Citations

Background SGLT2 (sodium‐glucose cotransporter 2) inhibitors reduce major adverse cardiovascular events (MACE) in type 2 diabetes. However, no direct comparison of individual SGLT2 inhibitor drugs has been conducted, particularly among adults with moderate cardiovascular risk who comprise most people with type 2 diabetes. Methods We used data for commercial, Medicare Advantage, and Medicare fee‐for‐service beneficiaries to emulate a target trial of adults (≥21 years) with type 2 diabetes and moderate cardiovascular risk who started canagliflozin, dapagliflozin, or empagliflozin between 2015 and 2020. We estimated propensity scores using the super learner ensemble method and incorporated them as inverse probability of treatment weights into Cox models, estimating risk of MACE, expanded MACE, and hyperglycemic and hypoglycemic crises through December 31, 2022. Results The weighted cohort, balanced on all baseline covariates, included 137 232 patients (mean age 65.7 years [SD, 8.1], 75.3% non‐Hispanic White, 57.0% male, 81.9% on metformin, 11.4% on glucagon‐like peptide‐1 receptor agonists) starting canagliflozin (N=42 877), dapagliflozin (N=17 871), or empagliflozin (N=7648). The risk of MACE was lower among patients starting empagliflozin versus canagliflozin (hazard ratio [HR], 0.92 [95% CI, 0.87–0.97]), driven by reduced risk of all‐cause mortality (HR, 0.86 [95% CI, 0.80–0.94]). There was no difference in MACE between empagliflozin versus dapagliflozin or dapagliflozin versus canagliflozin therapy. There was no difference in remaining outcomes between the three drugs. Conclusions The 3 most used SGLT2 inhibitor medications demonstrate similar effectiveness on cardiovascular outcomes among patients with type 2 diabetes at moderate cardiovascular risk, with differences between these drugs small in magnitude. Clinicians and health systems should prioritize enhancing access to these cardioprotective therapies.

The NCCN Guidelines for Bladder Cancer provide strategies for the diagnosis, treatment, and follow-up of patients with bladder cancer, which is the sixth most common cancer in the United States. Bladder cancer can be divided into 3 categories along a clinical spectrum: (1) non–muscle-invasive bladder cancer; (2) muscle-invasive bladder cancer; and (3) metastatic bladder cancer, with most patients falling into the category of non–muscle-invasive disease. Thus, the selected content featured in this issue specifically covers the clinical presentation and workup of and subsequent management recommendations for non–muscle-invasive bladder cancer.

The NCCN Guidelines for Prostate Cancer include recommendations for staging and risk assessment after a prostate cancer diagnosis and for the care of patients with localized, regional, recurrent, and metastatic disease. These NCCN Guidelines Insights summarize the panel’s discussions on select 2026 updates to the guidelines regarding nonmetastatic disease: the elimination of the very-low-risk group, updates to the Principles of Active Surveillance, and caution in the use of focal therapy in newly diagnosed patients.

Abstract Background T cell activation and polarization drive atherosclerosis. Among the mediators underlying T cell polarization, the epigenetic enzyme EZH2 catalyses the repressive mark H3K27me3. In humans, EZH2 is upregulated in T cells in advanced atherosclerosis, whereas its deficiency in T cells in mice limits plaque formation via an anti-inflammatory response. Emerging evidence indicates that EZH2 can also regulate lncRNAs and miRNAs by depositing H3K27me3 at their loci, repressing transcription. Purpose We hypothesize that EZH2 governs lncRNAs and miRNAs expression in T cells in the context of atherogenesis. Methods CD4+ T cells were isolated from spleens of atherosclerosis-prone T cell-specific Ezh2 (Ezh2cd4)-KO mice and WT littermates. Small RNA-seq (SMARTer® smRNA-Seq) and transcriptomic profiling (Prime-seq) were performed. Differential expression was assessed using edgeR. Selected miRNAs were validated by RT-qPCR. Putative miRNA targets were retrieved from miRTarBase (v. 8) and TargetScan, and gene ontology enrichment was performed using Metascape. Results In CD4+ T cells from Ezh2cd4-KO mice, 41 out of 2,950 mature miRNAs were differentially expressed (log2FC > |0.8|, FDR < 0.05), with 27 upregulated and 14 downregulated. Top upregulated miRNAs included miR-125a-5p, miR-130a-3p, miR-744-5p, miR-181a-5p, miR-181b-5p, miR-374b-5p, miR-99b, miR-3085, and miR-7049-3p. RT-qPCR confirmed that expression of miR-125a-5p, miR-181a-5p, miR-181b-5p, and miR-99b-5p were upregulated in Ezh2-deficient murine CD4+ T cells. GO enrichment analysis of downregulated genes revealed enrichment of IL-4, IL-9, IL-10, and TGF-β pathways, suggesting their relevance in T-cell function and differentiation. In human Jurkat T cells, pharmacological EZH2 inhibition using GSK126 or tazemetostat resulted only in the upregulation of miR-125a-5p and miR-99b-5p, confirming the conservation of the mechanisms in humans. Integration of our Prime-seq transcriptomics and smallRNAseq datasets with human and mouse predicted and experimentally validated targets of miR-125a-5p and miR-99b-5p identified six conserved target genes: STAT1, FAM169B, NDRG3, PSMB9, TRIB1, and RAB3IP. Conclusions Our findings indicate that Ezh2 represses miRNA expression in T cells during atherogenesis, thereby possibly promoting differentiation toward pro-atherogenic subsets while restraining anti-atherogenic transcriptional programs. Further research is needed to elucidate the underlying mechanisms. Ezh2-regulated miRNAs may represent promising targets to direct T cell plasticity to combat atherosclerosis.

Background: Metabolic-associated fatty liver disease (MAFLD) affects approximately 30% of the global population and is associated with obesity and metabolic syndrome. Anthropometric indices such as body mass index (BMI), waist circumference (WC), and weight are crucial markers for evaluating the progression of MAFLD. Curcumin, a bioactive compound with anti-inflammatory and antioxidant properties, has been investigated for its potential to improve metabolic outcomes. This umbrella review aimed to systematically evaluate the effects of curcumin supplementation on anthropometric indices in patients with MAFLD, considering epidemiological strength and power analysis. Methods: An umbrella review of meta-analyses from randomized controlled trials was conducted. PubMed, Scopus, and Web of Science were searched up to September 2024. Meta-analyses assessing curcumin’s effects on BMI, weight, and WC in MAFLD patients were included. Quality was assessed using the A Measurement Tool to Assess Systematic Reviews version (AMSTAR-2) tool, and heterogeneity was evaluated using the I 2 statistic. Statistical analyses were performed using R and Stata 18 software. Results: Curcumin supplementation had no significant effect on BMI (standardized mean difference [SMD]: −0.01; 95% confidence interval [CI]: −0.24 to 0.21, P = .91) with low power (1-β = 0.03) and a low epidemiological grade according to GRADE criteria. Similarly, curcumin showed no significant effect on WC (SMD: −0.27; 95% CI: −0.57 to 0.04, P = .08) with high power (1-β = 0.96) but low epidemiological strength. However, curcumin significantly reduced weight (SMD: −0.12; 95% CI: −0.19 to −0.04, P < .01) with moderate power (1-β = 0.56) and moderate epidemiological strength. No significant effect of dose or effect of supplementation duration was found. Conclusion: Curcumin supplementation may result in a statistically detectable but clinically modest reduction in body weight in patients with MAFLD, while showing limited or no efficacy on BMI and waist circumference. The epidemiological strength of the evidence varies across outcomes and is of low to moderate quality. Further well-designed, high-quality randomized controlled trials are needed to confirm the clinical relevance of curcumin’s effects on anthropometric indices.

Abstract Through emerging interpretations of individual “medical freedoms,” a panoply of state legislative bills seeks to undermine long-standing public health and health care requirements including recommendations to test, screen, treat, and vaccinate persons. To the extent these bills could upend decades of laws and policies protecting individual and communal health, especially among vulnerable individuals, they threaten the health — and freedoms — of all persons.