Citations

Abstract Background and Aims Type 1 short QT syndrome (SQT1) is a genetic channelopathy caused by gain-of-function variants in KCNH2, resulting in shortened cardiac repolarization and QT intervals, which predispose patients to ventricular arrhythmias and sudden cardiac death. This study aimed to investigate the therapeutic efficacy of KCNH2-specific suppression-and-replacement (KCNH2-SupRep) gene therapy in a transgenic rabbit model of SQT1. Methods KCNH2-SupRep was developed by combining a KCNH2-shRNA with its corresponding shRNA-immune KCNH2-cDNA into an AAV9 vector, delivered directly into the aortic root (1 × 1010 vg/kg). Therapeutic efficacy was evaluated in vivo by electrocardiogram, ex vivo by optical mapping, and at cellular levels by patch-clamp, calcium imaging, and qPCR in ventricular cardiomyocytes (VCMs). Results In vivo, KCNH2-SupRep normalized the heart rate-corrected QT interval (QTc) in SQT1 rabbits, without affecting repolarization heterogeneity. Ex vivo, KCNH2-SupRep corrected the action potential duration (APD90) and resolved the increased apicobasal APD90 heterogeneity observed in untreated (UT)-SQT1 hearts, supporting an antiarrhythmic effect, which was further validated by reduced re-entry formation in silico. At cellular levels, KCNH2-SupRep prolonged APD90 in VCMs from SupRep-SQT1 rabbits closer to wildtype levels compared with UT- and sham-SQT1. Additionally, KCNH2-SupRep restored the cellular surrogate of the electro-mechanical window and normalized IKr in nearly 50% of VCMs, in line with a 50%–60% suppression of the mutant KCNH2 transcript. Conclusions This proof-of-concept study is the first to demonstrate the efficacy of gene therapy for SQT1 in a medium-sized animal model. KCNH2-SupRep gene therapy successfully corrected the pathologic phenotype in vivo, ex vivo, and at cellular levels in transgenic SQT1 rabbits.

Abstract Background and Aims In the VICTOR trial (NCT05093933), vericiguat was neutral for the primary composite endpoint of cardiovascular death or hospitalization for heart failure (HF). VICTOR was powered to independently assess cardiovascular death. This study reports detailed analysis on the effects of vericiguat on mortality. Methods VICTOR, a double-blind, placebo-controlled, randomized trial, enrolled 6105 ambulatory patients with HF and reduced ejection fraction (HFrEF) without recent worsening and randomized them to vericiguat or placebo. The main outcome for this analysis was the pre-specified secondary endpoint of cardiovascular death. All-cause death, sudden cardiac death, and death related to HF were also assessed. Results Over a median of 19.7 months (inter-quartile range 14.6–25.4), cardiovascular deaths occurred in 292 patients (5.7 deaths per 100 patient-years) and 346 patients (6.8 deaths per 100 patient-years) in the vericiguat and placebo groups, respectively (hazard ratio [HR] 0.83, 95% confidence interval [CI] 0.71–0.97; P = .020). Risk of death from any cause was lower with vericiguat vs placebo (377 [7.3 deaths per 100 patient-years] vs 440 [8.6 deaths per 100 patient-years]; HR 0.84, 95% CI 0.74–0.97; P = .015). Sudden cardiac death and HF-related deaths were lower with vericiguat vs placebo (1.6 vs 2.2 events per 100 patient-years; HR 0.75, 95% CI 0.56–0.99; P = .042 and 1.7 vs 2.4 events per 100 patient-years; HR 0.71, 95% CI 0.54–0.94; P = .016, respectively). Lower mortality rates were consistent across subgroups including baseline therapy. Consistent cardiovascular and all-cause mortality benefit was seen across baseline N-terminal pro-B-type natriuretic peptide levels. Conclusions In ambulatory well-treated participants with HFrEF, vericiguat was associated with clinically meaningful reductions in the key secondary outcome of cardiovascular death, as well as all-cause mortality.

Abstract Purpose To describe the systemic benefits of sugammadex as a reversal agent for neuromuscular blockade. Summary Sugammadex is the preferred reversal agent for neuromuscular blockade as recommended in guidelines from the American Society of Anesthesiology. This recommendation is primarily based on a faster time to recovery from neuromuscular blockade as compared to that seen with neostigmine. Systemic adverse effects of neostigmine are often mitigated by the administration of glycopyrrolate. However, glycopyrrolate is an antimuscarinic agent that may be associated with its own adverse effects when used as part of a reversal strategy for neuromuscular blockade. This review describes the potential systemic benefits of sugammadex, compared to an acetylcholinesterase/anticholinergic strategy, related to postoperative nausea and vomiting, urinary retention, bowel recovery, and cognitive dysfunction while also discussing its role in enhanced recovery after surgery protocols. Conclusion Sugammadex is associated with a reduction in systemic effects when compared to combinations of neostigmine and glycopyrrolate. Further research is needed on important clinical and economic outcomes associated with a reduction in these adverse effects.

The integration of artificial intelligence (AI) in medical imaging has revolutionized diagnostic capabilities, yet the black-box nature of deep learning models poses significant challenges for clinical adoption. Current explainable AI (XAI) approaches, including SHAP, LIME, and Grad-CAM, predominantly focus on post hoc explanations that may inadvertently undermine clinical decision-making by providing misleading confidence in AI outputs. This paper presents a systematic review and meta-analysis of 67 studies (covering 23 radiology, 19 pathology, and 25 ophthalmology applications) evaluating XAI fidelity, stability, and performance trade-offs across medical imaging modalities. Our meta-analysis of 847 initially identified studies reveals that LIME achieves superior fidelity (0.81, 95% CI: 0.78–0.84) compared to SHAP (0.38, 95% CI: 0.35–0.41) and Grad-CAM (0.54, 95% CI: 0.51–0.57) across all modalities. Post hoc explanations demonstrated poor stability under noise perturbation, with SHAP showing 53% degradation in ophthalmology applications (ρ = 0.42 at 10% noise) compared to 11% in radiology (ρ = 0.89). We demonstrate a consistent 5–7% AUC performance penalty for interpretable models but identify modality-specific stability patterns suggesting that tailored XAI approaches are necessary. Based on these empirical findings, we propose a comprehensive three-pillar accountability framework that prioritizes transparency in model development, interpretability in architecture design, and a cautious deployment of post hoc explanations with explicit uncertainty quantification. This approach offers a pathway toward genuinely accountable AI systems that enhance rather than compromise clinical decision-making quality and patient safety.

BACKGROUND: The performance of estimated glomerular filtration rate (eGFR) among patients with heart failure (HF) may be worse than in the general population due to a higher prevalence of confounding factors affecting creatinine and cystatin C. Studies in this area are scarce and not stratified by type of HF. We evaluated the performance of current creatinine and cystatin C equations (eGFRcr, eGFRcys, and eGFRcrcys) compared with measured GFR (mGFR) among patients with HF stratified by ejection fraction. METHODS: We pulled data on Mayo Clinic patients with an mGFR performed for clinical indications from 2011 to 2023, with serum creatinine and cystatin C measured within 7 days and an echocardiogram performed up to 1 year before the mGFR date. HF was identified by the presence of International Classification of Diseases codes within 1 year before the mGFR and subgrouped into ejection fraction (EF) ≥50% (HFEF≥50%, n=182) or <50% (HFEF<50%, n=115) and compared with no-HF controls (n=1871). CKD-EPI (and EKFC) eGFRcr, eGFRcys, and eGFRcrcys equations were calculated and compared for bias (mGFR minus eGFR) and accuracy (1-P30, proportion of people with ≥30% difference between eGFR and mGFR). CIs were generated by bootstrapping. RESULTS: The HF groups were characterized by older age, higher proportion of males, more diabetes, higher creatinine, and higher cystatin C than controls. In terms of bias, eGFRcr overestimated mGFR to a greater extent in both HF groups compared with controls, whereas eGFRcys and eGFRcrcys showed similar bias in both HF groups and controls. In the HF groups, cystatin C-based equations were more accurate than eGFRcr, particularly within HFEF<50% (1-P30 of 28% and 34% for CKD-EPI eGFRcys and eGFRcrcys, respectively, versus 60% for eGFRcr), whereas eGFRcrcys was more accurate in controls. The CKD-EPI and EKFC equations were overall convergent, showing similar results. CONCLUSIONS: Among patients with HF, eGFRcr demonstrates inferior performance (more bias and less accuracy) compared with cystatin C-based eGFRs, with this effect being more pronounced in those with HFEF<50%.

Purpose: To evaluate the role of women physicians in thyroid eye disease (TED) research and clinical care and describe relevance for academic medicine and patient access. Methods: A cross-sectional study of TED-related publications indexed on PubMed in 2000, 2010, and 2020, and of completed or currently active clinical trials was conducted. Author, journal, and principal investigator (PI) characteristics were noted. Author/PI gender was determined from institutional profile or subsequently via a previously described Google-based algorithm. American Society of Ophthalmic Plastic and Reconstructive Surgery (ASOPRS), American Board of Ophthalmology (ABO), and American Thyroid Association (ATA) information was obtained via direct communication. Trends in participation of men and women were evaluated. Results: A total of 444 manuscripts (61 from 2000; 117 from 2010; 266 from 2020) were included. The percentage of women as first and senior authors increased from 2000 to 2020 (p < 0.0001 and p = 0.0003, resp.). First author gender distribution was near equal in 2020 (52.6% men, 47.4% women [p = 0.39]), whereas senior authors remained mostly men (68.0% men, 32.0% women [p < 0.0001]). As of 2020, the gender imbalance of senior authors was greater on multidisciplinary author teams (74.8% men, 25.2% women) compared with single specialty author teams (62.2% men, 37.8% women). Of the 98 TED-related clinical trials included, 34 had women PIs (35%). The percentage of women as members in ASOPRS, ABO, and ATA all increased significantly from 2000 to 2020, but remained disproportionately men in 2020 (all p < 0.0001). Conclusion: Gender-based discrepancies persist in TED research, especially among senior authors, who determine research direction, and on multidisciplinary teams, which reflect the preferred model of care. Further efforts are required to determine whether these findings affect patients with TED.

Due to extensive pathophysiological changes in critically ill patients, standard dosing of antibiotics may lead to inadequate drug exposure. This is concerning, as insufficient plasma drug concentrations may lead to treatment failure, whereas excessive drug exposure may increase the risk of toxic adverse events. The role of inflammation as a factor influencing the pharmacokinetics (PK) and pharmacodynamics (PD) of antibiotics remains largely unknown. PK/PD target attainment of antibiotics can be improved through therapeutic drug monitoring, i.e., measurement of drug concentrations in the blood with subsequent dosage adjustment to reach a certain target. Besides, population PK models may be used to predict drug exposure and tailor dosing in an individual patient (model‐informed precision dosing). Inflammatory biomarkers have been proposed to measure inflammation levels and guide antibiotic treatment. However, their potential to guide antibiotic dosing is unclear. This narrative review describes associations between inflammation and PK/PD of antibiotics in critically ill patients, and the role of biomarkers, therapeutic drug monitoring and model‐informed precision dosing in improving antibiotic dosing. A focus of future research should be on the interplay between inflammation and PK/PD of antibiotics by including inflammatory biomarkers in PK/PD models and using big data to predict antibiotic exposure in critically ill patients.

There is an increased clinical use of elbow orthoses. It is important to consider patient experiences in their use. Patient-reported outcome measures (PROMs) serve as essential tools for gathering patient perspectives. This review provides a comprehensive list of PROMs used in clinical trials of elbow orthoses, and documents their properties, uses, and quality. A systematic literature search across PubMed, Scopus, Embase, Cumulative Index to Nursing and Allied Health Literature, and Web of Science identified 31 clinical trials of elbow orthoses that used PROMs as outcome measures. Subsequently, manual searches were conducted to report on each PROM's characteristics. A total of 15 different PROMs were used as outcome measurements in clinical trials that used an elbow orthosis as an intervention for 11 different conditions. Researchers can use this review to aid in making informed decisions about which PROMs to use for future clinical trials.