Mutations in the potassium channel subunit KCNQ1 cause the human severe congenital deafness Jervell and Lange-Nielsen (JLN) syndrome. We applied a gene therapy approach in a mouse model of JLN syndrome (Kcnq1−/− mice) to prevent the development of deafness in the adult stage. A modified adeno-associated virus construct carrying a Kcnq1 expression cassette was injected postnatally (P0–P2) into the endolymph, which resulted in Kcnq1 expression in most cochlear marginal cells where native Kcnq1 is exclusively expressed. We also found that extensive ectopic virally mediated Kcnq1 transgene expression did not affect normal cochlear functions. Examination of cochlear morphology showed that the collapse of the Reissner’s membrane and degeneration of hair cells (HCs) and cells in the spiral ganglia were corrected in Kcnq1−/− mice. Electrophysiological tests showed normal endocochlear potential in treated ears. In addition, auditory brainstem responses showed significant hearing preservation in the injected ears, ranging from 20 dB improvement to complete correction of the deafness phenotype. Our results demonstrate the first successful gene therapy treatment for gene defects specifically affecting the function of the stria vascularis, which is a major site affected by genetic mutations in inherited hearing loss.

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Background While the inverse association between high-density lipoprotein cholesterol (HDL-C) and risk of (CVD) has been long established, it remains unclear whether low HDL-C remains a CVD risk factor when levels of low-density lipoprotein cholesterol (LDL-C) and triglycerides (TG) are not elevated. This is a timely issue because recent studies have questioned whether HDL-C is truly an independent predictor of CVD. Methods and Results 3590 men and women from the Framingham Heart Study offspring cohort without known CVD were followed between 1987 and 2011. Low HDL-C (<40 mg/dL in men and <50 mg/dL in women) was defined as “isolated” if TG and LDL-C were both low (<100 mg/dL). We also examined higher thresholds for TG (150 mg/dL) and LDL-C (130 mg/dL) and compared low versus high HDL-C phenotypes using logistic regression analysis to assess association with CVD. Compared to isolated low HDL-C, CVD risks were higher when low HDL-C was accompanied by LDL-C ≥100 mg/dL and TG <100 mg/dL (OR 1.3 [1.0, 1.6]), TG ≥100 mg/dL and LDL-C <100 mg/dL (OR 1.3 [1.1, 1.5]), or TG and LDL-C ≥ 100 mg/dL (OR 1.6, [1.2, 2.2]), after adjustment for covariates. When low HDL-C was analyzed with higher thresholds for TG (≥150 mg/dL) and/or LDL-C (≥130 mg/dL) results were essentially the same. In contrast, compared to isolated low HDL-C, high HDL-C was associated with 20-40% lower CVD risk except when TG and LDL-C were elevated. Conclusions CVD risk as a function of HDL-C phenotypes is modulated by other components of the lipid panel.

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Viral inoculation and expression in the inner ear for the restoration of hearing must not damage cochlear function. Using normal hearing mice as a model, we have achieved this necessary step, which is required for the treatment of many types of congenital deafness that require early intervention.

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Background: Mechanical circulatory support (MCS) with the Impella device (Abiomed, Danvers, MA) has been associated with higher in-hospital mortality than intra-aortic balloon pump (IABP) in the Premier Healthcare Database and National Cardiovascular Data Registry. Methods:The objective of this retrospective cohort study was to describe trends and outcomes of Impella usage in acute myocardial infarction complicated by cardiogenic shock (AMICS) treated with MCS (Impella or IABP) using real-world observational data from the National Inpatient Sample (NIS) including hospitalizations for AMICS managed with MCS between January 2012 to December 2017. The primary outcomes included in-hospital mortality, transfusion, acute kidney injury, stroke, total costs, and length of stay. Propensity score matching was performed with hierarchical models using risk factor and Elixhauser comorbidity variables. Results and Conclusion:We identified 54,480 hospitalizations for AMICS managed with MCS including 5750 (10.5%) utilizing Impella. Throughout the study period, Impella usage increased yearly to 19.9% of AMICS cases in 2017. After propensity score matching, Impella was associated with higher in-hospital mortality (odds ratio[OR] 1.74, 95% confidence interval [CI] 1.41-2.13) and transfusions (OR 1.97, 95% CI 1.40-2.78) than IABP, without association with acute kidney injury or stroke. Impella

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