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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 )

Abstract Multiple lines of evidence suggest that calorie restriction may slow biological processes related to aging and extend lifespan. To determine whether calorie restriction affects mitochondrial function, we treated fibroblasts from adult donors with serum samples obtained from participants of the CALERIE (Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy) study. The CALERIE study enrolled healthy, non-obese middle-aged (average 38y.o) participants to examine the effects of long-term calorie restriction. We studied the serum samples of 177 participants (calorie restriction CR = 121, ad libitum AL = 56) who had specimens available at two timepoints (12 and 24 months). We assessed the basal and maximal mitochondrial respiration of fibroblasts treated with dilute serum for 24 hours. Our results show that the baseline basal and maximal mitochondrial respiration of fibroblasts is positively correlated with the adiposity of the serum donor (R = 0.112, P = 0.137; R = 0.183, P = 0.015, respectively). Interestingly, treatment of fibroblasts with serum collected after 12 months of calorie restriction causes a decrease in both basal and maximal mitochondrial respiration (P = 0.1854; P = 0.0623, respectively). Fibroblasts treated with serum collected after 24 months of calorie restriction exhibited a further reduction in both basal and maximal mitochondrial respiration (P = 0.0174; P = 0.0092, respectively). These findings suggest that the serum of individuals on long term calorie restriction diet comprises factors that can reduce oxidative phosphorylation. This reduction in bioenergetic capacity may align with the theory that calorie restriction leads to a cellular energy-conserving state, which could have implications for cellular aging and metabolism.

Background This study aimed to evaluate outcomes of different antibiotic durations in patients with severe diverticulitis. Methods Initial electronic medical record review identified 2437 adult patients who underwent sigmoid colectomy. Manual chart review identified 133 patients who underwent sigmoid resection and proximal diversion for Hinchey stage 3 or 4 diverticulitis. Patients who received a short antibiotic course (SAC, ≤5 days) were compared with those who received a long antibiotic course (LAC, >5 days). The primary composite outcome included superficial, incisional, organ-space infections or death within 30 days post procedure. Results A total of 53 SAC patients and 55 LAC patients were identified. The composite outcome occurred more frequently in LAC patients than in SAC patients (40% vs 15%; P = .005). Organ-space infection occurred more frequently in LAC patients than in SAC patients (31% vs 13%; P = .04). Conclusions Extended duration of antibiotics after adequate source control does not improve outcomes even in the setting of extensive intra-abdominal contamination.

Abstract Microglia are essential for maintaining brain homeostasis, including the sleep-wake cycle, but the underlying mechanisms remain unclear. Here, using in vivo two-photon imaging in both head-fixed and freely moving mice with simultaneous electroencephalogram–electromyogram (EEG–EMG) recording, we investigated microglial process dynamics and their interactions with locus coeruleus (LC) noradrenergic (NE) axons in the frontal cortex across sleep-wake states. During sleep or chemogenetic suppression of LC neurons, microglia enhanced their surveillance and increased interactions with NE axons. Correlative electron microscopy at nanometer resolution identified structural contacts between microglial process endings and NE boutons. Mechanistically, microglia-bouton interaction is primed by NE–β2-adrenergic receptor (β2AR) signaling, leading to enhanced Ca²⁺ activity in NE axons. These findings suggest that microglial interactions with NE axons promote cortical norepinephrine transmission and maintain stable wakefulness.

ABSTRACT Objective To determine the test performance of cutaneous phosphorylated alpha‐synuclein (P‐SYN) in dementia with Lewy bodies (DLB), individuals with reduced Montreal Cognitive Assessment (MoCA) and healthy controls. Methods This is the first subgroup analysis of the Synuclein‐One study, a prospective, blinded study evaluating P‐SYN detection from skin biopsies in 218 subjects with a referral diagnosis of control ( N = 151) and DLB ( N = 67). All subjects completed detailed examinations, questionnaires, and had skin biopsies for detection of P‐SYN. DLB patients were included if meeting the 4th DLB consensus probable criteria. Control subjects, aged 40–99, had no history, examination findings, or symptoms suggestive of a synucleinopathy or neurodegenerative disease. An expert review panel, blinded to pathological data, determined the final diagnosis. Controls with reduced MoCA (MoCA < 26, N = 26) at screening were analyzed separately. Results After expert panel review, only 50/67 patients met consensus criteria for DLB, 26/151 controls had a reduced MoCA, and 120/151 controls had a normal MoCA. The proportions of subjects with cutaneous P‐SYN detected by skin biopsy were 96.0% (48 of 50) of the DLB group, 31% (8 of 26) of the controls with reduced MoCA, and 3.3% (4 of 120) of the controls with normal MoCA. Interpretation In this prospective, blinded, cross‐sectional study, a high proportion of subjects meeting clinical consensus criteria for DLB had P‐SYN detected in skin biopsies. Almost 1/3 of subjects with reduced MoCA testing also had P‐SYN detected. These results support a role for skin biopsy detection of P‐SYN in patients with DLB. Trial Registration NCT04700722

Abstract Purpose Patients presenting for iliopsoas tendinitis consultation after total hip arthroplasty (THA) often describe a prolonged time to diagnosis and subsequent surgical management. The purpose of this study was to quantify time from symptom onset to diagnosis and subsequent arthroscopic iliopsoas fractional lengthening, including number of providers seen. Methods Patients undergoing arthroscopic iliopsoas fractional lengthening after THA were prospectively identified between 2023-2025 at a single institution. Time from symptom onset to iliopsoas tendinitis diagnosis as well as arthroscopic lengthening were determined. Number of providers seen, diagnostic relief from preoperative iliopsoas bursal injections, and postoperative satisfaction after fractional lengthening were also evaluated to better quantify indications and outcomes of arthroscopic intervention in this population. Results A total of 44 hips in 41 patients (23 females and 18 males) were included (mean age: 64.7 ± 10.2, mean BMI: 29.9 ± 5.9 kg/m2). Of note, 7 patients (16%) had undergone revision THA prior to iliopsoas symptom onset. Patients had on average 2.2 ± 2.1 years of symptoms and saw 2.5 ± 1.7 [range: 1-8] providers prior to being diagnosed with iliopsoas tendinitis and referred for consideration of arthroscopic fractional lengthening. Preoperatively, 93% of patients underwent at least 1 iliopsoas bursal corticosteroid injection, with an average of 81.1% symptom relief during the diagnostic (anesthetic) phase. The mean time between THA and iliopsoas fractional lengthening was 4.8 ± 3.4 years, whereas the mean time between initial iliopsoas tendinitis symptoms to fractional lengthening was 3.1 ± 2.5 years. At a mean of 11.3 ± 6.8 months postoperatively, mean surgery satisfaction was 8.1 ± 2.6 on a scale of 1 to 10, with the vast majority of patients (89.5%) stating that they would undergo fractional lengthening again. Conclusion Patients often experience a protracted period of symptoms and see multiple clinicians prior to being diagnosed with iliopsoas tendinitis and undergoing arthroscopic management. In patients refractory to conservative management, arthroscopic fractional lengthening can provide high surgery satisfaction, with most patients stating they would undergo the procedure again. These findings highlight the importance of increased recognition and appropriate referral of patients with iliopsoas tendinitis following THA.

Living donor liver transplantation (LDLT) is a life-saving procedure for patients with end-stage liver disease. As its use expands worldwide, ensuring the safety and well-being of live liver donors (LLD) is of paramount importance. Published evidence on early postoperative complications after living donor hepatectomy—those occurring within 90 days of surgery—is limited, and standardized postoperative care protocols are lacking. The International Liver Transplantation Society (ILTS) and the International Living Donor Liver Transplantation Group (iLDLT Group) convened a consensus conference in Toronto in March 2025 to develop guidelines for the safe care of the LLDs. This manuscript details the recommendations on early postoperative considerations for the safety of LLDs developed by Working Group III (WGIII) of the Consensus Scientific Committee, using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) system for assessment of recommendations, and the Danish model of consensus. WGIII addressed four key areas: (1) standardized postoperative care, (2) early biliary complications, (3) early postoperative liver dysfunction, and (4) early postdischarge follow-up. This report emphasizes the need for vigilant postoperative monitoring in specialized units, with access to experienced providers and defined clinical pathways. Structured clinical and psychosocial follow-up protocols, perioperative prophylaxis for surgical site infections and venous thromboembolism, and management of early biliary and vascular complications are discussed. These may help standardize care, reduce complications and improve short-term outcomes in LLDs.

Living liver donation is a critical component for addressing organ shortage and improving outcomes for patients with end-stage liver disease. As the prevalence of living donor liver transplantation (LDLT) increases worldwide, understanding and optimizing long-term donor health is paramount. The 2025 International Liver Transplantation Society and International Living Donor Liver Transplantation Society (ILTS-iLDLT) Consensus Conference convened experts in the field of liver transplantation to establish evidence-based guidelines focused on the long-term medical, psychological, and social considerations following living liver donation. The aim of this working group was to integrate current evidence and expert consensus on donor follow-up protocols, risk assessment, and management strategies to promote long-term donor health, quality of life, and living liver donor programs globally to safeguard the welfare of this unique population.

Objective The purpose of this study was to determine the cumulative incidence of diagnosis switching, drug‐free remission, and initiation of a biologic or targeted synthetic disease‐modifying antirheumatic drug (b/tsDMARD) in individuals with seronegative rheumatoid arthritis (RA). Methods Adult residents of Olmsted County, Minnesota, with incident seronegative (rheumatoid factor negative/anti–cyclic citrullinated peptide antibody negative) RA meeting the 1987 and/or 2010 American College of Rheumatology classification criteria were included. Data were collected from January 1, 2005, to December 31, 2023, through manual chart review. Drug‐free remission was defined as a period of at least six months where the individual was no longer taking treatment for RA and did not have evidence of active inflammatory arthritis upon evaluation by a rheumatologist. We calculated the 10‐year cumulative incidence of a change in diagnosis, adjusting for the competing risk of death, and of drug‐free remission and initiation of a b/tsDMARD, adjusting for the competing risks of death or change in diagnosis. Results A total of 176 individuals with seronegative RA (68% women) were included. The 10‐year cumulative incidence of a change in diagnosis was 12.8% (95% confidence interval [CI] 8.7%–18.9%). The most common change in diagnosis was to spondyloarthritis (4%). The 10‐year cumulative incidence of drug‐free remission and initiation of a b/tsDMARD was 26.6% (95% CI 20.7%–34.2%) and 19.9% (95% CI 14.7%–26.9%), respectively. Over a median follow‐up of 11.8 years, 49 individuals entered drug‐free remission. Conclusion After initial diagnosis of seronegative RA, about 13% of individuals had a change in diagnosis and a quarter experienced drug‐free remission within 10 years.