ウィルソン病

IMPORTANCE: Whether frailty influences the benefit-risk balance of glucagon-like peptide-1 receptor agonists (GLP-1 RA) is uncertain. OBJECTIVE: To evaluate whether frailty modifies the efficacy and safety of the GLP-1 RA semaglutide in adults with cardiovascular disease and overweight/obesity. DESIGN, SETTING, AND PARTICIPANTS: In this secondary analysis of a randomized clinical trial, participants were adults with a body mass index of 27 or higher and established cardiovascular disease without diabetes. A 31-item frailty index (FI) was constructed using the Rockwood cumulative deficit approach; participants were categorized as not frail (FI ≤0.210), more frail (FI 0.211-0.310), and most frail (FI ≥0.311). INTERVENTIONS: Semaglutide, 2.4 mg, once weekly or placebo. MAIN OUTCOMES AND MEASURES: The primary composite outcome was cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke. Key secondary clinical outcomes, health-related quality-of-life (assessed by EuroQol 5-Dimension 5-Level [EQ-5D-5L] score), and safety events were additionally examined. RESULTS: Of 17 604 participants, the mean (SD) age was 61.6 (8.9) years; 12 732 patients (72.3%) were male and 4872 were female (27.7%). A total of 5432 patients (31%) had an FI up to 0.210, 8349 (47%) had an FI of 0.211 to 0.310, and 3823 (22%) had an FI 0.311 or higher. The incidence of the primary outcome increased with higher baseline FI. Benefits of semaglutide vs placebo on the primary outcome appeared consistent across the FI categories (hazard ratio [HR], 0.84; 95% CI, 0.65-1.07, if the FI was ≤0.210; HR, 0.70; 95% CI, 0.59-0.82, if the FI was 0.211-0.310; HR, 0.92; 95% CI, 0.76-1.10, if the FI was ≥0.311; P = .09 for interaction). Similar findings were observed when the FI was examined continuously (P = .30 for interaction). Semaglutide additionally reduced the composite heart failure outcome (P = .82 for interaction), all-cause hospitalization (P = .71 for interaction), and all-cause mortality (P = .28 for interaction) regardless of FI category. Benefits of semaglutide on EQ-5D-5L scores appeared larger with higher FI (P = .02 for interaction). Between baseline and week 104, FI category was more likely to improve (odds ratio [OR], 2.46; 95% CI, 1.80-3.37), and less likely to worsen (OR, 0.47; 95% CI, 0.34-0.65) with semaglutide vs placebo. The HRs for adverse events leading to permanent discontinuation of semaglutide vs placebo appeared lower among participants with higher baseline FI (P < .001 for interaction). CONCLUSIONS AND RELEVANCE: This study found that semaglutide demonstrated beneficial effects on a broad range of clinical outcomes in SELECT, without detectable heterogeneity by baseline FI. Benefits of semaglutide on health-related quality of life appeared greater with higher FI. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03574597.

Amyloid-targeted monoclonal antibody therapies have introduced a new era in the treatment of early Alzheimer disease. However, their use has increased the importance of detecting and monitoring amyloid-related imaging abnormalities (ARIA) on MRI, as such findings may influence treatment continuation, dose modification, and patient safety assessment. As anti-amyloid therapies expand into routine practice, increasing surveillance MRI volumes, interreader variability, and the potential for missed subtle abnormalities have generated interest in artificial intelligence (AI)-based clinical decision support tools. A multidisciplinary panel of neuroradiologists and Alzheimer disease clinicians examined the extent of evidence supporting clinical implementation of AI-assisted ARIA detection tools, these tools' safe integration into practice, and remaining evidence gaps. The panel concluded that AI-assisted ARIA detection is likely to enhance patient safety when used as clinical decision support within a radiologist-in-the-loop framework. Panelists also noted substantial variation among commercially available tools in regulatory status, technical capabilities, and validation evidence. Moreover, they emphasized the need for further studies to assess the impact of improved detection on clinical outcomes. Overall, the panel supported conditional implementation with radiologist oversight, ongoing quality assurance, and prospective monitoring of clinical performance.

To date, no bovine viral diarrhea virus-2 (BVDV-2) coding-complete genomes are available from white-tailed deer (WTD) in Florida. We determined the coding-complete genome sequences of four BVDV-2 isolates from farmed WTD that were found dead in 2018. These belonged to BVDV-2 sub-genotype a.

UNLABELLED: Acute myeloid leukaemia (AML) cases with rare fusion genes, such as ERG-related fusions, constitute less than 1% of AML. They often present with a normal karyotype by conventional cytogenetics but are increasingly detected by RNA sequencing (RNAseq), although their characteristics and the utility of fusion genes as an MRD marker are poorly defined. We report a case of a 19-year-old female presenting with HNRNPH1::ERG AML, the fifth reported case to our knowledge, who developed a second HNRNPH1::ERG fusion at relapse that was not detectable on the original MRD assay. This case highlights potential mechanisms driving disease recurrence and underscores the importance of characterizing MRD kinetics and transcript dynamics to inform prognosis and therapeutic decisions. We highlight the benefit of incorporating RNAseq into testing both at diagnosis and at relapse, and the need to further characterise MRD kinetics for rare fusion genes in AML. TRIAL REGISTRATION: The authors have confirmed clinical trial registration is not needed for this submission.

BACKGROUND: Melanoma is highly aggressive with limited options in advanced disease. Photodynamic therapy (PDT) has shown poor efficacy in pigmented melanoma due to restricted light penetration and intrinsic ROS resistance. A novel approach is investigated here. METHODS: Full-thickness (4 mm) S91 pigmented melanoma grown intradermally in syngeneic immunocompetent (DBA) mice was treated using dual photosensitizers targeting tumor cells and microvasculature, together with a topical optical clearing agent. Anti-tumor immune effects were investigated in multiple functional assays, and the mechanisms-of-action were explored. RESULTS: Primary tumor was eradicated in all mice, with 95% disease-free survival at 90 d, falling to 20% upon CD8 + T-cell depletion pre-treatment. The median survival in nude mice was 21 d. Treated DBA mice also rejected systemic tumor re-challenge at 30 d post treatment. There was delayed growth of untreated contralateral tumors and of tumors co-injected into naïve mice together with splenocytes from treated mice. Biomarker analysis showed rapid tumor infiltration by CD8+ and CD3+ T cells, reduced suppressive myeloid populations, and widespread immune activation. Gene expression profiling revealed enrichment of immune-related pathways and long-lasting memory. CONCLUSIONS: Photodynamic immune stimulation treatment can destroy primary pigmented melanoma far beyond the depth of light penetration and has potent anti-tumor systemic efficacy.