Earth Virtualization Engines (EVE)

To manage Earth in the Anthropocene, new tools, new institutions, and new forms of international cooperation will be required. Earth Virtualization Engines is proposed as an international federation of centers of excellence to empower all people to respond to the immense and urgent challenges posed by climate change

Atypical late diagnosis of Noonan syndrome revealed by bleedings due to platelet dysfunction.

International audienc

Five new F10 variants in hereditary factor x deficiency detected by high-throughput sequencing

International audienceFactor X deficiency is a rare inherited bleeding disorder. To date, 181 variants are reported in the recently updated F10-gene variant database.This study aimed to describe new F10 variants.The gene was analysed 16 consecutive families with FX by targeted high-throughput sequencing approach, including F10, F9, F8 genes, and 78 genes dedicated haematological malignancies.We identified 19 (17 missense, one nonsense frameshift) two copy number variations. Two patients presenting combined FVII-FX showed loss of (del13q34) associated missense on remaining allele, leading FX:C significantly lower than FVII:C level explaining their unusual history. We five novel variants. Three (p.Glu22Val affecting signal peptide cleavage site, p.Cys342Tyr removing disulphide bond between heavy light chains, p.Val385Met located peptidase S1 domain) were detected at compound heterozygosis status three severe symptoms below 10 IU/dL. truncating p.Tyr279* p.Thr434Aspfs*13 an altered protein found heterozygous state mild history.This feasibility interest approach for disorders, enabling report screening 3-weeks delay, suitable clinical use. The description may contribute better understanding phenotype-genotype correlation deficiency

Long-Term Antithrombotic Treatments Prescribed for Cardiovascular Diseases in Patients with Hemophilia: Results from the French Registry

International audienceCardiovascular diseases (CVDs) are a major issue in aging patients with hemophilia (PWHs). Antithrombotic agents are widely used in the general population for CVD treatment, but this recommendation is not fully applicable to PWHs. To improve treatment strategies, a prospective case-control study (COCHE) that analyzed CVD management and follow-up (2 years/patient) in PWHs was performed in France from 2011 to 2018. In total, 68 PWHs (median age: 65 years [39-89]; 48 mild, 10 moderate, and 10 severe hemophilia) were included ( n =50 with acute coronary syndrome, n =17 with atrial fibrillation, n =1 with both). They were matched with 68 control PWHs without antithrombotic treatment. In our series, bleeding was significantly influenced by (1) hemophilia severity, with a mean annualized bleeding ratio significantly higher in COCHE patients than in controls with basal clotting factor level up to 20%, (2) antihemorrhagic regimen (on-demand vs. prophylaxis) in severe (hazard ratio [HR]=16.69 [95% confidence interval, CI: 8.2-47.26]; p3 (odds ratio [OR]=33 [95% CI: 1.43-761.2]; p =0 . 0065). Gastrointestinal bleeding was also significantly higher in COCHE patients than in controls (OR=15 [95% CI: 1.84-268]; p =0 . 0141). The COCHE study confirmed that antithrombotic treatments in PWHs are associated with increased bleeding rates in function of hemophilia-specific factors and also of known factors in the general population

Reinvestigation of unidentified causative variants in FXI-deficient patients: Focus on gene segment deletions

International audienceIntroduction: Data on failure to identify the molecular mechanism underlying FXI deficiency by Sanger analysis and the contribution of gene segment deletions are almost inexistent. Aims and methods: Prospective and retrospective analysis was conducted on FXI-deficient patients’ DNA via Next Generation Sequencing (NGS), or Sanger sequencing and Multiplex Probe Ligation-dependent Assay (MLPA) to detect cryptic causative gene variants or gene segment deletions. Results: Sanger analysis or NGS enabled us to identify six severe and one partial (median activity 41 IU/dl) FXI deficient index cases with deletions encompassing exons 11–15, the whole gene, or both. After Sanger sequencing, retrospective evaluation using MLPA detected seven additional deletion cases in apparently homozygous cases in non-consanguineous families, or in previously unsolved FXI-deficiency cases. Among the 504 index cases with a complete genetic investigation (Sanger/MLPA, or NGS), 23 remained unsolved (no abnormality found [n = 14] or rare intronic variants currently under investigation, [n = 9]). In the 481 solved cases (95% efficiency), we identified F11 gene-deleted patients (14 cases; 2.9%). Among these, whole gene deletion accounted for four heterozygous cases, exons 11–15 deletion for five heterozygous and three homozygous ones, while compound heterozygous deletion and isolated exon 12 deletion accounted for one case each. Conclusion: Given the high incidence of deletions in our population (2.9%), MLPA (or NGS with a reliable bioinformatic pipeline) should be systematically performed for unsolved FXI deficiencies or apparently homozygous cases in non-consanguineous families

FranceCoag: a 22-year prospective follow-up of the national French cohort of patients with inherited bleeding disorders.

FranceCoag is an ongoing open prospective multicentre cohort project aimed at improving epidemiological knowledge about inherited bleeding disorders in France. The main objective of this article was to evaluate the project's progress as of the 30th December 2016. Between 1994 and this date, of the 10,047 patients included in the study, 384 (3.8%) were reported by clinicians to have died and 159 (1.6%) to be lost to follow-up. Among the remaining 9504 patients still being followed up, 5748 (60.5%) had haemophilia A, 1300 (13.7%) haemophilia B, 1980 (20.8%) von Willebrand Disease while 476 (5.0%) had another clotting factor deficiency (Factor I, II, V, combined V and VIII, VII, X, XI and XIII). The median age of the population was 32 years (Inter-quartile range (IQR) 18-50 years) at data extraction on December 30th, 2016. The subgroup of children (i.e., < 18 years old) with severe haemophilia and comprehensive information available since the first exposure to treatment was identified as the PUPs (Previously Untreated Patients) cohort. Data for the 643 children included in the PUPs' cohort had been collected since their birth. Follow-up data were collected by the clinicians in haemophilia treatment centres (HTC) every 12.9 months on median (IQR 11.4-21.3). In the PUPS cohort, data were updated every 6.2 months on median (IQR 3.7-11.7). A unique patient number assigned at study inclusion was kept at individual HTC by participating clinicians. The data collected included demographic, clinical, therapeutic and biological items on standard electronic forms. As of December 30th 2016, a plasma and serum samples was available for 2581 patients (27.1%)

Determinants of adherence and consequences of the transition from adolescence to adulthood among young people with severe haemophilia (TRANSHEMO): A multicentric French national observational cross‐sectional study based on the FranceCoag registry

International audienceAbstract Introduction It is necessary to gain insights into adherence to healthcare in people with severe haemophilia (PwSH), especially during the transition from paediatric to adult care, which is an important phase in lives of young people with childhood chronic disease. This adherence can be considered as a marker of successful transition. Objectives The main objective of the quantitative phase of the TRANSHEMO project was to compare the adherence to healthcare between adolescents and young adults (YAs) with severe haemophilia. The secondary objective was to identify the determinants (facilitators and barriers) of this adherence and associations between these determinants. Methods A multicentre, observational, cross‐sectional study was conducted in 2017–2019 on PwSH aged between 14 and 17 years (adolescents) or between 20 and 29 years (YAs), included in the FranceCoag registry and having completed the questionnaires. The adherence to healthcare (treatment regimens and clinical follow‐up) was compared between adolescents and YAs using the chi‐squared test. The determinants of this adherence were analysed by structural equation modelling. Results There were 277 participants, 107 adolescents, and 170 YAs. The rate of adolescents adhering to healthcare was 82.2%, while the rate of YAs was 61.2% ( p < .001). The barriers to the adherence to healthcare were being YA, having repeated at least one school grade and presenting mental health concerns. Conclusion Adolescents had better adherence to healthcare than YAs. According to the determinants enlightened in this project, targeted supportive strategies and adapted therapeutic education programs can be developed for young PwSH to facilitate their adherence to healthcare

Global Seroprevalence of Pre-existing Immunity Against AAV5 and Other AAV Serotypes in People with Hemophilia A.

Adeno-associated virus (AAV)-mediated gene therapy may provide durable protection from bleeding events and reduce treatment burden for people with hemophilia A (HA). However, pre-existing immunity against AAV may limit transduction efficiency and hence treatment success. Global data on the prevalence of AAV serotypes are limited. In this global, prospective, noninterventional study, we determined the prevalence of pre-existing immunity against AAV2, AAV5, AAV6, AAV8, and AAVrh10 among people ≥12 years of age with HA and residual FVIII levels ≤2 IU/dL. Antibodies against each serotype were detected using validated, electrochemiluminescent-based enzyme-linked immunosorbent assays. To evaluate changes in antibody titers over time, 20% of participants were retested at 3 and 6 months. In total, 546 participants with HA were enrolled at 19 sites in 9 countries. Mean (standard deviation) age at enrollment was 36.0 (14.87) years, including 12.5% younger than 18 years, and 20.0% 50 years of age and older. On day 1, global seroprevalence was 58.5% for AAV2, 34.8% for AAV5, 48.7% for AAV6, 45.6% for AAV8, and 46.0% for AAVrh10. Considerable geographic variability was observed in the prevalence of pre-existing antibodies against each serotype, but AAV5 consistently had the lowest seroprevalence across the countries studied. AAV5 seropositivity rates were 51.8% in South Africa (n = 56), 46.2% in Russia (n = 91), 40% in Italy (n = 20), 37.2% in France (n = 86), 26.8% in the United States (n = 71), 26.9% in Brazil (n = 26), 28.1% in Germany (n = 89), 29.8% in Japan (n = 84), and 5.9% in the United Kingdom (n = 17). For all serotypes, seropositivity tended to increase with age. Serostatus and antibody titer were generally stable over the 6-month sampling period. As clinical trials of AAV-mediated gene therapies progress, data on the natural prevalence of antibodies against various AAV serotypes may become increasingly important