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Abstract Background Health-related quality of life (HRQoL) is impaired in patients with Crohn’s disease (CD). Upadacitinib (UPA), a Janus kinase inhibitor, demonstrated efficacy and safety in the phase 3 U-EXCEED (NCT03345836) and U-EXCEL (NCT03345849) induction, and U-ENDURE (NCT03345823) maintenance trials in patients with moderately to severely active CD. We assessed the effect of UPA maintenance treatment on HRQoL in patients with moderately to severely active CD from the U-ENDURE long-term extension (LTE) study. Methods Patients who completed the 52-week U-ENDURE maintenance study were eligible to participate in the LTE study, continuing their previously assigned maintenance treatment. Of the 337 patients receiving UPA (168, UPA 30 mg; 169, UPA 15 mg) in the U-ENDURE maintenance trial, a total of 244 patients (137, UPA 30 mg; 107, UPA 15 mg) were included in this analysis. All 244 patients completed week 96 of the LTE. Endpoints included percentage of patients who achieved Inflammatory Bowel Disease Questionnaire (IBDQ) response (≥16-point increase from induction baseline), IBDQ remission (total score ≥170 points), a meaningful within-person change (MWPC) of ≥ 9point increase from baseline in the Functional Assessment of Chronic Illness Therapy – Fatigue Scale (FACIT-F) and a MWPC of ≥ 4.1- and ≥3.9-point increase from baseline on the 36-item Short Form Health Survey (SF-36) physical (PCS) and mental (MCS) component summary score, respectively, at maintenance week 52 and LTE week 96. We also assessed MWPC in Work Productivity and Activity Impairment in CD (WPAI-CD) domains defined as a decrease of ≥ 6.1% in presenteeism, ≥6.5% in absenteeism, ≥7.3% in overall work impairment and ≥8.5% in activity impairment. Data were reported using nonresponder imputation. Results The proportion of patients in the UPA 30 mg group achieving HRQoL outcomes was maintained from maintenance week 52 to LTE week 96, including achievement of IBDQ response (61.3% vs 57.7%), IBDQ remission (53.3% vs 53.3%), MWPC improvement in FACIT-F (50.4% vs 40.9%), SF-36 PCS (56.9% vs 56.2%), SF-36 MCS (47.4% vs 40.9%) and MWPC improvements in WPAI-CD domains presenteeism (45.6% vs 48.1%), overall work impairment (49.4% vs 51.9%) and daily activity impairment (57.7% vs 56.9%). Patients in the UPA 15 mg group also maintained achievement of these HRQoL outcomes over time (Table). Conclusion UPA (15 and 30 mg) maintenance treatment over a 3-year period was associated with sustained and clinically meaningful disease-specific and generic HRQoL improvement in patients with moderately to severely active CD. Despite the overall trend favouring UPA 30 mg, differences in patient-reported outcomes between the 2 dose groups were small. Conflict of interest: Panés, Julián: Personal Fees: J. Panés received consultancy fees/honorarium from AbbVie, Alimentiv, Boehringer Ingelheim, Ferring, Galapagos, Genentech/Roche, GlaxoSmithKline, Janssen, Mirum, Nimbus, Pfizer, Progenity, Prometheus, Protagonist, Revolo, Sanofi, Sorriso, Spyre Therapeutics, Surrozen, Takeda, and Wasserman, and has served on data safety monitoring boards for Alimentiv, Mirum, Roche, Sorriso, Sanofi, and Surrozen Louis, Edouard: Education and Reserach Grants for my department: Abbvie, Takeda, Johnson and Johnson, Pfizer, Fresenius-Kabi, Celltrion, EG pharma, Sandoz, Falk Personal Fees for conferences, advisory boards and consultancy: Abbvie, Takeda, Ferring, Pfizer, Johnson and Johnson, Lilly, Galapagos, Celltrion, Arena, BMS, Falk, Biokuris, Fresenius-Kabi, Thabor Bossuyt, Peter: Grant support for research from AbbVie, EG Consulting fee from AbbVie, Bristol Meyers Squibb, CIRC, Galapagos, Janssen, Jeito capital, Lilly, Pentax, Pfizer, PSI-CRO, Roche, Takeda, Tetrameros Speakers fee from AbbVie, AMC ICP, Amgen, Bristol Myers Squibb, Celltrion, Dr Falk Benelux, EG, Galapagos, Globalport, Lilly, Medtalks, Materia Prima, Pentax, Springer Media Joshi, Namita: Namita Joshi is a full-time employees/contractor of AbbVie and may own AbbVie stock or options. Xuan, Si: Full-time employee/contractor of AbbVie and may own AbbVie stock or options. Shukla, Nidhi: Full-time employee/contractor of AbbVie and may own AbbVie stock or options. Dubcenco, Elena: Full-time employee/contractor of AbbVie and may own AbbVie stock or options. Aponte, Fernando: Full-time employee/contractor of AbbVie and may own AbbVie stock or options. Perkovic, Ashley: Full-time employee/contractor of AbbVie and may own AbbVie stock or options. Loftus, Jr, Edward: Grant: AbbVie, Amgen, Bristol-Myers Squibb, Celgene, Genentech, Gilead, Janssen, Pfizer, Receptos, Robarts Clinical Trials, Takeda, Theravance, UCB. Personal Fees: AbbVie, Allergan, Amgen, Arena, Boehringer Ingelheim, Bristol-Myers Squibb, Calibr, Celgene, Celltrion, Eli Lilly, Genentech, Gilead, Iterative Scopes, Janssen, Ono Pharma, Pfizer, Sun Pharma, Takeda, UCB.

Abstract Background Endoscopic healing is an important treatment goal in Crohn’s disease (CD), in line with European Crohn’s and Colitis Organisation CD guidelines, as it is associated with improved long-term disease outcomes. We assessed the relationship between endoscopic healing and long-term clinical outcomes, patient-reported outcomes (PROs) and hospitalisations in patients (pts) with moderately to severely active CD receiving upadacitinib (UPA) maintenance treatment in the U-ENDURE long-term extension (LTE) study. Methods Pts completing the 52-week U-ENDURE maintenance study were eligible to participate in the LTE study, continuing their previously assigned maintenance treatment. Pts receiving UPA 15 mg or 30 mg once daily in LTE were included in this analysis. Clinical remission based on CD activity index (CDAI <150), CDAI response (≥100-point decrease in CDAI from induction baseline), clinical remission based on stool frequency/abdominal pain (SF/AP) score (average daily soft or liquid SF ≤ 2.8 and average daily AP ≤ 1.0, and neither greater than induction baseline), Inflammatory Bowel Disease Questionnaire (IBDQ) response (≥16-point increase in total IBDQ score from induction baseline) and remission (IBDQ total score ≥170 points), Functional Assessment of Chronic Illness Therapy – Fatigue Scale (FACIT-F) response (≥9-point increase from induction baseline), and economic outcomes (CD-related hospitalisations or surgeries) were evaluated at LTE week 96. Outcomes were compared between pts who achieved vs those who did not achieve endoscopic response, endoscopic remission, or ulcer-free endoscopy (endoscopic outcomes defined in Table footnote) at maintenance week 52 using chi-square testing (nominal P values). Pts with missing outcomes at LTE week 96 were imputed as nonresponders. Results Of 244 pts, 153/244 (62.7%), 112/244 (45.9%) and 89/242 (36.8%) achieved endoscopic response, endoscopic remission, and ulcer-free endoscopy, respectively, at LTE week 0. Significantly (all nominal P≤0.05) more pts who achieved endoscopic response, endoscopic remission or had an ulcer-free endoscopy at LTE Week 0 achieved CDAI response, CDAI remission, SF/AP clinical remission, IBDQ response, IBDQ remission and FACIT-F response at LTE week 96 (Table). CD-related hospitalisations or surgeries at LTE week 96, were significantly (nominal P≤0.05) lower in pts with endoscopic remission and ulcer-free endoscopy at LTE week 0, and numerically lower in pts with endoscopic response. Conclusion A significantly higher proportion of pts who achieved endoscopic outcomes at 52 weeks and received up to 3 years of UPA maintenance treatment achieved long-term improvements in clinical and PROs and reduced CD-related hospitalisations or surgeries. Conflict of interest: Loftus, Jr, Edward: Edward V. Loftus, Jr. has received consulting fees from AbbVie, Abivax, Astellas, Avalo Therapeutics, Biocon, BMS, Celltrion Healthcare, Eli Lilly, Fresenius Kabi, Genentech, Gilead, Iota Biosciences, Iterative Health, Janssen, Merck, Morphic Therapeutics, Ono Pharma, Spyre Therapeutics, Takeda, and TR1X Bio has received research support from AbbVie, Genentech, Gilead, Janssen, Merck, and Takeda and holds stock in Exact Sciences and Moderna. Louis, Edouard: Education and Reserach Grants for my department: Abbvie, Takeda, Johnson and Johnson, Pfizer, Fresenius-Kabi, Celltrion, EG pharma, Sandoz, Falk Personal Fees for conferences, advisory boards and consultancy: Abbvie, Takeda, Ferring, Pfizer, Johnson and Johnson, Lilly, Galapagos, Celltrion, Arena, BMS, Falk, Biokuris, Fresenius-Kabi, Thabor Bossuyt, Peter: Grant support for research from AbbVie, EG Consulting fee from AbbVie, Bristol Meyers Squibb, CIRC, Galapagos, Janssen, Jeito capital, Lilly, Pentax, Pfizer, PSI-CRO, Roche, Takeda, Tetrameros Speakers fee from AbbVie, AMC ICP, Amgen, Bristol Myers Squibb, Celltrion, Dr Falk Benelux, EG, Galapagos, Globalport, Lilly, Medtalks, Materia Prima, Pentax, Springer Media Joshi, Namita: Namita Joshi is a full-time employees/contractor of AbbVie and may own AbbVie stock or options. Shukla, Nidhi: Full-time employee/contractor of AbbVie and may own AbbVie stock or options. Dubcenco, Elena: Full-time employee/contractor of AbbVie and may own AbbVie stock or options. Aponte, Fernando: Full-time employee/contractor of AbbVie and may own AbbVie stock or options. Perkovic, Ashley: Full-time employee/contractor of AbbVie and may own AbbVie stock or options. Panés, Julián: Personal Fees: J. Panés received consultancy fees/honorarium from AbbVie, Alimentiv, Boehringer Ingelheim, Ferring, Galapagos, Genentech/Roche, GlaxoSmithKline, Janssen, Mirum, Nimbus, Pfizer, Progenity, Prometheus, Protagonist, Revolo, Sanofi, Sorriso, Spyre Therapeutics, Surrozen, Takeda, and Wasserman, and has served on data safety monitoring boards for Alimentiv, Mirum, Roche, Sorriso, Sanofi, and Surrozen

Bone scintigraphy is a valuable adjunct to cross-sectional imaging and can be used to evaluate disease extent in multifocal processes such as blastic osseous metastatic disease, provide diagnostic information to aid in problem solving in challenging cases, and serve as the primary diagnostic modality for diseases that manifest with pathognomonic scintigraphic appearances.

334 Background: Sarcopenia, or decreased skeletal muscle mass, has been associated with worse surgical and oncologic outcomes across multiple malignancies. This study investigates the impact of sarcopenia on outcomes after multimodal therapy for esophageal cancer. Methods: Retrospective observational cohort study including adult patients who underwent neoadjuvant therapy followed by esophagectomy for primary esophageal cancer from January 2000 - December 2021. A fully automated abdominal segmentation using deep convolutional neural network was utilized to calculate skeletal muscle index (SMI) from preoperative CT scans performed at our institution. Males with SMI <52.4 cm 2 /m 2 and females with SMI <38.5 cm 2 /m 2 at any point before surgery were classified as sarcopenic. The relationship between sarcopenia and patient demographics, operative details, and complications were explored using chi-square tests. The relationship between sarcopenia and disease-free survival and overall survival were investigated using parsimonious multivariable analysis retaining variables with p-value <0.05 using backward selection method. Results: We identified 200 patients meeting the study criteria with 142 (71%) having sarcopenia at any time prior to surgery. Patients with sarcopenia were significantly older [65.2 (59.6, 71.2) vs 63 (53.6, 67.5), p = .023] and more likely to have had open surgery [129 (90.8%) vs 46 (79.3%), p = .034]. There were no significant differences in sex, history of diabetes, coronary artery disease, renal disease, smoking, cancer type, cancer stage, tumor size, tumor location, or margin status between sarcopenic groups ( p > .05). Sarcopenic patients were significantly more likely to require blood transfusion ≥3 units after esophagectomy [79 (55.6%) vs 8 (13.8%), p < .001] or to experience complications requiring surgical intervention [36 (24.6%) vs 7 (12.1%), p = .048]. Multivariate analysis revealed that sarcopenia was associated with disease-free and overall survival (Table). Conclusions: Sarcopenia is a prognostic factor in patients undergoing multimodal therapy for esophageal cancer. Interventions that aim to prevent decreases in SMI after initiating neoadjuvant therapy should be investigated. Multivariate analysis with sarcopenia predicting outcomes. Disease free survivalHR (95% CI) p-value Overall survivalHR (95% CI) p-value Age 1.04 (1.02, 1.06) < .001 1.04 (1.02, 1.07) < .001 Epicenter Middle Upper 1.88 (1.21, 2.86)3.16 (1.67, 5.98) .001.005< .001 1.96 (1.26, 3.04)4.00 (1.90, 8.44) < .001.003< .001 Stage Stage II Stage III Stage IV 1.88 (0.95, 3.71)2.90 (1.46, 5.75)16.02 (6.12, 41.93) < .001.069.002< .001 1.65 (0.83, 3.25)2.76 (1.37, 5.55)10.14 (4.03, 25.53) < .001.151.005< .001 Cancer type - - 1.76 (1.03, 3.02) .039 Transfusion > 3 pRBC - - 1.54 (0.99, 2.40) .057 BMI prior to cancer diagnosis - - 0.98 (0.94, 1.01 .208 Sarcopenic 1.76 (1.16, 2.67) .007 1.64 (1.04, 2.60) .033

Key Points α Klotho as an antiaging protein can extend the lifespan of healthy animals; serum α Klotho was lower in patients with autosomal dominant polycystic kidney disease. Transgenic α Klotho and recombinant α Klotho delayed cyst growth in Pkd1 mutant mouse kidneys. α Klotho exerted its proapoptotic and anti-inflammatory function through interacting with and destabilizing cellular inhibitor of apoptosis protein 1. Background α -Klotho ( α Klotho) is expressed mainly in the kidney, which is encoded by the KL gene, existing in a membrane-bound form and a soluble circulating form. Soluble serum α Klotho was lower in patients with autosomal dominant polycystic kidney disease (ADPKD). However, the role of α Klotho in ADPKD remains unknown. Methods To investigate the roles of α Klotho in ADPKD, we generated transgenic α Klotho and Pkd1 mutant Pkd1-HOMO-KL Tg mice to evaluate cyst growth and investigated underlying mechanisms with single-cell RNA sequencing analysis. Results We showed that α Klotho was lower in diverse kidney cell types in Pkd1 mutant kidneys, which was restored by transgenic α Klotho. We identified differential expression genes and pathways mediated by transgenic α Klotho at single-cell resolution and determined the cytokines and their receptors mediated cell-to-cell communication networks in Pkd1 mutant and Pkd1-HOMO-KL Tg kidneys by CellChat analysis. We further showed that α Klotho exerted a proapoptotic and anti-inflammatory function through interacting with and destabilizing cellular inhibitor of apoptosis protein 1, which disturbed TNF and its receptor mediated prosurvival complex, leading to ( 1 ) the formation of predeath complex to increase cystic cell death and ( 2 ) the decrease of the activation of NF-κB, the expression of cytokines, and the recruitment of macrophages, resulting in a delay of cyst growth. Treatment with recombinant α Klotho also delayed cyst growth in Pkd1 mutant kidneys. Conclusions This study defined an unknown role and mechanism of α Klotho in the regulation of a TNF-dependent cystic cell apoptosis and inflammation in Pkd1 mutant kidneys.

Abstract Aim To assess the long‐term efficacy of vagus nerve stimulation (VNS) in Dravet syndrome and identify key factors influencing treatment response. Method We conducted a two‐center, retrospective cohort study of 15 patients (six females, nine males; median age at seizure onset 4 months [range 2–12 months]) with Dravet syndrome who underwent VNS implantation. Seizure frequency was evaluated over 12 months and up to 10 years after implantation. Linear mixed‐effects regression was used to analyze the impact of antiseizure medications (ASMs) and VNS parameters on seizure outcomes. Results A 50% or greater reduction in seizure frequency was observed in 93.3% (14 of 15) of patients at 12 months and 86.7% (13 of 15) of patients across the 10‐year follow‐up. This seizure reduction was independent of ASM use; the VNS duty cycle was a significant predictor of seizure reduction. Two individuals (13.3%) experienced minor adverse events. Interpretation VNS provides durable seizure reduction in Dravet syndrome, independent of ASM adjustments. These findings highlight the importance of early VNS initiation and parameter optimization in managing genetically defined epilepsy syndromes.

Living donor liver transplantation (LDLT) is an established therapy with curative intent for pediatric and adult patients with acute liver failure and end-stage liver disease. Donor safety remains paramount and commences during preoperative evaluation and assessment. Given the importance of the topic, the International Liver Transplantation Society and International Living Donor Liver Transplantation Group consensus conference on Living Liver Donor Safety was convened in March 2025 (Toronto, Canada). Recommendations were based on the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) system for assessment of recommendations, and the Danish model of consensus was followed. This report presents 28 recommendations from the working group focused on addressing clinically relevant questions related to the preoperative aspects of living donor safety including assessment of donor acceptability (age, body mass index and hepatic steatosis; medical conditions and contraindications), medical and surgical workup (liver function and procoagulant workup; anatomical considerations and safe remnant), and psychosocial evaluation (timing and team; underlying conditions; non-directed, paired, and anonymous directed donors; urgent living donor workups for acute liver failure).

Sustained injury to renal tubular epithelial cells (TECs), driven by excessive autophagy, is a critical mechanism underlying kidney fibrosis. Our previous work identified JLP — a TEC-expressed scaffolding protein — as an endogenous antifibrotic factor that counteracts TGF-β1–induced autophagy and fibrogenesis. However, the mechanism underlying JLP downregulation in renal fibrosis remains unclear. Here, we delineated a TGF-β1/LEF1/β-catenin/JLP axis that governs TEC autophagy through a dichotomous regulatory circuit. Under physiological conditions, low levels of β-catenin and LEF1 with minimal nuclear localization permitted normal JLP expression, which in turn maintained autophagy in check. In contrast, during renal injury, TGF-β1 promoted the expression and nuclear translocation of β-catenin and LEF1, which together suppressed JLP transcription. This loss of JLP-mediated inhibition led to unchecked autophagy and exacerbated fibrotic damage. Analyses of kidney tissues from patients with CKD, murine fibrotic kidneys, and cultured HK-2 cells confirmed consistent JLP downregulation accompanied by upregulation and nuclear accumulation of LEF1 and β-catenin. Therapeutic intervention using the β-catenin/LEF1 inhibitor iCRT3 or LEF1-targeted silencing in murine fibrosis models restored JLP expression, attenuated TEC autophagy, and ameliorated renal fibrosis. These findings revealed an autoregulatory circuit controlling TEC autophagy and fibrogenesis, and supported LEF1 and β-catenin as potential therapeutic targets in CKD.

BACKGROUND: Chronic anal fissures are a painful condition characterized by a tear in the anal mucosa. Botulinum toxin injection is a minimally invasive treatment option, but long-term effectiveness in recurrent or persistent cases remains unclear. OBJECTIVE: This study evaluates the long-term outcomes of botulinum toxin injections for the treatment of chronic anal fissures. DESIGN: This study is a retrospective review. SETTINGS: The study was conducted at a tertiary academic center. PATIENTS: Adults with chronic anal fissures treated with botulinum toxin between 2018 and 2023 were included. MAIN OUTCOME MEASURES: Short- and long-term healing, recurrence, or persistence after botulinum toxin injection. Persistent or recurrent fissure(s) were followed for outcomes after subsequent repeat injections or surgery (lateral internal sphincterotomy or fissurectomy). RESULTS: Among 161 patients, 45.3% (n = 73) experienced short-term healing after botulinum toxin as first-line therapy, but only 26% (n = 42) had sustained healing. Subsequent treatment patterns were similar for recurrent (n = 31) and persistent (n = 88) fissures: 35% versus 31% no further intervention, 55% versus 42% multiple subsequent injections, 10% versus 23% surgery, respectively. Sustained healing was achieved in 63% (n = 10/16) of patients who underwent surgery compared with 37% (n = 14/38) who had repeat botulinum toxin injections ( p = 0.06). Only 49% achieved sustained healing after a single injection, multiple injections, or injection(s) with surgery. Complications included 5 episodes of mild fecal incontinence in the botulinum toxin group and 2 instances of surgical site infection in the surgery group. LIMITATIONS: Limitations include a single-institution, retrospective study design and loss to follow-up. CONCLUSION: Botulinum toxin remains a valuable therapy for chronic anal fissures. Many patients have persistent or recurrent fissures after botulinum toxin injection and undergo additional interventions. Despite multiple interventions, only half of the patients achieved sustained healing, regardless of the treatment pattern. These data do not support the use of botulinum toxin over surgery for the treatment of chronic fissures, are helpful for counseling patients on the safety profile of each, and set expectations regarding the need for multiple interventions. See Video Abstract . RESULTADOS A LARGO PLAZO DEL USO DE TOXINA BOTULÍNICA EN EL TRATAMIENTO DE FISURAS ANALES CRÓNICAS: UN ENFOQUE GRADUAL PARA EL MANEJO DE CASOS RECURRENTES Y PERSISTENTES ANTECEDENTES: Las fisuras anales crónicas son una afección dolorosa caracterizada por un desgarro en la mucosa anal. La inyección de toxina botulínica es una opción de tratamiento mínimamente invasiva, pero su eficacia a largo plazo en casos recurrentes o persistentes sigue sin estar clara. OBJETIVO: Evaluar los resultados a largo plazo de las inyecciones de toxina botulínica para el tratamiento de las fisuras. DISEÑO: Revisión retrospectiva. ENTORNO: Centro académico terciario. PACIENTES: Adultos con fisuras crónicas tratados con toxina botulínica entre 2018 y 2023. PRINCIPALES MEDIDAS DE RESULTADO: Curación a corto y largo plazo, recurrencia o persistencia después de la inyección de toxina botulínica. Se realizó un seguimiento de las fisuras persistentes o recurrentes para evaluar los resultados después de repetidas inyecciones o cirugía (esfinterotomía interna lateral o fisurectomía). RESULTADOS: Entre los 161 pacientes, el 45,3 % (n = 73) experimentó una curación a corto plazo tras la toxina botulínica como terapia de primera línea, pero solo el 26 % (n = 42) tuvo una curación sostenida. Los patrones de tratamiento posteriores fueron similares para las fisuras recurrentes (n = 31) o persistentes (n = 88): 35 % frente a 31 % sin intervención adicional, 55 % frente a 42 % con múltiples inyecciones posteriores, 10 % frente a 23 % con cirugía, respectivamente. Se logró una curación sostenida en el 63 % (n = 10/16) de los pacientes que se sometieron a cirugía, en comparación con el 37 % (n = 14/38) que recibió inyecciones repetidas de toxina botulínica ( p = 0,06). Solo el 49 % logró una curación sostenida después de una sola inyección, múltiples inyecciones o inyecciones con cirugía. Las complicaciones incluyeron 5 episodios de incontinencia fecal leve en el grupo de la toxina botulínica y dos casos de infección en el sitio quirúrgico en el grupo de la cirugía. LIMITACIONES: Estudio retrospectivo de una sola institución y pérdida de seguimiento. CONCLUSIÓN: La toxina botulínica sigue siendo una terapia valiosa para las fisuras anales crónicas. Muchos pacientes presentan fisuras persistentes o recurrentes tras la inyección de toxina botulínica y se someten a intervenciones adicionales. A pesar de las múltiples intervenciones, solo la mitad de los pacientes lograron una curación sostenida, independientemente del patrón de tratamiento. Estos datos no respaldan el uso de la toxina botulínica frente a la cirugía para el tratamiento de las fisuras crónicas, pero son útiles para asesorar a los pacientes sobre el perfil de seguridad de cada una y establecer expectativas con respecto a la necesidad de múltiples intervenciones. ( AI-generated translation )