Citations

ABSTRACT Background Left atrial appendage occlusion (LAAO) has emerged as a non‐pharmacological alternative to oral anticoagulation (OAC) for stroke prevention in patients with atrial fibrillation (AF). Following the publication of recent CHAMPION‐AF and CLOSURE‐AF trials, an updated synthesis of evidence is warranted to clarify the long‐term comparative efficacy and safety of LAAO versus OAC in patients with AF. Methods We conducted a systematic review and meta‐analysis of randomized controlled trials (RCTs) comparing LAAO with OAC in adults with AF. A comprehensive search of major databases was performed from inception to April 2026. The primary efficacy outcomes were major adverse cardiovascular events (MACE) and stroke. The primary safety outcome was non–procedure‐related bleeding. Random‐effects models were used to calculate pooled risk ratios (RRs) with 95% confidence intervals (CIs). Results Six RCTs including 7,004 patients (3,681 LAAO; 3,323 OAC) were analyzed. No statistically significant difference was observed for MACE (7.5% vs 6.9%; RR 1.03, 95% CI 0.79‐1.34) or stroke (3.7% vs 3.2%; RR 1.07, 95% CI 0.80‐1.43). LAAO was associated with a significantly lower risk of non‐procedure‐related bleeding (9.8% vs 16.7%; RR 0.63, 95% CI 0.52‐0.77), corresponding to an absolute risk reduction of 6.9% and an approximate number needed to treat of 15 based on crude pooled event rates over the observed trial follow‐up. Trial sequential analysis indicated that the accumulated evidence for MACE and stroke remained inconclusive. Comparator‐type subgroup analyses showed no significant interaction for MACE ( p = 0.67) or stroke ( p = 0.81) between contemporary predominantly‐DOAC and VKA comparator trials. Conclusions LAAO was associated with lower non‐procedure‐related bleeding, while no statistically significant differences were observed for MACE or stroke. The available efficacy evidence remains inconclusive regarding equivalence or non‐inferiority, and larger trials are needed. These findings support individualized consideration of LAAO when the long‐term bleeding burden of anticoagulation is clinically important.

Abstract Everolimus 10 mg daily is the standard dose for advanced neuroendocrine tumors (NETs), but adverse events frequently necessitate dose reduction. As a result, oncologists often adopt a dose‐escalation strategy starting at 5 mg and increasing the dose as tolerated. In this multicenter study, we evaluated the effect of reduced dose (RD) and standard dose (SD) everolimus on survival, progression, and toxicity in patients with advanced NETs. We conducted a multicenter retrospective cohort study of patients with advanced NETs treated with everolimus at Mayo Clinic and University Hospitals (Cleveland, OH). Patients were grouped by starting dose (5 mg vs. 10 mg). Primary endpoints were overall survival (OS), real‐world progression‐free survival (rwPFS), and adverse events. Multivariable Cox models, inverse probability of treatment weighting (IPTW), and time‐varying dose sensitivity analysis were used to account for confounding and dose crossover. Among 170 patients (48 started on 5 mg; 122 on 10 mg), the 5 mg cohort was older, had worse ECOG PS, and was more heavily pretreated. Median OS was 43.7 months (5 mg) versus 81.5 months (10 mg; log‐rank p = .02). However, after multivariable adjustment ( N = 124 G1–G2 patients; 51 events), the association was no longer statistically significant (adjusted HR, 0.59; 95% CI, 0.31–1.12; p = .11). Median rwPFS was 7.0 versus 12.4 months (log‐rank p = .05); the adjusted rwPFS difference was not statistically significant (HR, 0.95; 95% CI, 0.56–1.61; p = .84). Nearly half (46.7%) of 10 mg starters required dose reduction. Any‐grade toxicity was more common with 10 mg (89% vs. 75%; p = .05). The apparent survival advantage of standard‐dose everolimus was substantially attenuated after adjustment. These findings do not establish dose equivalence and should be interpreted in the context of limited statistical power. Given its more favorable observed tolerability profile, RD everolimus warrants prospective evaluation as a starting strategy for patients at increased risk of treatment‐related toxicity who may not tolerate SD.

Abstract Stroke thrombi are heterogeneous; their composition influences their mechanical properties, including stiffness, elasticity, and adhesiveness, which in turn affect their response to therapy. Systemic characterization of the thrombi components could help select therapeutic techniques and anticipate outcomes. We conducted a systematic review and meta-analysis to evaluate associations between thrombi composition and angiographic and functional outcomes in acute ischemic stroke (AIS). Up to May 2025, relevant studies were sourced from four databases: PubMed, Web of Science, Scopus, and Embase. We included cohort studies whose populations are patients with AIS in relation to thrombi composition. Thirty-six studies involving 5,462 patients matched our eligibility criteria. Angiographic success (Thrombolysis in Cerebral Infarction ≥ 2b/3) did not differ significantly between red blood cell (RBC)-rich and fibrin-rich thrombi (risk ratio [RR] 1.02, 95% confidence interval [CI] 0.85–1.22; p = 0.84; I 2 = 63.8%; very low certainty). However, thrombi from patients with good angiographic outcomes had a significantly higher RBC content compared to patients with poor outcomes (mean difference = 7.22%, 95% CI 3.31–11.13; p < 0.001; low certainty). No significant difference was observed between RBC-rich and fibrin-rich thrombi regarding functional independence at 90 days (modified Rankin Scale 0–2) (RR = 1.22, 95% CI 0.73–2.05; p = 0.31; low certainty). While RBC-rich thrombi are associated with more favorable angiographic performance, thrombus composition alone does not predict functional outcomes. Stroke outcomes remain multifactorial, dominated by time to reperfusion, collateral circulation, and baseline severity. Preinterventional assessment of clot composition via imaging or biomarkers may support individualized therapy but should complement, not replace, other prognostic determinants.

Purpose Neutropenic diet (ND) has historically been recommended to reduce infectious complications in patients with cancer. Although its use has declined over the past decade, recent studies, particularly in patients undergoing hematopoietic stem-cell transplantation (HSCT), have renewed concern regarding the safety of a liberalized diet (LD). We performed a meta-analysis of studies comparing ND with LD in patients with cancer. Methods We searched MEDLINE, Embase, and Cochrane databases from inception through January 2026. Comparative studies evaluating ND versus LD in adults or children with cancer were included. Primary outcomes were major infections and bacteremia/fungemia; secondary outcomes were pneumonia, diarrhea, and mortality. Random-effects meta-analyses were performed to calculate pooled relative risks (RRs) with 95% CIs. Results Fifteen studies including 4,320 patients met criteria for analysis. ND was not associated with significant differences in major infections (RR, 1.02 [95% CI, 0.88 to 1.18]; P = .795), bacteremia/fungemia (RR, 0.97 [95% CI, 0.78 to 1.22]; P = .805), pneumonia (RR, 0.98 [95% CI, 0.59 to 1.63]; P = .933), diarrhea (RR, 1.12 [95% CI, 0.96 to 1.31]; P = .159), or mortality (RR, 0.94 [95% CI, 0.77 to 1.15]; P = .632). Sensitivity analyses restricted to randomized controlled trials (RCTs) were consistent. In hematologic malignancy/HSCT studies (9 studies; 1,769 patients), no differences were observed across outcomes. In RCTs limited to these patients (6 studies; 855 patients), ND was associated with lower bacteremia/fungemia risk (RR, 0.67 [95% CI, 0.47 to 0.95]; P = .023), with no differences in other outcomes. Conclusion ND was not associated with reductions in major infections, pneumonia, diarrhea, or mortality compared with LD. These findings do not support routine implementation of ND for patients with short-term neutropenia or lower-risk cancer populations although selected high-risk patients, particularly those undergoing HSCT or experiencing prolonged neutropenia related to hematologic malignancies, may still warrant cautious dietary practices.

Background Individuals with schizophrenia spectrum disorders are at increased risk of cardiometabolic complications, largely due to antipsychotic-associated metabolic effects. Effective management strategies remain limited. Semaglutide, a glucagon-like peptide-1 receptor agonist, has shown metabolic benefits in the general population, but its role in this population remains unclear. Objective To evaluate the efficacy and safety of semaglutide compared with placebo in individuals with schizophrenia spectrum disorders receiving antipsychotic therapy and experiencing metabolic abnormalities. Design Systematic review and meta-analysis of randomized controlled trials. Data Sources and Methods: A systematic review and meta-analysis was conducted following PRISMA guidelines. PubMed, Cochrane Library, Embase, and ScienceDirect were searched from inception to February 2026. Randomized controlled trials comparing semaglutide with placebo were included. The longest follow-up time point from each study was used for pooled analysis. Mean differences (MD) and odds ratios (OR) with 95% confidence intervals (CIs) were calculated using RevMan 5.4. The certainty of evidence for critical outcomes was assessed using the GRADE framework. Results Three randomized controlled trials (n = 258) were included. Semaglutide was associated with reductions in body weight (MD: -11.01 kg), BMI (MD: -3.63 kg/m 2 ), and waist circumference (MD: -6.33 cm). Improvements were also observed in body composition. No significant differences were found in lipid or glycemic parameters except HbA1c which showed a significant reduction. Psychiatric outcomes remained unchanged. Gastrointestinal adverse particularly nausea and vomiting events were more frequent with semaglutide. Conclusion Semaglutide appears to improve anthropometric outcomes without worsening psychiatric symptoms in individuals receiving antipsychotic therapy. However, evidence is limited, and larger, long-term trials are required. According to the GRADE framework, the certainty of evidence ranged from moderate for key anthropometric and safety outcomes to low or very low for several metabolic and psychiatric outcomes, highlighting the need for larger, long-term randomized trials.

Abstract Background Immunosuppression is a recognized risk factor for severe and disseminated coccidioidomycosis; however, data describing outcomes in patients with inflammatory bowel disease (IBD) receiving advanced therapy, including biologics and small molecules, remain limited. We aim to describe the prevalence, clinical presentation, treatment patterns, and outcomes of coccidioidomycosis in IBD patients receiving advanced therapy at an endemic tertiary care center. Methods We performed a retrospective observational study of adult patients with IBD at Mayo Clinic Arizona diagnosed with coccidioidomycosis between 2023 and 2026. Patients were included if IBD diagnosis preceded coccidioidomycosis diagnosis and advanced therapy had been active for at least 4 weeks before infection. Cases were classified as proven, probable, or possible based on microbiologic, clinical, radiographic, and serologic criteria. Clinical outcomes included antifungal treatment duration, hospitalization related to coccidioidomycosis or IBD, IBD treatment modification after diagnosis, re-emergence of coccidioidomycosis symptoms, and IBD-related surgery. Results A total of 48 patients met inclusion criteria. Among 1083 tested IBD patients receiving advanced therapy, coccidioidomycosis positivity prevalence was 4.4% when including all serologically positive patients and 1.9% when restricted to proven or probable cases. The median age at coccidioidomycosis diagnosis was 40 years (range 19-87 years), and 30 (62.5%) of 48 had Crohn’s disease. Proven or probable infection was identified in 21 (43.8%) of 48 patients, while 14 (29.2%) of 48 patients were classified as possible. Antifungal therapy was prescribed in 32 (66.7%) of 48 patients, including all proven cases, 15 (88.2%) of 17 probable cases, 9 (64.3%) of 14 possible cases, and 3 (25.0%) of 12 nondiagnostic cases. Among proven/probable/possible cases, the median antifungal treatment duration was 174 days (range 8-831 days). Advanced IBD therapy was continued in 3 (75.0%) of 4 proven cases, 9 (52.9%) of 17 probable cases, 12 (85.7%) of 14 possible cases, and all nondiagnostic cases. Hospitalization occurred in 6 (12.5%) of 48 of the cohort, all of which were proven/probable cases. Most patients remained on advanced therapy after diagnosis, although tumor necrosis factor α inhibitors were the most interrupted or discontinued agents. Conclusions In this endemic tertiary care cohort, management decisions varied according to diagnostic certainty. Patients with proven or probable coccidioidomycosis were more likely to receive antifungal therapy and undergo advanced IBD therapy modification, whereas most patients with possible or nondiagnostic serologic findings remained on advanced therapy without major IBD-related complications. Prolonged antifungal treatment was common, highlighting the complexity of managing coccidioidomycosis in immunosuppressed patients with IBD.

Importance Elevated low-density lipoprotein cholesterol (LDL-C) is a modifiable risk factor for cardiovascular disease, the leading cause of premature death worldwide. Assessing the LDL-C–related burden is critical for guiding prevention and treatment strategies. Objectives To estimate the global, regional, and national burden of ischemic heart disease and ischemic stroke attributable to elevated LDL-C (relative to 35-54 mg/dL) from 1990 to 2023 and to quantify the contributions of population growth, aging, risk-deleted burden, and exposure changes to burden trends. Design, Setting, and Population This comparative risk assessment, part of the Global Burden of Disease Study 2023, estimated population-level LDL-C exposure and associated health loss in 204 countries and territories. Mean LDL-C levels were estimated using spatiotemporal gaussian process regression based on 806 studies across 161 countries. Relative risks were derived from meta-analyses of 38 randomized clinical trials. Population-attributable fractions for deaths and disability-adjusted life-years (DALYs) were estimated by age and sex for adults aged 25 years or older from 1990 to 2023, with 95% uncertainty intervals. Exposure Population-level LDL-C concentrations. Main Outcomes and Measures Population-attributable fractions, counts, and rates (all ages and age standardized per 100 000) of LDL-C–attributable deaths and DALYs from ischemic heart disease and ischemic stroke, with uncertainty intervals. Results In 2023, elevated LDL-C accounted for 3.6 million deaths (95% uncertainty interval, 2.2-5.4 million; 6.0% of global mortality) and 90.7 million DALYs (95% uncertainty interval, 58.9-123.3 million; 3.2% of DALYs). Although global all-ages rates remained stable, age-standardized death and DALY rates decreased by 45.6% and 39.5%, respectively, since 1990. In 2023, age-standardized LDL-C–attributable DALY rates were highest in Eastern Europe and lowest in high-income Asia-Pacific. One-third of the global LDL-C burden occurred in India and China. Population growth and aging drove the increasing burden, with notable regional disparities in LDL-C exposure and risk-deleted DALY rates shifting toward middle-sociodemographic settings. Conclusions and Relevance Despite declining age-standardized rates, the absolute LDL-C burden has increased since 1990 due to demographic changes and has shifted toward middle-sociodemographic countries. Measurement and surveillance gaps persist. Strengthened prevention, diagnosis, and treatment access strategies are essential to mitigate the health burden of LDL-C.

ABSTRACT Background Disparities in management of atrial fibrillation in rural and urban hospitals across the U.S. have been reported. However, studies investigating disparities regarding outcomes and complications after left atrial appendage occlusion (LAAO) based on hospital location are lacking. Objective To evaluate differences in outcomes and complications related to LAAO among rural and urban hospitals. Methods The National Inpatient Sample was used to identify patients who underwent LAAO implantations in the U.S. from 2016−2020. Study endpoints assessed included inpatient complications, outcomes, and resource utilization after LAAO procedures among rural and urban hospitals. Results From 2016−2020, there were a total of 87 315 and 1985 LAAO device placements in urban and rural hospitals, respectively. Baseline characteristics were similar among both groups, with a few exceptions. After multivariable adjustment for confounders, odds of inpatient complications and mortality were similar among both groups. However, rural LAAO recipients experienced greater rates of discharge to an acute care facility (3.3% vs 2.4%, p = 0.01), as well as lower costs (aOR: 0.58, 95% CI: 0.49–0.69) and length of stay (aOR: 0.89, 95% CI: 0.81–0.98). Conclusions A majority of LAAO implantations occurred in urban hospitals in the U.S. Baseline characteristics and adjusted odds of inpatient complications and mortality were similar in rural and urban recipients. However, important differences were described regarding resource utilization and disposition. Further investigation into the specific factors driving these inequities is encouraged to promote improved access to and outcomes of cardiovascular care for rural residents.