR: 1.163, 95% CI: 0.749-1.808), major bleeding (OR: 1.079, 95% CI: 0.857-1.358) and venous thromboembolism (OR: 0.923, 95% CI: 0.759-1.123) between the two groups. Conclusion: Early reimplantation of CIED following TLE of infected devices was associated with worse outcomes in all-cause hospitalization and repeated device infection. Further large prospective studies are needed to define the optimal timing of device reimplantation.

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 Background and Aims Malignancy is commonly seen in patients with membranous Nephropathy (MN) with a prevalence up to 22%. M-type phospholipase A2 receptor (PLA2R) antigen and its associated antibody account for up to 80% of the cases but its association with malignancy is less clear. To date, no study has specifically evaluated cancer incidence and risk factors in patients with PLA2R associated MN as most studies were conducted in an era before many MN antigens were identified. Here, we report cancer incidence, types of cancer, and effect of immunosuppressive therapy and clinical parameters in a cohort of patients with PLA2R-associated MN. Method A single center retrospective cohort study in adults with diagnosis of PLA2R associated MN from 1/1/1996 to 12/31/2021. Follow-up was defined as the time from MN diagnosis to the last follow-up or if the patient initiated dialysis or underwent transplantation. The primary outcome in this study was the incidence of cancer events reported as cancer incidence/1000 patients/year. The cancer events were compared to the age-adjusted United States (U.S.) general population using Centers for Disease Control (C.D.C) data. The standardized incidence ratio (SIR) was calculated by dividing the cancer rates in our cohort to the cancer rates in general population. Time-to-event analysis was conducted using the Kaplan-Meier method. The log-rank test compared age, sex, smoking habits, hypertension, diabetes, body mass index (BMI), previous immunosuppression (IS), remission of the MN, PLA2R titers at the time of diagnosis. Cox proportional hazards regression was used to evaluate the associations between baseline characteristics and cancer incidence. For the multivariate model of cancer incidence, we evaluated variables clinically relevant for the outcome. Results We identified 239 patients with PLA2R-associated MN, with mean (±SD) age of 52 (±13) years, with 72.8% male (n = 174), median [IQR] BMI of 29.8 [26.3, 33.6] kg/m2, median eGFR of 68 [45, 94] ml/min, median proteinuria of 8.2 [5.1, 11.2] g/24h, and median PLA2R titers of 38 [9, 122] RU/ml. Common comorbidities included hypertension (60.2%), and diabetes (17.1%). Majority of patients drank alcohol (90.7%) and 32.6% were smokers (active or former). Of 239 patients, 15 had a history of cancer before the MN diagnosis. But in all these patients, cancer had been treated and was considered to be in full remission. A diagnosis of cancer was made in 37 patients (15.4%) during a median follow-up of 60 [27.5, 145.5] months. Incidence of cancer in our cohort was 22.6 [95% CI, 15.9 to 31.1] per 1000 persons/year. In comparison, age adjusted U.S. general population has a lower cancer incidence of 15.9 [95% CI, 15.9 to 16.1] cases per 1000 person/year. The resulting SIR of cancer in our cohort was 1.42. This SIR is lower than the one reported by Bjørneklett and al. (2007) in a Norwegian cohort that included all patients with MN and was not limited to PLA2R-positive MN. The cumulative incidence of cancer diagnosis is shown in Fig. 1. Mean age at cancer diagnosis was 66 (±10.2) years old. Prostate cancer was the most common (n = 11) type of cancer, followed by skin cancer (n = 9), followed by cancer of the urinary tract (n = 5). In univariate and multivariate analysis (Table 1), only older age (>65 years) and tobacco use were associated with statistically significant increased risk of cancer. Other clinical parameters such as sex, eGFR, baseline proteinuria, BMI, hypertension, diabetes, alcohol use, anti-PLA2R antibody titer, type of immunosuppression, remission status (partial, complete, no response) were not associated with a significant increased risk of cancer. Conclusion Patients with PLA2R associated MN are at increased risk of developing cancer following diagnosis compared to general population and routine age-appropriate cancer screening in this population is essential. The increased incidence of cancer is independent of IS therapy, response to therapy or other comorbidities. These data suggests that there are likely mechanisms beyond the traditional risk factors at play that may be unique to the presence of PLA2R antibodies.

Abstract Background and Aims Sodium-glucose cotransporter-2 inhibitors (SGLT2i) are emerging as an essential part of the new standard of care for proteinuria, alongside renin-angiotensin system (RAS) inhibitors in patients with proteinuric chronic kidney disease (CKD). Subgroup analysis of EMPA-KIDNEY and DAPA-CKD trials done in patients with glomerular diseases [IgA Nephropathy (IgAN) and focal and segmental glomerulosclerosis (FSGS)] showed these agents are less effective in reducing proteinuria compared to other agents like Sparsentan, or Double RAS Blockade. Also, the antiproteinuric effects of SGLT2i in patients with glomerular diseases is not well understood. To date, no study has specifically evaluated the effects of body mass index (BMI) on the antiproteinuric efficacy of SGLT2. Here we report the impact of BMI on the antiproteinuric efficacy of SGLT2i in non-diabetic patients with glomerular diseases. Method Single-center retrospective cohort study. Inclusion criteria (1) adult patients with a biopsy-proven glomerular disease or genetic diagnosis [i.e., Collagen IV mutations] from January 1st, 2019, to December 31st, 2023, (2) no Diabetes Mellitus, (3) proteinuria more than 0.75 g/24 h at the time of initiation of treatment despite optimized blood pressure control with renin-angiotensin system (RAS) inhibition at maximum tolerated dose (5) no concomitant use of induction immunosuppression therapy—stable maintenance immunosuppression was allowed. Patients with active neoplasia, no follow-up available after initiation of therapy or kidney transplant were excluded. Baseline was defined as the time of the initiation of SGLT2i. Laboratory values, including proteinuria, serum creatinine, and estimated glomerular filtration rate (eGFR), were obtained at baseline and 6 months. Changes in laboratory values over time were analyzed using the paired t-test and the signed-rank test, depending on the distribution. Weight status was classified based on BMI in three categories: regular (BMI < 25 kg/m2), overweight (25–29.9 kg/m2), and obese (>30 kg/m2). Results We identified 115 non-diabetic patients with glomerular diseases. Median age [IQR] at the time of SGLT2i initiation was 49.1 [35.4, 61.5] years; 74 (64.3%) patients were male, and 96 (83.5%) patients were white, with the second most common ethnicity being Asian with 10 (8.7%) patients. Median BMI for the entire cohort was 28.2 [26.0, 33.1] Kg/m2. Fifty-three (46.1%) patients had IgAN, 22 (19.1%) had secondary FSGS (sFSGS), 3 (2.6%) primary FSGS (pFSGS), and 12 (10.4%) genetic FSGS (gFSGS), with collagen IV mutations as the most common cause of gFSGS. Kidney function and proteinuria over time are presented in Table 1. Significant declines in eGFR [−1.77 ml/min/1.73m2 95% CI: (−4.2, −1.19)] and proteinuria [−0.58 g/24h 95% CI (−0.91, −0.44)] were observed at 6 months in the entire cohort compared to baseline. However, in the subgroup analysis by BMI strata, i.e., <25, 25-29.9, ≥30, the reduction in proteinuria was statistically significant only in overweight and obese patients. The expected early drop in eGFR was not observed in patients with a normal BMI. However, the decline in eGFR progressively increased and was statistically significant in the obese group (Fig. 1). Conclusion The principal finding of the present study is the lack of significant proteinuria reduction in patients with BMI<25 kg/m², which contrasts with the significant reductions observed in overweight and obese patients. SGLT2i's main antiproteinuric mechanism of action involves reducing glomerular hyperfiltration, which is commonly seen in patients with diabetes and obesity. In non-diabetic patients with glomerulopathies, proteinuria may be sustained by mechanisms not dependent on glomerular hyperfiltration, especially in those patients with normal BMI. These findings are crucial to advocate a personalized approach to treatment, challenging the “one-size-fits-all” strategy.

Variations in liver allocation systems worldwide are presented, with a specific focus on regional differences and their potential impact on outcomes, with the goal of serving as a reference for future policy development. Summaries of liver allocation across multiple European, Scandinavian, and Asian systems, as well as the combined allocation system of Australia plus Canada, the United States, and the systems in Central America, South America, and the Caribbean are reviewed. A comprehensive comparison of how different regions address MELD exceptions, primarily focusing on hepatocellular carcinoma, along with the most common etiologies of liver disease requiring transplantation is presented. In addition, the adoption of living donation and donation after circulatory death is discussed. The study involves contributions from a diverse group of world experts in liver transplantation and may serve as an essential resource to foster international dialogue as countries strive to optimize organ allocation policies, including MELD exceptions.

Abstract Perioperative low cardiac output syndrome (LCOS) remains a significant complication in adult cardiac surgery, contributing to substantial morbidity, prolonged intensive care, and increased mortality. Its incidence is expected to rise further due to the evolving complexity of referred surgical patients, often characterised by advanced age, multiple comorbidities, challenging anatomy, and impaired haemodynamics. Despite advances in pharmacological and perioperative care, outcomes for high-risk patients have not shown significant improvement, prompting interest in temporary mechanical circulatory support (tMCS) as a proactive strategy. This Expert Consensus Document from the European Association for Cardio-Thoracic Surgery (EACTS) presents the first dedicated guidance on the pre-emptive use of tMCS in high-risk adult cardiac surgical patients. Developed by a multidisciplinary task force, it emphasises structured risk stratification, early initiation, and individualised device management informed by interdisciplinary Heart Team discussions. The document proposes clinical pathways for patient selection, defines criteria for tMCS initiation, and provides practical algorithms for various scenarios, including advanced heart failure, cardiogenic shock, and post-cardiotomy LCOS. It reviews the current evidence on available tMCS devices, such as intra-aortic balloon pumps, microaxial flow pumps, veno-arterial extracorporeal life support and hybrid strategies, and addresses perioperative care, intensive care unit protocols, ethical considerations, as well as informed consent and support withdrawal. Despite promising results, substantial knowledge gaps remain, including long-term outcome data, device selection criteria, and cost-effectiveness analyses. This consensus aims to support clinical decision-making, standardise practice, and stimulate research to improve outcomes in a growing population of high-risk surgical patients.

ABSTRACT Background Sodium–glucose co-transporter 2 inhibitors (SGLT2is) are emerging as an essential part of the standard of care for proteinuria in patients with chronic kidney disease. To date, no study has specifically evaluated the effects of body mass index (BMI) on the antiproteinuric efficacy of SGLT2is. Here we report the impact of BMI on the antiproteinuric efficacy of SGLT2is in non-diabetic patients with glomerular diseases. Methods This is a retrospective, multicentre, international observational cohort study that included non-diabetic patients with biopsy-proven glomerular disease and proteinuria >0.5 g/24 h who received SGLT2is between 2016 and 2023. Laboratory values, including proteinuria and estimated glomerular filtration rate (eGFR), were obtained at baseline and after 3–6 months. Changes in laboratory values over time were analysed using the paired signed-rank test. Results A total of 300 patients met the inclusion criteria. The median age was 51.82 years [interquartile range (IQR) 41–62.65], 64.7% were male and 92.7% were white. The most common glomerular disease was immunoglobulin A nephropathy (40.3%). The median eGFR was 52.26 ml/min/1.73 m2 (IQR 36.41–74.01), the median proteinuria was 1.60 g/24 h (IQR 1.15–2.91) and the median serum albumin was 4.08 g/dl (IQR 3.80–4.30). Proteinuria reduction after SGLT2i initiation was significant only in overweight and obese patients (P < .001 versus 0.18). Patients with normal BMI did not experience the expected early decrease in eGFR (P = .16). Conclusions SGLT2is are ineffective in proteinuria reduction in patients with a BMI <25 kg/m2, which contrasts with the significant proteinuria reduction in overweight and obese patients with glomerulopathies.