Citations

Abstract Background and Aims The aim of the study was to assess the effect of guideline-directed medical therapy (GDMT) on cardiac function, neurohormonal activation, and mortality in adults with congenitally corrected transposition of the great arteries (cc-TGA) presenting with systemic right ventricular (RV) systolic dysfunction. The study hypothesis was that GDMT use (assessed using the GDMT score) was associated with improved cardiac function (higher RV free wall strain [RVFWS]), less neurohormonal activation (lower N-terminal pro-B-type natriuretic peptide [NT-proBNP] levels), and lower mortality. Methods GDMT score, RVFWS, and NT-proBNP levels were assessed at baseline and 1-year follow-up. GDMT uptitration was assessed using ΔGDMT (GDMT at 1-year minus GDMT at baseline). Improvements in RV systolic function and neurohormonal activation were defined as a relative increase in RVFWS of >20% and a relative decrease in NT-proBNP levels of >20%, respectively. Results Of 213 patients (age 43 ± 15 years; 54% male), baseline GDMT score was 1.97 ± 1.27, and ΔGDMT score was 0.74 ± 0.39. Baseline RVFWS was −18 ± 5%; 25% had improved RV systolic function. Baseline NT-proBNP was 369 (142, 1004) pg/mL; 56% had improved neurohormonal activation. Higher baseline GDMT score and ΔGDMT score were associated with improvement in RV systolic function and neurohormonal activation. Overall, 34 (16%) patients died, and higher baseline GDMT score and ΔGDMT score were associated with a lower risk of mortality and of the composite adverse event endpoint (heart failure hospitalization, death, and heart transplantation). Clinical benefits of GDMT use were observed only in patients with moderate/severe RV systolic dysfunction, and not in patients with mild RV systolic dysfunction. Conclusions GDMT use was associated with improved outcomes in patients with moderate/severe RV systolic dysfunction.

Purpose To compare short‐term outcomes of intratunnel anchor fixation versus transtibial pull‐through repair for meniscus root tears with a minimum of 12‐month follow‐up. Methods Patients who underwent primary meniscus root repair between 2011 and 2024 at a single institution were retrospectively reviewed. Inclusion criteria consisted of primary medial or lateral meniscus root repair using either intratunnel anchor fixation or transtibial pull‐through repair, availability of preoperative radiographs, and completion of postoperative patient‐reported outcome measures with a minimum of 12‐month follow‐up. The groups were propensity‐matched by age, sex, body mass index, operative side, root laterality, and concomitant procedures. Baseline radiographic characteristics (hip‐knee‐ankle angle and posterior tibial slope) were measured. Outcomes included Lysholm score, International Knee Documentation Committee score, Tegner activity score (preoperative and postoperative), Visual Analog Scale for pain at rest and with activity, satisfaction, subjective surgical outcome, and reoperations. Results Fifty patients who underwent intratunnel anchor fixation (mean age, 44 years) were propensity‐matched to 100 patients who underwent transtibial pull‐through repair (mean age, 41 years). Mean follow‐up was 1.5 years (range, 1.0‐2.3) in the intratunnel anchor group and 6.1 years (range, 2.7‐13.7) in the transtibial pull‐through group. Reoperation rates were 8% and 14%, respectively ( P = .43), with repair failure occurring in 4% and 6% ( P > .99). Preoperative and postoperative Tegner scores were similar between groups. Tegner minimal clinical important difference was 0.8, and 26.5% of intratunnel anchor patients achieved this compared with 0% of transtibial pull‐through patients. Patients in the intratunnel anchor cohort reported slightly lower Visual Analog Scale pain with activity (1.8 vs 2.5, P = .02). Postoperative Lysholm (87 vs 83, P = .05) and International Knee Documentation Committee scores (79 vs 76, P = .09) were comparable between groups. A greater proportion of intratunnel anchor patients achieved Patient Acceptable Symptomatic State compared with transtibial pull‐through patients for Visual Analog Scale with activity (74% vs 56%, P = .03) and Lysholm (66% vs 47%, P = .01). Most patients in both cohorts rated their outcome as “much better” or “slightly better” ( P = .49), and satisfaction scores were high. Conclusions At short‐term follow‐up, both the intratunnel anchor and transtibial pull‐through techniques showed high patient satisfaction and comparable overall clinical outcomes. There were no differences in reoperation rates between techniques. Level of Evidence Level III, retrospective comparative case series.

Abstract Purpose: Inhibitors of the Ataxia telangiectasia and Rad3-related (ATR) protein kinase, a critical component of the DNA damage repair response, have synergistic anti-cancer activity with platinum compounds in preclinical models. We therefore conducted a Phase 2 study of the ATR inhibitor berzosertib+carboplatin vs. docetaxel+carboplatin in metastatic castration-resistant prostate cancer. Patients and Methods: Patients previously treated with at least one androgen receptor pathway inhibitor and taxane underwent mandatory biopsy and were randomized 1:1 to receive Arm A (docetaxel 60 mg/m2+carboplatin AUC4 day 1; or carboplatin AUC5 if not a docetaxel candidate) or Arm B (berzosertib 90 mg/m2 days 2,9+carboplatin AUC5 day 1) every 21 days. The primary endpoint was overall response rate (ORR; ≥50% PSA decline or radiographic response). Results: Of 73 randomized patients, 65 received protocol treatment: 34 on Arm A (26 docetaxel+carboplatin; 8 carboplatin alone) and 31 on Arm B. Thirteen patients (38%) in Arm A and 20 (65%) in Arm B had ≥Grade 3 treatment-related adverse events (TrAEs). ORR was 15% in Arm A (5/34; 5/26[19%] with docetaxel+carboplatin) and 0% in Arm B (0/31). At interim analysis after 65 of planned 130 patients were treated, enrollment was halted due to futility. Homologous recombination repair deficiency status from tissue and blood did not correlate with clinical outcomes, but ATM-deficiency or high levels of phoshpo-KAP1 detected in tissue was associated with clinical benefit across both arms of the trial. Conclusions: Berzosertib+carboplatin demonstrated lower ORR and more frequent ≥grade 3 TrAEs compared to docetaxel+carboplatin in this heavily pre-treated, biomarker-unselected population. NCT03517969

PURPOSE Age ≥40 years is regarded as a high-risk feature and an indication for adjuvant chemoradiotherapy for patients with lower-grade glioma in clinical practice guidelines. It is unclear whether age remains a relevant prognostic factor for contemporary definitions of lower-grade gliomas in the molecular era. METHODS The Prospective Gliomas Research (PROGRES) database contains individual patient-level data from 11 prospective clinical trials or observational registries of histologically defined lower-grade 2-3 oligodendroglioma or astrocytoma. We determined the association of age (18-39 years v ≥40 years) with progression-free survival (PFS) stratified by isocitrate dehydrogenase 1 or 2 ( IDH1/2 ) status, using log-rank tests and Cox regression models. We validated our findings in a separate multi-institutional retrospective cohort (Retrospective Glioma Research [REGRES] database). RESULTS We identified 1,619 and 1,292 eligible patients in the PROGRES and REGRES cohorts, respectively. IDH -wildtype tumors were more common in patients 40 years and older (38% v 5%, odds ratio: 11.3 [95% CI, 6.5 to 19.7]). Age was associated with PFS in IDH -wildtype (5-year PFS for ≥40 v 18-39 years: 6% v 24%, hazard ratio [HR], 1.74 [95% CI, 1.21 to 2.50]) but not in IDH -mutant glioma (60% v 59%, HR, 0.89 [95% CI, 0.76 to 1.05], P interaction < .001). In IDH -wildtype tumors, older age predicted aggressive molecular features, including TERT promoter mutation (65% v 28%), EGFR amplification (41% v 15%), and chromosome +7/–10 alteration (57% v 25%). In a pooled analysis of four clinical trials, age was not predictive of a benefit from chemoradiotherapy versus radiotherapy alone for IDH -mutant glioma. CONCLUSION In the absence of additional clinical or molecular risk factors, age alone should not be considered an indication for administration or deferral of adjuvant treatment. Practice guidelines should be revised to reflect contemporary prognostic factors in the molecular era.

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.

Treatment of participants with intermediate-risk prostate cancer with focal irreversible electroporation and radiation therapy was technically feasible and showed acceptable patient-reported outcomes and no severe adverse events over 1 year.

PURPOSE Bone metastases (BM) occur in approximately 30% of patients with metastatic renal cell carcinoma (mRCC) and are associated with poor survival and symptomatic skeletal events (SSEs). Radium-223, an alpha-emitting bone-seeking radioisotope, and cabozantinib, a tyrosine kinase inhibitor, have demonstrated activity in BM. RADICAL (Alliance A031801; ClinicalTrials.gov identifier: NCT04071223 ) evaluated cabozantinib ± radium-223 in mRCC with BM. METHODS This phase II trial enrolled patients with mRCC of any histology with ≥1 BM. Patients were randomly assigned 1:1 to cabozantinib ± radium-223, stratified by osteoclast-targeted therapy (OTT), prior therapy, opioid use, and International mRCC Database Consortium (IMDC) risk. The primary end point was SSE-free survival (SSE-FS). Secondary end points included safety, objective response rate (ORR), progression-free survival, and overall survival (OS). A target of 124 evaluable patients was planned, with a prespecified interim futility analysis at 50% of expected SSE-FS events; the trial would stop if the stratified hazard ratio (sHR) > 1.0. RESULTS The prespecified interim futility analysis was conducted after 90 patients were enrolled and crossed the futility boundary, leading to closure at 98 patients. The final analysis included all 98 patients. Median age was 63 years, 82.7% had clear cell histology, and 79.6% were using an OTT. IMDC risk was favorable (18.4%), intermediate (67.3%), and poor (14.3%). Median follow-up was 13.1 months. Median SSE-FS for cabozantinib with radium-223 versus cabozantinib was 16.7 versus 17.6 months (sHR, 1.46 [90% CI, 0.86 to 2.51]). Median OS was 28.3 versus 19.7 months (sHR, 1.40 [95% CI, 0.70 to 2.79]). ORR was 19.4% versus 25.0% ( P = .78). Grade ≥3 adverse events were similar across arms (69.6% v 75.5%). CONCLUSION Radium-223 did not improve SSE-FS when added to cabozantinib. The combination demonstrated a manageable safety profile.

Abstract Aims Nutritional counselling is a core component of cardiac rehabilitation (CR), yet the evidence base for specific dietary interventions within CR remains fragmented. This scoping review aimed to map the range of nutritional interventions evaluated in adult CR programmes, characterize their reported outcomes, and identify key gaps in current evidence and practice. Methods and results Following the Arksey and O’Malley framework and reporting according to PRISMA-ScR, a systematic search of PubMed, Embase, Web of Science, and Cochrane Library was conducted from inception to June 2026. Eligible studies included randomized controlled trials, non-randomized trials, and observational studies evaluating an explicitly described nutritional intervention within a structured CR programme in adults with established cardiovascular disease. Of 2765 identified records, 35 studies met eligibility criteria. Interventions spanned Mediterranean and heart-healthy dietary patterns, calorie-restriction and weight-loss programmes, comprehensive lifestyle interventions, structured nutrition education and counselling, supplementation, functional foods, and individualized diet prescriptions. Across categories, improvements in body weight, central adiposity, and adherence to cardioprotective dietary recommendations were commonly reported, particularly when nutrition was delivered with repeated contact and individualized support. Effects on lipid profiles, inflammatory markers, blood pressure, functional capacity, and clinical outcomes were more variable. Conclusion Nutritional interventions within CR were most consistently associated with improvements in intermediate behavioural, anthropometric, and cardiometabolic outcomes, particularly when structured and reinforced over time. However, heterogeneity in study design, intervention delivery, comparator groups, outcome reporting, and follow-up duration precludes definitive conclusions about comparative efficacy, optimal intervention format, or the magnitude of benefit. Greater standardization, longer follow-up, and further evaluation of personalized nutritional strategies are needed to strengthen the nutritional component of CR.