Transgenic Rescue of the LARGEmyd Mouse: A LARGE Therapeutic Window?

LARGE is a glycosyltransferase involved in glycosylation of α-dystroglycan (α-DG). Absence of this protein in the LARGEmyd mouse results in α-DG hypoglycosylation, and is associated with central nervous system abnormalities and progressive muscular dystrophy. Up-regulation of LARGE has previously been proposed as a therapy for the secondary dystroglycanopathies: overexpression in cells compensates for defects in multiple dystroglycanopathy genes. Counterintuitively, LARGE overexpression in an FKRP-deficient mouse exacerbates pathology, suggesting that modulation of α-DG glycosylation requires further investigation. Here we demonstrate that transgenic expression of human LARGE (LARGE-LV5) in the LARGEmyd mouse restores α-DG glycosylation (with marked hyperglycosylation in muscle) and that this corrects both the muscle pathology and brain architecture. By quantitative analyses of LARGE transcripts we also here show that levels of transgenic and endogenous LARGE in the brains of transgenic animals are comparable, but that the transgene is markedly overexpressed in heart and particularly skeletal muscle (20–100 fold over endogenous). Our data suggest LARGE overexpression may only be deleterious under a forced regenerative context, such as that resulting from a reduction in FKRP: in the absence of such a defect we show that systemic expression of LARGE can indeed act therapeutically, and that even dramatic LARGE overexpression is well-tolerated in heart and skeletal muscle. Moreover, correction of LARGEmyd brain pathology with only moderate, near-physiological LARGE expression suggests a generous therapeutic window

Variation of Liver Transplant Practice and Outcomes During Public Holidays in the United States: Analysis of United Network for Organ Sharing Registry

Background:. It has been reported that patients hospitalized outside regular working hours have worse outcomes. This study aims to compare outcomes following liver transplantation (LT) performed during public holidays and nonholidays. Methods:. We analyzed the United Network for Organ Sharing registry data for 55 200 adult patients who underwent an LT between 2010 and 2019. Patients were grouped according to LT receipt during public holidays ±3 d (n = 7350) and nonholiday periods (n = 47 850). The overall post-LT mortality hazard was analyzed using multivariable Cox regression models. Results:. LT recipient characteristics were similar between public holidays and nonholidays. Compared with nonholidays, deceased donors during public holidays had a lower donor risk index (median [interquartile range]: holidays 1.52 [1.29–1.83] versus nonholidays 1.54 [1.31–1.85]; P = 0.001) and shorter cold ischemia time (median [interquartile range]: holidays 5.82 h [4.52–7.22] versus nonholidays 5.91 h [4.62–7.38]; P < 0.001). Propensity score matching 4-to-1 was done to adjust for donor and recipient confounders (n = 33 505); LT receipt during public holidays (n = 6701) was associated with a lower risk of overall mortality (hazard ratio 0.94 [95% confidence interval, 0.86-0.99]; P = 0.046). The number of livers that were not recovered for transplant was higher during public holidays compared with nonholidays (15.4% versus 14.5%, respectively; P = 0.03). Conclusions:. Although LT performed during public holidays was associated with improved overall patient survival, liver discard rates were higher during public holidays compared with nonholidays

The effectiveness of cardiac resynchronization therapy for patients with New York Heart Association class IV non-ambulatory heart failure

Background: We reviewed the effectiveness and safety of cardiac resynchronization therapy (CRT) for patients with New York Heart Association (NYHA) class IV non-ambulatory heart failure (NAHF). Methods: From 2006 to 2011, 310 patients underwent CRT at Kobe University Hospital and Himeji Cardiovascular Center because of heart failure. Of these, 29 NAHF patients were retrospectively analyzed. The control group comprised 21 age- and ejection fraction-matched patients with NAHF who did not undergo CRT from the ICU database of Kobe University Hospital. The primary endpoint was all-cause death and hospitalization for heart failure. Response was defined as a >15% reduction in left ventricular end-systolic volume (LVESV). Results: CRT was performed successfully without serious complications in all patients. Twenty-three patients (79%) were discharged 19±15 days after CRT implantation, while 6 (21%) died during their hospital stay due to progressive heart failure. Compared with the control group, patients in the CRT group showed significant improvements in the primary endpoint (log-rank p=0.04). Six patients (21%) were defined as responders and the Kaplan–Meier curve showed that responders experienced a better outcome than non-responders (log-rank p=0.029). LV dyssynchrony before implantation was significantly related to the occurrence of the primary endpoint (p=0.02). Conclusions: CRT can be safely used in patients with NAHF and can improve long-term patient outcomes, especially in treatment responders

Pembrolizumab Plus Amrubicin in Patients With Relapsed SCLC: Multi-Institutional, Single-Arm Phase 2 Study

Introduction: In patients with relapsed SCLC, amrubicin (AMR) is the current standard treatment in Japan. Nevertheless, its efficacy is not satisfactory and prognosis is poor. Preclinical study suggested that anthracycline agent might induce immunogenic cell death and work synergistically with immune checkpoint inhibitors. Methods: Patients with relapsed SCLC who relapsed after completion of platinum-containing regimen were registered. Patients were treated with pembrolizumab (200 mg, flat dose on d 1, every 3 wk for 2 y) plus AMR (40 mg/m2 on d 1–3, every 3 wk until progression). Primary end point was overall response rate (ORR). Secondary end points consisted of progression-free survival (PFS), overall survival, and safety. On the basis of the hypothesis that this treatment will improve ORR from 20% to 40% (0.1 of one-sided α and power of 0.8), 25 patients are required (trial identifier: NCT03253068). Results: Between November 2017 and October 2019, a total of 25 patients were enrolled. Most participants (88%) relapsed within 90 days after platinum-containing therapy and all patients were immune checkpoint inhibitor-naive. ORR, the primary end point, was 52.0% (95% confidence interval [CI]: 31.3%–72.2%). Median PFS was 4.0 months (95% CI: 2.8–7.0 mo), and PFS rate at 1 year was 14.4%. Median overall survival was 10.6 months (95% CI: 7.3–21.3 mo). Common adverse events greater than or equal to grade 3 were neutropenia (64%), leukopenia (40%), and febrile neutropenia (16%). No treatment-related deaths occurred. Conclusions: Among patients with relapsed SCLC, pembrolizumab plus AMR was effective and tolerable

Prophylactic catheter ablation of ventricular tachycardia before cardioverter-defibrillator implantation in patients with non-ischemic cardiomyopathy: Clinical outcomes after a single endocardial ablation

Background: Outcomes related to prophylactic catheter ablation (PCA) for ventricular tachycardia (VT) before implantable cardioverter-defibrillator (ICD) implantation in non-ischemic cardiomyopathy (NICM) are not well characterized. We assessed the efficacy of single endocardial PCA in NICM patients. Methods: We retrospectively analyzed 101 consecutive NICM patients with sustained VT. We compared clinical outcomes of patients who underwent PCA (ABL group) with those who did not (No ABL group). Successful PCA was defined as no inducible clinical VT. We also compared the clinical outcomes of patients with successful PCA (PCA success group) with those of the No ABL group. Endpoints were appropriate ICD therapy (shock and anti-tachycardia pacing) and the occurrence of electrical storm (ES). Results: PCA was performed in 42 patients, and it succeeded in 20. The time to ES occurrence was significantly longer in the ABL group than in the No ABL group (p=0.04). The time to first appropriate ICD therapy and ES occurrence were significantly longer in the PCA success group than in the No ABL group (p=0.02 and p<0.01, respectively). Conclusion: Single endocardial PCA can decrease ES occurrence in NICM patients. However, high rates of VT recurrence and low success rates are issues to be resolved; therefore, the efficacy of single endocardial PCA is currently limited