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IntroductionConcurrent Staphylococcus aureus bacteremia (SAB) worsens outcomes and increases mortality in patients with complicated skin and skin structure infections (cSSSI), hospital-acquired bacterial pneumonia, and ventilator-associated bacterial pneumonia (HABP/VABP). These challenges highlight the need for alternative treatments. Telavancin (TLV), a bactericidal lipoglycopeptide with high in vitro potency, effectively treats patients with cSSSI and HABP/VABP caused by Gram-positive pathogens, particularly S. aureus.MethodsThis retrospective analysis evaluated patients from the Assessment of Telavancin in Complicated Skin and Skin Structure Infections and Assessment of Telavancin for Treatment of Hospital-Acquired Pneumonia studies with baseline, concurrent SAB. Differences in the clinical cure rates at test-of-cure and safety outcomes were compared for TLV vs vancomycin (VAN) treatment groups.ResultsA total of 105 patients, 32 cSSSI and 73 HABP/VABP, had baseline, concurrent SAB. The clinical cure rates for all-treated SAB patients in the cSSSI (TLV 57.1% and VAN 54.5%) and HABP/VABP (TLV 54.3% and VAN 47.2%) groups were comparable. For both types of infections, the safety profile of TLV and VAN showed similar incidences of adverse events (AEs), serious AEs, or AEs leading to discontinuation. One VAN-treated patient died in the cSSSI group, and there were 13 deaths in each treatment arm of the HABP/VABP group.ConclusionThis retrospective analysis demonstrated that TLV is clinically comparable in both efficacy and safety to VAN, and, therefore, may be an appropriate therapeutic option for the treatment of patients with HABP/VABP or cSSSI and concurrent SAB. Given the limited sample size in this subgroup, the interpretation of these results is limited.FundingTheravance Biopharma Antibiotics, Inc.

INTRODUCTION: Estimating treatment effects as time savings in disease progression may be more easily interpretable than assessing the absolute difference or a percentage reduction. In this study, we investigate the statistical considerations of the existing method for estimating time savings and propose alternative complementary methods. METHODS: We propose five alternative methods to estimate the time savings from different perspectives. These methods are applied to simulated clinical trial data that mimic or modify the Clinical Dementia Rating Sum of Boxes progression trajectories observed in the Clarity AD lecanemab trial. RESULTS: Our study demonstrates that the proposed methods can generate more precise estimates by considering two crucial factors: (1) the absolute difference between treatment arms, and (2) the observed progression rate in the treatment arm. DISCUSSION: Quantifying treatment effects as time savings in disease progression offers distinct advantages. To provide comprehensive estimations, it is important to use various methods. Highlights: We explore the statistical considerations of the current method for estimating time savings.We proposed alternative methods that provide time savings estimations based on the observed absolute differences.By using various methods, a more comprehensive estimation of time savings can be achieved. [ABSTRACT FROM AUTHOR]

Pathogenic variants in the MYBPC3 gene are the leading genetic cause of hypertrophic cardiomyopathy (HCM) resulting in reduced functional myosin-binding protein C (MyBP-C) levels. Studies have shown that adult patients with pathogenic sarcomere variant-HCM exhibit higher incidence of major clinical events than genotype-negative HCM patients. With the emergence of gene replacement therapies, characterizing the natural history of MYBPC3 + HCM is essential to inform future development of this class of targeted therapies. We conducted an analysis of all adult MYBPC3 + HCM patients enrolled in SHaRe (Sarcomeric Human Cardiomyopathy Registry) based on their primary diagnosis at the age of 18-39, 40-59, and ≥60 years. As of September 2023, 1493 adult HCM patients with a pathogenic or likely pathogenic variant in MYBPC3 had enrolled in SHaRe, a multicenter registry involving 12 cardiac centers in the US, EU, and Australia. This analysis included 635 patients (42.5%) diagnosed at 18–39 years, 659 (44.1%) at 40–59 years, and 199 (13.3%) at ≥60 years. Duration of follow-up in the three cohorts was 8.4, 6.6, and 4.5 years, respectively. Demographics, genotype, first echocardiographic metrics, and time to major clinical events were compared across the three groups. Most patients diagnosed at 18–39 and 40–59 years were males (67.0% and 56.3% respectively), while those diagnosed at ≥60 years were primarily female (59.5%). Family history of HCM and proband status were comparable across cohorts (range of 56.3 – 65.7% and 88.0 – 91.5%, respectively). Patients in the youngest cohort presented with the greatest left ventricular maximal wall thickness (median of 19 mm, 18 mm, and 17 mm for the 18 – 39, 40 – 59, and ≥60 years cohorts, respectively). Symptom burden was comparable across cohorts, as the proportion of patients with NYHA III/IV was 13.1%, 10.5%, and 11.4%, respectively. The prevalence of patients having SRT, syncope and need for transplant or left ventricular assist device (LVAD) were highest in the youngest cohort (see Table). Across all three cohorts, patients experienced atrial fibrillation (AF) at 13.7%, the ventricular arrhythmia (VA) composite at 5.3%, and the heart failure (HF) composite at 9.1%. Adult MYBPC3 + HCM patients of all ages are at risk for serious clinical manifestations including heart failure, arrhythmias, and sudden cardiac death (SCD). These findings underscore the importance of genetic diagnosis and development of targeted therapies to restore MyBP-C levels, which could potentially modify the natural history of the disease. [ABSTRACT FROM AUTHOR]

The drug ranolazine may benefit patients who have chronic chest pain caused by coronary artery disease, according to a study of 823 patients. The patients who took the drug were able to exercise longer on a treadmill and got chest pain less frequently than patients who took a placebo, or inactive substance. Ranolazine reduces the heart's need for oxygen so it can continue to function at low oxygen levels.

Heterozygous MYBPC3 variants are the leading genetic cause of hypertrophic cardiomyopathy (HCM). Pathogenic and likely pathogenic (P/LP) MYBPC3 variants (MYBPC3 +) are predominantly truncating variants and result in reduced functional protein (MyBP-C) levels. Despite a common genetic basis, there is wide variability in disease severity and onset. Prior work demonstrates pediatric-onset HCM associated with sarcomeric mutations has worse outcomes, but limited studies have examined this by genotype. To better understand the natural history of pediatric-onset MYBPC3+ HCM, we analyzed data of all MYBPC3 + HCM patients enrolled in SHaRe (Sarcomeric Human Cardiomyopathy Registry). As of December 2023, 1,713 HCM patients with ≥1 P/LP MYBPC3 variants had been enrolled in SHaRe, a multicenter registry spanning 12 cardiac centers in the US, EU, and Australia. Pediatric-onset (218/1713 patients) and adult-onset MYBPC3 + HCM (1495/1713) were defined as <18 and ≥18 years of age, respectively. Both cohorts were followed for a similar median duration of 7 years. Analysis of demographics, genotype, first echocardiographic metrics, and time to major clinical events was performed and compared across pediatric and adult groups. Compound heterozygosity for MYBPC3 P/LP variants was more common in pediatric disease onset (8.3%) compared to adult-onset (3.7%) (p=0.002). Pediatric-onset MYBPC3 + HCM had more prominent hypertrophy with median left ventricular wall thickness (LVMWT) Z score 11.5 vs 8.9 in adult-onset disease (p=0.006). While the prevalence of overall composite events (i.e. death, transplant, heart failure, or ventricular arrhythmia events) was similar in pediatric- and adult-onset MYBPC3 + HCM patients (16.1% and 20.2%, respectively), events occurred 27 years earlier in the pediatric-onset cohort (median age at event 30.5 vs 57.5 years, p<0.001). Heart failure (HF) composite outcomes and septal reduction therapy (SRT) demonstrated a pattern of similar prevalence between pediatric- and adult-onset disease (HF: 11.5% pediatric and 9.1% adult; SRT: 11.5% pediatric and 13.2% adult) but with earlier onset (HF: median 23 years earlier; SRT: median 23 years earlier, p<0.001). Pediatric-onset MYBPC3+ HCM patients had more severe hypertrophy and showed an earlier age of disease morbidity than adult-onset MYBPC3+ HCM. These results underscore the critical importance of early clinical diagnosis with genetic confirmation to understand prognostic implications and guide treatment. [ABSTRACT FROM AUTHOR]

Introduction: Estimating treatment effects as time savings in disease progression may be more easily interpretable than assessing the absolute difference or a percentage reduction. In this study, we investigate the statistical considerations of the existing method for estimating time savings and propose alternative complementary methods., Methods: We propose five alternative methods to estimate the time savings from different perspectives. These methods are applied to simulated clinical trial data that mimic or modify the Clinical Dementia Rating Sum of Boxes progression trajectories observed in the Clarity AD lecanemab trial., Results: Our study demonstrates that the proposed methods can generate more precise estimates by considering two crucial factors: (1) the absolute difference between treatment arms, and (2) the observed progression rate in the treatment arm., Discussion: Quantifying treatment effects as time savings in disease progression offers distinct advantages. To provide comprehensive estimations, it is important to use various methods., Highlights: We explore the statistical considerations of the current method for estimating time savings. We proposed alternative methods that provide time savings estimations based on the observed absolute differences. By using various methods, a more comprehensive estimation of time savings can be achieved., (© 2024 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)