A high-dose pharmacokinetic study of a new IgG4 monoclonal antibody temelimab/GNbAC1 antagonist of an endogenous retroviral protein pHERV-W Env

PURPOSE : Temelimab/GNbAC1 is a humanized immunoglobulin G4 monoclonal antibody antagonist of the human endogenous retrovirus W envelope protein, which is associated with multiple sclerosis (MS) pathophysiology and possibly with other autoimmune disorders. Human endogenous retrovirus W envelope protein is expressed in the central nervous system of patients with MS, and sufficient amount of temelimab must reach the target. The safety of very high dosages of temelimab should be tested to support further clinical trials in MS. METHODS : This randomized, placebo-controlled, dose-escalation study evaluated the safety and pharmacokinetic profile of temelimab in 24 healthy volunteers after a single intravenous infusion at doses of 36, 60, 85, and 110 mg/kg administered sequentially. FINDINGS : Temelimab was well tolerated, with no particular adverse drug reactions at any dose. The maximal dose of 110 mg/kg could be administered, and no antidrug antibodies were induced. After administration of 36–110 mg/kg, mean temelimab Cmax increased from 859 to 2450 μg/mL, and AUC values increased from 319,900 to 1,030,000 μg·h/mL. There was an approximate dose-proportional increase in exposure, similar to observations at lower doses. IMPLICATIONS : The favorable data in terms of safety and pharmacokinetic variables support temelimab use at high doses in future MS trials to optimally neutralize the temelimab target in the central nervous system. ClinicalTrials.gov identifier: NCT03574428.GeNeuro SAhttps://www.journals.elsevier.com/clinical-therapeutics2020-09-01hj2020Pharmacolog

Evaluation objective d'algorithmes de segmentation de l'intervalle RT

Nous menons dans cette communication une comparaison objective entre trois approches dédiées à l'estimation de la durée de la phase de repolarisation des ventricules, qui correspond à l'intervalle RT du signal électrocardiographique (ECG). La première méthode s'appuie sur le calcul d'une dérivée lissée du signal pour extraire les points caractéristiques de l'ECG, la deuxième se fonde, pour la recherche de ces points, sur une représentation temps-échelle alors que la troisième repose sur une modélisation inspirée des processus physiologiques qui sont à la base du signal cardiaque. Globalement les résultats montre que cette dernière méthode semble donner les performances les plus stables

Bio-Optical Sensors on Argo Floats

The general objective of the IOCCG BIO-Argo working group is to elaborate recommendations for establishing a framework for the future development of a cost-effective, bio-optical float network corresponding to the needs and expectations of the scientific community. In this context, our recommendations will necessarily be broad; they range from the identification of key bio-optical measurements to be implemented on floats, to the real-time management of the data flux resulting from the deployment of a "fleet of floats". Each chapter of this report is dedicated to an essential brick leading towards the goal of implementing a bio-optical profiling float network. The following topics are discussed in the Chapters listed below: - Chapter 2 reviews the scientific objectives that could be tackled through the development of such networks, by allowing some of the gaps in the present spatio-temporal resolution of bio-optical variables to be progressively filled. - Chapter 3 identifies the optical and bio-optical properties that are now amenable to remote and autonomous measurement through the use of optical sensors mounted on floats. - Chapter 4 addresses the question of sensor requirements, in particular with respect to measurements performed from floats. - Chapter 5 proposes and argues for the development of dedicated float missions corresponding to specific scientific objectives and relying on specific optical sensor suites, as well as on specific modes of float operation. - Chapter 6 identifies technological issues that need to be addressed for the various bio-optical float missions to become even more cost-effective. - Chapter 7 covers all aspects of data treatment ranging from the development of various quality control procedures (from real-time to delayed mode) to the architecture required for favoring easy access to data. - Chapter 8 reviews the necessary steps and experience required before the operational implementation of different types of float networks can become a reality.JRC.H.5-Land Resources Managemen

D.C. Josephson transport by quartets and other Andreev resonances in superconducting bijunctions

7 pagesInternational audienceBijunctions are three-terminal Josephson junctions where three superconductors are connected by a single weak link made of a metallic region or of quantum dots. Biasing two of the superconductors with commensurate voltages yields Andreev resonances that produce d.c. Josephson currents made of correlated Cooper pairs. For instance with applied voltages (0, V, -V ), quartets formed by two entangled Cooper pairs are emitted by one reservoir towards the two others. Theory involving non-equilibrium Green's functions reveal the microsopic mechanism at play, e.g multiple coherent Andreev reflections that provide an energy-conserving and fully coherent channel. Recent experiments on dffusive Aluminum-Copper bijunctions show transport anomalies that are interpreted in terms of quartet resonances

A new therapeutic approach for type 1 diabetes : rationale for GNbAC1, an anti‐HERV‐W‐Env monoclonal antibody

We describe a newly identified therapeutic target for type 1 diabetes (T1D): an envelope protein of endogenous retroviral origin, human endogenous retrovirus W envelope (HERV‐W‐Env). HERV‐W‐Env was found to be detected in the blood of ~60% of patients with T1D and is expressed in acinar pancreatic cells of 75% of patients with T1D at post mortem examination. Preclinical experiments showed that this protein displays direct cytotoxicity on human β‐islet cells. In vivo HERV‐W‐Env impairs the insulin and glucose metabolism in transgenic mice expressing HERV‐W‐Env. GNbAC1, an IgG4 monoclonal antibody, has been developed to specifically target HERV‐W‐Env and to neutralize the effect of HERV‐W‐Env in vitro and in vivo. GNbAC1 is currently in clinical development for multiple sclerosis and > 300 subjects have been administered with GNbAC1 so far. GNbAC1 is now being tested in T1D in the RAINBOW‐T1D study, which is a randomized placebo‐controlled study with the objective of showing the safety and pharmacodynamic response of GNbAC1 in patients who have had T1D with a maximum of 4 years' duration. GNbAC1 is being tested vs placebo at the dose of 6 mg/kg in 60 patients during six repeated administrations for 6 months; a 6‐month open‐label extension will follow. The primary endpoint is to assess safety, and secondary endpoints are the pharmacodynamic responses to GNbAC1. GNbAC1 targeting HERV‐W‐Env is currently in clinical development in T1D, with the first safety and pharmacodynamic study. If the study results are positive, this may open the door to the development of an innovative non‐immunomodulatory disease‐modifying treatment for T1D.The RAINBOW-T1D study is financed by GeNeuro Australia Pty Ltd, a subsidiary of GeNeuro SA, Switzerland.http://wileyonlinelibrary.com/journal/dom2019-09-01hj2018Pharmacolog

International Continence Society consensus on the diagnosis and treatment of nocturia

Introduction: Patients with nocturia have to face many hurdles before being diagnosed and treated properly. The aim of this paper is to: summarize the nocturia patient pathway, explore how nocturia is diagnosed and treated in the real world and use the Delphi method to develop a practical algorithm with a focus on what steps need to be taken before prescribing desmopressin. Methods: Evidence comes from existing guidelines (Google, PubMed), International Consultation on Incontinence-Research Society (ICI-RS) 2017, prescribing information and a Delphi panel (3 rounds). The International Continence Society initiated this study, the authors represent the ICI-RS, European Association of Urology, and Society of Urodynamics, Female Pelvic Medicine and Urogenital Reconstruction (SUFU). Results: Diagnostic packages: consensus on, history taking for all causalities, intake diary (fluid, food) and bladder diary, not for its duration. Pelvic (women) or rectal (men) examination, prostate-specific antigen, serum sodium check (SSC), renal function, endocrine screening: when judged necessary. Timing or empty stomach when SSC is not important. Therapeutic packages: the safe candidates for desmopressin can be phenotyped as no polydipsia, heart/kidney failure, severe leg edema or obstructive sleep apnea syndrome. Lifestyle interventions may be useful. Initiating desmopressin: risk management consensus on three clinical pictures. Follow-up of desmopressin therapy: there was consensus on SSC day 3 to 7, and at 1 month. Stop therapy if SSC is Conclusion: A summary of the nocturia patient pathway across different medical specialists is useful in the visualization and phenotyping of patients for diagnosis and therapy. By summarizing basic knowledge of desmopressin, we aim to ease its initiation and shorten the patient journey for nocturia

Rehydration of calves : Presentation of an expert system

In addition to dehydration, diarrheic enteritis in calves is generally associated with acid-base disturbances and fluid and electrolyte imbalances. The evaluation of these disorders, based on the measure of blood pH and Na+, K+, C1-, HCO3- concentrations, and on the calculation of the serum anion gap (difference between the concentrations of the major cation and the major anions) and of the base excess, helps optimise the treatment and further refine the prognosis. Acidosis is the most frequent disorder, with or without an increased serum anion gap depending on the etiology of the diarrhoea. This problem is corrected by the administration of bicarbonate or carbonate solutions. Less common disorders include alkalosis and dyskalemia. An expert system, providing a clinical and therapeutic protocol, was developed to evaluate acid-base and hydroelectric disorders associated with diarrheic enteritis in calves.En plus de la déshydratation, l'entérite diarrhéique du veau est généralement associée à des déséquilibres hydro-électrolytiques et acido-basiques. L'évaluation de ces troubles par la mesure du pH sanguin et des concentrations sériques de Na+, K+, C1-, HCO3-, et par le calcul du trou anionique (concentration sérique des cations diminuée de celle des anions) et de l'excès de base, permet d'ajuster au mieux le traitement et de préciser le pronostic. Le déséquilibre le plus fréquemment observé est l'acidose avec ou sans augmentation du trou anionique selon l'étiologie de la diarrhée. L'acidose est corrigée par l'administration de solutés bicarbonatés ou de carbonates. Les autres troubles moins fréquents sont l'alcalose et les dyskaliémies. Un système expert, sous forme d'un protocole clinique et thérapeutique, a été développé pour évaluer les troubles acido-basiques et hydro-ioniques associés aux entérites diarrhéiques du veau

Introducing Trait Networks to Elucidate the Fluidity of Organismal Evolution Using Palaeontological Data

International audienceExplaining the evolution of animals requires ecological, developmental, paleontological, and phylogenetic considerations because organismal traits are affected by complex evolutionary processes. Modeling a plurality of processes, operating at distinct timescales on potentially interdependent traits, can benefit from approaches that are complementary treatments to phylogenetics. Here, we developed an inclusive network approach, implemented in the command line software ComponentGrapher, and analyzed trait co-occurrence of rhinocerotoid mammals. We identified stable, unstable, and pivotal traits, as well as traits contributing to complexes, that may follow to a common developmental regulation, that point to an early implementation of the postcranial Bauplan among rhinocerotoids. Strikingly, most identified traits are highly dissociable, used repeatedly in distinct combinations and in different taxa, which usually do not form clades. Therefore, the genes encoding these traits are likely recruited into novel gene regulation networks during the course of evolution. Our evo-systemic framework, generalizable to other evolved organizations, supports a pluralistic modeling of organismal evolution, including trees and networks

Structured Biotinylated Poly(3,4-Ethylenedioxypyrrole) Electrodes for Biochemical Applications

The immobilization of biotin on transducer surfaces is a very important step for the fabrication of biosensors for many applications (immunoassay, DNA-hybridization assays, targeted imaging). Biotinylated polypyrroles have been studied and tested but gave rise to problems of polymerization and stability due to the intrinsic properties of pyrrole. As an alternative, biotinylated pyrroles were often used in a copolymerization with pyrrole or with an amphiphilic pyrrole derivative in a copolymerization to reduce the problems due to the pyrrole substitution. To find a new strategy, this paper presents the homopolymerization, instead of the use of a copolymerization, by replacing pyrrole by 3,4-ethylenedioxypyrrole bearing biotinylated substituent. We report the synthesis, characterization and electrochemical properties of two biotinylated 3,4-ethylenedioxypyrroles differing by the length of the alkyl spacer (ethyl or dodecyl) as well as the characterization of the corresponding polymer films. We successfully show, by cyclic voltammetry, that these monomers polymerize perfectly and give relatively stable polymer films. The increase of the alkyl spacer improves the polymerization and increases the polymer stability. For the first time, we also studied the surface morphology of an electrodeposited biotinylated polymer. The electrodeposition of these biotinylated derivatives gave rise to the ability to modulate the surface microstructuration, which consists of microspheres or cauliflower-like microstructures according to the length of the alkyl spacer.JRC.I.4-Nanobioscience

The INDC counter, aggregation of national contributrions and 2°C trajectories

Rapport du groupe interdisciplinaire sur les contributions nationalesConsidering that limiting global warming to below 2°C implies a CO2 budget not to be exceeded and near-zero emissions by 21OO (IPCC), we can assess global 2030 greenhouse gas emissions implied by INDCs in comparison to long-term trajectories. Ahead of the COP21, we estimate that submitted INDCs would bring global greenhouse gas emissions in the range of 55 to 64 GtC02eq in 2030.Under this assumption,global emissions in 2030 are thus higher than the level of 51GtC0 2eq for the year 2012. However, this is not in contradiction with a peaking of global emissions that can only be expected after 2020, given in particular the projected dynamics of emissions in China and other developing countries.The published INDCs represent a significant step towards trajectories compatible with the 2°C goal,but remain insufficient to join trajectories presenting a reasonable probability of success.ln order to increase the chance of meeting the 2°C objective, the ambition of the short-term contributions needs to be strengthened in future negotiations.ln order to sustain a high pace in emissions reductions after 2030,structural measures are also needed, which, in order to have a rapi impact, should be prepared as early as possible. Continued efforts are needed to accelerate the development of low carbon solutions on the one hand,and demonstrate the feasibility of negative emissions on the other hand