Alatout, Mayar H.

Abstract The optimal management of diverticulitis in young and immunocompromised patients remains controversial, particularly regarding whether these groups warrant a lower threshold for surgery. Historically, young patients were often offered elective colectomy after the first episode of diverticulitis because of concerns regarding recurrence and more aggressive disease. However, contemporary evidence shows that although younger patients may experience higher recurrence rates, they are not at increased risk for complicated recurrence, emergency surgery, or mortality compared with older adults. Nonoperative management is successful in most cases, supporting an individualized rather than age-based surgical approach. Immunocompromised patients, including those with solid organ transplantation, malignancy, chemotherapy exposure, chronic steroid use, or autoimmune disease requiring immunosuppression, represent a higher-risk population. These patients more commonly present with complicated diverticulitis, perforation, sepsis, and atypical symptoms that may delay diagnosis. Although uncomplicated disease can often be managed nonoperatively, immunocompromised patients experience higher rates of emergent surgery, stoma creation, postoperative complications, and mortality, particularly when surgery is performed in a non-elective setting. Current evidence does not support lowering the surgical threshold solely on the basis of young age or immunosuppression status. Instead, management should remain individualized, incorporating disease severity, recurrence pattern, comorbidities, operative risk, and patient preferences. Further research is needed to better define optimal surgical timing and patient selection in these two populations.

Abstract Aim Rectal prolapse is a full‐thickness intussusception of the rectum beyond the anal canal. It is often mistaken for other anorectal pathologies, leading to inaccurate referrals to colorectal surgeons and inappropriate management. However, the frequency of misdiagnosis is not well characterized. We aimed to assess the diagnostic accuracy of rectal prolapse referrals to three tertiary medical centres. Methods This is a retrospective study of patients referred for rectal prolapse to colorectal surgeons at the Mayo Clinic in Rochester, Jacksonville, and Phoenix from 2020 to 2024. The primary outcome is the accuracy of rectal prolapse diagnosis. The secondary outcomes are factors that correlate with diagnostic accuracy. Results Rectal prolapse was inaccurately diagnosed in 38.7% (186/480) of patients. Among misdiagnosed patients, the correct diagnosis was haemorrhoids (68.0%, n = 134), pelvic floor dysfunction (24.3%, n = 48) and rectocele (18.7%, n = 37). A diagnosis of rectal cancer was found in 3 patients (1.5%). The most common presenting symptoms were protrusion (66.3%, n = 345) and bleeding (33.6%, n = 175). Among the referring physicians, only 50.5% ( n = 227) performed an anorectal examination. Overall, there was significant variability in diagnostic accuracy across different specialties, with the highest accuracy from colorectal practices (84.0%) and the lowest from urologists (50.0%). Internal medicine physicians had a lower diagnostic accuracy with anorectal examination than without, though it did not reach statistical significance (44.0% vs. 59.5%, p = 0.2). Conclusion Over one‐third of rectal prolapse referrals were incorrectly diagnosed. This study highlights the opportunity for further training of referring providers on anorectal pathologies to improve diagnostic accuracy which could reduce treatment delays and optimize clinical outcomes.

Background: Transthyretin (TTR) cardiac amyloidosis is a progressive cardiomyopathy with high mortality; however, the role of implantable cardioverter-defibrillators (ICDs) in this population remains unclear. Methods: This retrospective cohort study included patients with confirmed TTR cardiac amyloidosis, with or without ICDs, from January 1, 2001, to December 31, 2024, across all three Mayo Clinic sites (Arizona, Florida, and Minnesota). Diagnosis was confirmed by endomyocardial biopsy or abnormal technetium pyrophosphate (PYP) scintigraphy. A 1:4 propensity score-matched cohort of non-ischemic cardiomyopathy (NICM) patients with ICDs served as a control group. The primary outcome was all-cause mortality, comparing transthyretin cardiac amyloidosis (TTR-CA) patients by ICD status and against matched NICM patients. Secondary analyses evaluated predictors of mortality, including the use of tafamidis and the indication for ICD (primary vs. secondary prevention). Kaplan–Meier and Cox regression analyses were used to assess predictors of survival and mortality. Results: A total of 463 patients with confirmed TTR cardiac amyloidosis were included. The median follow-up duration was 7.4 years (interquartile range (IQR): 5.3–9.2 years) for the non-ICD group and 6.8 years (IQR: 4.5–9.0 years) for the ICD group. The median age was 74.5 years (IQR: 68.0–80.0 years), and 92.9% of patients were male. Among them, 206 (44.5%) received ICDs and 257 (55.5%) did not. ICD recipients were younger (71.0 vs. 77.0 years; p = 0.001) and had higher rates of hypertension (62.6% vs. 45.6%; p = 0.001), chronic kidney disease (CKD) (62.6% vs. 44.4%; p = 0.001), and diabetes (30.1% vs. 21.8%; p = 0.043). Median left ventricular ejection fraction was lower in the ICD groups (43% vs. 54%; p = 0.007), and N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels were higher in the ICD group (2259.0 pg/mL vs. 1503.0 pg/mL; p = 0.007). Among ICD recipients, 157 (76.2%) received the device for primary prevention, while 48 (23.3%) received the ICD for secondary prevention. Appropriate shocks were delivered in 22 patients (10.6%), primarily for ventricular tachycardia (n = 18) and ventricular fibrillation (n = 4). Inappropriate shocks occurred in six patients (3.0%), and 12 patients (5.8%) experienced device-related complications. Over 10 years of follow-up, ICD implantation did not confer a survival benefit for patients with TTR-CA compared to those without an ICD (p = 0.74). In contrast, a 1:4 propensity-matched NICM cohort with ICDs, which had a median follow-up of 7.1 years (IQR: 4.6–8.8 years), showed significantly improved survival than TTR-CA patients with ICDs (p = 0.034). Among the TTR-CA patients with ICDs, neither the use of tafamidis (p = 0.10) nor the ICD indication (primary vs. secondary prevention; p = 0.85) influenced mortality. In the Cox regression analysis, predictors of mortality in TTR-CA patients included older age (hazard ratio (HR) 1.048; p = 0.001), CKD (HR 1.637; p = 0.029), troponin T >50 ng/L (HR 1.594; p = 0.031), NT-proBNP >3000 pg/mL (HR 1.514; p = 0.050), and ejection fraction <40% (HR 1.935; p = 0.003). ICD implantation was not associated with improved survival (HR 0.932; p = 0.763). Conclusions: In conclusion, our data suggest that ICD therapy may not provide a significant overall survival benefit in older TTR-CA patients with impaired pump function; thus, prospective studies are warranted before any changes to clinical practice are considered. Key predictors of mortality included reduced ejection fraction and elevated cardiac biomarkers. Additional prospective studies are needed to clarify the role of ICDs in treatment strategies for patients with TTR-CA.

BACKGROUND: Metachronous cancer risk varies by mismatch repair mutation in patients with hereditary nonpolyposis colorectal cancer. Total colectomy offers decreased risk of metachronous colorectal cancers but decreased quality of life compared with segmental colectomy. OBJECTIVE: Compare segmental versus total colectomy for colon cancer via a mutation-specific Markov decision model. DESIGN: Simulated survival and colorectal metachronous occurrence among patients with MLH1, MSH2 , or MSH6 mutations undergoing either segmental or total colectomy. SETTINGS: National databases, literature review. PATIENTS: Simulated patients with hereditary nonpolyposis colorectal cancer. MAIN OUTCOME MEASURES: Overall survival, quality-adjusted life years based on procedure-specific utility states (segmental colectomy 0.99, total colectomy 0.95). RESULTS: Among patients aged 25 years, total colectomy offered less than 1 year of increased mean survival compared with segmental resection across all mutations ( MLH1: 0.8 years, MSH2: 0.9, MSH6: 0.3). This difference in survival decreased with increasing age. Segmental resection offered a small increase in quality-adjusted life years compared with total colectomy across all ages. This difference was highest for MSH6 (0.9 years vs MLH1 : 0.6 and MSH2 : 0.4 at age 25), particularly at younger ages of diagnosis. In a sensitivity analysis, lower total colectomy utility states resulted in greater increases in quality-adjusted life years with segmental colectomy across all mutations. LIMITATIONS: Metachronous cancer risk data do not distinguish between colon and rectal cancers and is extrapolated beyond age 70 years. CONCLUSIONS: Segmental and total colectomy offer similar survival and quality-adjusted life year outcomes. With decreased risk of metachronous cancers, patients with MSH6 mutations across all ages may prefer segmental resection owing to higher quality-adjusted life years and lower survival benefits from total colectomy compared with MLH1 and MSH2 patients. Operative strategy in patients with hereditary nonpolyposis colorectal cancer should be individualized, and this study shows that mutation-specific differences in survival and quality-adjusted life years are small. See Video Abstract . MODELO DE DECISIÓN ESPECÍFICO PARA LA MUTACIÓN EN LA COLECTOMÍA ABDOMINAL SEGMENTARIA FRENTE A LA COLECTOMÍA ABDOMINAL TOTAL EN EL CÁNCER COLORRECTAL HEREDITARIO NO POLIPOSO ANTECEDENTES: El riesgo de cáncer metacrónico varía según la mutación de reparación de desajustes en pacientes con cáncer colorrectal hereditario no poliposo. La colectomía total ofrece un menor riesgo de cánceres colorrectales metacrónicos, pero una menor calidad de vida en comparación con la colectomía segmentaria. OBJETIVO: Comparar la colectomía segmentaria con la colectomía total para el cáncer de colon mediante un modelo de decisión de Markov específico para mutaciones. DISEÑO: Simulación de la supervivencia y la aparición metacrónica de cáncer colorrectal en pacientes con mutaciones MLH1, MSH2 o MSH6 sometidos a colectomía segmentaria o total. ENTORNO: Bases de datos nacionales, revisión de la literatura. PACIENTES: Pacientes simulados con cáncer colorrectal hereditario no poliposo. PRINCIPALES MEDIDAS DE RESULTADO: Supervivencia global, años de vida ajustados por calidad basados en estados de utilidad específicos del procedimiento (colectomía segmentaria 0,99, colectomía total 0,95). RESULTADOS: Entre los pacientes de 25 años, la colectomía total ofreció menos de un año de aumento de la supervivencia media en comparación con la resección segmentaria en todas las mutaciones ( MLH1: 0,8 años, MSH2: 0,9, MSH6: 0,3). Esta diferencia en la supervivencia disminuyó con el aumento de la edad. La resección segmentaria ofreció un pequeño aumento en los años de vida ajustados por calidad en comparación con la colectomía total en todas las edades. Esta diferencia fue mayor para MSH6 (0,9 años frente a MLH1 : 0,6 y MSH2 : 0,4 a los 25 años), especialmente en las edades más jóvenes de diagnóstico. En un análisis de sensibilidad, los estados de utilidad más bajos de la colectomía total dieron lugar a mayores aumentos en los años de vida ajustados por calidad con la colectomía segmentaria en todas las mutaciones. LIMITACIONES: Los datos sobre el riesgo de cáncer metacrónico no distinguen entre cánceres de colon y recto y se extrapolan más allá de los 70 años. CONCLUSIONES: La colectomía segmentaria y la colectomía total ofrecen resultados similares en cuanto a la supervivencia y los años de vida ajustados por calidad. Con la disminución del riesgo de cánceres metacrónicos, los pacientes con mutaciones MSH6 de todas las edades pueden preferir la resección segmentaria debido a los mayores años de vida ajustados por calidad y los menores beneficios de supervivencia de la colectomía total en comparación con los pacientes MLH1 y MSH2 . La estrategia quirúrgica en pacientes con cáncer colorrectal hereditario no poliposo debe individualizarse, y este estudio muestra que las diferencias específicas de la mutación en la supervivencia y los años de vida ajustados por calidad son pequeñas. ( AI-generated translation )

Primary biliary cholangitis (PBC) is a chronic autoimmune liver disease marked by cholestasis and progressive fibrosis. While ursodeoxycholic acid (UDCA) remains the first-line therapy, approximately 30–40% of patients have an inadequate biochemical response, increasing the risk of disease progression. Obeticholic acid (OCA), a potent farnesoid X receptor (FXR) agonist, was the first second-line agent approved by the only Food and Drug Administration (FDA) and has demonstrated moderate biochemical efficacy but limited tolerability due to dose-dependent pruritus and safety concerns in cirrhosis. Fenofibrate, a peroxisome proliferator-activated receptor alpha (PPAR-α) agonist, showed substantial alkaline phosphatase (ALP) reductions when added to UDCA, although its long-term benefit remains unconfirmed in large-scale trials and its use remains off-label in the United States, unlike FDA-approved agents. Seladelpar, a selective peroxisome proliferator-activated receptor delta (PPAR-δ) agonist, and elafibranor, a dual PPAR-α/δ agonist, have both recently received FDA accelerated approval after demonstrating significant improvements in ALP, biochemical response rates, and pruritus relief in phase 3 trials. This review summarizes these second-line therapies’ mechanisms, efficacy, safety, and limitations emphasizing the need for individualized treatment decisions and ongoing research into long-term clinical outcomes.

Metabolic dysfunction-associated steatotic liver disease (MASLD) and its progressive form, metabolic dysfunction-associated steatohepatitis (MASH), are among the most prevalent causes of chronic liver disease worldwide, closely linked to the global rise in overweight and obesity, type 2 diabetes, and metabolic syndrome. Until recently, treatment options were limited to lifestyle interventions, with no approved pharmacologic therapies. Resmetirom, a liver-directed, selective thyroid hormone receptor beta (THR-β) agonist, is a promising disease-modifying agent that targets hepatic lipid metabolism, inflammation, and fibrosis. Clinical trials, including the pivotal phase 3 MAESTRO-NASH and MAESTRO-NAFLD-1 trials, have demonstrated significant improvements in liver fat reduction, lipid profiles, histological endpoints, and health-related quality of life, with a favorable safety profile. In March 2024, the FDA granted accelerated approval of resmetirom for adults with MASH and moderate-to-advanced fibrosis, marking a significant milestone in MASLD treatment. This review discusses the mechanistic rationale, preclinical data, and pivotal clinical trial outcomes supporting resmetirom’s role in MASLD/MASH management, while outlining ongoing research needs, including long-term safety, pediatric evaluation, and biomarker development for optimized patient selection.

Recent findings suggest that autophagy plays a role in the development of aging-related neuromuscular dysfunction; however, the contribution of autophagy impairment to the maintenance of diaphragm force generation in old age is unknown. This study shows that in old mice, chloroquine administration decreases maximal transdiaphragmatic pressure generation. These chloroquine effects suggest a susceptibility to impairments in autophagy in old age.