FGFR inhibition blocks NF-ĸB-dependent glucose metabolism and confers metabolic vulnerabilities in cholangiocarcinoma.

Genomic alterations that activate Fibroblast Growth Factor Receptor 2 (FGFR2) are common in intrahepatic cholangiocarcinoma (ICC) and confer sensitivity to FGFR inhibition. However, the depth and duration of response is often limited. Here, we conduct integrative transcriptomics, metabolomics, and phosphoproteomics analysis of patient-derived models to define pathways downstream of oncogenic FGFR2 signaling that fuel ICC growth and to uncover compensatory mechanisms associated with pathway inhibition. We find that FGFR2-mediated activation of Nuclear factor-κB (NF-κB) maintains a highly glycolytic phenotype. Conversely, FGFR inhibition blocks glucose uptake and glycolysis while inciting adaptive changes, including switching fuel source utilization favoring fatty acid oxidation and increasing mitochondrial fusion and autophagy. Accordingly, FGFR inhibitor efficacy is potentiated by combined mitochondrial targeting, an effect enhanced in xenograft models by intermittent fasting. Thus, we show that oncogenic FGFR2 signaling drives NF-κB-dependent glycolysis in ICC and that metabolic reprogramming in response to FGFR inhibition confers new targetable vulnerabilities.

An exploration of footwear preferences, attitudes and beliefs in people with knee osteoarthritis: A qualitative study.

BACKGROUND: Although footwear can improve pain and function in individuals with knee osteoarthritis (OA), perspectives about footwear in this population have not been explored. OBJECTIVES: This qualitative study explored preferences, attitudes and beliefs about footwear in adults with knee OA. METHODS: Twenty individuals with a clinical diagnosis of knee OA (aged 45-79 years, 65% women) participated in semi-structured interviews about factors which influence footwear selection, the effect of footwear on knee symptoms, and footwear modifications. Data were analysed thematically. RESULTS: Four themes, with sub-themes, were identified: i) there are specific footwear characteristics people look for, with comfort as their top priority; ii) shoe appearance is important; iii) footwear can aggravate or ease symptoms; and iv) people with knee OA find footwear in a variety of ways. Participants related built-in arch support, a cushioned insole and low/no heel, without addition of foot orthoses, to comfort, and were willing to pay more for comfort and quality. Appearance was also a consideration, and participants indicated they would tolerate short periods of symptom aggravation for aesthetic shoes. Participants felt that footwear choice affected their knee symptoms and risk of slipping/twisting. Participants reported that their footwear choices were determined through trial-and-error, and sometimes on advice from health professionals or shoe store salespersons. CONCLUSIONS: There are specific footwear features important to individuals with knee OA. Knowledge of these features can be used by health professionals to inform footwear discussions with knee OA patients and serve as considerations when developing footwear targeted for this population.

Metabolomics in Primary Open Angle Glaucoma: A Systematic Review and Meta-Analysis.

Glaucoma is a leading cause of blindness worldwide. It is suggested that primary open angle glaucoma (POAG), the most common form of glaucoma, may be associated with significant metabolic alternations, but the systemic literature review and meta-analysis in the area have been missing. Altered metabolomic profiles in the aqueous humor and plasma may serve as possible biomarkers for early detection or treatment targets. In this article, we performed a systematic meta-analysis of the current literature surrounding the metabolomics of patients with POAG and metabolites associated with the disease. Results suggest several metabolites found to be specifically altered in patients with POAG, suggesting broad generalizability and pathways for future research.

Associations Between Stroke Localization and Delirium: A Systematic Review and Meta-Analysis.

OBJECTIVES: Delirium is common among patients with acute stroke and associated with worse outcomes. However, it is unclear which stroke locations or types are most associated with delirium. MATERIALS AND METHODS: We systematically reviewed studies of patients with acute stroke that reported stroke locations and types by delirium status. We included papers in any language, through a combined search from January 2010 to June 2021. Case studies with less than 20 patients, case-control studies, and randomized controlled trials were excluded. MEDLINE, EMBASE, PsycINFO, CINAHL, and Alois databases were searched. Pooled relative risks were calculated using bivariate random effects models or network meta-analysis. Methodological quality was assessed across 8 factors. RESULTS: 31 patient samples representing 8329 patients were included. Delirium was more common in patients with supratentorial lesions than infratentorial (RR [Relative Risk] 2.01, CI [Confidence Interval] 1.49-2.72); anterior circulation lesions than posterior (RR 1.41, CI 1.13-1.78); and cortical lesions than subcortical (RR 1.54, CI 1.25-1.89). Stroke side was not associated with delirium (right vs. left: RR 0.99, CI 0.77-1.28). Delirium was more common in patients with hemorrhagic strokes than ischemic (RR 1.74, CI 1.42-2.11) and patients with preexisting qualitative atrophy (RR 1.66, CI 1.21-2.27). CONCLUSION: Several brain localizations and types of strokes were associated with delirium. Conclusions were in part limited by the heterogeneity of studies and broad or qualitative lesion descriptions. These results may assist in anticipating the risk of delirium in acute stroke and highlight brain networks and pathologies that may be involved in the pathophysiology of delirium.

Beyond the Barefoot Doctors: Using Community Health Workers to Translate HIV Research to Service.

Miami-Dade leads the nation in new HIV infections, and its Black communities experience the greatest disparities in outcomes. Our prior research found that street-based HIV testing facilitated by community health workers improved access to testing and care among Black adults in a controlled trial setting. Herein, we describe our efforts translating this CHW-led intervention into a community service for diverse Blacks in Miami. From December 2016 through August 2017, CHWs educated 1672 individuals about HIV transmission, prevention methods, and risk factor modification; 529 received HIV testing and/or linkage to care services. Approximately 5% of participants (n = 26) had rapid reactive results. This efficacious and culturally-acceptable model represents a powerful change in the delivery of HIV care and demonstrates how public health leaders can foster community engagement in the transition from research to service.