Central Clinic and Hospital

Importance:The efficacy and safety of guideline-recommended treatments for heart failure (HF) are uncertain in patients with Chagas disease. Objective:To evaluate the efficacy and safety of the angiotensin receptor-neprilysin inhibitor sacubitril/valsartan in patients with HF with reduced ejection fraction due to Chagas disease. Design, Setting, and Participants:From December 10, 2019, through September 13, 2023, patients with HF, confirmed diagnosis of Chagas disease, left ventricular ejection fraction of 40% or less, and N-terminal pro-B-type natriuretic peptide (NT-proBNP) of 600 pg/mL or greater (or B-type natriuretic peptide [BNP] ≥150 pg/mL) or 400 pg/mL or greater (or BNP ≥100 pg/mL) if hospitalized for HF within the previous 12 months were screened at 83 sites in Argentina, Brazil, Colombia, and Mexico. Statistical analysis was conducted between May and July 2025. Interventions:Patients were randomized to receive sacubitril/valsartan (target dose, 200 mg twice daily) or enalapril (target dose, 10 mg twice daily), in addition to standard therapy. Main Outcomes and Measures:The primary end point was a hierarchical composite outcome tested, in order, of death from cardiovascular causes, hospitalization for HF, or relative change in NT-proBNP from baseline to 12 weeks. The primary analysis was done using a win ratio approach. Results:Overall, 462 participants were randomized to receive sacubitril/valsartan and 460 to receive enalapril (mean [SD] age, 64.2 [10.8] years; 387 [42.0%] were female). Over a median (IQR) follow-up of 25.2 (18.4-33.2) months, cardiovascular death occurred in 110 patients (23.8% [18.3% wins in the hierarchical comparison]) in the sacubitril/valsartan group and 117 patients (25.4% [17.5% wins]) in the enalapril group. A total of 102 patients (22.1% [7.7% wins]) in the sacubitril/valsartan group and 111 (24.1% [6.9% wins]) in the enalapril group experienced a first hospitalization for HF. Patients in the sacubitril/valsartan group had a median (IQR) decrease in NT-proBNP of 30.6% (-54.3% to -0.9%) at 12 weeks, leading to 22.5% wins, while those in the enalapril group had a 5.5% (-31.9% to 37.5%) decrease (7.2% wins). The resulting stratified win ratio was 1.52 (95% CI, 1.28-1.82; P < .001) for sacubitril/valsartan compared with enalapril. Conclusions and Relevance:In patients with HF with reduced ejection fraction due to Chagas disease, there was no significant difference in clinical outcomes between sacubitril/valsartan and enalapril, but there was a greater reduction in NT-proBNP at 12 weeks in patients in the sacubitril/valsartan group. Trial Registration:ClinicalTrials.gov Identifier: NCT04023227.

At the first interim analysis of the phase 3 KEYNOTE-426 trial, first-line pembrolizumab plus axitinib showed superior overall survival (OS), progression-free survival (PFS) and objective response rate (ORR) over sunitinib for advanced renal cell carcinoma (RCC). To assess long-term durability of clinical outcomes and elucidate predictive biomarkers for RCC, we performed efficacy and prespecified exploratory biomarker analyses from KEYNOTE-426 with ≥5 years of follow-up. Pembrolizumab plus axitinib showed sustained benefits in OS (hazard ratio: 0.84; 95% confidence interval: 0.71–0.99), PFS (hazard ratio: 0.69; 95% confidence interval: 0.59–0.81) and ORR (60.6% versus 39.6%) compared to sunitinib. An 18-gene T-cell-inflamed gene expression profile (Tcell inf GEP) was positively associated with OS ( P = 0.002), PFS ( P < 0.0001) and ORR ( P < 0.0001) within the pembrolizumab plus axitinib arm. An angiogenesis signature was positively associated with OS ( P = 0.004) within the pembrolizumab plus axitinib arm and with OS ( P < 0.0001), PFS ( P < 0.001) and ORR ( P = 0.002) within the sunitinib arm. Across arms, programmed cell death ligand 1 combined positive score was only associated (negatively) with OS within the sunitinib arm ( P = 0.025). Additionally, PBRM1 (polybromo-1) mutation had a positive association with ORR ( P = 0.002) within the pembrolizumab plus axitinib arm. Within the sunitinib arm, OS was positively associated with VHL (von Hippel–Lindau tumor suppressor gene) ( P = 0.040) and PBRM1 ( P = 0.010) mutations and was negatively associated with BAP1 ( BRCA1- associated protein 1) mutation ( P = 0.019). Results showed a sustained clinical benefit with pembrolizumab plus axitinib over sunitinib and provide valuable information on biomarkers for immunotherapy-based treatment combinations in advanced RCC. Prospective clinical investigations are needed for biomarker-directed treatment for advanced RCC. ClinicalTrials.gov identifier: NCT02853331 .

Inflammatory bowel disease (IBD) represents a diverse variety of chronic inflammatory intestinal conditions. Sexuality is often disturbed in patients with IBD, more often affecting women than men. Many factors seem to contribute to intimacy concerns. The most popular questionnaires used in empirical research around the world are the Female Sexual Function Index (FSFI) for women and the International Index of Erectile Function (IIEF) for men. Sexual satisfaction was negatively correlated with depression, anxiety, sexual problems, and illness perceptions. When analysing the problem of IBD, disorders of sexual function should not be ignored. Patients should be screened for psychological diseases and sexual dysfunction, and necessary treatments should be given as soon as possible. By understanding what factors contribute to poor sexual functioning in patients with IBD, we may try to minimise adverse psychosocial events. Screening for sexual disorders should be a part of daily medical practice.

Background:Anaplastic thyroid carcinoma (ATC) is a highly aggressive malignancy, and there is currently a lack of up-to-date epidemiological data. Traditional survival analysis fails to capture the dynamic changes in prognosis for long-term survivors, while conditional survival (CS) analysis, a critical tool for adaptive risk stratification, remains underexplored in ATC. Methods:Patients diagnosed with ATC between 2000 and 2021 were identified from the Surveillance, Epidemiology, and End Results (SEER) database. Temporal trends in age-adjusted incidence and incidence-based mortality were analyzed using Joinpoint regression to calculate annual percentage changes (APCs) with 95% confidence intervals (CIs). Overall survival (OS) was estimated using the Kaplan-Meier method. CS rates were calculated using the formula: CS(y/x) = OS(y+x)/OS(x). Prognostic factors were identified using Best Subset Regression (BSR), LASSO, and univariate and multivariate Cox regression analyses, and these factors were incorporated into a CS-nomogram model. The predictive performance of the model was validated using evaluation metrics, including the area under the receiver operating characteristic curve (AUC). Point values were assigned to the model's predictive factors, and a risk stratification system was developed based on the optimal threshold of the total score. Results:From 2000 to 2021, the age-adjusted incidence of ATC increased from 0.066 to 0.077 per 100,000 (APC: 2.308%, 95% CI: 1.187-3.441), peaking at 0.119 in 2018. Mortality trends paralleled this rise, with age-adjusted mortality increasing from 0.037 to 0.051 per 100,000 (APC: 2.380%, 95% CI: 1.129-3.646). CS analysis demonstrated a progressive increase in survival rates over time, with the 24-month cumulative survival rate rising from 14.0% to 93.8%, with the most pronounced temporal changes observed in patients with distant disease. Prognostic factors identified through BSR, LASSO, and Cox regression included age, SEER stage, and treatment. A novel CS-nomogram was successfully developed and validated for dynamic real-time survival prediction, enabling identification of high- and low-risk patient groups. Conclusion:The incidence and incidence-based mortality of ATC have increased over the past few decades. The CS rates of ATC patients have dynamically improved over time. The CS-nomogram, integrating age, SEER stage, and treatment, provides clinicians with a personalized, dynamic, and real-time survival prediction tool that helps alleviate survivors' psychological distress, reduces anxiety, and optimizes precision follow-up strategies.

The high clinical burden of antimicrobial resistance (AMR) and the dwindling antibiotic pipeline demand standardised tools to monitor resistance development to new antibiotics. The Emerging Resistance Index (ERI) is a novel quantitative tool designed to track resistance to newly developed antibiotics. The ERI incorporates various parameters: AMR pooled proportions and trends, availability of AMR and antimicrobial consumption surveillance systems, time lag between antibiotic approval and resistance detection, and the average annual number of outbreaks caused by resistant strains. AMR and antimicrobial consumption data on 13 new antibiotics were extracted by reviewing the literature and the reports from 38 surveillance systems included in the European Clinical Research Alliance on Infectious Diseases-The Epidemiology Network central data repository, encompassing 27 EU countries, four European Free Trade Association countries, and the UK. Our analysis revealed rapid resistance development to all new Gram-negative-targeting antibiotics, with particularly high ERI values for imipenem-relebactam and cefiderocol. Combinations of old β-lactams with novel inhibitors were especially prone to rapid resistance development. The ERI could offer a quantitative and dynamic tool for monitoring resistance trends. Also, the ERI could support more timely surveillance efforts, inform antibiotic policy decisions, and aid in prioritising antibiotic research and development.