Learning stable reduced-order models for hybrid twins

The concept of “hybrid twin” (HT) has recently received a growing interest thanks to the availability of powerful machine learning techniques. This twin concept combines physics-based models within a model order reduction framework—to obtain real-time feedback rates—and data science. Thus, the main idea of the HT is to develop on-the-fly data-driven models to correct possible deviations between measurements and physics-based model predictions. This paper is focused on the computation of stable, fast, and accurate corrections in the HT framework. Furthermore, regarding the delicate and important problem of stability, a new approach is proposed, introducing several subvariants and guaranteeing a low computational cost as well as the achievement of a stable time-integration

Novel ABCC6 Mutations in Pseudoxanthoma Elasticum

Pseudoxanthoma elasticum (PXE) is a heritable connective tissue disorder caused by mutations in an ABC (ATP-Binding Cassette) transporter gene (ABCC6), which manifests with cutaneous, ophthalmologic, and cardiovascular findings. We studied a cohort of 19 families with PXE, and identified 16 different mutations, nine of which were novel variants. The mutation detection rate was about 77%. We found that arginine codon 518 was, with the previously described R1141X and EX23_29del, a recurrently mutated amino acid (11.5% of the mutations detected for each variant R518Q and R518X). No clear delineation of genotype/phenotype correlation was identified, and marked intra-familial variability of the disease was seen in one family. One family with pseudodominant inheritance displayed three distinct ABCC6 mutations, providing further evidence for the probable exclusive recessive transmission of PXE. These data contribute to the expanding database of ABCC6 mutations, to the description of phenotypic variability, and inheritance in PXE, and should be helpful for genetic counselling

Learning stable reduced-order models for hybrid twins

The concept of Hybrid Twin (HT) has recently received a growing interest thanks to the availability of powerful machine learning techniques. This twin concept combines physics-based models within a model-order reduction framework-to obtain real-time feedback rates-and data science. Thus, the main idea of the HT is to develop on-the-fly data-driven models to correct possible deviations between measurements and physics-based model predictions. This paper is focused on the computation of stable, fast and accurate corrections in the Hybrid Twin framework. Furthermore, regarding the delicate and important problem of stability, a new approach is proposed, introducing several sub-variants and guaranteeing a low computational cost as well as the achievement of a stable time-integration

Review of the current status of RAS mutation testing in patients with metastatic colorectal cancer (mCRC): Flash-RAS study

Présentation PosterInternational audienceOBJECTIVES: In 2013, it was shown that mutations in KRAS exons 3 and 4, or NRAS exons 2 to 4 had a similar effect. The primary objective was to assess the practices in conducting RAS testing in 2014. The secondary objectives were to describe the evolution of the RAS testing prescription rates from 2011, the process and time required to obtain the results, and to analyze their impact on the therapeutic strategy. METHODS: FLASH-RAS is an observational retrospective French multicenter study. RESULTS: 375 mCRC patients diagnosed and initiating a 1st line treatment (L1) between March and June 2014 were analyzed. For 90.1% of the patients (IC95%= [87.1%; 93.2%]), a genotyping request for RAS biomarkers was made in L1, i.e. a significantly increased rate compared to 2011 (81.1% in 2011, p<0.001). For 75% of the patients, the request was made before or at least one month after the diagnosis of the first metastases (1st M). No increase was observed in the median and mean times to obtain the test results between 2011 and 2014 despite the increased number of exons tested. CONCLUSIONS: In 2014, the rate of RAS genotyping requests has been increasing since 2011. For a majority of patients, the request is made before or at the latest one month after 1st M diagnosis. Nevertheless, for 24.5% of the patients, the request is made more than one month after 1st M diagnosis, which is not compatible with an informed treatment decision in L1

WOod OPtical Scope (WOOPS) : Détermination des propriétés du bois par interaction lumineuse interprétation, mesure et identification des mécanismes et des paramètres d'influence

Le bois sera l'un des matériaux de construction de base du 21ème siècle. Ses propriétés de légèreté, de rigidité, d'isolation et sa capacité à capturer le carbone font de lui un matériau incontournable dans le contexte actuel, où les préoccupations écologiques sont omniprésentes. Une de ses particularités réside dans sa structure multi-échelle complexe et hétérogène qui résulte de la croissance adaptative et singulière d’un arbre dans son environnement (Figure 1). Comme toute ressource issue du vivant, sa variabilité naturelle est très forte et représente un enjeu essentiel dans sa valorisation comme matériau de construction, d’emballage ou d’aménagement intérieur ou extérieur. Les pays nordiques, aidés par l'homogénéité de leur ressource forestière, ont su industrialiser sa transformation et inonder le marché français si bien que près d’une planche sur deux mise en œuvre sur notre territoire est importée. Le principal frein à l’utilisation de bois local dans la construction réside dans la difficulté à prédire ses propriétés mécaniques du fait de son hétérogénéité intrinsèque plus forte que celle des bois du nord. En particulier, la construction à partir de bois feuillus, qui représentent les 2/3 de notre ressource, est aujourd'hui freinée par la complexité à modéliser leur comportement mécanique. Le premier paramètre d'hétérogénéité du bois réside dans l'orientation de ses fibres, qui gouverne ses propriétés mécaniques et physiques. La connaissance de cette orientation pour un placage ou un sciage peut améliorer son usage. Aujourd'hui, cette mesure peut être réalisée par des techniques laser et l'effet trachéide : lorsqu'un point laser rouge est appliqué sur une surface de bois, la lumière se distord et une ellipse est observée chez les résineux dont le grand axe suit les fibres. Ce phénomène, peu coûteux à instrumenter, peut être utilisé pour développer des modèles de comportement mécanique et de séchage. La plupart des auteurs se contente de l'utiliser et personne n'a véritablement publié sur le potentiel réel de l'exploitation de cet effet qui est considérable pour valoriser les bois locaux riches en nœuds

Risk of Parkinson disease in carriers of parkin mutations : estimation using the kin-cohort method

Objective: To estimate the risk of Parkinson disease (PD) in individuals with mutations in the Parkin gene. Design: We assessed point mutations and exon deletions and duplications in the Parkin gene in 247 probands with PD (age at onset 50 years) and 104 control probands enrolled in the Genetic Epidemiology of Parkinson's Disease (GEPD) study. For each first-degree relative, a consensus diagnosis of PD was established. The probability that each relative carried a mutation was estimated from the proband's Parkin carrier status using Mendelian principles and from the relationship of the relative to the proband. Setting: Tertiary care movement disorders center. Patients: Cases, controls, and their first-degree relatives were enrolled in the GEPD study. Main Outcome Measures: Estimated age-specific penetrance in first-degree relatives. Results: Parkin mutations were identified in 25 probands with PD (10.1%), 18 (72.0%) of whom were heterozygotes. One Parkin homozygote was reported in 2 siblings with PD. The cumulative incidence of PD to age 65 years in carrier relatives (age-specific penetrance) was estimated to be 7.0% (95% confidence interval, 0.4%-71.9%), compared with 1.7% (95% confidence interval, 0.8%-3.4%) in noncarrier relatives of the cases (P = .59) and 1.1% (95% confidence interval, 0.3%-3.4%) in relatives of the controls (compared with noncarrier relatives, P = .52). Conclusions: The cumulative risk of PD to age 65 years in a noncarrier relative of a case with an age at onset of 50 years or younger is not significantly greater than the general population risk among controls. Age-specific penetrance among Parkin carriers, in particular heterozygotes, deserves further study. Mutations in the Parkin gene (PARK2; GenBank AB009973) are associated primarily with early-onset Parkinson disease (PD), defined as age at onset (AAO) ranging from 45 years or younger to 55 years or younger, but have also been described in PD cases with an AAO older than 70 years. In PD cases with an AAO of 45 years or younger with a mode of inheritance consistent with autosomal recessive transmission, the frequency of Parkin mutations may be as high as 49%, whereas in cases without a family history of PD the range is 15% to 18%. Age at onset is inversely correlated with the frequency of Parkin mutations in both familial and sporadic cases. Several studies have compared the AAO of PD in heterozygous, compound heterozygous, and homozygous Parkin mutation carriers and found that heterozygous cases, both familial and sporadic, have an older AAO. Heterozygous Parkin mutation carriers are more frequently reported among sporadic than familial cases. Information on the risk of PD in individuals who carry Parkin mutations in either the homozygous, compound heterozygous, or heterozygous state (or penetrance) is essential for genetic counseling. The penetrance of Parkin mutations has only been reported for isolated families. Most of the previous study designs sampled PD cases based on family history of PD, which would bias penetrance estimates upwards. To obtain an unbiased estimate of risk, a population-based random sample would be desirable, but Parkin mutations are so rare in the population that such a sample would have to be extremely large to obtain sufficient precision in penetrance estimates. To obtain unbiased estimates of the risk of PD in Parkin carriers despite the low population frequency of Parkin mutations, we used a kin-cohort study design applied to participants in the Genetic Epidemiology of Parkinson's Disease (GEPD) study. The kin-cohort design is highly efficient for estimating penetrance because the relatives' mutation status is not required for the analyses, thus reducing costs for genetic analysis

Case-control study of the parkin gene in early-onset Parkinson disease

Background: Mutations in parkin are estimated to account for as much as 50% of familial Parkinson disease (PD) and 18% of sporadic PD. Single heterozygous mutations in parkin in both familial and sporadic cases may also increase susceptibility to PD. To our knowledge, all previous studies have been restricted to PD cases; this is the first study to systematically screen the parkin coding regions and exon deletions and duplications in controls. Objective: To determine the frequency and spectrum of parkin variants in early-onset PD cases (aged 50 years) and controls participating in a familial aggregation study. Patients and Methods: We sequenced the parkin gene in 101 cases and 105 controls. All cases and controls were also screened for exon deletions and duplications by semiquantitative multiplex polymerase chain reaction. Results: Thirteen (12.9% [95% confidence interval, 7%-21%]) of the 101 cases had a previously described parkin mutation: 1 was homozygous, 11 were heterozygous, and 1 was a compound heterozygote. The mutations Arg42Pro (exon 2) and Arg275Trp (exon 7) were recurrent. The previously reported synonymous substitution Leu261Leu (c.884A>G) was identified in 4 (3.9%) of 101 cases and 2 (2%) of 105 controls (P = .44). Excluding the synonymous substitution Leu261Leu (heterozygotes), 10 (9.9% [95% confidence interval, 4.6%-17.5%]) carried mutations. Conclusions: The frequency of mutations among cases that were not selected based on family history of PD is similar to what has previously been reported in sporadic PD. The similar frequency of Leu261Leu in cases and controls suggests it is a normal variant rather than a disease-associated mutation. We confirmed that heterozygous parkin mutations may increase susceptibility for early-onset PD

Respiratory Syncytial Virus-related Death in Children with down Syndrome: The RSV GOLD Study

Background: Respiratory syncytial virus (RSV) is a major cause of mortality in children younger than 5 years worldwide. Systematic reviews have shown that Down syndrome (DS) is an independent risk factor for severe RSV infection. We aimed to describe demographic and clinical characteristics of children with DS who died with RSV infection. Methods: We performed a retrospective case series in which data were shared by individual researchers, research networks and physicians worldwide as part of the RSV Global Online Database study. We included children with DS who died when younger than 5 years of age with laboratory-confirmed RSV infection. Results: We included 53 children with DS and RSV-related mortality from 20 countries in 5 continents. Five (9.4%) children were from low-income or lower-middle-income countries. Median age at time of death was 6.0 months [interquartile range (IQR): 3.00-12.0]. Thirteen (24.5%) children were born term and had no other risk factors for severe RSV disease. In total, 36 (67.9%) children had congenital heart disease, 8 (15.1%) had chronic lung disease and 1 (1.9%) had congenital immunodeficiency. Duration of hospitalization was significantly longer for children with DS compared with children without DS [median length of stay, 13 days (IQR: 6.8-21.0) vs. 8 days (IQR: 3.0-18.5), P=0.005]. Conclusions: One-fourth of children with DS and RSV-confirmed death did not have risk factors for severe RSV disease, indicating that DS is an important risk factor for RSV-related mortality. Age distribution at time of death demonstrates that maternal vaccination would not be sufficient to protect children with DS against RSV-related mortality

Appréhender le stock de métal monnayé au ive siècle après J.-C.

Parmi les thématiques abordées en numismatique à l’aide de l’archéométrie, les recherches spécifiques sur le stock de métal monnayé au ive siècle s’avèrent fascinantes mais délicates. Afflux de nouvelles ressources métalliques, refontes volontaires de monnaies : tous ces phénomènes sont de grande conséquence pour les monnayages produits dans les différents ateliers de l’Empire romain tardif. Certaines données de ce type sont mesurables. Les alliages métalliques (donc ici monétaires) contiennent en effet des éléments mineurs ou en traces, constituant la « carte d’identité » de l’approvisionnement des ateliers monétaires. Il y a 10 ans Isabelle Bollard et Jean-Noël Barrandon réunissaient plusieurs analyses de monnaies en alliage cuivreux émises au cours du ive siècle. Nos propres observations, obtenues dans le cadre d’un projet de recherche financé par la région Normandie (intitulé FANUM), sur 14 528 monnaies (nummi) de la période constantinienne contenues dans un trésor découvert fortuitement à Saint-Germain-de-Varreville (Manche), nous ont incités à reprendre, de façon plus approfondie, l’étude des alliages utilisés au cours de cette période, en portant notamment notre attention sur les teneurs en or et en argent. En effet, la grande variété des ateliers représentés au sein du trésor favorisait idéalement une telle enquête. Le choix de la fluorescence X portable a permis d’élaborer un protocole d’analyse précis et adapté à un grand nombre de monnaies. L’exploitation de 774 analyses réalisées sur des nummi frappés dans les ateliers occidentaux a permis de compléter les travaux antérieurs, mais également de mettre en évidence l’utilisation de stocks métalliques différents à partir des années 320.Among the thematics studied in numismatics using archeometry, specific research on the stock of metal struck in the 4th century turns out to be fascinating but complex. Influx of new metallic resources, voluntary recasts of coins: these phenomena have great consequences for the coinage produced in all the workshops throughout the late Roman Empire. Some of these data can be measurable. Metallic alloys (coins in this case) contain minor or trace elements that constitute a kind of “identity card” for the supply of monetary workshops. Ten years ago, Isabelle Bollard and Jean-Noël Barrandon collected several analyzes of bronzes struck during the 4th century. Our own observations, obtained within the FANUM project, funded by the Normandy region, on 14 528 coins (nummi) of the Constantinian period, contained in a fortuitously discovered treasure in Saint-Germain-de-Varreville (Manche) have motivated a thorough new study of the alloys used during this period, focusing on the traces of gold and silver. Indeed, the variety of workshops represented in the treasure has encouraged such an inquiry. The choice of portable X-ray fluorescence has enabled to develop a protocol of analysis adapted to a large number of coins. The use of 774 analyzes carried out on nummi struck in the Western workshops has completed previous works, but also enabled to highlight the use of different metal stocks from the 320s