Genome-wide association analyses identify new Brugada syndrome risk loci and highlight a new mechanism of sodium channel regulation in disease susceptibility.

Brugada syndrome (BrS) is a cardiac arrhythmia disorder associated with sudden death in young adults. With the exception of SCN5A, encoding the cardiac sodium channel Na1.5, susceptibility genes remain largely unknown. Here we performed a genome-wide association meta-analysis comprising 2,820 unrelated cases with BrS and 10,001 controls, and identified 21 association signals at 12 loci (10 new). Single nucleotide polymorphism (SNP)-heritability estimates indicate a strong polygenic influence. Polygenic risk score analyses based on the 21 susceptibility variants demonstrate varying cumulative contribution of common risk alleles among different patient subgroups, as well as genetic associations with cardiac electrical traits and disorders in the general population. The predominance of cardiac transcription factor loci indicates that transcriptional regulation is a key feature of BrS pathogenesis. Furthermore, functional studies conducted on MAPRE2, encoding the microtubule plus-end binding protein EB2, point to microtubule-related trafficking effects on Na1.5 expression as a new underlying molecular mechanism. Taken together, these findings broaden our understanding of the genetic architecture of BrS and provide new insights into its molecular underpinnings

Hétérogénéités compositionnelles dans les réservoirs de gaz acides : compréhension et modélisation du rôle d'un aquifère actif

The H2S occurrence in gas reservoirs is an important factor of economic depreciation. Thus, the knowledge of its content and distribution is a critical parameter when planning field development. Under typical reservoirs conditions of pressure and temperature, H2S is far more soluble than hydrocarbons and other gases. The preferential leaching of H2S by an active aquifer over time could explain the creation of compositional heterogeneities. The thesis aims at illustrating and quantifying this process based on numerical simulations performed with the two-phase transport and geochemical software Hytec, developed by Mines ParisTech (France). This mechanism may be controlled by: Differential solubility of gases, which changes the relative amounts of each gas near the gas-watercontact; Contact with an active aquifer, which can export the dissolved gases thus enhancing dissolution on the long-term; Diffusional transport in the gas phase, which transfers the compositional anomalies farther from the gas-water contact; Geological parameters (type of aquifer, permeability heterogeneities) which can modify the transport scenario.La présence d'H2S dans un gisement est un important facteur de dévalorisation économique, c'est pourquoi connaitre sa concentration et sa distribution est capital pour optimiser toutes les étapes de l'exploration à la production d'un champ. Dans les conditions de pression et température des réservoirs, l'H2S est beaucoup plus soluble que les hydrocarbures et autres gaz. Le lessivage préférentiel de l'H2S par un aquifère actif pourrait ainsi entrainer la création d'hétérogénéités compositionnelles au cours du temps. L'objectif de la thèse est d'illustrer et quantifier ce processus à l'aide de simulations numériques réalisées avec Hytec, logiciel couplé géochimie-transport diphasique développé par MINES ParisTech. Le lessivage préférentiel de l'H2S est contrôlé par : la solubilité différentielle des gaz qui modifie les quantités relatives de chacun des gaz à proximité de l'aquifère ; le transport aqueux qui exporte les gaz dissous et améliore ainsi la dissolution des gaz sur le long terme ; le transport gazeux qui renouvelle les gaz dissous à l'interface et étend le lessivage du gaz à toute la structure ; les caractéristiques d'un réservoir (type d'aquifère, hétérogénéité des perméabilités)

Compositional heterogeneities in acid gas reservoirs : role of an active aquifer, mechanisms and simulation

La présence d'H2S dans un gisement est un important facteur de dévalorisation économique, c'est pourquoi connaitre sa concentration et sa distribution est capital pour optimiser toutes les étapes de l'exploration à la production d'un champ. Dans les conditions de pression et température des réservoirs, l'H2S est beaucoup plus soluble que les hydrocarbures et autres gaz. Le lessivage préférentiel de l'H2S par un aquifère actif pourrait ainsi entrainer la création d'hétérogénéités compositionnelles au cours du temps. L'objectif de la thèse est d'illustrer et quantifier ce processus à l'aide de simulations numériques réalisées avec Hytec, logiciel couplé géochimie-transport diphasique développé par MINES ParisTech. Le lessivage préférentiel de l'H2S est contrôlé par : la solubilité différentielle des gaz qui modifie les quantités relatives de chacun des gaz à proximité de l'aquifère ; le transport aqueux qui exporte les gaz dissous et améliore ainsi la dissolution des gaz sur le long terme ; le transport gazeux qui renouvelle les gaz dissous à l'interface et étend le lessivage du gaz à toute la structure ; les caractéristiques d'un réservoir (type d'aquifère, hétérogénéité des perméabilités).The H2S occurrence in gas reservoirs is an important factor of economic depreciation. Thus, the knowledge of its content and distribution is a critical parameter when planning field development. Under typical reservoirs conditions of pressure and temperature, H2S is far more soluble than hydrocarbons and other gases. The preferential leaching of H2S by an active aquifer over time could explain the creation of compositional heterogeneities. The thesis aims at illustrating and quantifying this process based on numerical simulations performed with the two-phase transport and geochemical software Hytec, developed by Mines ParisTech (France). This mechanism may be controlled by: Differential solubility of gases, which changes the relative amounts of each gas near the gas-watercontact; Contact with an active aquifer, which can export the dissolved gases thus enhancing dissolution on the long-term; Diffusional transport in the gas phase, which transfers the compositional anomalies farther from the gas-water contact; Geological parameters (type of aquifer, permeability heterogeneities) which can modify the transport scenario

Tackling Water/Gas/Rock Interactions for Reactive-Transport Codes - an Insight into the CHESS/HYTEC Codes

International audienceNumerous and various applications of reactive-transport codes in geosciences require handling gases and water/gas/rock interactions. On the one hand, models have to be accurate and complex, but, on the other hand, algorithms have to remain efficient and fast. In this paper a few hints for tackling these important water/gas/rock interactions and their implementation in reactive-transport codes will be addressed. Some applications at both laboratory and field scales will come to illustrate the concepts

Reactive transport simulation of uranium ISR: effect of the density driven flow

International audienceThe ISR (in situ recovery) operation of a perched uranium mineralization within a thick, permeable aquifer can become a sensitive issue. Indeed, density difference between the injected high-density acidic solutions and fresh groundwater can bring a high quantity of solutions toward the bottom of the aquifer. This phenomenon has to be taken into account from an operational point of view because the loss of solution can involve both an acid overconsumption and a lower production of uranium; and from an environmental point of view for the remediation of the exploited aquifer. The main topics of this study are: (1) to represent the hydrogeological behaviour of such an ISL operation for quantifying the lost part of uranium and acid linked to the density driven flow, (2) to test the sensitivity of operational parameters (flow rates, well field patterns, positioning of well screens) to optimize the uranium recovery and acid consumption. 3D simulations have been realised with a reactive transport code including a density driven flow module (code HYTEC). The simulations take into account for the reaction processes within the ore body: flow and transport of dissolved reagents, oxidative dissolution of uranium, effect of pH buffers. The results of simulations have shown that the permeability of porous media is a key parameter as it controls the rate of the solution sinking towards the bottom of the aquifer. Using a variety of injection scenarios and geometrical designs, the simulations indicate that possible means to reduce the solutions loss can be identified and tested with such a modelling approach

A scenario for the creation of H2S heterogeneities in acid gas reservoirs in contact with an active aquifer: a simulation study

International audienceCompositional heterogeneities of H2S have been noticed in many sour gas reservoirs. Its occurrence is an important factor of economic depreciation. Thus, the knowledge of its content and distribution is a critical parameter when planning field development. The paper aims at exploring the role of an active aquifer in the creation of H2S heterogeneities in high H2S-bearing gas reservoir. Indeed, under conditions of pressure and temperature of typical reservoirs, H2S is far more soluble than hydrocarbons and other gases. A preferential leaching of H2S (e.g. versus CH4) over time is thus possible. This mechanism is controlled by: (1) Differential solubility of gases, which change the relative amounts of each gas near the gas-water contact (GWC); (2) Contact with an active aquifer, which can export the dissolved gases thus enhancing dissolution on the long-term; (3) Diffusional transport in the gas phase, which transfers the compositional anomalies farther from the gas-water contact; (4) Geological parameters (type of aquifer, permeability heterogeneities) which can modify the transport scenario. To illustrate and quantify this process, we show the results of numerical simulations, performed with the two-phase transport and geochemical software Hytec. First, a very schematic reservoir with a composition considered uniformly distributed within the reservoir, has been simulated to quantify the leaching of H2S. The results highlight the potential role of the active aquifer, which can leach the gases and export them outside the reservoir. In a second phase, the effect of geological parameters on the H2S heterogeneity development was studied: additional simulations were performed on geometries closer to natural cases. The amount of leached H2S depends strongly on the geometry: the larger the GWC area, the larger the amounts leached

Role of hydrodynamism in compositional heterogeneities in acid gas reservoir

International audienceAcid gases (H2S and CO2) compositional heterogeneities have been noticed in many sour gas reservoirs. Their occurrence is an important factor of economic depreciation. Thus, the knowledge of the acid gases distribution is a critical parameter for the design of field development. The mechanisms to explain compositional heterogeneities of acid gas in a reservoir are various. The paper aims at exploring the role of an active aquifer in contact with an initial high H2S content reservoir. The major mechanisms may be controlled by: * Differential solubility of gases which can change the relative amounts of each gas near the contact; * Active aquifer solubilization and transport which can export dissolved gases thus enhancing dissolution on the long-term; * Diffusional transport in the gas phase which can transfer the compositional anomalies farther from the gas-water contact. To test the influence of several parameters on the efficiency of the acid gases leaching, simulations on basic geometries have been performed with the diphasic transport and geochemical software Hytec. The simulation results show a major role of the occurrence of horizontal impermeable barriers yields to sharp heterogeneities, including a decrease in acid gas near the contact, while farther areas H2S concentration remain unaffected

Les déterminants managériaux de la qualité de vie au travail des soignants dans les services d'hémato-oncologie

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0185 : Genetic screening identifies a high proportion of mutations in patients with idiopathic ventricular fibrillation and sudden cardiac death

International audienceIntroduction Several gene defects are associated with idiopathic ventricular fibrillation (IVF) and sudden cardiac death (SCD). The recent development of NGS-based mutation screening provides a unique opportunity to estimate extensively the spectrum and prevalence of rare variants in genes associated with cardiac diseases. Methods Cohort 1 was composed of 75 patients resuscitated from cardiac arrest due to IVF. All patients have undergone a complete clinical cardiac examination including 12 lead-ECG, cardiac echography, coronography and exercise test. Cohort 2 was composed of 99 victims of SCD related to ventricular fibrillation younger than 45 years old and without explanation for the SCD at the time of the reanimation. Genetic screening was based on the use of the HaloPlex(tm) Target Enrichment System (Agilent Technologies) prior to HiSeq sequencing (Illumina). The custom kit designed for this study covers 163 genes previously reported as involved in cardiac arrhythmias, conduction defect and cardiomyopathies. Results In cohort 1, the mean age was 36±10 years with a male predominance (52 males, 69%). In cohort 2, the mean age was 37±7 years with a male predominance (76 males, 79%). In cohort 1, we identified 50 putative mutations in 35 patients (47%). In cohort 2, we identified 30 putative mutations in 24 patients (24%). Conclusion Our study identified mutations in almost 50 % of IVF patients after a complete cardiac evaluation. These results suggest that molecular analysis must be part of the work up in this kind of patients. In young patients affected by unexplained sudden death, the molecular analyses are less contributive probably because of a more important percentage of patients affected by ischemic cardiomyopathies

Burden of rare variants in arrhythmogenic cardiomyopathy with right dominant form associated genes provides new insights for molecular diagnosis and clinical management.

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