Search

Online ahead of print; International audience; Introduction: It is important to confirm the effectiveness and tolerability of disease-modifying treatments for relapsing-remitting multiple sclerosis (RRMS) in real-world treatment settings. This prospective observational cohort study (VIRGILE) was performed at the request of the French health authorities. The primary objective was to evaluate the effectiveness of fingolimod 0.5 mg in reducing the annualised relapse rate (ARR) in patients with RRMS.Methods: Participating neurologists enrolled all adult patients with RRMS starting fingolimod treatment between 2014 and 2016, who were followed for 3 years. Follow-up consultations took place at the investigator's discretion. The primary outcome measure was the change in ARR at month 24 after fingolimod initiation. Relapses and adverse events were documented at each consultation; disability assessment (EDSS) and magnetic resonance imagery were performed at the investigator's discretion.Results: Of 1055 eligible patients, 633 patients were assessable at month 36; 405 (64.0%) were treated continuously with fingolimod for 3 years. The ARR decreased from 0.92 ± 0.92 at inclusion to 0.31 ± 0.51 at month 24, a significant reduction of 0.58 [95% CI - 0.51 to - 0.65] relapses/year (p < 0.001). Since starting fingolimod, 461 patients (60.9%) remained relapse-free at month 24 and 366 patients (55.5%) at month 36. In multivariate analysis, no previous disease-modifying treatment, number of relapses in the previous year and lower EDSS score at inclusion were associated with a greater on-treatment reduction in ARR. The mean EDSS score remained stable over the course of the study. Sixty-one out of 289 (21.1%) patients presented new radiological signs of disease activity. Treatment-related serious adverse events were lymphopenia (N = 21), bradycardia (N = 19), elevated transaminases (N = 9) and macular oedema (N = 9).Conclusions: The effectiveness and tolerability of fingolimod in everyday clinical practice are consistent with findings of previous phase III studies. Our study highlights the utility of fingolimod for the long-term management of patients with multiple sclerosis.

Introduction Detecting safety signals attributed to a drug in scientific literature is a fundamental issue in pharmacovigilance. The constant increase in the volume of publications requires the automation of this tedious task, in order to find and extract relevant articles from the pack. This task is critical, as serious Adverse Drug Reactions (ADRs) still account for a large number of hospital admissions each year. Objectives The aim of this study is to develop an augmented intelligence methodology for automatically identifying relevant publications mentioning an established link between a Drug and a Serious Adverse Event, according to the European Medicines Agency (EMA) definition of seriousness. Methods The proposed pipeline, called LiSA (for Literature Search Application), is based on three independent deep learning models supporting a precise detection of safety signals in the biomedical literature. By combining a Bidirectional Encoder Representations from Transformers (BERT) algorithms and a modular architecture, the pipeline achieves a precision of 0.81 and a recall of 0.89 at sentences level in articles extracted from PubMed (either abstract or full-text). We also measured that by using LiSA, a medical reviewer increases by a factor of 2.5 the number of relevant documents it can collect and evaluate compared to a simple keyword search. In the interest of re-usability, emphasis was placed on building a modular pipeline allowing the insertion of other NLP modules to enrich the results provided by the system, and extend it to other use cases. In addition, a lightweight visualization tool was developed to analyze and monitor safety signal results. Conclusions Overall, the generic pipeline and the visualization tool proposed in this article allows for efficient and accurate monitoring of serious adverse drug reactions from the literature and can easily be adapted to similar pharmacovigilance use cases. To facilitate reproducibility and benefit other research studies, we also shared a first benchmark dataset for Serious Adverse Drug Events detection.

Venous-thromboembolism (VTE) is increased in lung cancer patients (LCP) treated with immune-checkpoint inhibitors (ICIs) but risk factors are not identified and the Khorana Score (KS) is not validated. To assess VTE incidence and its clinical impact, to investigate potential clinical risk factors and KS performance in LCP. Retrospective analysis of LCP initiating ICIs treatment between June 2015 and November 2020 in a for-profit cancer center. 481 patients were included: 62% adenocarcinoma, 70% PDL1 + , 86% stage-IV-disease. Over a median follow-up of 9.8 months, 47 VTE were observed: 28 pulmonary embolisms, 15 deep venous thromboses (distal n = 9, proximal n = 6), 3 inferior vena cava thromboses, 1 other VTE, no superficial or digestive vein thrombosis. Median time from ICIs' initiation to VTE was 180 (11-1277) days. Overall survival was significantly lower in patients who experienced VTE (42.5 vs. 86.8 months, p = 0.006). In univariate analysis patients VTE was more frequent in metastatic patients (11.1% vs. 1.5%, p = 0.015) and lower in those treated with durvalumab (1.9% vs. 9.6%, p = 0.046). Logistic regression analysis showed that non-metastatic status (OR 0.13; 0.02-0.95, p = 0.04) and BMI (OR 1.07; 1.01-1.14, p = 0.028) were associated with VTE. The rate of VTE was the same in patients with a KS or ≥ 2 (10.2% vs. 9.3%, p = 0.87). ICIs-treated LCP are at high risk of thromboembolism. VTE has a negative impact on survival. KS does not perform well in LCP. It is important to identify which VTE prediction models are available to be used in adult ambulatory lung cancer patients.

Extracellular matrix (ECM) proteins are major components of most tissues and organs. In addition to their crucial role in tissue cohesion and biomechanics, they chiefly regulate various important biological processes during embryonic development, tissue homeostasis and repair. In essence, ECM proteins were defined as secreted proteins that localized in the extracellular space. The characterization of the human and mouse matrisomes provided the first definition of ECM actors by comprehensively listing ECM proteins and classified them into categories. Because zebrafish is becoming a popular model to study ECM biology, we sought to characterize the zebrafish matrisome using an in-silico gene-orthology-based approach. We report the identification of 1002 genes encoding the in-silico zebrafish matrisome. Using independent validations, we provide evidence for the robustness of the orthology-based approach. Moreover, we evaluated the orthology relationships between human and zebrafish genes at the whole-genome and matrisome levels and showed that the different categories of ECM genes are differentially subjected to evolutionary pressure. Last, we illustrate how the zebrafish matrisome list can be employed to annotate big data using the example of a previously published proteomic study of the skeletal ECM. The establishment of the zebrafish matrisome will undoubtedly facilitate the analysis of ECM components in "-omic" data sets.

The current globalization is faced to the rapid development of product design process with the different structure of the actor relationships in the process. Currently, the risk in the failure relationship among different actors in the project is shaped by the complexity towards the future all kinds of challenges. When it comes to the interdependent failure effect, the risk management for future organization structure in design process will be much more complex to grasp. In order to cope with adaption of Product-Process-Organization (P-P-O) model for industry of the future, we propose a risk management methodology to cope with this interdependent relationship structure. The main objective of this research is to manage the risks, so that the project manager can find the priority order of all the actors' total effect to the project with the consideration of interdependent failure affection, and according to the order, project manager can release corresponding respond measures.

Additional file 1. Description of bioinformatic analysis and supplementary results for pilot and patient studies.

Die durch Dieckmann-Cyclisierung der Diester (I) unter der Einwirkung von K-tert.- butylat in tert-Butanol bei 25°C dargestellten Ketoester (II) reagieren mit aquimolaren Erz-Mengen zu Monobromderivaten; deren Dehydrobromierung mit Triathylamin liefert die ungesatigten Ester (III) (Ausbeute 66-78%).

Die Kondensation des Pyrimidins (I) mit dem Ester (II) liefert das Pyrirnidinderivat (III), das nach Dieckmann mit K-tert.-butylat (tBuO) zum Pyridopyrimidin (IV) cyclisiert wird.

Described is method for introducing a desired nucleic acid into a eukaryotic host cell, said method comprising a) admixing the desired nucleic acid, a mono- and/or divalent metal cation and a eukaryotic host cell lacking a cell wallb) incubating the mixture to allow the eukaryotic host cell to take up the nucleic acid.

The invention relates to a new and efficient staged gasification process characterized by a close integration of the gas cleaning part. The unit and process use a new device named Total Char Combustion and Tar Cracking Chamber (TCC) positioned between a pyrolysis unit (PYR) and a char reduction reactor (CRC), in a stage divided gasifier. The char conversion takes place in 2 steps. In the first step, the char produced in the pyrolysis unit (PYR) is introduced in the (CRC) whose main purpose is to convert as much as possible carbon of the char. The (CRC) belongs to the fluidized bed type. The second step takes place in the (TCC) whose purpose is to perform both a complete conversion of the remaining carbon still present after reaction in the (CRC); and the thermal cracking of the tar contained in the pyrolysis gases, the residual ashes being vitrified simultaneous and eliminated as a slag. Low grade feedstock with low melting point ashes can be used: straw and bark. A new vibrofluidized pyrolysis unit is implated to achieve an appropriate and constant quality of char with a minimum preparation of the biomass, and offers the opportunity to orientate the process for gas or solid. The invention leads to the following advantages: higher tolerance toward different quality of feedstocks including low grade feedstocks; recovery of the residual carbon content in ashes; production of a clean gas (low residual tar, ashes and alkali) for a direct injection in an engine/turbine. These results will induce a higher efficiency of the process and consequently bring to maturity the gasification technology.

This paper presents an extension of the GRAI approach in the scope of the control of design systems of manufactured products and its validation with an industrial application. The product design is defined as the evolution of a flow of informations representing the product knowledge. It is enlightened that both the design process and the product knowledge should be simultaneously and concurrently managed. We propose a model to control the design system, based on the study of the decision sub-system. This control is determined by objectives linked on the one hand, to the product (quality, cost, delay) and, on the other hand, to the system (resources, multi-projects management, cost of activities). The industrial experimentation allows us to conclude on the pertinence of the elements of control which are proposed.

Within the frame of the development of GRAI methodology in the Concurrent Engineering domain, we propose to model jointly and simultaneously engineering activities and product. From an extension of GRAI nets to represent and pilot engineering activities, we model their nature (design, execution, decision) and their logic succession in the development process. For the description and the management of product knowledge, we use a model based on the concepts of functions and technological entities.