Can discrete event simulation be of use in modelling major depression?

BACKGROUND: Depression is among the major contributors to worldwide disease burden and adequate modelling requires a framework designed to depict real world disease progression as well as its economic implications as closely as possible. OBJECTIVES: In light of the specific characteristics associated with depression (multiple episodes at varying intervals, impact of disease history on course of illness, sociodemographic factors), our aim was to clarify to what extent "Discrete Event Simulation" (DES) models provide methodological benefits in depicting disease evolution. METHODS: We conducted a comprehensive review of published Markov models in depression and identified potential limits to their methodology. A model based on DES principles was developed to investigate the benefits and drawbacks of this simulation method compared with Markov modelling techniques. RESULTS: The major drawback to Markov models is that they may not be suitable to tracking patients' disease history properly, unless the analyst defines multiple health states, which may lead to intractable situations. They are also too rigid to take into consideration multiple patient-specific sociodemographic characteristics in a single model. To do so would also require defining multiple health states which would render the analysis entirely too complex. We show that DES resolve these weaknesses and that its flexibility allow patients with differing attributes to move from one event to another in sequential order while simultaneously taking into account important risk factors such as age, gender, disease history and patients attitude towards treatment, together with any disease-related events (adverse events, suicide attempt etc.). CONCLUSION: DES modelling appears to be an accurate, flexible and comprehensive means of depicting disease progression compared with conventional simulation methodologies. Its use in analysing recurrent and chronic diseases appears particularly useful compared with Markov processes

Un ancien lac au pied de l’<i>oppidum</i> de Gergovie (Puy-de-Dôme) : interactions sociétés-milieux dans le bassin de Sarliève à l’Holocène

International audienceZiel der seit 1997 im Becken von Sarliève, am Fuß des Oppidums von Gergovia (Puy-de-Dôme) durchgeführten Studien ist es, die wechselseitigen Beziehungen zwischen Mensch und Umwelt über einen langen Zeitraum aus einem systemischen und interdisziplinären Blickwinkel zu betrachten. Die Untersuchungen beziehen sich auf ein Niederschlagsgebiet mittlerer Größe in einer Region von eminenter geschichtlicher Bedeutung. Drei Untersuchungsachsen wurden definiert: •die Analyse der Entwicklung der Umwelt im Bereich dieses Niederschlagsgebietes in Hinsicht auf seine unterschiedlichen biophysikalischen Komponenten; •die Analyse der Geschichte der Flächennutzung und der Bewirtschaftung des Beckens durch die sich ablösenden Bevölkerungsgruppen; •die Analyse der durch den Menschen hervorgerufenen Umweltbelastung (Pflanzendecke, hydrosedimentäre Kräfte). Die Ergebnisse dieser Forschungen liefern die Elemente für die Erstellung eines sozialökologischen Modells, das das von 1970-1980 für die Grande Limagne ausgearbeitete Modell ablöst. Eine Abfolge von Agrarzyklen ist deutlich erkennbar. Diese stehen im Zusammenhang mit Phasen starker menschlicher Einflussnahme, die für das Mittelneolithikum, die Früh-und Spätbronzezeit, die ältere Eisenzeit, die späte Latène-und frühe Kaiserzeit, das Mittelalter und die Neuzeit erkannt wurden. Diese Zyklen sind eng verknüpft nicht nur mit der Entwicklung der Pflanzen und der Sedimentierungsdynamik, sondern auch mit den Schwankungen des Wasserstandes. In der Bronzezeit und im Mittelalter werden Transgressionsphasen mit besonders umfangreichen und einengenden Auswirkungen nachgewiesen. Der niedrige Pegel des Paläosees in der jüngeren Eisenzeit und der frühen Kaiserzeit begünstigt dagegen die Besiedlung der Uferregionen und sogar der Sohle des Beckens, das um die Zeitenwende durch ein Entwässerungssystem vollständig trocken gelegt wird. In der ersten Hälfte des 2. Jh. v. Chr. wird mit der starken Intensivierung der Siedlungstätigkeit in sämtlichen topographischen Kontexten eine deutliche quantitative Schwelle überschritten. Die Ergebnisse der archäologischen und paläoökologischen Untersuchungen lassen die methodische Erschließung der fruchtbarsten Böden im Zusammenhang mit einem stetigen wirtschaftlichen und demographischen Wachstum erkennen, das mit dem Bau großer als “zentrale Plätze“ interpretierter Siedlungen (La Grande Borne in Aulnat, Oppida von Corent, Gergovia und Gondole) zusammenfällt. In den ersten beiden Jahrhunderten unseres Zeitalters setzt sich diese Tendenz im Rahmen der Ökonomie der villae, die sich infolge der Gründung von Augustonemetum, der neuen Hauptstadt der avernischen civitas herausbildet, mit der von den Geländeformen unabhängigen Ausweitung der landwirtschaftlichen Nutzung auf das gesamte Becken fort. In der Spätantike und im frühen Mittelalter gewinnt der Sumpf in einem feuchteren Klima wieder an Boden, besonders durch die grundlegenden Veränderungen in der Art und Weise das Gebiet zu nutzen. Die mittelalterlichen Texte und die neuzeitliche Ikonographie bezeugen die Existenz eines Sees, der zu Beginn des 17. Jh. schließlich endgültig trockengelegt wird.The aim of the researches conducted since 1997 in the basin of Sarliève, at the foot of the oppidum of Gergovia (Puy-de-Dôme), is to detect in a systemic and interdisciplinary perspective the longlasting interactions societies/environment on the scale of a mediumsized basin located in a major area from an historical point of view. Three axes have been defined : * the characterization of the evolution of the environment on the scale of the basin inside its various biophysical components ; * the characterization of the history of land occcupation and of the exploitation of environment by successive populations settled in the basin ; * the characterization of the impact of human pressure on the environment (plant cover, hydro-sedimentary dynamics). Results provide elements of a new socioenvironmental model after the model completed in Limagne in the 1970'-1980'. A succession of land cycles has been detected and connected to phases of strong human pressure identified for Middle Neolithic, Early and Late Bronze Age, Early Iron Age, Early Empire, Middle Age and Modern period. These cycles are tightly connected with vegetation evolution and sedimentary dynamics but also with vertical variations of the lake level. Some phases of encroachment, particularly wide and constraining, have been revealed for Bronze Age and Middle Age. The low level of the lake during the Late Iron Age and the Early Empire in the other hand is favourable to the occupation of the edges and even at the bottom of the basin which is entirely drained due to a draining system at the turn of our era. A definite quantitative step, during the first half of the 2nd century BC, is represented by the high densification of the populated area in all kinds of physical units. Archaeological and environmental datas reveal a methodic exploitation of the most fertile lands in a context of continuous economic and demographic environment which coincides with the birth of towns identified as "central places" (such as la Grande Borne at Aulnat and the oppida of Corent at Veyre-Monton, Gergovia at La Roche-Blanche and Gondole at Le Cendre). This tendency goes on during the first two centuries AD, with the generalization of agrosystem to the whole basin, for any kind of relief, in the context of economic estates growing since the foundation of Augustonemetum, the new capital of the Arverni. The return of marsh in Late Antiquity and Early Middle Age is due to a more humid climate and to deep changes in the methods of environmental management. A real lake is attested by medieval sources and modern iconography and is definitely dried out at the beginning of the 17th century.Les recherches conduites depuis 1997 dans le bassin de Sarliève, au pied de l'oppidum de Gergovie (Puy-de-Dôme), visent à appréhender, dans une perspective systémique et interdisciplinaire, les interactions sociétés-milieux dans la longue durée, à l'échelle d'un bassin-versant de taille moyenne localisé dans une zone de première importance sur le plan historique. Trois axes de recherche ont été définis : * la caractérisation de l'évolution du milieu à l'échelle du bassin-versant dans ses différentes composantes biophysiques ; * la caractérisation de l'histoire de l'occupation du sol et de l'exploitation du milieu par les populations successives établies dans le bassin ; * la caractérisation de l'impact de la pression anthropique sur le milieu (couverture végétale, dynamiques hydrosédimentaires). Les résultats obtenus fournissent les éléments d'un modèle socio-environnemental qui renouvelle celui élaboré pour la Grande Limagne dans les années 1970-1980. Une succession de cycles agraires est clairement mise en évidence. Ceux-ci sont liés à des phases de forte pression humaine identifiées au Néolithique moyen, au Bronze ancien, au Bronze final, au premier âge du Fer, à La Tène finale, au Haut-Empire, au Moyen Âge et à l'époque moderne. Ces cycles sont étroitement corrélés avec l'évolution de la végétation et la dynamique sédimentaire, mais également avec les variations verticales du plan d'eau. Des phases de transgression particulièrement amples et contraignantes sont mises en évidence durant l'âge du Bronze et le Moyen Âge. Le bas niveau du paléolac durant le second âge du Fer et le Haut-Empire est, en revanche, propice à l'occupation des bordures et même du fond de la cuvette, qui est complètement asséchée grâce à un système de drainage aménagé aux environs du changement d'ère. Un seuil quantitatif très net est franchi dans la première moitié du IIe s. av. J.-C., avec la forte densification de l'habitat dans tous les types d'unités physiques. Les données archéologiques et paléoenvironnementales traduisent la mise en valeur méthodique des sols les plus fertiles, dans un contexte de croissance économique et démographique continue qui coïncide avec l'apparition de vastes agglomérations interprétées comme des " places centrales " (agglomération de la Grande Borne à Aulnat, oppida de Corent à Veyre-Monton, Gergovie à La Roche-Blanche et Gondole au Cendre). Cette tendance se poursuit durant les deux premiers siècles de notre ère, avec la généralisation de l'agrosystème à l'ensemble du bassin, quels que soient les types de reliefs, dans le cadre de l'économie domaniale qui se développe à la suite de la fondation d'Augustonemetum, nouvelle capitale de la cité arverne. La fin de l'Antiquité et le haut Moyen Âge voient le retour du marais à la faveur d'un climat plus humide et, surtout, de profonds changements dans les modalités de gestion du milieu. Un véritable lac est attesté par les textes médiévaux et par l'iconographie moderne. Il est définitivement asséché au début du XVIIe s

Epilepsy Caused by an Abnormal Alternative Splicing with Dosage Effect of the SV2A Gene in a Chicken Model

Photosensitive reflex epilepsy is caused by the combination of an individual's enhanced sensitivity with relevant light stimuli, such as stroboscopic lights or video games. This is the most common reflex epilepsy in humans; it is characterized by the photoparoxysmal response, which is an abnormal electroencephalographic reaction, and seizures triggered by intermittent light stimulation. Here, by using genetic mapping, sequencing and functional analyses, we report that a mutation in the acceptor site of the second intron of SV2A (the gene encoding synaptic vesicle glycoprotein 2A) is causing photosensitive reflex epilepsy in a unique vertebrate model, the Fepi chicken strain, a spontaneous model where the neurological disorder is inherited as an autosomal recessive mutation. This mutation causes an aberrant splicing event and significantly reduces the level of SV2A mRNA in homozygous carriers. Levetiracetam, a second generation antiepileptic drug, is known to bind SV2A, and SV2A knock-out mice develop seizures soon after birth and usually die within three weeks. The Fepi chicken survives to adulthood and responds to levetiracetam, suggesting that the low-level expression of SV2A in these animals is sufficient to allow survival, but does not protect against seizures. Thus, the Fepi chicken model shows that the role of the SV2A pathway in the brain is conserved between birds and mammals, in spite of a large phylogenetic distance. The Fepi model appears particularly useful for further studies of physiopathology of reflex epilepsy, in comparison with induced models of epilepsy in rodents. Consequently, SV2A is a very attractive candidate gene for analysis in the context of both mono- and polygenic generalized epilepsies in humans

Effect of a Dual Task on Postural Control in Dyslexic Children

Several studies have examined postural control in dyslexic children; however, their results were inconclusive. This study investigated the effect of a dual task on postural stability in dyslexic children. Eighteen dyslexic children (mean age 10.3±1.2 years) were compared with eighteen non-dyslexic children of similar age. Postural stability was recorded with a platform (TechnoConcept®) while the child, in separate sessions, made reflex horizontal and vertical saccades of 10° of amplitude, and read a text silently. We measured the surface and the mean speed of the center of pressure (CoP). Reading performance was assessed by counting the number of words read during postural measures. Both groups of children were more stable while performing saccades than while reading a text. Furthermore, dyslexic children were significantly more unstable than non-dyslexic children, especially during the reading task. Finally, the number of words read by dyslexic children was significantly lower than that of non-dyslexic children and, in contrast to the non-dyslexic children. In line with the U-shaped non-linear interaction model, we suggest that the attention consumed by the reading task could be responsible for the loss of postural control in both groups of children. The postural instability observed in dyslexic children supports the hypothesis that such children have a lack of integration of multiple sensorimotor inputs

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

Missions du pharmacien référent d'un Etablissement d'Hébergement pour Personnes Agées Dépendantes

Le pharmacien référent d un Etablissement d Hébergement pour Personnes Âgées Dépendantes (EHPAD) est garant de l utilisation sécuritaire des médicaments. Il doit travailler en coordination avec les autres professionnels de santé, autour du patient, afin de s assurer de la bonne gestion et du bon usage des médicaments, notamment grâce aux nouveaux systèmes d automatisation de préparation des doses à administrer (PDA). Actuellement, il n existe aucun texte réglementaire concernant les PDA à l officine. Cependant, il est recommandé aux établissements, de disposer de procédures afin d assurer la qualité et ainsi permettre d entretenir une dynamique d amélioration.DIJON-BU Médecine Pharmacie (212312103) / SudocSudocFranceF

Seas and oceans : a complex history.

Consultable en ligne : http://www.cnrs.fr/inee/communication/breves/docs/The_ocean_revealed_ENG.pdfInternational audienc

Mers et océans, toute une histoire.

International audienc

BIKE Key-Recovery: Combining Power Consumption Analysis and Information-Set Decoding

International audienceIn this paper, we present a single-trace attack on a BIKE Cortex-M4 implementation proposed by Chen et al. at CHES 2021. BIKE is a key-encapsulation mechanism, candidate to the NIST post-quantumcryptography standardisation process. We attack by exploiting the rotation function that circularly shifts an array depending on the private key. Chen et al. implemented two versions of this function, one in C andone in assembly. Our attack uses subtraces clustering combined with a combinatorial attack to recover the full private key. We obtained a high clustering accuracy in our experiments, and we provide ways to deal withthe errors. We are able to recover all the private keys for the C implementation, and while the assembly version is harder to attack using our technique, we still manage to reduce BIKE Level-1 security from 128 to65 bits for a significant proportion of the private keys