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Background. – Fetal alcohol syndrome (FAS) is a major problem in the Reunion Island and the Public Health Authorities decided to determine its prevalence in their medico-social centers on 31 December 1996.Material and methods. – A questionnaire was etablished to identify affected patients in the 20 medico-social centers in charge of 1320 children. Eighty-eight children were selected and 87 could be analyzed.Results. – Sixty-four of 87 (76.3%) were FAS and 23 of 87 (23.7%) had closely alcohol-related diseases. The prevalence was between 7.1 and 14.1% and lower than expected from available data.Conclusion. – The study allowed to precise the social and familial factors predisposing to alcohol addiction during pregnancy. A TV prevention message will be broadcasted after this study. [ABSTRACT FROM AUTHOR]

Abstract: Nonlinear supersymmetry is used to compute the general form of the effective D-brane action in type I string theory compactified to four dimensions in the presence of internal magnetic fields. In particular, the scalar potential receives three contributions: (1) a nonlinear part of the D-auxiliary component, associated to the Dirac–Born–Infeld action; (2) a Fayet–Iliopoulos (FI) D-term with a moduli-dependent coefficient; (3) a D-auxiliary independent (but moduli dependent) piece from the D-brane tension. Minimization of this potential leads to three general classes of vacua with moduli stabilization: (i) supersymmetric vacua allowing in general FI terms to be cancelled by non-trivial vacuum expectation values (VEV''s) of charged scalar fields; (ii) anti-de Sitter vacua of broken supersymmetry in the presence of a non-critical dilaton potential that can be tuned at arbitrarily weak string coupling; (iii) if the dilaton is fixed in a supersymmetric way by three-form fluxes and in the absence of charged scalar VEV''s, one obtains non-supersymmetric vacua with positive vacuum energy. [Copyright &y& Elsevier]

Congenital pseudarthrosis of the tibia (CPT) is a severe pathology marked by spontaneous bone fractures that fail to heal, leading to fibrous nonunion. Half of patients with CPT are affected by the multisystemic genetic disorder neurofibromatosis type 1 (NF1) caused by mutations in the NF1 tumor suppressor gene, a negative regulator of RAS-mitogen-activated protein kinase (MAPK) signaling pathway. Here, we analyzed patients with CPT and Prss56-Nf1 knockout mice to elucidate the pathogenic mechanisms of CPT-related fibrous nonunion and explored a pharmacological approach to treat CPT. We identified NF1 -deficient Schwann cells and skeletal stem/progenitor cells (SSPCs) in pathological periosteum as affected cell types driving fibrosis. Whereas NF1 -deficient SSPCs adopted a fibrotic fate, NF1 -deficient Schwann cells produced critical paracrine factors including transforming growth factor-β and induced fibrotic differentiation of wild-type SSPCs. To counteract the elevated RAS-MAPK signaling in both NF1 -deficient Schwann cells and SSPCs, we used MAPK kinase (MEK) and Src homology 2 containing protein tyrosine phosphatase 2 (SHP2) inhibitors. Combined MEK-SHP2 inhibition in vivo prevented fibrous nonunion in the Prss56-Nf1 knockout mouse model, providing a promising therapeutic strategy for the treatment of fibrous nonunion in CPT.

Background: Fetal Alcohol Spectrum Disorders are the leading cause of non-genetic intellectual disability. The damage caused, although completely preventable, is irreversible and requires lifelong support. General Practitioners have an important role in the prevention of Fetal Alcohol Spectrum Disorders. However, evidence suggests that General Practitioners do not monitor systematically alcohol consumption among pregnant women., Objectives: The aim of this study was to understand the barriers and motivations of General Practitioners in the prevention of Fetal Alcohol Spectrum Disorders on Reunion Island., Methods: A qualitative research study was conducted by conducting semi-structured individual interviews with general practitioners. Participants were selected by random or snowball sampling. General practitioners who worked only in unscheduled care services were excluded from this study. After the interviews were transcribed, a verbatim analysis was performed according to the principles of grounded theory., Results: Twenty interviews were conducted by two researchers between November and December 2020. General practitioners expressed discomfort in addressing alcohol consumption and excessive drinking in women. They had inaccurate theoretical knowledge and a lack of practical experience with Fetal Alcohol Spectrum Disorders. They also showed little knowledge of the Fetal Alcohol Spectrum Disorders care pathway available on Reunion Island. Both patients and general practitioners expressed discomfort when discussing women's alcohol consumption. Conflicting government policies were highlighted as alcohol promotion campaigns overshadowed Fetal Alcohol Spectrum Disorders prevention initiatives., Conclusion: General practitioners should be open and non-judgmental in their interactions with women and couples, with a focus on early detection and short-term intervention. General practitioners should be better educated about Fetal Alcohol Spectrum Disorders and have a clearer understanding of the Fetal Alcohol Spectrum Disorders care pathway., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Leruste, Baelen, Doray, Maillard, Marimoutou and Spodenkiewicz.)

Background: Foetal alcohol spectrum disorder (FASD) is the leading preventable cause of nongenetic mental disability. Given the patient care pathway, the General Practitioner (GP) is in the front line of prevention and identification of FASD. Acknowledging the importance of the prevalence of FASD, general practitioners are in the front line both for the detection and diagnosis of FASD and for the message of prevention to women of childbearing age as well as for the follow-up., Objectives: The main objective of the scoping review was to propose a reference for interventions that can be implemented by a GP with women of childbearing age, their partners and patients with FASD. The final aim of this review is to contribute to the improvement of knowledge and quality of care of patients with FASD., Methods: A scoping review was performed using databases of peer-reviewed articles following PRISMA guidelines. The search strategy was based on the selection and consultation of articles on five digital resources. The advanced search of these publications was established using the keywords for different variations of FASD: "fetal alcohol syndrome," "fetal alcohol spectrum disorder," "general medicine," "primary care," "primary care"; searched in French and English., Results: Twenty-three articles meeting the search criteria were selected. The interventions of GPs in the management of patients with FASD are multiple: prevention, identification, diagnosis, follow-up, education, and the role of coordinator for patients, their families, and pregnant women and their partners. FASD seems still underdiagnosed., Conclusion: The interventions of GPs in the management of patients with FASD are comprehensive: prevention, identification, diagnosis, follow-up, education, and the role of coordinator for patients, their families, and pregnant women and their partners. Prevention interventions would decrease the incidence of FASD, thereby reducing the incidence of mental retardation, developmental delays, and social, educational and legal issues. A further study with a cluster randomized trial with a group of primary care practitioners trained in screening for alcohol use during pregnancy would be useful to measure the impact of training on the alcohol use of women of childbearing age and on the clinical status of their children., (© 2024. The Author(s).)

Introduction: Fetal alcohol exposure is the most common preventable cause of non-genetic intellectual disability. Fetal Alcohol Syndrome (FAS) is characterized by intellectual disability and distinctive facial features and affects 0.1% of live births, representing approximately 800 cases per year in France. Fetal Alcohol Spectrum Disorder (FASD) are 10 times more common than FAS, with an estimated 8,000 cases per year, and are associated with behavioral and social maladjustment in both children and adults, as well as various malformations. General practitioners play a key role in preventing and identifying FASD through their involvement in pregnancy and child monitoring., Methods: Qualitative study using the Delphi method. Items were developed from the literature and semi-structured interviews with field professionals and health institutions. A panel of multi-professional experts, mostly general practitioners, was recruited., Results: 24 initial actions were submitted to the experts. At the end of the first round, six actions reached a consensus and six were reformulated for the second round. At the end of the second round, three actions reached a consensus, for a total of 11 consensus actions. Four of these actions seem particularly relevant for rapid implementation, namely systematic proposal of pre-conceptional consultations for women planning pregnancy, systematic identification of environmental factors during child monitoring, systematic distribution of information on fetal alcohol exposure during pre-conception or early pregnancy, and the publication of a leaflet for general practitioners on the identification of children with FAS or FASD and the contact details of relevant associations., Conclusion: Prevention and identification of FASD can be improved through short and general training supports for general practitioners. Early screening of FASD is crucial for children, and should be maintained throughout their monitoring. This study could be used for communication and dissemination of information based on the consensus obtained., Competing Interests: SL is a doctoral thesis student funded by the Doctoral School of the University of Réunion. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Leruste, Pouilley-Bax, Doray, Maillard, Monin, Loubaresse, Marimoutou and Spodenkiewicz.)

Neurofibromatosis type-1 is a genetic disorder caused by loss-of-function variants in the tumor-suppressor NF1. Approximately 4% to 11% of neurofibromatosis type-1 patients have a NF1 locus complete deletion resulting from nonallelic homologous recombination between low copy repeats. Codeleted genes probably account for the more severe phenotype observed in NF1-deleted patients. This genotype-phenotype correlation highlights the need for a detailed molecular description. A droplet digital PCR (ddPCR) set along the NF1 locus was designed to delimitate the three recurrent NF1 deletion breakpoints. The ddPCR was tested in 121 samples from nonrelated NF1-deleted patients. Classification based on ddPCR versus multiplex ligation-dependent probe amplification (MLPA) was compared. In addition, microsatellites were analyzed to identify parental origin of deletions. ddPCR identified 77 type-1 (64%), 20 type-2 (16%), 7 type-3 (6%), and 17 atypical deletions (14%). The results were comparable with MLPA, except for three atypical deletions misclassified as type-2 using MLPA, for which the SUZ12 gene was not deleted. A significant maternal bias (25 of 30) in the origin of deletions was identified. This study proposes a fast and efficient ddPCR quantification to allow fine NF1 deletion classification. It indicates that ddPCR can be implemented easily into routine diagnosis to complement the techniques dedicated to NF1 point variant identification. This new tool may help unravel the genetic basis conditioning phenotypic variability in NF1-deleted patients and offer tailored genetic counseling., Competing Interests: Disclosure Statement None declared., (Copyright © 2024 Association for Molecular Pathology and American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Background: Fetal Alcohol Spectrum Disorder (FASD) is the leading cause of non-genetic intellectual disability and social maladjustment in children. International guidelines recommend abstinence from alcohol during pregnancy. Réunion is the most affected of all French regions with an estimated Fetal Alcohol Spectrum (FAS) prevalence of 1.2‰ births. General practitioners (GPs) are at the forefront of identifying patients with FASD., Objective: To understand how GPs identify FASD., Methods: Qualitative study using a grounded theory approach, through semi-structured face-to-face interviews with GPs. Interviews were conducted with the aim of reaching theoretical saturation. These were transcribed verbatim and then analyzed by four researchers to ensure triangulation of the data., Results: GPs reported barriers to the identification of FASD: challenges in overcoming social taboos and paradoxical injunctions, the influence of limited knowledge and experience, non-specific and highly variable symptoms, ambiguous classification and method of diagnosis involving the mobilization of a multidisciplinary team and lengthy consultations. Conversely, they felt competent to identify neurodevelopmental disorders of any cause, but were concerned about the long waiting time to access specialized care. From the perspective of GPs, it is crucial to prioritize promotion and training aimed at improving the identification and coordination of care pathways for children diagnosed with neurodevelopmental disorders, such as FASD., (© 2023. The Author(s).)

The center of mass dynamics of the seated posture of humans in a work environment under hypogravity (0 < g < 1) have rarely been investigated, and such research is yet to be carried out. The present study determined the difference in the body system of 32 participants working under simulated 1/6 g (Moon) and 1 g (Earth) for comparison using static and dynamic task measurements. This was based on a markerless motion capture method that analyzed participants' center of mass at the start, middle and end of the task when they began to get fatigued. According to this analysis, there is a positive relationship ( p < 0.01) with a positive coefficient of correlation between the downward center of mass body shift along the proximodistal axis and gravity level for males and females. At the same time, the same positive relationship ( p < 0.01) between the tilt of the body backward along the anterior-posterior axis and the level of gravity was found only in females. This offers fresh perspectives for comprehending hypogravity in a broader framework regarding its impact on musculoskeletal disorders. It can also improve workplace ergonomics, body stability, equipment design, and biomechanics.

Experiments on the lower limbs are the only approaches being used to study how hypogravity (HG) (0 < g < 1, e.g., Moon: 1/6 g, Mars: 3/8 g) affects human movement. The goal of this study was to expand this field experimentally by investigating the effect of HG on the upper extremities during one-handed manual handling tasks in a sitting posture: static weight holding with an outstretched arm, and slow repetitive weight lifting and lowering motions. The hypothesis was that while completing static and dynamic tasks with elements of repetition in HG, the upper body's tilt (angle regarding the vertical axis) would change differently from Earth's gravity. Specifically, upper arm and spine angles, joint torques, and forces were investigated. Twenty-four healthy participants aged 33.6 ± 8.2 years were involved in the trial. Joint angles were examined using vision-based 3D motion analysis. According to this investigation, there is a correlation between a body tilting backward and a gravity level reduction ( p < 0.01). Thus, HG causes postural deviation, and this shows that workplace design must be adapted according to the level of gravity to promote comfortable and balanced body alignment, minimizing stress on muscles and joints. To lower the risk of musculoskeletal disorders (MSDs), enhance overall performance, and increase job satisfaction, proper support systems and restrictions for sitting positions should be taken into account, concerning different levels of gravity., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Maillard.)

Neurofibromatosis type 1 (NF1) is an autosomal dominant disease with complete penetrance but highly variable expressivity. In most patients, Next Generation Sequencing (NGS) technologies allow the identification of a loss-of-function pathogenic variant in the NF1 gene, a negative regulator of the RAS-MAPK pathway. We describe the 5-year diagnosis wandering of a patient with a clear NF1 clinical diagnosis, but no molecular diagnosis using standard molecular technologies. The patient presented with a typical NF1 phenotype but NF1 targeted NGS, NF1 transcript analysis, MLPA, and array comparative genomic hybridization failed to reveal a genetic aberration. After 5 years of unsuccessful investigations, trio WGS finally identified a de novo mosaic (VAF ~ 14%) 24.6 kb germline deletion encompassing the promoter and first exon of NF1. This case report illustrates the relevance of WGS to detect structural variants including copy number variants that would be missed by alternative approaches. The identification of the causal pathogenic variant allowed a tailored genetic counseling with a targeted non-invasive prenatal diagnosis by detecting the deletion in plasmatic cell-free DNA from the proband's pregnant partner. This report clearly highlights the need to make WGS a clinically accessible test, offering a tremendous opportunity to identify a molecular diagnosis for otherwise unsolved cases., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Complete deletion of the NF1 gene is identified in 5-10% of patients with neurofibromatosis type 1 (NF1). Several studies have previously described particularly severe forms of the disease in NF1 patients with deletion of the NF1 locus, but comprehensive descriptions of large cohorts are still missing to fully characterize this contiguous gene syndrome. NF1 -deleted patients were enrolled and phenotypically characterized with a standardized questionnaire between 2005 and 2020 from a large French NF1 cohort. Statistical analyses for main NF1-associated symptoms were performed versus an NF1 reference population. A deletion of the NF1 gene was detected in 4% (139/3479) of molecularly confirmed NF1 index cases. The median age of the group at clinical investigations was 21 years old. A comprehensive clinical assessment showed that 93% (116/126) of NF1 -deleted patients fulfilled the NIH criteria for NF1. More than half had café-au-lait spots, skinfold freckling, Lisch nodules, neurofibromas, neurological abnormalities, and cognitive impairment or learning disabilities. Comparison with previously described "classic" NF1 cohorts showed a significantly higher proportion of symptomatic spinal neurofibromas, dysmorphism, learning disabilities, malignancies, and skeletal and cardiovascular abnormalities in the NF1 -deleted group. We described the largest NF1 -deleted cohort to date and clarified the more severe phenotype observed in these patients.

Dried blood spots (DBS) are widely proposed as a plasma surrogate for monitoring antiretroviral treatment efficacy based on the HIV-1 RNA level (viral load [VL]) in resource-limited settings. Interfering coamplification of cell-associated HIV-1 DNA during reverse transcription (RT)-PCR can be avoided by using nucleic acid sequence-based amplification (NASBA) technology, which is based on an RNA template and isothermic conditions. We analyzed VL values obtained with DBS and plasma samples by comparing isothermic NASBA (NucliSENS EasyQ HIV-1 V2.0; bioMérieux) with real-time RT-PCR (Cobas TaqMan HIV-1 V2.0; Roche). Samples from 197 HIV-1-infected patients were tested (non-B subtypes in 51% of the cases). Nucleic acid extractions were performed by use of NucliSENS EasyMAG (bioMérieux) and Cobas AmpliPrep (Roche) before the NASBA and RT-PCR quantifications, respectively. Both quantification assays have lower limits of detection of 20 (1.3) and 800 (2.9) log10 copies/ml (log) in plasma and DBS, respectively. The mean (DBS minus plasma) differences were -0.39 and -0.46 log, respectively, for RT-PCR and NASBA. RT-PCR on DBS identified virological failure in 122 of 126 patients (sensitivity, 97%) and viral suppression in 58 of 70 patients (specificity, 83%), yielding 12 false-positive results (median, 3.2 log). NASBA on DBS identified virological failure in 85 of 96 patients (sensitivity, 89%) and viral suppression in 95 of 97 patients (specificity, 98%) and yielded 2 false-positive results (3.0 log for both). Both technologies detected HIV-1 RNA in DBS at a threshold of 800 copies/ml. This higher specificity of NASBA technology could avoid overestimation of poor compliance or the emergence of resistance when monitoring antiretroviral efficacy with the DBS method.

Whole-exome or gene targeted resequencing in hundreds to thousands of individuals has shown that the majority of genetic variants are at low frequency in human populations. Rare variants are enriched for functional mutations and are expected to explain an important fraction of the genetic etiology of human disease, therefore having a potential medical interest. In this work, we analyze the whole-exome sequences of French-Canadian individuals, a founder population with a unique demographic history that includes an original population bottleneck less than 20 generations ago, followed by a demographic explosion, and the whole exomes of French individuals sampled from France. We show that in less than 20 generations of genetic isolation from the French population, the genetic pool of French-Canadians shows reduced levels of diversity, higher homozygosity, and an excess of rare variants with low variant sharing with Europeans. Furthermore, the French-Canadian population contains a larger proportion of putatively damaging functional variants, which could partially explain the increased incidence of genetic disease in the province. Our results highlight the impact of population demography on genetic fitness and the contribution of rare variants to the human genetic variation landscape, emphasizing the need for deep cataloguing of genetic variants by resequencing worldwide human populations in order to truly assess disease risk., Competing Interests: The authors have declared that no competing interests exist.