Long-Term Survival and Quality of Life Following Transcatheter Aortic Valve Replacement in Nonagenarians.

Transcatheter aortic valve replacement (TAVR) has emerged as a successful treatment option for severe aortic stenosis. However, the long-term outcomes of TAVR in nonagenarians is lacking. We aimed to examine the long-term mortality and quality of life in nonagenarians after TAVR. This is a multicenter, retrospective analysis on patients with severe aortic stenosis who underwent TAVR. Patients were divided into 2 groups: nonagenarians (age ≥90 years) and age <90 years. The Kansas City cardiomyopathy questionnaire (KCCQ) and New York Heart Association (NYHA) scores were compared before and after TAVR. All-cause mortality was compared between both groups at 30 days, 1 year, and 5 years after TAVR using the Cox proportional hazard model. A total of 6,896 patients were included, of whom 591 were nonagenarians. Nonagenarians had a higher Society of Thoracic Surgeons perioperative risk of mortality (8.1 ± 4.6% vs 5.4 ± 4.2%, p <0.001) before TAVR. Both groups were similar in KCCQ and NYHA scores at baseline. At 1 year after TAVR, there was no significant difference in improvement in the KCCQ overall score between those aged <90 years and nonagenarians (-4.76, 95% confidence interval [CI] -11.4 to 1.9, p = 0.161). Similarly, there was no statistically significant difference in improvement in NYHA class between the 2 groups at 1 year (odds ratio 1.07, 95% CI 0.85 to 1.25), p = 0.526). The unadjusted 30-day (3.2% vs 2.7%, hazard ratio 1.11, 95% CI 0.70 to 1.80, p = 0.667) and 5-year (28.0% vs 26.6%, hazard ratio 1.05, 95% CI 0.89 to 1.24, p = 0.60) all-cause mortality were similar between the 2 groups. In conclusion, this study demonstrates an excellent long-term mortality rate at 5 years after TAVR in nonagenarians, comparable to patients younger than 90 years. There is a significant and enduring improvement in functional status in nonagenarians, observed up to 1 year after TAVR.

How electrically evoked compound action potentials in chronically implanted guinea pigs relate to auditory nerve health and electrode impedance.

This study examined how multiple measures based on the electrically evoked compound action potential (ECAP) amplitude-growth functions (AGFs) were related to estimates of neural [spiral ganglion neuron (SGN) density and cell size] and electrode impedance measures in 34 specific pathogen free pigmented guinea pigs that were chronically implanted (4.9-15.4 months) with a cochlear implant electrode array. Two interphase gaps (IPGs) were used for the biphasic pulses and the effect of the IPG on each ECAP measure was measured ("IPG effect"). When using a stimulus with a constant IPG, SGN density was related to the across-subject variance in ECAP AGF linear slope, peak amplitude, and N1 latency. The SGN density values also help to explain a significant proportion of variance in the IPG effect for AGF linear slope and peak amplitude measures. Regression modeling revealed that SGN density was the primary dependent variable contributing to across-subject variance for ECAP measures; SGN cell size did not significantly improve the fitting of the model. Results showed that simple impedance measures were weakly related to most ECAP measures but did not typically improve the fit of the regression model.

Defining the Optimal FVIII Transgene for Placental Cell-Based Gene Therapy to Treat Hemophilia A.

The delivery of factor VIII (FVIII) through gene and/or cellular platforms has emerged as a promising hemophilia A treatment. Herein, we investigated the suitability of human placental cells (PLCs) as delivery vehicles for FVIII and determined an optimal FVIII transgene to produce/secrete therapeutic FVIII levels from these cells. Using three PLC cell banks we demonstrated that PLCs constitutively secreted low levels of FVIII, suggesting their suitability as a transgenic FVIII production platform. Furthermore, PLCs significantly increased FVIII secretion after transduction with a lentiviral vector (LV) encoding a myeloid codon-optimized bioengineered FVIII containing high-expression elements from porcine FVIII. Importantly, transduced PLCs did not upregulate cellular stress or innate immunity molecules, demonstrating that after transduction and FVIII production/secretion, PLCs retained low immunogenicity and cell stress. When LV encoding five different bioengineered FVIII transgenes were compared for transduction efficiency, FVIII production, and secretion, data showed that PLCs transduced with LV encoding hybrid human/porcine FVIII transgenes secreted substantially higher levels of FVIII than did LV encoding B domain-deleted human FVIII. In addition, data showed that in PLCs, myeloid codon optimization is needed to increase FVIII secretion to therapeutic levels. These studies have identified an optimal combination of FVIII transgene and cell source to achieve clinically meaningful levels of secreted FVIII.