A Solve-RD ClinVar-based reanalysis of 1522 index cases from ERN-ITHACA reveals common pitfalls and misinterpretations in exome sequencing

Purpose Within the Solve-RD project (https://solve-rd.eu/), the European Reference Network for Intellectual disability, TeleHealth, Autism and Congenital Anomalies aimed to investigate whether a reanalysis of exomes from unsolved cases based on ClinVar annotations could establish additional diagnoses. We present the results of the “ClinVar low-hanging fruit” reanalysis, reasons for the failure of previous analyses, and lessons learned. Methods Data from the first 3576 exomes (1522 probands and 2054 relatives) collected from European Reference Network for Intellectual disability, TeleHealth, Autism and Congenital Anomalies was reanalyzed by the Solve-RD consortium by evaluating for the presence of single-nucleotide variant, and small insertions and deletions already reported as (likely) pathogenic in ClinVar. Variants were filtered according to frequency, genotype, and mode of inheritance and reinterpreted. Results We identified causal variants in 59 cases (3.9%), 50 of them also raised by other approaches and 9 leading to new diagnoses, highlighting interpretation challenges: variants in genes not known to be involved in human disease at the time of the first analysis, misleading genotypes, or variants undetected by local pipelines (variants in off-target regions, low quality filters, low allelic balance, or high frequency). Conclusion The “ClinVar low-hanging fruit” analysis represents an effective, fast, and easy approach to recover causal variants from exome sequencing data, herewith contributing to the reduction of the diagnostic deadlock

Caractérisation des objets dans une image en vue d'une aide à l'interprétation et d'une compression adaptée au contenu (application aux images échographiques)

Cette thèse, réalisée dans le cadre d une convention CIFRE avec la société ECA-Sinters, se situe dans la continuité de projets de robotique télé-opérée pour des applications médicales non-invasives réalisés au laboratoire de Vision et Robotique ; l application médicale télé-opérée concerne ici la télé-échographie. Notre travail a porté plus précisément sur le traitement des images ultrasonores sur lesquelles se base l expert me dical pour le contrôle à distance du robot porteur de la sonde échographique positionné sur le patient. Une étude des méthodes actuelles de segmentation d image ainsi que sur les méthodes permettant d évaluer un résultat de segmentation, nous conforte dans l idée d une non universalité des méthodes de segmentation. La difficulté de partitionner une image ultrasonore en composantes illustre cette affirmation. Nous proposons donc, via l utilisation combinée d approches floue et fractale, une caractérisation des divers objets présents au sein de l image sans réelle segmentation. De plus, le lien démontré entre ces deux approches nous permet de prendre en compte, dans le calcul de la complexité des divers objets, le bruit initialement présent au sein de l image ultrasonore. Ces résultats obtenus d un point de vue théorique sont alors appliqués à différents domaines tels que la segmentation ou la compression d images.ORLEANS-BU Sciences (452342104) / SudocSudocFranceF

Surveiller à distance les effets de la microgravité

National audienceExamen fréquemment pratiqué en milieu hospitalier sur Terre, l'échographie sera primordial lors de prochains vols spatiaux de longue durée pour évaluer les effets de la microgravité. Elle sera aussi indispensable pour diagnostiquer, chez un astronaute, une des nombreuses pathologies " terriennes " qu'il emmènera malheureusement avec lui dans l'espace

Calf venous volume during stand-test after a 90-day bed-rest study with or without exercise countermeasure

The objectives to determine both the contribution to orthostatic intolerance (OI) of calf venous volume during a stand-test, and the effects of a combined eccentric–concentric resistance exercise countermeasure on both vein response to orthostatic test and OI, after 90-day head-down tilt bed-rest (HDT). The subjects consisted of a control group (Co-gr, n = 9) and an exercise countermeasure group (CM-gr, n = 9). Calf volume and vein cross-sectional area (CSA) were assessed by plethysmography and echography during pre- and post-HDT stand-tests. From supine to standing (post-HDT), the tibial and gastronemius vein CSA increased significantly in intolerant subjects (tibial vein, +122% from pre-HDT; gastronemius veins, +145%; P < 0.05) whereas it did not in tolerant subjects. Intolerant subjects tended to have a higher increase in calf filling volume than tolerant subjects, in both sitting and standing positions. The countermeasure did not reduce OI. Absolute calf volume decreased similarly in both groups. Tibial and gastrocnemius vein CSA at rest did not change during HDT in either group. During the post-HDT stand-test, the calf filling volume increased more in the CM-gr than in the Co-gr both in the sitting (+1.3 ± 5.1%, vs.–7.3 ± 4.3%; P < 0.05) and the standing positions (+56.1 ± 23.7%vs.+1.6 ± 9.6%; P < 0.05). The volume ejected by the muscle venous pump increased only in the CM-gr (+38.3 ± 21.8%). This study showed that intolerant subjects had a higher increase in vein CSA in the standing position and a tendency to present a higher calf filling volume in the sitting and standing positions. It also showed that a combined eccentric–concentric resistance exercise countermeasure had no effects on either post-HDT OI or on the venous parameters related to it

Piezoelectric P(VDF-TrFE) film inkjet printed on silicon for high-frequency ultrasound applications

International audienc

High Acoustic Impedance and Attenuation Backing for High-Frequency Focused P(VDF-TrFE)-Based Transducers

Backing materials with tailored acoustic properties are beneficial for miniaturized ultrasonic transducer design. Whereas piezoelectric P(VDF-TrFE) films are common elements in high-frequency (>20 MHz) transducer design, their low coupling coefficient limits their sensitivity. Defining a suitable sensitivity–bandwidth trade-off for miniaturized high-frequency applications requires backings with impedances of >25 MRayl and strongly attenuating to account for miniaturized requirements. The motivation of this work is related to several medical applications such as small animal, skin or eye imaging. Simulations showed that increasing the acoustic impedance of the backing from 4.5 to 25 MRayl increases transducer sensitivity by 5 dB but decreases the bandwidth, which nevertheless remains high enough for the targeted applications. In this paper, porous sintered bronze material with spherically shaped grains, size-adapted for 25–30 MHz frequency, was impregnated with tin or epoxy resin to create multiphasic metallic backings. Microstructural characterizations of these new multiphasic composites showed that impregnation was incomplete and that a third air phase was present. The selected composites, sintered bronze–tin–air and sintered bronze–epoxy–air, at 5–35 MHz characterization, produced attenuation coefficients of 1.2 and >4 dB/mm/MHz and impedances of 32.4 and 26.4 MRayl, respectively. High-impedance composites were adopted as backing (thickness = 2 mm) to fabricate focused single-element P(VDF-TrFE)-based transducers (focal distance = 14 mm). The center frequency was 27 MHz, while the bandwidth at −6 dB was 65% for the sintered-bronze–tin–air-based transducer. We evaluated imaging performance using a pulse-echo system on a tungsten wire (diameter = 25 μm) phantom. Images confirmed the viability of integrating these backings in miniaturized transducers for imaging applications

Mowat Wilson syndrome and Hirschsprung disease: a retrospective study on functional outcomes

International audienceAim of the study: Mowat Wilson syndrome (MWS) is a complex genetic disorder due to mutation or deletion of the ZEB2 gene (ZFHX1B), including multiple clinical features. Hirschsprung disease is associated with this syndrome with a prevalence between 43 and 57%. The aim of this study was to demonstrate the severe outcomes and the high complication rates in children with MWS, focusing on their complicated follow-up.Methods: A retrospective comparative study was conducted on patients referred to Robert-Debré Children's Hospital for MWS from 2003 to 2018. Multidisciplinary follow-up was carried out by surgeons, geneticists, gastroenterologists, and neurologists. Data regarding patient characteristics, surgical management, postoperative complications, and functional outcomes were collected.Results: Over this period of 15 years, 23 patients were diagnosed with MWS. Hirschsprung disease was associated with 10 of them (43%). Of these cases, two patients had recto-sigmoïd aganglionosis (20%), three had aganglionic segment extension to the left colic angle (30%), two to the right colic angle (20%), and three to the whole colon (30%). The median follow-up was 8.5 years (2 months-15 years). All patients had seizures and intellectual disability. Six children (60%) presented with cardiac defects. At the last follow-up, three patients still had a stoma diversion and 7 (70%) were fed orally. One patient died during the first months. Eight (80%) of these children required a second surgery due to complications. At the last follow-up, three patients reported episodes of abdominal bloating (42%), one recurrent treated constipation (14.3%), and one soiling (14.3%). Genetic analysis identified three patients with heterozygous deletions, three with codon mutations, and three with frameshift mutations.Conclusions: MWS associated with Hirschsprung disease has a high rate of immediate surgical complications but some patients may achieve bowel function comparable with non-syndromic HD patients. A multidisciplinary follow-up is required for these patients

MARTE Project : Tele-echography between kyperounta and nicosia (Cyprus)

International audienceUltrasound experts, who are few and not always on hand when needed, have now the tool and the possibility to examine patients from a distance, and thus perform a complete diagnosis without being in the same geographical position with the patient. This is possible thanks to a telemedicine system aiming to provide the possibility to examine a remote patient using a tele-operated controlled robot. In the frame of this project, different validations have been performed to show the technical performances of the teleoperated chain and the repercussions on the clinical aspect. The clinical validation is the crucial part for the validation of the overall concept of tele-echography. Thus, various specialities were investigated all throughout the project life, with the participation of different medical experts from several countries, namely France, Spain and Cyprus

Growth patterns of patients with Noonan syndrome: correlation with age and genotype

International audienceBackground: Growth patterns of patients with Noonan syndrome (NS) were established before the involved genes were identified.Objective: The goal of this study was to compare growth parameters according to genotype in patients with NS.Subjects and methods: The study population included 420 patients (176 females and 244 males) harboring mutations in the PTPN11, SOS1, RAF1, or KRAS genes. NS-associated PTPN11 mutations (NS-PTPN11) and NS with multiple lentigines-associated PTPN11 mutations (NSML-PTPN11) were distinguished. Birth measures and height and body mass index (BMI) measures at 2, 5, 10 years, and adulthood were compared with the general population and between genotypes.Results: Patients with NS were shorter at birth (mean birth length standard deviation score (SDS): -1.0 +/- 1.4; P < 0.001) and throughout childhood than the healthy population, with height SDS being -2.1 +/- 1.3 at 2 years, and -2.1 +/- 1.2 at 5 and 10 years and adulthood (P < 0.001). At birth, patients with NS-PTPN11 were significantly shorter and thinner than patients with NSML-PTPN11, SOS1, or KRAS. Growth retardation was significantly less severe and less frequent at 2 years in patients with NSML-PTPN11 and SOS1 than in patients with NS-PTPN11 (P < 0.001 and P = 0.002 respectively). Patients with NS had lower BMI at 10 years (P < 0.001). No difference between genotypes was demonstrated.Conclusion: Determining the growth patterns of patients with NS according to genotype should better inform clinicians about the natural course of growth in NS so that they can optimize the follow-up and management of these patients