New functionalities in Orphanet for orphan drugs, R&D and marketing authorisations to better serve the rare diseases community

International audiencen.

Klinička praksa temeljena na dokazima: pregled prijetnji valjanosti dokaza i kako ih spriječiti

Using the best quality of clinical research evidence is essential for choosing the right treatment for patients. How to identify the best research evidence is, however, difficult. In this narrative review we summarise these threats and describe how to minimise them. Pertinent literature was considered through literature searches combined with personal files. Treatments should generally not be chosen based only on evidence from observational studies or single randomised clinical trials. Systematic reviews with meta-analysis of all identifiable randomised clinical trials with Grading of Recommendations Assessment, Development and Evaluation (GRADE) assessment represent the highest level of evidence. Even though systematic reviews are trust worthier than other types of evidence, all levels of the evidence hierarchy are under threats from systematic errors (bias); design errors (abuse of surrogate outcomes, composite outcomes, etc.); and random errors (play of chance). Clinical research infrastructures may help in providing larger and better conducted trials. Trial Sequential Analysis may help in deciding when there is sufficient evidence in meta-analyses. If threats to the validity of clinical research are carefully considered and minimised, research results will be more valid and this will benefit patients and heath care systems.Primjena najkvalitetnijih dokaza kliničkih istraživanja ključna je u odabiru ispravnog liječenja pacijenata. No, način na koji će se odabrati najbolji dokazi predstavlja često poteškoću. Ovim preglednim člankom prikazujemo opasnosti navedenog odabira, kao i načine kako ih umanjiti. Relevantni izvori razmatrani su pretragom literature u kombinaciji s osobnim datotekama. Izbor liječenja uglavnom se ne bi smio temeljiti isključivo na opservacijskim ili pojedinačnim randomiziranim kliničkim studijama. Sustavni pregledi s metaanalizom svih identificiranih randomiziranih kliničkih studija procijenjenih sustavom stupnjevanja procjene, razvoja i evaluacije preporuka (engl. Grading of Recommendations Assessment, Development and Evaluation; GRADE) predstavljaju najvišu razinu dokaza. Iako su sustavni pregledi pouzdaniji od drugih vrsta dokaza, sve razine hijerarhije dokaza ugrožene su sustavnim pogreškama (engl. bias); pogreškama dizajna studije (zloupotreba surogatnih ishoda, složenih ishoda itd.) i slučajnim pogreškama (igra slučaja). Kliničke istraživačke infrastrukture mogu pomoći u pružanju većih i adekvatnije provedenih ispitivanja. Sekvencijska analiza studija može pomoći pri odlučivanju kada postoji dovoljna razina dokaza u metaanalizama. Ako se prijetnje valjanosti kliničkih istraživanja pažljivo razmatraju i minimiziraju, rezultati istraživanja bit će vrjedniji i korisniji pacientima i zdravstvenim sustavima

Régulation de l'expression et de la phosphorylation de la protéine HEF1

La protéine HEF1 est localisée principalement au niveau des adhérences focales et est impliquée dans la régulation du cytosquelette, l'adhérence et la migration cellulaires. Ses propriétés et ses interactions avec différents partenaires sont régulées par phosphorylation sur des résidus tyrosine. Elle est également phosphorylée sur des résidus sérine/thréonine en réponse à l'adhérence et au cours du cycle cellulaire. Nous avons montré que l'expression de HEF1 et régulée au niveau transcriptionnel par l'IL-4 dans les kératinocytes humains. Dans un deuxième temps, nous nous sommes intéressés à la phosphorylation sur sérine de HEF1. Nous avons identifié la sérine 369 comme étant la cible d'une kinase inhibée par l'Hesperadin, un inhibiteur d'Aurora-B. Cette phosphorylation a pour conséquence d'induire la dégradation protéasomale de HEF1. Ainsi, nous avons mis en évidence deux aspects, transcriptionnel et post-traductionnel, de la régulation de l'expression de la protéine HEF1.HEF belongs to p130Cas protein family. HEF1 is expressed in lymphocytes, fibroblasts and epithelial cells and is mainly localized at focal adhesions. This protein has been related to cytoskeleton regulation and cell adhesion and migration. Tyrosine phosphorylation influences HEF1 properties and protein-protein interactions with different partners. Cell adhesion and cell cycle progression induce also serine/threonine phosphorylation. We showed that IL-4 regulates HEF1 expression at transcriptional level in human keratinocytes. Then, we investigated HEF1 serine phosphorylation and identified serine 369 as a target for a Hesperadin inhibited kinase. Hesperadin used to be described as an inhibitor for Aurora-B kinase. Serine 369 phosphorylation induces proteasomal degradation of HEF1 protein. Here we studied the regulation of HEF1 expression at least two levels, transcriptional and post-translational.CHATENAY M.-PARIS 11-BU Pharma. (920192101) / SudocSudocFranceF

Parcs 2050 - Connaissance et prospective des parcs automobiles (rapport intermédiaire pour la sous-action 1 des "projets de recherche sur les infrastructures et la mobilité")

This work is part of the DGITM convention aimed at supporting research on transport infrastructure and mobility. They relate specifically to vehicle fleets, mobilizing several IFSTTAR laboratories, and of interest to many actors around mobility and transport, energy and environmental issues, and public policies. The work aims at a state of the art of important or emerging issues as well as the mobilization of a national GT-PARCS working group around the problem of car fleets. Work has begun on the evolution of the composition of the vehicle fleet, the characteristics of vehicles (weight and power) and the emergence of different categories (SUVs, quads, cars without a driving licence). In relation to the 2019 version, an update of the IFSTTAR modelling of the French car fleet is underway, integrating the latest years of registration data as well as the consideration of prospective scenarios up to 2050 integrating the hypotheses of the national low carbon strategy. Finally, the GT-PARCS working group on vehicle fleets organised a seminar in June 2021 on the future of vehicle fleets and mobility, based on the major foresight exercises underway (Ademe, CGEDD, IDDRI-Université Eiffel), and integrating analyses of the evolution of emerging mobilities. This seminar brought together about 70 participants.Ces travaux s'inscrivent dans le cadre de la convention DGITM visant à soutenir des recherches sur les infrastructures et la mobilité. Ils portent spécifiquement sur les parcs automobiles, mobilisant plusieurs laboratoires de l'IFSTTAR, et intéressant de nombreux acteurs autour de problématiques mobilités et transports, énergétiques et environnementales, et les politiques publiques. Les travaux visent un état de l'art de questions importantes ou émergentes ainsi que la mobilisation d'un groupe national de travail GT-PARCS autour de la problématique des parcs automobiles. Des travaux ont débuté autour de l'évolution de la composition du parc automobile, des caractéristiques des véhicules (masses et puissances) et de l'émergence de différentes catégories (SUV, quads, voitures sans permis). Par rapport à la version 2019, une mise à jour de la modélisation IFSTTAR du parc automobile français est en cours, intégrant les dernières années de données d'immatriculations et la prise en compte de scénarios prospectifs à l'horizon 2050 intégrant les hypothèses de la stratégie nationale bas carbone. Enfin, le groupe de travail GT-PARCS sur les parcs automobile a organisé en juin 2021 un séminaire sur la prospective des parcs automobiles et des mobilités, autour des grands exercices de prospective en cours (Ademe, CGEDD, IDDRI-Université Eiffel), et intégrant les analyses d'évolution des mobilités émergentes. Ce séminaire, dont ce rapport rend essentiellement compte, a réuni près de 70 participants

IRDiRC: 1000 new rare diseases treatments by 2027, identifying and bringing forward strategic actions

In 2017, the International Rare Diseases Research Consortium (IRDiRC) set out ambitious goals, one of which specifically aimed to stimulate the development and approval of 1000 new therapies for rare diseases by 2027. This goal was part of IRDiRC’s concerted efforts to foster research and provide better diagnostics and care options for the estimated 400 million patients suffering from the more than 6000 rare diseases (RD) worldwide. Lack of therapeutic options for rare disease patients is an urgent issue. Treatments are estimated to be available for less than 6% of RD conditions, and fewer than 50 new therapies per year are approved by regulatory agencies worldwide, leaving a major discrepancy between patient needs and therapeutic solutions. This paper describes the recent key steps the IRDiRC Therapies Scientific Committee (TSC) has taken to support the future approval of 1000 new therapies, namely Step 1 (conducting a gap analysis of the rare diseases drug development landscape) and Step 2 (developing strategic themes to advance IRDiRC Goal 2 and act upon them). The IRDiRC TSC created a multi-stakeholder group to run a gap analysis of the RD drug development field. The analysis identified four main priority needs: (1) the definition of a new master plan for RD medicines suitable for all developers (large and small pharmaceutical companies, academics, and not-for-profit organizations) incorporating stakeholders’ perspectives and best practices in the field to increase efficiency in the development and registration of innovative drugs and generate more value for patients and the healthcare system; (2) the elicitation of a research framework and business model for repurposing of existing drugs for RD indications to enact a quantum enlargement of the existing therapeutic armamentarium; (3) the definition of standards and practices for data collection in healthcare practice and their implementation in drug development to provide real-world evidence; and (4) the re-focusing of the current international RD research agenda pushing for concentrated research efforts and funding in support of the development of future treatments. In addition to identifying where efforts should be put, the TSC has concretely contributed to advance the IRDiRC goal by creating tools (e.g., the Orphan Drug Development Guidebook) and recommendations and making them available to the whole RD community. However, much remains to be done, and the TSC has refined its approach to incorporate progress made and reflect on new challenges

Connaissance et prospective des parcs automobiles

Ces travaux s'inscrivent dans le cadre de la convention DGITM visant à soutenir des recherches sur les transports et leurs infrastructures. Ils portent spécifiquement sur les parcs automobiles, mobilisant plusieurs laboratoires de l'IFSTTAR, et intéressant de nombreux acteurs autour de problématiques mobilités et transports, énergétiques et environnementales, et les politiques publiques. Les travaux visaient un état de l'art de questions importantes ou émergentes ainsi que la mobilisation d'un groupe national de travail GT-PARCS autour de la problématique des parcs automobiles. Des travaux ont été menés autour des fonctions de survie et utilisation qui entrent dans la modélisation de la composition des parcs automobiles, ainsi que sur la départementalisation des compositions de parcs automobiles afin de tenir compte des spécificités locales. Une analyse de la démotorisation a été menée à partir des données de l'enquête Parcauto. Enfin une mise à jour complète de la modélisation IFSTTAR du parc automobile français a été réalisée avec notamment le réexamen de nombreuses hypothèses, la construction de scénarios prospectifs étendus à l'horizon 2050, et la prise en compte des immatriculations des années 2013 à 2018. Ce rapport fait également état des travaux du groupe de travail GT-PARCS sur les parcs automobile, qui - bien que ne s'étant réuni que 2 fois au cours des 3 dernières années - témoigne d'un intérêt accru et d'une grande richesse des contributions et des échanges

The Drosophilidae (Diptera) of the Scattered Islands, with the description of a novel association with Leptadenia madagascariensis Decne. (Apocynaceae).

International audienceThirteen drosophilid species belonging to seven genera and two subfamilies are reported from three coral islands (namely Europa, Juan de Nova and Glorioso) that belong to the Scattered Islands in the Indian Ocean. Five species are cosmopolitan and five are African. Three are endemic to the insular Western Indian Ocean, including a presumably new Scaptodrosophila species. On the island of Juan de Nova, most captured flies had pollinia attached to the bases of their proboscis. DNA analysis using the rbcl gene revealed that these pollinia belong to the genus Leptadenia (Apocynaceae), of which a single species L. madagascariensis, endemic in Madagascar and Comoros, is present in this island. This is the first reported association between this plant and drosophilids