Predicting leakage of the VERCORS mock-up and concrete containment buildings - a digital twin approach

EDF operates a nuclear power generation fleet made up of 56 reactors. This fleet contains 24 reactors designed as double-walled concrete containment building. The inner concrete containment vessel has no metallic liner and is a prestressed reinforced concrete building. The inner concrete containment vessel is designed to withstand a severe accident, in terms of mechanical and sealing behaviour. The tightness of the containment is tested every 10 years, by carrying out a pressurization test and by measuring the leak rate. The leak rate is required to be below a regulatory threshold to continue operation of the concrete containment building for the next ten years. Ageing of concrete due to drying, creep and shrinkage leads to increase prestress loss and then leak rate with time. For some containment buildings, the leak rate gets closer to the regulatory threshold with time, so important coating programs are planned to mitigate and limit the leak rate under the regulatory threshold. Therefore, it is very important for EDF to have a concrete containment building leak rate prediction tool. To address this issue, an important research program around a 1/3 scale concrete containment building mock-up called "VERCORS" have been launched at EDF. The mock-up is heavily instrumented, and its materials (concrete, prestressing cables) have been widely characterized and studied. An important numerical effort has also been made to implement structural computations of the mock-up and to capitalize these computations as well as their post-processing (so as to compare automatically with the monitoring data) in what can be called a digital twin of the mock-up. This digital twin is now used to predict the leakage of VERCORS mock-up before yearly pressure test, and also to optimize the repair programs on the real containments

Genetic diversity and population structure of Botryosphaeria dothidea and Neofusicoccum parvum on English walnut (Juglans regia L.) in France.

Botryosphaeriaceae species are the major causal agents of walnut dieback worldwide, along with Diaporthe species. Botryosphaeria dothidea and Neofusicoccum parvum are the only two Botryosphaeriaceae species associated with this recently emergent disease in France, and little is known about their diversity, structure, origin and dispersion in French walnut orchards. A total of 381 isolates of both species were genetically typed using a sequence-based microsatellite genotyping (SSR-seq) method. This analysis revealed a low genetic diversity and a high clonality of these populations, in agreement with their clonal mode of reproduction. The genetic similarity among populations, regardless of the tissue type and the presence of symptoms, supports the hypothesis that these pathogens can move between fruits and twigs and display latent pathogen lifestyles. Contrasting genetic patterns between N. parvum populations from Californian and Spanish walnut orchards and the French ones suggested no conclusive evidence for pathogen transmission from infected materials. The high genetic similarity with French vineyards populations suggested instead putative transmission between these hosts, which was also observed with B. dothidea populations. Overall, this study provides critical insight into the epidemiology of two important pathogens involved in the emerging dieback of French walnut orchards, including their distribution, potential to mate, putative origin and disease pathways

The Effect of Elective Ligation of the Arteriovenous Fistula on Cardiac and Renal Functions in Kidney Transplant Recipients.

peer reviewed[en] KEY POINTS: Surgical AVF ligation in KTRs is associated with a significant increase in diastolic BP while systolic BP remains stable. AVF closure in KTRs leads to an improvement of LV and LA morphology and a decrease in serum NT-proBNP levels. There is no significant effect of AVF ligation on kidney allograft function: The eGFR remains stable over time. BACKGROUND: Kidney transplantation is considered as the best kidney replacement therapy, and arteriovenous fistula (AVF) is the preferred vascular access for hemodialysis. The systematic ligation of a functioning AVF in stable kidney transplant recipients (KTRs) remains debatable. METHODS: In this prospective study, we investigated the hemodynamic effect of the surgical closure of AVF in KTRs. Forty-three KTRs underwent an ambulatory BP monitoring before surgical closure of AVF (T0) and 12 months later (M12), as well as measurement of serum cardiac biomarkers (i.e., soluble suppression of tumorigenicity 2, N-terminal pro b-type natriuretic peptide [NT-proBNP], and galectin-3). Serum tests were also performed 6 months after AVF closure (M6). An echocardiographic examination was performed at each time point. All serum creatinine values were collected to compare the individual eGFR slopes before versus after AVF closure. The latest measure of the AVF flow before kidney transplantation was recorded. RESULTS: Diastolic BP significantly rose from T0 to M12: +4.4±7.3 mm Hg (P = 0.0003) for 24h, +3.8±7.4 mm Hg (P = 0.0018) during the day, and +6.3±9.9 mm Hg (P = 0.0002) during the night, leading to an increased proportion of KTRs with European Society of Hypertension (ESH)-defined arterial hypertension after AVF ligation. No change was observed for systolic BP. NT-proBNP significantly dropped between T0 and M6 (345 [190; 553] to 230 [118; 458] pg/ml, P = 0.0001) and then remained stable from M6 to M12 while suppression of tumorigenicity 2 and galectin-3 levels did not change from T0 to M12. We observed a significant decrease in left ventricular (LV) end-diastolic volume, LV end-systolic volume, LV mass, interventricular septum diameter, left atrial volume, and tricuspid annular plane systolic excursion from T0 to M6 and then a stability from M6 to M12. LV ejection fraction and eGFR slope remained stable during the whole study. These observations remained unchanged after adjustment for AVF flow. CONCLUSION: The closure of a patent AVF in KTRs is associated with elevation of diastolic BP, drop in serum NT-proBNP levels, reduction of left ventricular and atrial dimensions, and stability of eGFR slope

Assessment of the longitudinal humoral response in non-hospitalized SARS-CoV-2-positive individuals at decentralized sites: Outcomes and concordance

IntroductionEarly in the COVID-19 pandemic, reagent availability was not uniform, and infrastructure had to be urgently adapted to undertake COVID-19 surveillance.MethodsBefore the validation of centralized testing, two enzyme-linked immunosorbent assays (ELISA) were established independently at two decentralized sites using different reagents and instrumentation. We compared the results of these assays to assess the longitudinal humoral response of SARS-CoV-2-positive (i.e., PCR-confirmed), non-hospitalized individuals with mild to moderate symptoms, who had contracted SARSCoV-2 prior to the appearance of variants of concern in Québec, Canada.ResultsThe two assays exhibited a high degree of concordance to identify seropositive individuals, thus validating the robustness of the methods. The results also confirmed that serum immunoglobulins persist ≥ 6 months post-infection among non-hospitalized adults and that the antibodies elicited by infection cross-reacted with the antigens from P.1 (Gamma) and B.1.617.2 (Delta) variants of concern.DiscussionTogether, these results demonstrate that immune surveillance assays can be rapidly and reliably established when centralized testing is not available or not yet validated, allowing for robust immune surveillance

Mutations in TUBG1, DYNC1H1, KIF5C and KIF2A cause malformations of cortical development and microcephaly.

International audienceThe genetic causes of malformations of cortical development (MCD) remain largely unknown. Here we report the discovery of multiple pathogenic missense mutations in TUBG1, DYNC1H1 and KIF2A, as well as a single germline mosaic mutation in KIF5C, in subjects with MCD. We found a frequent recurrence of mutations in DYNC1H1, implying that this gene is a major locus for unexplained MCD. We further show that the mutations in KIF5C, KIF2A and DYNC1H1 affect ATP hydrolysis, productive protein folding and microtubule binding, respectively. In addition, we show that suppression of mouse Tubg1 expression in vivo interferes with proper neuronal migration, whereas expression of altered γ-tubulin proteins in Saccharomyces cerevisiae disrupts normal microtubule behavior. Our data reinforce the importance of centrosomal and microtubule-related proteins in cortical development and strongly suggest that microtubule-dependent mitotic and postmitotic processes are major contributors to the pathogenesis of MCD

Cross-validation of ELISA and a portable surface plasmon resonance instrument for IgG antibody serology with SARS-CoV-2 positive individuals.

We report on the development of surface plasmon resonance (SPR) sensors and matching ELISAs for the detection of nucleocapsid and spike antibodies specific to the novel coronavirus 2019 (SARS-CoV-2) in human serum, plasma and dried blood spots (DBS)

A polygenic risk score for alcohol-associated cirrhosis among heavy drinkers with European ancestry

BACKGROUND: Polygenic Risk Scores (PRS) based on results from genome-wide association studies offer the prospect of risk stratification for many common and complex diseases. We developed a PRS for alcohol-associated cirrhosis by comparing single-nucleotide polymorphisms among patients with alcohol-associated cirrhosis (ALC) versus drinkers who did not have evidence of liver fibrosis/cirrhosis. METHODS: Using a data-driven approach, a PRS for ALC was generated using a meta-genome-wide association study of ALC (N=4305) and an independent cohort of heavy drinkers with ALC and without significant liver disease (N=3037). It was validated in 2 additional independent cohorts from the UK Biobank with diagnosed ALC (N=467) and high-risk drinking controls (N=8981) and participants in the Indiana Biobank Liver cohort with alcohol-associated liver disease (N=121) and controls without liver disease (N=3239). RESULTS: A 20-single-nucleotide polymorphisms PRS for ALC (PRSALC) was generated that stratified risk for ALC comparing the top and bottom deciles of PRS in the 2 validation cohorts (ORs: 2.83 [95% CI: 1.82 -4.39] in UK Biobank; 4.40 [1.56 -12.44] in Indiana Biobank Liver cohort). Furthermore, PRSALC improved the prediction of ALC risk when added to the models of clinically known predictors of ALC risk. It also stratified the risk for metabolic dysfunction -associated steatotic liver disease -cirrhosis (3.94 [2.23 -6.95]) in the Indiana Biobank Liver cohort -based exploratory analysis. CONCLUSIONS: PRSALC incorporates 20 single-nucleotide polymorphisms, predicts increased risk for ALC, and improves risk stratification for ALC compared with the models that only include clinical risk factors. This new score has the potential for early detection of heavy drinking patients who are at high risk for ALC

Evaluation of laboratory tests for cirrhosis and for alcohol use, in the context of alcoholic cirrhosis

International audienceLaboratory tests can play an important role in assessment of alcoholic patients, including for evaluation of liver damage and as markers of alcohol intake. Evidence on test performance should lead to better selection of appropriate tests and improved interpretation of results. We compared laboratory test results from 1578 patients between cases (with alcoholic cirrhosis; 753 men, 243 women) and controls (with equivalent lifetime alcohol intake but no liver disease; 439 men, 143 women). Comparisons were also made between 631 cases who had reportedly been abstinent from alcohol for over 60 days and 364 who had not. ROC curve analysis was used to estimate and compare tests' ability to distinguish patients with and without cirrhosis, and abstinent and drinking cases. The best tests for presence of cirrhosis were INR and bilirubin, with areas under the ROC curve (AUCs) of 0.91~\textpm~0.01 and 0.88~\textpm~0.01, respectively. Confining analysis to patients with no current or previous ascites gave AUCs of 0.88~\textpm~0.01 for INR and 0.85~\textpm~0.01 for bilirubin. GGT and AST showed discrimination between abstinence and recent drinking in patients with cirrhosis, including those without ascites, when appropriate (and for GGT, sex-specific) limits were used. For AST, a cut-off limit of 85~units/L gave 90% specificity and 37% sensitivity. For GGT, cut-off limits of 288~units/L in men and 138~units/L in women gave 90% specificity for both and 40% sensitivity in men, 63% sensitivity in women. INR and bilirubin show the best separation between patients with alcoholic cirrhosis (with or without ascites) and control patients with similar lifetime alcohol exposure. Although AST and GGT are substantially increased by liver disease, they can give useful information on recent alcohol intake in patients with alcoholic cirrhosis when appropriate cut-off limits are used

Genome-wide Association Study and Meta-analysis on Alcohol-Associated Liver Cirrhosis Identifies Genetic Risk Factors

International audienceBackground and aims - Only a minority of heavy drinkers progress to alcohol-associated cirrhosis (ALC). The aim of this study was to identify common genetic variants that underlie risk for ALC. Approach and results - We analyzed data from 1,128 subjects of European ancestry with ALC and 614 heavy-drinking subjects without known liver disease from Australia, the United States, the United Kingdom, and three countries in Europe. A genome-wide association study (GWAS) was performed, adjusting for principal components and clinical covariates (alcohol use, age, sex, body mass index, and diabetes). We validated our GWAS findings using UK Biobank. We then performed a meta-analysis combining data from our study, the UK Biobank, and a previously published GWAS. Our GWAS found genome-wide significant risk association of rs738409 in patatin-like phospholipase domain containing 3 (PNPLA3) (odds ratio [OR] = 2.19 [G allele], P = 4.93 × 10 ) and rs4607179 near HSD17B13 (OR = 0.57 [C allele], P = 1.09 × 10 ) with ALC. Conditional analysis accounting for the PNPLA3 and HSD17B13 loci identified a protective association at rs374702773 in Fas-associated factor family member 2 (FAF2) (OR = 0.61 [del(T) allele], P = 2.56 × 10 ) for ALC. This association was replicated in the UK Biobank using conditional analysis (OR = 0.79, P = 0.001). Meta-analysis (without conditioning) confirmed genome-wide significance for the identified FAF2 locus as well as PNPLA3 and HSD17B13. Two other previously known loci (SERPINA1 and SUGP1/TM6SF2) were also genome-wide significant in the meta-analysis. GeneOntology pathway analysis identified lipid droplets as the target for several identified genes. In conclusion, our GWAS identified a locus at FAF2 associated with reduced risk of ALC among heavy drinkers. Like the PNPLA3 and HSD17B13 gene products, the FAF2 product has been localized to fat droplets in hepatocytes. Conclusions - Our genetic findings implicate lipid droplets in the biological pathway(s) underlying ALC

Effects of eight neuropsychiatric copy number variants on human brain structure

Many copy number variants (CNVs) confer risk for the same range of neurodevelopmental symptoms and psychiatric conditions including autism and schizophrenia. Yet, to date neuroimaging studies have typically been carried out one mutation at a time, showing that CNVs have large effects on brain anatomy. Here, we aimed to characterize and quantify the distinct brain morphometry effects and latent dimensions across 8 neuropsychiatric CNVs. We analyzed T1-weighted MRI data from clinically and non-clinically ascertained CNV carriers (deletion/duplication) at the 1q21.1 (n = 39/28), 16p11.2 (n = 87/78), 22q11.2 (n = 75/30), and 15q11.2 (n = 72/76) loci as well as 1296 non-carriers (controls). Case-control contrasts of all examined genomic loci demonstrated effects on brain anatomy, with deletions and duplications showing mirror effects at the global and regional levels. Although CNVs mainly showed distinct brain patterns, principal component analysis (PCA) loaded subsets of CNVs on two latent brain dimensions, which explained 32 and 29% of the variance of the 8 Cohen’s d maps. The cingulate gyrus, insula, supplementary motor cortex, and cerebellum were identified by PCA and multi-view pattern learning as top regions contributing to latent dimension shared across subsets of CNVs. The large proportion of distinct CNV effects on brain morphology may explain the small neuroimaging effect sizes reported in polygenic psychiatric conditions. Nevertheless, latent gene brain morphology dimensions will help subgroup the rapidly expanding landscape of neuropsychiatric variants and dissect the heterogeneity of idiopathic conditions