Citations

Abstract Isolated/idiopathic rapid-eye-movement (REM)-Sleep Behavior Disorder (iRBD) is characterized by dream enactment behaviors associated with loss of REM atonia. iRBD is in most cases a prodromal synucleinopathy, and emerging evidence suggests associations between RBD and other neurological and psychiatric conditions. In this study, we performed pathway-based polygenic risk score (PRS) and rare variant burden analyses to examine these potential associations. Pathway-specific PRS were constructed from genome-wide association study summary statistics of five neurodegenerative and seven psychiatric traits across 10 biologically relevant pathway categories, including a total of 279 pathways, in 1,573 iRBD cases and 16,022 controls from the International RBD Study Group and UK Biobank. Rare variant burden tests were performed in 1,264 iRBD cases and 2,581 controls. We identified multiple potential pathways indicating shared polygenic risk between RBD and both neurodegenerative and psychiatric disorders. Lewy body diseases and post-traumatic stress disorder had the most shared polygenic risk pathways in neurological and psychiatric disorders, respectively. Two pathways, the serotonin transport pathway and the chaperone-mediated autophagy pathway, showed the strongest association with iRBD, and gene-based rare variants analyses revealed five genes associated with iRBD: GBA1 , PLEKHM1 , LRP2 , P2RX1 , and HAP1. Subsequent analysis of these genes in Parkinson’s disease and dementia with Lewy bodies replicated several associations. Together, these findings provide novel insights into the shared genetic architecture underlying iRBD, neurodegenerative disorders, and psychiatric traits, with implications for early identification and mechanistic understanding.

Abstract Background There is an unmet need for ulcerative colitis (UC) treatments that show improved effectiveness while maintaining safety profiles comparable with existing advanced therapies. Dual targeted therapy (DTT) has been proposed as a strategy to combine benefits of different advanced therapies to improve outcomes. The ExiGem study (NCT06095128) aims to assess the efficacy and safety of combined therapy with vedolizumab (VDZ) and tofacitinib (TOF) in adults with UC. We report results for the induction phase from the first 24 patients. Methods ExiGem is an ongoing phase 4, single-arm, multicentre study including adults with moderately to severely active UC (complete Mayo [cMayo] score of 6–12 with a rectal bleeding subscore ≥ 1 and centrally read endoscopic subscore ≥ 2). Eligible patients have previously had an inadequate response, loss of response, or intolerance to 1 or 2 anti-tumour necrosis factor α treatments. Patients receive induction therapy with intravenous (IV) VDZ 300 mg at weeks 0, 2, and 6 plus twice-daily oral TOF 10 mg for 8 weeks and then VDZ 300 mg IV monotherapy as maintenance from week 14. The primary endpoint is the proportion of patients in clinical remission by cMayo score at week 8. Secondary endpoints include clinical response and clinical remission by modified Mayo (mMayo) score at week 8. Changes in faecal calprotectin (FCP) levels and endoscopic improvement were evaluated. Efficacy data were analysed using non-responder imputation. For the final analysis a pre-specified Bayesian approach will be used. The safety profile of DTT was evaluated. Results Patient baseline characteristics are shown in Table 1. At week 8, 12/24 patients (50%) and 14/24 patients (58%) had clinical remission assessed by cMayo and mMayo scores, respectively; these rates were higher than pre-specified benchmark rates (Figure 1). Clinical response was observed in 21/24 patients (88%). At week 8, 14/24 patients (58%) showed endoscopic improvement, and 12/21 patients (57%) had normalization of FCP levels (< 250 µg/g). Treatment-emergent adverse events (TEAEs) were experienced by 10 patients (42%), and 1 serious TEAE was reported (suspected viral infection). One severe adverse event (AE; cough) and 2 moderate AEs (herpes zoster, drug intolerance) were considered related to TOF. No moderate or severe AEs were considered related to VDZ. One patient withdrew from the study before week 8 owing to intolerance to TOF. Conclusion Initial data suggest that induction with a combination of VDZ and TOF can produce improved rates of response and remission in patients with UC with a comparable safety profile to existing advanced monotherapies. Further data, including outcomes of VDZ maintenance as monotherapy, are pending. Conflict of interest: Prof. Dr. Yarur, Andres: Andres Yarur has served as an advisory board member for Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly, Johnson & Johnson, Merck, Roche/Genentech, and Takeda. This study was funded by Takeda Pharmaceuticals U.S.A., Inc. Medical writing support was provided by Adam Errington PhD of PharmaGenesis Cardiff, Cardiff, UK, and funded by Takeda Pharmaceuticals U.S.A., Inc. Barnes, Edward: Personal Fees: Consultant for Takeda, Pfizer, Roche, Merck, Abbvie, Eli Lilly. Bristol Myers Squibb, Celltrion, Johnson and Johnson. Deepak, Parakkal: Parakkal Deepak has received research support under a sponsored research agreement unrelated to the data in the abstract from AbbVie, Johnson and Johnson, Sanofi, Merck, Teva, Direct Biologics, Tr1x, Boehringer Ingelheim, Bristol Myers Squibb, Pfizer, Prometheus Biosciences, Takeda Pharmaceuticals, Roche Genentech, Eli Lilly, AstraZeneca, Spyre and Agomab, has received consulting fees from Johnson and Johnson, Abbvie, Merck, Sobi, Celltrion, Fresenius Kabi, Asahi Kasei Pharma, Sandoz and CorEvitas, LLC and has served on the board of the Srategic Alliance for Intercultural Advocacy in GI. Ha, Christina: Christina Ha has served as an advisory board member for AbbVie, Bausch Health, Johnson & Johnson, Lilly, Merck, Takeda, and Sanofi has received educational programming support from AbbVie, Celltrion, Johnson & Johnson, Lilly, Pfizer, and Takeda and has received consulting fees from AbbVie. Hudesman, David: Consultant: Abbvie, Abivax, BMS, Biocon, Eli Lilly, Fresenius Kabi, Pfizer, Prometheus, CorEvitas, Takeda, Johnson and Johnson, Sanofi Research Support: Johnson and Johnson, Pfizer Jairath, Vipul: Consulting Fees: Abbvie, Alimentiv, Amgen, Anaptys Bio, Asahi Kasei, Asieris, Astra Zeneca, Attovia, Blackbird Labs, BMS, Boehringer Ingleheim, Biomebank, Caldera, Calluna, Catalytic Health, Celltrion, Ensho, Enthera, Exeliome Biosciences, Ferring, Fresenius Kabi, Gilead, Granite Bio, GSK, Janssen, Lilly, Merck, Mountainfield, MRM Health, Nxera, Organon, OSE Immunotherapeutics, Pendopharm, Pioneering Medicine, Pfizer, Prometheus, Roche/Genentech, Sanofi, SCOPE, Shattuck Labs, Sorriso, Spyre, Synedgen, Takeda, Teva, Tillotts, Union Therapeutics, Ventus, Ventyx, Vividion, Xencor, Zealand Pharma. Lukin, Dana: Dana Lukin has served as a consultant/advisory board member for AbbVie, AltruBio, Boehringer Ingelheim, Eli Lilly, Johnson & Johnson, Palatin, Pfizer, Prime, PSI, Takeda, and Vedanta has received grants from Boehringer Ingelheim and Johnson & Johnson and serves as a speaker for AbbVie and Johnson & Johnson. Rubin, David T.: Grant support: Takeda Pharmaceuticals. Consultant: Abbvie, Abivax SA, Altrubio, Athos Therapeutics, Inc, Bristol-Myers Squibb, Celltrion, Connect BioPharma, Eli Lilly & Co., Genentech (Roche) Inc., Iterative Health, Janssen Pharmaceuticals, Johnson & Johnson, Merck & Co., Mirador, Odyssey Therapeutics, Pfizer, Sanofi, Spyre, Takeda Pharmaceuticals, Vedanta Biosciences, and Ventyx. Schreiber, Stefan Wolfgang: Stefan Schreiber has received consulting fees from AbbVie, Amgen, Arena, Boehringer Ingelheim, Bristol Myers Squibb, Celltrion, Dr Falk Pharma, Eli Lilly, Ferring, Fresenius, Galapagos, Genentech, Gilead, GlaxoSmithKline, I-MAB Biopharma, Janssen, Merck, Novartis/Sandoz, Pfizer, Protagonist, Takeda, and Ventyx Biosciences. Gower, Megan: Megan Gower is an employee and hold stock/stock options at Takeda Pharmaceuticals U.S.A., Inc. Jones, Stephen: Stephen Jones is an independent medical consultant who provides services for Takeda Pharmaceuticals U.S.A., Inc. Robinson, Ian: Ian Robinson is an employee and hold stock/stock options at Takeda Pharmaceuticals U.S.A., Inc. Sanchirico, Marie: Marie Sanchirico is an employee and hold stock/stock options at Takeda Pharmaceuticals U.S.A., Inc. Yajnik, Vijay: Vijay Yajnik is an employee and hold stock/stock options at Takeda Pharmaceuticals U.S.A., Inc.

126 Background: NNT/NNH analyses can estimate the magnitude of benefit vs harm of therapeutic agents and can inform clinical decision making. We quantified the benefit/risk profile of fruquintinib (F; a highly selective, oral inhibitor of all 3 VEGFRs) vs other later-line mCRC monotherapies. Methods: Six phase 3 randomized (2:1), placebo (P)-controlled trials (F: FRESCO, FRESCO-2; regorafenib [rego]: CONCUR, CORRECT; TAS-102: TERRA, RECOURSE) were identified. NNT (average number of pts needing treatment to prevent 1 additional death/progression event) for overall survival (OS) and progression-free survival (PFS) was calculated as the inverse of difference in survival function between treatment and P. NNH (average number of pts needing treatment for 1 additional pt to have an adverse event; AE) for treatment-emergent AEs (TEAEs) was calculated as the inverse of absolute risk increase relative to P. Low NNTs and high NNHs suggest a more favorable treatment profile. Results: F had the lowest NNT (most favorable) for 6-month OS (FRESCO-2) and PFS (FRESCO) vs rego and TAS-102 (Table). F had the highest NNH (most favorable) for grade ≥3 TEAEs, palmar-plantar erythrodysesthesia (PPE; FRESCO-2), and fatigue (FRESCO). TAS-102 (TERRA) had the highest NNH for diarrhea, followed by F (FRESCO-2). Consistent with mechanism of action of anti-VEGFRs, F and rego had lower NNHs for hypertension (HTN) vs TAS-102 (TERRA). F (FRESCO) had the lowest NNH for discontinuation due to TEAEs. Conclusions: In this cross-trial comparison, F had the lowest NNT for OS (FRESCO-2) and PFS (FRESCO/FRESCO-2), indicating survival benefit. F had the highest NNHs for grade ≥3 TEAEs, PPE (FRESCO-2), and fatigue (FRESCO), indicating a low risk profile. The analysis highlights fruquintinib as a favorable treatment for pts with mCRC. Clinical trial information: NCT02314819 , NCT04322539 , NCT01584830 , NCT01103323 , NCT01955837 , NCT01607957 . NNT/NNH (95% CI) for mCRC treatments.* F Rego TAS-102 FRESCO NCT02314819 N=416 FRESCO-2 NCT04322539 N=691 CONCUR NCT01584830 N=204 CORRECT NCT01103323 N=760 TERRA NCT01955837 N=406 RECOURSE NCT01607957 N=800 6-month OS 6.5(5.5–8.1) 5.3(4.8–5.9) 5.9(NA) 9.8(NA) 14.1(NA) 7.2(NA) 6-month PFS 4.2(3.7–4.8) 4.4(3.9–5.1) 5.0(NA) 9.1(NA) 7.1(NA) 7.2(NA) Grade ≥3 TEAEs 2.4 (2.0–3.1) 8.1 (5.0–22.5) 2.6 (2.0–3.7) 2.5 (2.2–3.0) 2.8 (2.3–3.6) 5.9 (4.1–10.2) TEAE leading to discontinuation 10.8 (6.7–28.5) NA † (18.0–NA) 12.5 (6.2–NA) 17.5(11.3–39.2) 250.0 (15.3–NA) 50.0 (22.9–NA) PPE 2.2 (1.9–2.5) 6.0 (4.8–8.0) 1.4 (1.3–1.7) 2.6 (2.2–3.0) NA (NA) NA (46.0–NA) HTN 2.4 (2.0–3.0) 3.6 (3.0–4.5) 5.3 (3.6–9.5) 4.5 (3.7–5.8) 14.3 (10.0–25.2) NA (NA) Diarrhea 5.1 (3.8–7.4) 7.3 (5.2–12.3) 6.2 (4.3–11.4) 3.8 (3.2–4.8) 7.9 (5.7–13.0) 5.0 (3.9–6.9) Fatigue 32.5 (10.3–NA) 25.8 (10.1–NA) 10 (5.3–80.3) 5.3 (3.8–8.4) 7.4 (5.0–13.9) 8.3 (5.4–18.1) *All trials except TERRA included best supportive care in both arms. † Lower rate of pts discontinued F vs P due to TEAEs, thus NNH was not applicable (NA).

Background The association between lifestyle factors and Alzheimer's disease (AD) pathophysiology remains incompletely understood. Objective The aim of this study was to assess the association of alcohol consumption, smoking behavior, sleep quality and physical, cognitive, and social activity with cerebral amyloid pathology. Methods For this cross-sectional study, we selected participants from the Amyloid Biomarker Study data pooling initiative. We used generalized estimating equations to assess associations of dichotomized lifestyle measures with amyloid pathology. Results We included 9171 participants with normal cognition (NC) and 2555 participants with mild cognitive impairment (MCI) from the Amyloid Biomarker Study. Of participants with NC, 58% were women, 34% were APOE ε4 carrier, and 27% had amyloid pathology. Of participants with MCI, 48% were women, 47% were APOE ε4 carrier, and 57% had amyloid pathology. In NC, cognitively active participants were less likely to have amyloid pathology (OR = 0.77, 95%CI 0.66–0.89, p < 0.001). In MCI, participants who had ever smoked or had sleep problems were less likely to have amyloid pathology (OR = 0.85, 95%CI 0.73–0.99, p = 0.029; OR = 0.62, 95%CI 0.45–0.86, p = 0.004). Conclusions In NC, cognitive activity was associated with a lower frequency of amyloid pathology. In MCI, favorable lifestyle behaviors were not associated with a lower frequency of amyloid pathology. The results of the current study contribute to the broader evidence base on lifestyle and AD by further characterizing the role of lifestyle behaviors in AD pathology across different clinical stages.

Abstract Background Short bowel syndrome (SBS) is a chronic condition requiring parenteral nutrition (PN) support and multidisciplinary management. However, disparities in access to care and standardized treatment pathways, in addition to economic burden, remain considerable for patients. Understanding healthcare resource utilization (HCRU) and treatment patterns, especially in relation to patient‐reported outcomes (PROs), is critical for improving care. Methods A cross‐sectional, multiphase study was conducted in 2023. This analysis focuses on phase 3, using a deidentified database that integrated claims and PROs from 68 patients in phase 2. Twenty‐three patients were included in the analytic cohort after applying additional criteria. Descriptive statistics summarized patient demographics, HCRU, and treatment patterns for the overall cohort and stratified by median SBS–quality of life (QoL) score. Results The median age at SBS diagnosis was 35 years, and 91% of patients were female. Patients saw a median of 35 different healthcare providers and underwent approximately five procedures before diagnosis. In the 6 months after diagnosis, 39% had been hospitalized, and 26% had emergency room (ER) visits. Healthcare costs increased after diagnosis, with long‐term PN use accounting for 34% of total costs. Patients with worse QoL had a higher number of ER visits than patients with better QoL. Patients who self‐reported being treated by SBS specialists had lower healthcare costs than patients who did not receive specialized care. Conclusion SBS is associated with high HCRU and costs, particularly for patients with poor QoL. Multidisciplinary care, especially from SBS specialists, may help reduce healthcare costs and improve patient outcomes.

Background The purpose of this study was to clarify the usefulness of the ‘hot cross bun’ sign (HCBS) as a diagnostic imaging marker in a large cohort of patients with multiple system atrophy (MSA) and spinocerebellar ataxia (SCA). Methods This multicentre study included 97 patients with neuropathologically confirmed MSA, and 105 patients with genetically confirmed SCA. Neuroimaging features, including HCBS and middle cerebellar peduncle (MCP) hyperintensities, were assessed. HCBS was graded from 0 to 2: 0, none; 1, only a vertical hyperintense line; and 2, a cruciform hyperintense line. The neuropathological correlates of HCBS were evaluated in 15 patients with MSA with ≤3 months between MRI and autopsy. Results In patients with a disease duration <3 years, grade 1 or 2 HCBS was detected in 100% patients with MSA with predominant cerebellar ataxia (MSA-C) and 39.0% with SCA; whereas grade 2 HCBS was observed in 50% with MSA-C and 2.4% with SCA. Moreover, the coexistence of grade 2 HCBS and MCP hyperintensities exhibited a specificity of 100%. A neuropathological assessment revealed myelin loss, alpha-synuclein aggregates and astrocytic reaction in the MCP, transverse fibres, central zone between longitudinal fasciculi and raphe nucleus, with relative preservation in the longitudinal fasciculi and medial lemniscus in patients with MSA and grade 2 HCBS. Conclusions Grade 1 or 2 HCBS is a highly sensitive finding in patients with MSA-C, and the observation of grade 2 HCBS within 3 years of motor symptom onset has excellent specificity for discriminating MSA-C from SCA, especially when accompanied by MCP hyperintensities.

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 Patients with short bowel syndrome–associated intestinal failure (SBS‐IF) require complex, personalized, and multidisciplinary care; however, there are disparities in access. This study measured the impact of unmet needs and treatment burden among patients and their caregivers. Methods This cross‐sectional, mixed‐method study included US adults self‐reporting SBS‐IF and receiving home parenteral nutrition for ≥6 months and their caregivers. One‐hour interviews informed the development of a 30‐min survey administered to participants from an online health community. Results Among 68 patients, the mean age was 42 years, 79% were female, and 88% were White. Most of the 16 caregivers were female (69%), and younger than 45 years (69%). Of 32 patients (47%) receiving care from an SBS specialist, only 19 (59%) were referred after diagnosis; in 58% of these, referral occurred >6 months after diagnosis. Depression was reported in 44 patients (65%), with 54% not receiving professional mental health care. Financial concerns were common, with 44 patients (65%) unable to work and 40 patients (59%) reporting annual household income of <$50,000. Of 32 patients reporting difficulty paying medical bills, 22 (32%) could not fill prescriptions and 19 (28%) canceled/delayed healthcare provider visits. Social determinant of health challenges were reported by 44 patients (65%). Caregivers' responsibilities impacted their ability to work (50%) and future outlook (63%). Conclusion Patients with SBS‐IF face difficulties accessing specialized healthcare, and are at risk of adverse healthcare outcomes, financial hardships, and poor quality of life. Mental health and work/financial issues were common among both patients and caregivers.

Abstract Background Primary aldosteronism (PA) is a common treatable cause of hypertension. When caused by unilateral adrenal disease, it is potentially curable by adrenalectomy. However, specialized tests and other factors may delay definitive treatment. We assessed the time to adrenalectomy (TTA) for patients worldwide. Methods We conducted an international, multicentre retrospective study involving 39 centres from 15 countries to determine the total time taken from the first presentation to adrenalectomy and the intervals between each stage (screening, confirmatory, subtyping, and adrenalectomy). We included patients with PA who underwent adrenalectomy from January 1, 2018, to October 30, 2022. Post-adrenalectomy outcomes were evaluated using the Primary Aldosteronism Surgery Outcome criteria. We performed multivariable quantile and linear regression to identify characteristics associated with longer TTA. Results We included 861 patients, mean age 49.3 ± 11.1 years, and 44.5% were women. Overall median TTA was 13.5 months, IQR: 6.6-24.5. Median intervals were 0.1 months (screening), 1.0 months (confirmatory), 4.1 months (subtyping), and 4.3 months (adrenalectomy). On multivariable analysis, median TTA was increased by 5.4 months for each additional adrenal vein sampling (AVS) procedure. Other factors associated with longer TTA included adrenalectomy post-COVID-19, younger age, and additional screening tests. Compared with countries with routine AVS, those without AVS had a shorter TTA (6.1 vs 15.1 months, P &lt; .001), but greater likelihood of absent/partial biochemical success post-adrenalectomy (27.4% vs 12.4%, P &lt; .001). Conclusion Primary aldosteronism management is time-consuming worldwide, especially for subtyping tests and adrenalectomy. While omitting AVS reduces overall time, patients are less likely to achieve biochemical cure post-adrenalectomy.