Occupation et inhumations du Néolithique récent à Illfurth « Naegelberg » (Haut-Rhin)

À l’est de la Trouée de Belfort, à proximité de Mulhouse, une occupation des premiers siècles du quatrième millénaire a récemment été reconnue à travers une dizaine de structures en creux. La céramique se rapporte en majorité au style A de la culture de Munzingen (vers 3800-3600 av. J.-C.). Deux de ces fosses accueillaient des inhumations. La première (st. 89) rassemble deux enfants d’environ 10 ans, déposés simultanément autour de 3650 av. J.-C. et traités de manière asymétrique. La seconde inhumation (st. 10) est légèrement plus ancienne (vers 3800 av. J.-C.). Un adulte a été déposé sur le flanc, membres inférieurs repliés, accompagné d’un viatique constitué de mobilier rare et pour partie importé (os long scié de grand oiseau, gobelet en bois de cerf, cristal de roche et céramique). Dans cet article, après la présentation de ces nouvelles données, l’attribution culturelle est discutée en détail. Le viatique de la tombe 10 est constitué de mobilier de tradition Cortaillod, mais le rite funéraire ne peut être rapproché de celui des habitants du Plateau suisse. Le dépôt apparaît comme une mise en scène où intervient du mobilier exceptionnel. La présence de chacun de ces éléments peut certes être expliquée par les réseaux de circulations, mais leur association au sein d’une même inhumation demande de considérer sérieusement l’hypothèse d’un individu originaire de l’aire Cortaillod. En conclusion, nous rappelons que les traditions domestiques, définies sur des objets de la vie quotidienne, doivent être distinguées des rites funéraires.East of the Belfort Gap, close to Mulhouse, a dozen pits containing Jungneolithikum pottery were recently excavated and attributed to style A of the Munzingen culture (3800-3600 BC). Funerary deposits were found in two of the pits. In the first (pit 89), two children of approximately 10 years of age were simultaneously buried around 3650 BC. Judging by the different arrangements of their bodies, it seems that they were not treated in a similar manner. The second grave (pit 10) is a little older (around 3800 BC). A single adult individual was buried on his side with both legs folded, and provided with rare artefacts, partly from abroad (a large sawn bird bone, an antler cup from the Swiss Plateau, rock-crystal from the Alps, and pottery). In this paper, we present these new findings and discuss which culture they should be assigned to. The artefacts and the raw materials from grave 10 belong to the Cortaillod tradition, while the funerary ritual cannot be regarded as originating on the Swiss Plateau. The funerary deposit seems to follow a codified staging in which exceptional artefacts play a leading role. The presence of each artefact can obviously be explained by the exchange networks, but not their joint occurrence in the same grave. Therefore, the hypothesis of an individual native of the Cortaillod area must be taken seriously into account. In conclusion, it should be remembered that domestic traditions, as suggested by everyday artefacts, are not to be confused with funerary rituals.Im Osten der Burgundischen Pforte wurde in der Nähe von Mulhouse vor kurzem anhand von ca. 10 eingetieften Strukturen eine Siedlung der ersten Jahrhunderte des 4. Jahrtausends identifiziert. Die Keramik ist überwiegend Munzingen A zuzuordnen (um 3800-3600 v. Chr.). In zwei der Gruben wurden Körpergräber entdeckt. In der ersten Grube (st. 89) lagen zwei Kinder von ungefähr 10 Jahren, die zur gleichen Zeit, um 3650 v. Chr., bestattet worden waren und eine ungleiche Behandlung erfahren hatten. Das zweite Körpergrab (st. 10) ist etwas älter (um 3800 v. Chr.). Hier war ein Erwachsener in Seitenlage mit angewinkelten unteren Gliedmaßen niedergelegt worden. Die Beigaben umfassen seltene und zum Teil importierte Gegenstände (abgesägter Langknochen von einem großen Vogel, Becher aus Hirschgeweih, Bergkristall und Keramik). Anschließend an die Präsentation dieser neuen Erkenntnisse wird die kulturelle Zuweisung im Detail diskutiert. Die Beigaben aus Grab 10 setzen sich aus Mobiliar der Cortaillod-Tradition zusammen, der Bestattungsbrauch ist jedoch nicht vergleichbar mit dem der Bewohner des Schweizer Mittellandes. Das Depot sieht wie eine Inszenierung aus, in der außergewöhnliche Grabbeigaben eine Rolle spielen. Die Präsenz jedes einzelnen dieser Elemente kann sicher durch Tauschnetze erklärt werden, doch ihre Präsenz in demselben Grab legt die Hypothese eines Individuums aus dem Bereich der Cortaillod-Kultur nahe. Abschließend erinnern wir daran, dass die häuslichen Traditionen, die anhand der Alltagsgegenstände definiert werden, von den Bestattungssitten zu unterscheiden sind

The Use of Baclofen as a Treatment for Alcohol Use Disorder: A Clinical Practice Perspective

Alcohol use disorder (AUD) is a brain disorder associated with high rates of mortality and morbidity worldwide. Baclofen, a selective gamma-aminobutyric acid-B (GABA-B) receptor agonist, has emerged as a promising drug for AUD. The use of this drug remains controversial, in part due to uncertainty regarding dosing and efficacy, alongside concerns about safety. To date there have been 15 randomized controlled trials (RCTs) investigating the use of baclofen in AUD; three using doses over 100 mg/day. Two additional RCTs have been completed but have not yet been published. Most trials used fixed dosing of 30–80 mg/day. The other approach involved titration until the desired clinical effect was achieved, or unwanted effects emerged. The maintenance dose varies widely from 30 to more than 300 mg/day. Baclofen may be particularly advantageous in those with liver disease, due to its limited hepatic metabolism and safe profile in this population. Patients should be informed that the use of baclofen for AUD is as an “off-label” prescription, that no optimal fixed dose has been established, and that existing clinical evidence on efficacy is inconsistent. Baclofen therapy requires careful medical monitoring due to safety considerations, particularly at higher doses and in those with comorbid physical and/or psychiatric conditions. Baclofen is mostly used in some European countries and Australia, and in particular, for patients who have not benefitted from the currently used and approved medications for AUD

Solve-RD: systematic pan-European data sharing and collaborative analysis to solve rare diseases.

For the first time in Europe hundreds of rare disease (RD) experts team up to actively share and jointly analyse existing patient's data. Solve-RD is a Horizon 2020-supported EU flagship project bringing together >300 clinicians, scientists, and patient representatives of 51 sites from 15 countries. Solve-RD is built upon a core group of four European Reference Networks (ERNs; ERN-ITHACA, ERN-RND, ERN-Euro NMD, ERN-GENTURIS) which annually see more than 270,000 RD patients with respective pathologies. The main ambition is to solve unsolved rare diseases for which a molecular cause is not yet known. This is achieved through an innovative clinical research environment that introduces novel ways to organise expertise and data. Two major approaches are being pursued (i) massive data re-analysis of >19,000 unsolved rare disease patients and (ii) novel combined -omics approaches. The minimum requirement to be eligible for the analysis activities is an inconclusive exome that can be shared with controlled access. The first preliminary data re-analysis has already diagnosed 255 cases form 8393 exomes/genome datasets. This unprecedented degree of collaboration focused on sharing of data and expertise shall identify many new disease genes and enable diagnosis of many so far undiagnosed patients from all over Europe

Solving unsolved rare neurological diseases-a Solve-RD viewpoint.

Funder: Durch Princess Beatrix Muscle Fund Durch Speeren voor Spieren Muscle FundFunder: University of Tübingen Medical Faculty PATE programFunder: European Reference Network for Rare Neurological Diseases | 739510Funder: European Joint Program on Rare Diseases (EJP-RD COFUND-EJP) | 44140962

Solving patients with rare diseases through programmatic reanalysis of genome-phenome data.

Funder: EC | EC Seventh Framework Programm | FP7 Health (FP7-HEALTH - Specific Programme "Cooperation": Health); doi: https://doi.org/10.13039/100011272; Grant(s): 305444, 305444Funder: Ministerio de Economía y Competitividad (Ministry of Economy and Competitiveness); doi: https://doi.org/10.13039/501100003329Funder: Generalitat de Catalunya (Government of Catalonia); doi: https://doi.org/10.13039/501100002809Funder: EC | European Regional Development Fund (Europski Fond za Regionalni Razvoj); doi: https://doi.org/10.13039/501100008530Funder: Instituto Nacional de Bioinformática ELIXIR Implementation Studies Centro de Excelencia Severo OchoaFunder: EC | EC Seventh Framework Programm | FP7 Health (FP7-HEALTH - Specific Programme "Cooperation": Health)Reanalysis of inconclusive exome/genome sequencing data increases the diagnosis yield of patients with rare diseases. However, the cost and efforts required for reanalysis prevent its routine implementation in research and clinical environments. The Solve-RD project aims to reveal the molecular causes underlying undiagnosed rare diseases. One of the goals is to implement innovative approaches to reanalyse the exomes and genomes from thousands of well-studied undiagnosed cases. The raw genomic data is submitted to Solve-RD through the RD-Connect Genome-Phenome Analysis Platform (GPAP) together with standardised phenotypic and pedigree data. We have developed a programmatic workflow to reanalyse genome-phenome data. It uses the RD-Connect GPAP's Application Programming Interface (API) and relies on the big-data technologies upon which the system is built. We have applied the workflow to prioritise rare known pathogenic variants from 4411 undiagnosed cases. The queries returned an average of 1.45 variants per case, which first were evaluated in bulk by a panel of disease experts and afterwards specifically by the submitter of each case. A total of 120 index cases (21.2% of prioritised cases, 2.7% of all exome/genome-negative samples) have already been solved, with others being under investigation. The implementation of solutions as the one described here provide the technical framework to enable periodic case-level data re-evaluation in clinical settings, as recommended by the American College of Medical Genetics

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

Les pratiques funéraires en Alsace du Néolithique à l'époque moderne. Lecture typo-chronologique des sépultures à inhumation

International audienc

Vers une nouvelle lecture typo-chronologique des inhumations en Alsace, du Néolithique à l’Époque moderne

International audienceLa région Alsace, d’un point de vue administratif, est bordée, à l’ouest, par le Massif Vosgien et à l’est, par le Rhin. Cependant, d’un point de vue géographique et géologique, elle est en tout point comparable à son symétrique d’outre-Rhin, qui s’étend du Rhin à l’ouest à la Forêt noire à l’est. À tel point que pour les archéologues régionaux, il est plus pertinent d’étudier l’ensemble du sud de la plaine du Rhin supérieur, plutôt que de se cantonner aux frontières administratives.La diversité des pratiques funéraires en Alsace est remarquable, quelle que soit la période concernée. La pluralité de ces pratiques est inhérente au caractère frontalier de la région et aux problématiques qui en découlent (invasions et migrations, influences extérieures, échanges culturels et populationnels, guerres frontalières, etc.). Cette position géographique particulière explique également le rattachement marqué de la région vers l’espace germanique plutôt que vers les cultures connues sur le territoire national, de la Préhistoire à nos jours. Certains modes d’inhumation ont pu être précisés ces dernières années, à la lumière des fouilles récentes menées en contexte préventif et également sous l’impulsion de plusieurs travaux de recherche collectifs, regroupant les différents acteurs de l’archéologie alsacienne. En outre, l’environnement lœssique de la plupart des découvertes funéraires a permis une excellente conservation des restes osseux, du mobilier funéraire et même parfois d’éléments de l’architecture funéraire.Au cours de cette communication, nous nous proposons de faire un état des lieux des connaissances sur les typo-chronologies des sépultures alsaciennes, en insistant sur les méthodologies employées pour leur définition. Cette présentation se voudra diachronique, mais faute de données disponibles ou exhaustives pour toutes les périodes, nous insisterons essentiellement sur le Néolithique dans son ensemble, certaines phases de la Protohistoire et le haut Moyen Âge, périodes pour lesquelles l’inhumation est la pratique funéraire dominante. Cette typo-chronologie diachronique portera sur une grande partie du corpus alsacien et constituera une base qui se voudra à la fois factuelle, méthodologique et interprétative, permettant les comparaisons nécessaires avec les régions avoisinantes, mais également avec le reste du territoire