Protocadherin-15 (Pcdh15) is a component of the tip-links, the extracellular filaments that gate hair cell mechano-electrical transduction channels in the inner ear. There are three Pcdh15 splice isoforms (CD1, CD2 and CD3), which only differ by their cytoplasmic domains; they are thought to function redundantly in mechano-electrical transduction during hair-bundle development, but whether any of these isoforms composes the tip-link in mature hair cells remains unknown. By immunolabelling and both morphological and electrophysiological analyses of post-natal hair cell-specific conditional knockout mice (Pcdh15ex38-fl/ex38-fl Myo15-cre+/−) that lose only this isoform after normal hair-bundle development, we show that Pcdh15-CD2 is an essential component of tip-links in mature auditory hair cells. The finding, in the homozygous or compound heterozygous state, of a PCDH15 frameshift mutation (p.P1515Tfs*4) that affects only Pcdh15-CD2, in profoundly deaf children from two unrelated families, extends this conclusion to humans. These results provide key information for identification of new components of the mature auditory mechano-electrical transduction machinery. This will also serve as a basis for the development of gene therapy for deafness caused by PCDH15 defects.

Background: The severity of Coronavirus Disease 2019 (COVID-19) is a multifactorial condition. An increasing body of evidence argues for a direct implication of vitamin D deficiency, low serum calcium on poor outcomes in COVID-19 patients. This study was designed to investigate the relationship between these two factors and COVID-19 in-hospital mortality. Materials: This is a prospective study, including 120 severe cases of COVID-19, admitted at the department of Reanimation-Anesthesia. Vitamin D was assessed by an immuno-fluoroassay method. Total serum calcium by a colorimetric method, then, corrected for serum albumin levels. The association with in-hospital mortality was assessed using the Kaplan-Meier survival curve, proportional Cox regression analyses and the receiver operating characteristic curve. Results: Hypovitaminosis D and hypocalcemia were very common, occurring in 75% and 35.8% of patients. When analyzing survival, both were significantly associated with in-hospital mortality in a dose-effect manner (p Log-Rank ¼ 0.009 and 0.001 respectively). A cutoff value of 39 nmol/l for vitamin D and 2.05 mmol/l for corrected calcemia could predict poor prognosis with a sensitivity of 76% and 84%, and a specificity of 69% and 60% respectively. Hazard ratios were (HR ¼ 6.9, 95% CI [2.0-24.1], p ¼ 0.002 and HR ¼ 6.2, 95% CI [2.1-18.3], p ¼ 0.001) respectively. Conclusion: This study demonstrates the high frequency of hypocalcemia and hypovitaminosis D in severe COVID-19 patients and provides further evidence of their potential link to poor shortterm prognosis. It is, therefore, possible that the correction of hypocalcemia, as well as supplementation with vitamin D, may improve the vital prognosis.

BackgroundAlmost 90% of all cases of congenital, non-syndromic, severe to profound inherited deafness display an autosomal recessive mode of transmission (DFNB forms). To date, 47 causal DFNB genes have been identified, but many others remain to be discovered. We report the study of two siblings born to consanguineous Algerian parents and affected by isolated, profound congenital deafness.MethodWhole-exome sequencing was carried out on these patients after a failure to identify mutations in the DFNB genes frequently involved.ResultsA biallelic nonsense mutation, c.88C > T (p.Gln30*), was identified in EPS8 that encodes epidermal growth factor receptor pathway substrate 8, a 822 amino-acid protein involved in actin dynamics. This mutation predicts a truncated inactive protein or no protein at all. The mutation was also present, in the heterozygous state, in one clinically unaffected sibling and in both unaffected parents, and was absent from the other two unaffected siblings. It was not found in 120 Algerian normal hearing control individuals or in the Exome Variant Server database. EPS8 is an F-actin capping and bundling protein. Mutant mice lacking EPS8 (Eps8−/− mice), which is present in the hair bundle, the sensory antenna of the auditory sensory cells that operate the mechano-electrical transduction, are also profoundly deaf and have abnormally short hair bundle stereocilia.ConclusionThis new DFNB form is likely to arise from abnormal hair bundles resulting in compromised detection of physiological sound pressures.

Coronavirus Disease 2019 is a very fast-spreading infectious disease. Severe forms are marked by a high mortality rate. The objective of this study is to identify routine biomarkers that can serve as early predictors of the disease progression. This is a prospective, single-center, cohort study involving 330 SARS-CoV-2 infected patients who were admitted at the University Hospital of Blida, Algeria in the period between the 27th of March and 22nd of April 2020. The ROC curve was used to evaluate the predictive performance of biomarkers, assessed at admission, in the early warning of progression toward severity. Multivariate logistic regression was used to quantify the independent risk for each marker. After an average follow-up period of 13.9 ± 3.5 days, 143 patients (43.3%) were classified as severe cases. Six biological abnormalities were identified as potential risk markers independently related to the severity: elevated urea nitrogen (>8.0 mmol/L, OR ¼ 9.3 [2.7-31.7], p < .00001), elevated CRP (>42mg/L, OR ¼ 7.5 [2.4-23.3], p ¼ .001), decreased natremia (<133. 6 mmol/L, OR ¼ 6.0 [2.0-17.4], p ¼ .001), decreased albumin (<33.5 g/L, OR ¼ 5.2 [1.7-16.6], p ¼ .003), elevated LDH (>367 IU/L, OR ¼ 4.9 [1.7-14.2], p ¼ .003) and elevated neutrophil to lymphocyte ratio (>7.99, OR ¼ 4.2, [1.4-12.2], p ¼ .009). These easy-to-measure, time-saving and very low-cost parameters have been shown to be effective in the early prediction of the COVID-19 severity. Their use at the early admission stage can improve the risk stratification and management of medical care resources in order to reduce the mortality rate.