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Background: With the development of next generation sequencing technologies in France, exome sequencing (ES) has recently emerged as an opportunity to improve the diagnosis rate of patients presenting an intellectual disability (ID). To help French policy makers determine an adequate tariff for ES, we aimed to assess the unit cost per ES diagnostic test for ID from the preparation of the pre-analytical step until the report writing step and to identify its main cost drivers.Methods: A micro-costing bottom-up approach was conducted for the year 2018 in a French setting as part of the DISSEQ study, a cost-effectiveness study funded by the Ministry of Health and performed in collaboration with the GAD (Génétique des Anomalies du Développement), a genetic team from the Dijon University Hospital, and a public sequencing platform, the Centre National de Recherche en Génomique Humaine (CNRGH). The analysis was conducted from the point of view of these two ES stakeholders. All of the resources (labor, equipment, disposables and reagents, reusable material) required to analyze blood samples were identified, collected and valued. Several sensitivity analyses were performed.Results: The unit nominal cost per ES diagnostic test for ID was estimated to be €2,019.39. Labor represented 50.7% of the total cost. The analytical step (from the preparation of libraries to the analysis of sequences) represented 88% of the total cost. Sensitivity analyses suggested that a simultaneous price decrease of 20% for the capture kit and 50% for the sequencing support kit led to an estimation of €1,769 per ES diagnostic test for ID.Conclusion: This is the first estimation of ES cost to be done in the French setting of ID diagnosis. The estimation is especially influenced by the price of equipment kits, but more generally by the organization of the centers involved in the different steps of the analysis and the time period in which the study was conducted. This information can now be used to define an adequate tariff and assess the efficiency of ES.Trial registration: ClinicalTrials.gov identifier NCT03287206 on September 19, 2017.

Additional file 2. Raw data and ULM values for P1NP and Osteocalcin in the 19 patients.

Additional file 1. References for normal biological values for children and adults.

Background and ObjectivesPurine-rich element-binding protein A (PURA) gene encodes Pur-alpha, a conserved protein essential for normal postnatal brain development. Recently, a PURA syndrome characterized by intellectual disability, hypotonia, epilepsy, and dysmorphic features was suggested. The aim of this study was to define and expand the phenotypic spectrum of PURA syndrome by collecting data, including EEG, from a large cohort of affected patients.MethodsData on unpublished and published cases were collected through the PURA Syndrome Foundation and the literature. Data on clinical, genetic, neuroimaging, and neurophysiologic features were obtained.ResultsA cohort of 142 patients was included. Characteristics of the PURA syndrome included neonatal hypotonia, feeding difficulties, and respiratory distress. Sixty percent of the patients developed epilepsy with myoclonic, generalized tonic-clonic, focal seizures, and/or epileptic spasms. EEG showed generalized, multifocal, or focal epileptic abnormalities. Lennox-Gastaut was the most common epilepsy syndrome. Drug refractoriness was common: 33.3% achieved seizure freedom. We found 97 pathogenic variants in PURA without any clear genotype-phenotype associations.DiscussionThe PURA syndrome presents with a developmental and epileptic encephalopathy with characteristics recognizable from neonatal age, which should prompt genetic screening. Sixty percent have drug-resistant epilepsy with focal or generalized seizures. We collected more than 90 pathogenic variants without observing overt genotype-phenotype associations.

In dit onderzoek is nagegaan of de inzet van tablets bij fictielezen verschil maakt ten opzichte van lezen van papier. 89 brugklassers uit een iPad- en reguliere mavo/havo-klassen lazen een kort verhaal van een tablet of van papier. Leerlingen uit iPad-klassen vonden het motiverender om vanaf papier te lezen dan vanaf de tablet, terwijl de tekstdrager voor leerlingen uit de reguliere klassen niet uitmaakte. Tabletlezers ervoeren minder immersie tijdens het lezen van de tablet dan de papierlezers, terwijl leerlingen uit iPad-klassen minder immersie ervoeren dan leerlingen uit reguliere klassen. Tot slot begrepen leerlingen het verhaal beter als ze dit van papier lazen dan van het scherm, ongeacht hun iPad-ervaring op school. De resultaten geven aanleiding om binnen de leesbevordering de voorkeur te geven aan papieren boeken boven digitale dragers.

Predators have evolved many different ways to detect hidden prey by using advanced sensory organs. However, in some environmental contexts sensory information may be obscured. The relation between sensory organs, obstruction and searching efficiency remains little explored. In this study we experimentally examined the ways in which a sensory system (‘remote detection’), which enables red knots, Calidris canutus, to detect hard objects buried in wet soft sediments, is obstructed by plants. At an important coastal nonbreeding site of this species, the Banc d'Arguin (Mauritania, West Africa), most of the intertidal foraging area is covered by sea grass. The structurally complex networks of belowground roots and rhizomes and aboveground sea grass may obstruct information on the presence of buried bivalves and thus affect searching efficiency. Under aviary conditions we offered red knots buried bivalves in either bare soft sediments or in sea grass patches and measured prey encounter rates. Red knots detected prey by direct touch in sea grass but remotely in bare sediment. Physical modelling of the pressure field build-up around a probing bill showed that within a layer of sea grass rhizomes, permeability is reduced to the extent that the pressure field no longer reveals the presence of an object. In bare sediment, where searching efficiency is constant, red knot intake rate levelled off with increasing prey density (described by a so-called type II functional response). In the sea grass beds, however, prey density increases with sea grass density and simultaneously decreases searching efficiency, which will at some point lead to a decrease in intake rate when prey densities increase (i.e. a type IV functional response). Clearly, prey detection mechanisms dictate that the combined effects of prey density and habitat complexity should be taken into account when predicting forager distributions and habitat preference.

Background: Triggered by the requirement of Water Framework Directive for a good ecological status for European river systems till 2015 and by still existing lacks in tools for cause identification of insufficient ecological status MODELKEY (http://www.modelkey.org), an Integrated Project with 26 partners from 14 European countries, was started in 2005. MODELKEY is the acronym for 'Models for assessing and forecasting the impact of environmental key pollutants on freshwater and marine ecosystems and biodiversity'. The project is funded by the European Commission within the Sixth Framework Programme. Objectives: MODELKEY comprises a multidisciplinary approach aiming at developing interlinked tools for an enhanced understanding of cause-effect-relationships between insufficient ecological status and environmental pollution as causative factor and for the assessment and forecasting of the risks of key pollutants on fresh water and marine ecosystems at a river basin and adjacent marine environment scale. New modelling tools for risk assessment including generic exposure assessment models, mechanistic models of toxic effects in simplified food chains, integrated diagnostic effect models based on community patterns, predictive component effect models applying artificial neural networks and GIS-based analysis of integrated risk indexes will be developed and linked to a user-friendly decision support system for the prioritisation of risks, contamination sources and contaminated sites. Approach: Modelling will be closely interlinked with extensive laboratory and field investigations. Early warning strategies on the basis of sub-lethal effects in vitro and in vivo are provided and combined with fractionation and analytical tools for effect-directed analysis of key toxicants. Integrated assessment of exposure and effects on biofilms, invertebrate and fish communities linking chemical analysis in water, sediment and biota with in vitro, in vivo and community level effect analysis is designed to provide data and conceptual understanding for risk arising from key toxicants in aquatic ecosystems and will be used for verification of various modelling approaches. Conclusion and Perspective: The developed tools will be verified in case studies representing European key areas including Mediterranean, Western and Central European river basins. An end-user-directed decision support system will be provided for cost-effective tool selection and appropriate risk and site prioritisation.

Voor geneesmiddelen zijn de rwzi’s de belangrijkste route naar het oppervlaktewater. We hebben een model ontwikkeld waarmee we de invloed van rwzi’s op de kwaliteit van het oppervlaktewater in Nederland kunnen voorspellen. Dat maakt inzichtelijk waar maatregelen het meest effectief zijn. We hebben het model doorgerekend voor twee verschillende geneesmiddelen en twee extreme afvoercondities.