A targeted next-generation sequencing assay for the molecular diagnosis of genetic disorders with orodental involvement.

BACKGROUND: Orodental diseases include several clinically and genetically heterogeneous disorders that can present in isolation or as part of a genetic syndrome. Due to the vast number of genes implicated in these disorders, establishing a molecular diagnosis can be challenging. We aimed to develop a targeted next-generation sequencing (NGS) assay to diagnose mutations and potentially identify novel genes mutated in this group of disorders. METHODS: We designed an NGS gene panel that targets 585 known and candidate genes in orodental disease. We screened a cohort of 101 unrelated patients without a molecular diagnosis referred to the Reference Centre for Oro-Dental Manifestations of Rare Diseases, Strasbourg, France, for a variety of orodental disorders including isolated and syndromic amelogenesis imperfecta (AI), isolated and syndromic selective tooth agenesis (STHAG), isolated and syndromic dentinogenesis imperfecta, isolated dentin dysplasia, otodental dysplasia and primary failure of tooth eruption. RESULTS: We discovered 21 novel pathogenic variants and identified the causative mutation in 39 unrelated patients in known genes (overall diagnostic rate: 39%). Among the largest subcohorts of patients with isolated AI (50 unrelated patients) and isolated STHAG (21 unrelated patients), we had a definitive diagnosis in 14 (27%) and 15 cases (71%), respectively. Surprisingly, COL17A1 mutations accounted for the majority of autosomal-dominant AI cases. CONCLUSIONS: We have developed a novel targeted NGS assay for the efficient molecular diagnosis of a wide variety of orodental diseases. Furthermore, our panel will contribute to better understanding the contribution of these genes to orodental disease. TRIAL REGISTRATION NUMBERS: NCT01746121 and NCT02397824.journal articleresearch support, non-u.s. gov't2016 Feb2015 10 26importe

Extracorporeal Membrane Oxygenation for Severe Acute Respiratory Distress Syndrome associated with COVID-19: An Emulated Target Trial Analysis.

RATIONALE: Whether COVID patients may benefit from extracorporeal membrane oxygenation (ECMO) compared with conventional invasive mechanical ventilation (IMV) remains unknown. OBJECTIVES: To estimate the effect of ECMO on 90-Day mortality vs IMV only Methods: Among 4,244 critically ill adult patients with COVID-19 included in a multicenter cohort study, we emulated a target trial comparing the treatment strategies of initiating ECMO vs. no ECMO within 7 days of IMV in patients with severe acute respiratory distress syndrome (PaO2/FiO2 <80 or PaCO2 ≥60 mmHg). We controlled for confounding using a multivariable Cox model based on predefined variables. MAIN RESULTS: 1,235 patients met the full eligibility criteria for the emulated trial, among whom 164 patients initiated ECMO. The ECMO strategy had a higher survival probability at Day-7 from the onset of eligibility criteria (87% vs 83%, risk difference: 4%, 95% CI 0;9%) which decreased during follow-up (survival at Day-90: 63% vs 65%, risk difference: -2%, 95% CI -10;5%). However, ECMO was associated with higher survival when performed in high-volume ECMO centers or in regions where a specific ECMO network organization was set up to handle high demand, and when initiated within the first 4 days of MV and in profoundly hypoxemic patients. CONCLUSIONS: In an emulated trial based on a nationwide COVID-19 cohort, we found differential survival over time of an ECMO compared with a no-ECMO strategy. However, ECMO was consistently associated with better outcomes when performed in high-volume centers and in regions with ECMO capacities specifically organized to handle high demand. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/)

Influence des incertitudes des données d'inspection CND sur la cartographie d'alarme de corrosion des armatures: modèle de prévision du risque de corrosion avec un réseau bayésien

International audienceL'article présente une méthodologie pour établir une cartographie d'alarme de corrosion liée aux niveaux de corrosion des armatures de la première couche dans des structures en béton armé (RC). Les données d'inspection par contrôle non destructif (CND) obtenues à partir de campagnes d'inspection sur différentes structures RC sont utilisées pour construire un modèle prédictif basé sur un réseau bayésien (RB). La méthodologie consiste en trois étapes principales : la construction de la base de données à partir des données d'inspection CND, l'apprentissage de la structure du RB et de ses paramètres à partir des données CND, et l'utilisation du RB pour avoir la cartographie des alarmes de corrosion. L'incertitude des mesures sur site est prise en compte dans ce modèle prédictif pour améliorer la précision des probabilités d'alarme de corrosion obtenues. Les paramètres de la structure RB physiquement optimale sont le potentiel de corrosion, le taux de corrosion, la résistivité électrique et l'alarme de corrosion. Les données d'inspection CND d'une face de pile d'un pont sont utilisées comme nouvelles informations pour mettre à jour le RB dans la dernière étape. La méthodologie permet d'estimer la probabilité d'alarme de corrosion lorsque les indicateurs ne sont pas disponibles simultanément (en raison des contraintes de mesures CND sur site). La cartographie obtenue à partir du modèle prédictif RB peut être utilisée comme un outil efficace pour la stratégie de maintenance en indiquant les zones les plus critiques de la structure inspectée vis-à-vis de la corrosion

Enhancement of Predictive Bayesian Network Model for Corrosion Alarm of Steel Reinforcement with Uncertainty of NDT Measurements

International audienceIn this paper, a methodology based on a Bayesian Network (BN) is proposed to create reliable corrosion alarm maps of first layer reinforcements, which is related to corrosion levels. The methodology consists of three principal steps: building the database, learning the BN structure and its parameters from non-destructive testing (NDT) data, and using the BN for corrosion alarm mapping. Uncertainty of the on-site measurement is accounted in the predictive model to enhance accuracy of the obtained corrosion alarm probability. The parameters of the physically optimal BN structure are corrosion potential, corrosion rate, electrical resistivity, and corrosion alarm. NDT inspection data of a bridge pier face (1.3 m wide and 2 m high) is used as new information for updating the BN in the last step. The methodology allows the probability of corrosion alarm to be estimated where the NDT indicators are not simultaneously available. Accounting the uncertainty of measurement in the BN model allows more nuanced estimates of the corrosion alarm probability, and decrease the number of points for which the probability of a corrosion alarm is 50% (undetermined state between “alarm” and “no alarm”)

Olfactory stimulation or inhibition of sexual behavior of stallions in non-breeding season

Remerciements : Plateforme Phénotypage-Endocrinologie, INRA, UMR PRC 0085, Centre Tours Val de LoireInternational audienceStallions show decreased sexual responses and activities during short days in winter. To evaluate the importance of sexual olfactory communication in horses, we tested whether sexual responses could be stimulated through various sexual olfactory stimulations in winter. To this end, we presented stallions with various olfactory stimulations (urine from mares at different stages of the reproductive cycle, urine from stallions or geldings, or chemically defined synthetic odorant) during the non-breeding season and measured their behavioral responses through (1) a test of olfactory investigation (olfactory investigation and flehmen behavior) and (2) a test of sexual activity in the context of semen collection for artificial insemination. It appears that the duration of olfactory investigation and flehmen behavior is longer after presentation of urine (stallion, gelding, anestrous, diestrous and estrous mare) than after presentation of water or synthetic odorant. By contrast, geldings showed reduced flehmen behavior that did not differ from that after water presentation. It is of interest that during the mounting test, mare estrous urine was associated with significantly reduced latency to ejaculation when spread in the nostril of the stallion, compared to anestrous mare urine or water. Anestrous mare urine seems to even inhibit stallion sexual motivation as measured through a longer latency to reach mounting and ejaculation. It appears therefore that during the season of sexual rest, stallion sexual motivation can be stimulated by mare estrous urine and inhibited by mare anestrous urine. These results also suggest that the physiological state of the mare influence the content of urinary chemosignals

Melatonin does not reduce mortality in adult hospitalized patients with COVID-19: a multicenter retrospective observational study

International audienceNo abstract availabl

New insights into the role of matrix metalloproteinase 3 ( MMP3 ) in bone

International audienceThe Matrix Metalloproteinases are important regulators of bone metabolism and can influence bone mass and bone remodeling. We investigate the role of Matrix Metalloproteinase 3 (MMP3) on bone in mice, by using Mmp3 knockout (Mmp3 KO) in the context of estrogen deficiency, and in human, by analyzing the association of promoter polymorphism with bone mineral density in postmenopausal women and with MMP3 expression. We presented evidence in this paper that Mmp3 KO significantly increases trabecular bone mass and trabecular number and does not affect cortical bone thickness. We also found that Mmp3 KO protects from the deleterious effects of ovariectomy on bone mineral density in mice by preventing deterioration of bone microarchitecture. The effect of Mmp3 KO does not involve bone formation parameters but instead acts by inhibition of bone resorption, leading to a reduced bone loss associated to ovariectomy. By studying a human cohort, we found that a polymorphism located in the promoter of the human MMP3 gene is associated with bone mineral density in postmenopausal women and found that MMP3 rs632478 promoter variants are associated with change in promoter activity in transfection experiments. In conclusion MMP3, although weakly expressed in bone cells, could be one of the important regulators of sex hormone action in bone and whose activity could be targeted for therapeutic applications such as in Osteoporosis

EVALUATION OF THE CARDIOMYOTOXIC EFFECTS OF DOXYCYCLINE OVERDOSE IN CALVES USING 2-DIMENSIONAL SPECKLE TRACKING.

Doxycycline (DOXY) is associated with left ventricular (LV) dysfunction in calves in accidental overdose but not in experimental models when evaluated with classical and Doppler echocardiography. Two-dimensional-speckle tracking (2DST) is used to evaluate LV dysfunction in numerous species but not in cattle. The aim of this study was to evaluate the cardiotoxic effects of an experimental overdose of DOXY using 2DST in calves. Ten healthy male Holstein calves. Group 1: 5 calves (mean age 58.0 +/- 16.3 days; mean body weight 72.2 +/- 13.0 kg) received 25 mg/kg of DOXY orally for 5 days. Group 2: 5 calves (mean age 56.4 +/- 15.7 days; mean body weight 73.4 +/- 7.0 kg) received a placebo. Electrocardiography (ECG) and 2DST echocardiography were performed at day 0 and day 8. ECG tracings were analysed for occurrence of arrhythmias. 2DST measurements included global and segmental, peak values for radial and circumferential strains (SR, SC), strain rates (SrR, SrC), rotation (Rot), rotation rates (RotR) and radial displacement (DR). All calves completed the study. ECG recordings were unremarkable in both groups. Heart rate was neither significantly different between groups nor before and after treatment. LV systolic function was affected in calves receiving an overdose of DOXY as shown by a significant decrease of segmental SR (P < 0.05), SC (P < 0.05) and DR (P < 0.05) in treated calves compared to the placebo group in several segments. The SrC in early diastole was also significantly decreased in 1 segment (<0.05). In calves, DOXY overdose induces a LV dysfunction in systole, and to a lesser extent, in diastole. A better comprehension of the pathophysiology involved in the DOXY overdose will help in the treatment of accidental cases