First observations and performance of the RPW instrument onboard the Solar Orbiter mission

The Radio and Plasma Waves (RPW) instrument on the ESA Solar Orbiter mission is designed to measure in situ magnetic and electric fields and waves from the continuum up to several hundred kHz. The RPW also observes solar and heliospheric radio emissions up to 16 MHz. It was switched on and its antennae were successfully deployed two days after the launch of Solar Orbiter on February 10, 2020. Since then, the instrument has acquired enough data to make it possible to assess its performance and the electromagnetic disturbances it experiences. In this article, we assess its scientific performance and present the first RPW observations. In particular, we focus on a statistical analysis of the first observations of interplanetary dust by the instrument’s Thermal Noise Receiver. We also review the electro-magnetic disturbances that RPW suffers, especially those which potential users of the instrument data should be aware of before starting their research work

Advanced Methods for Dose and Regimen Finding During Drug Development: Summary of the EMA/EFPIA Workshop on Dose Finding (London 4-5 December 2014)

Inadequate dose selection for confirmatory trials is currently still one of the most challenging issues in drug development, as illustrated by high rates of late-stage attritions in clinical development and postmarketing commitments required by regulatory institutions. In an effort to shift the current paradigm in dose and regimen selection and highlight the availability and usefulness of well-established and regulatory-acceptable methods, the European Medicines Agency (EMA) in collaboration with the European Federation of Pharmaceutical Industries Association (EFPIA) hosted a multistakeholder workshop on dose finding (London 4-5 December 2014). Some methodologies that could constitute a toolkit for drug developers and regulators were presented. These methods are described in the present report: they include five advanced methods for data analysis (empirical regression models, pharmacometrics models, quantitative systems pharmacology models, MCP-Mod, and model averaging) and three methods for study design optimization (Fisher information matrix (FIM)-based methods, clinical trial simulations, and adaptive studies). Pairwise comparisons were also discussed during the workshop; however, mostly for historical reasons. This paper discusses the added value and limitations of these methods as well as challenges for their implementation. Some applications in different therapeutic areas are also summarized, in line with the discussions at the workshop. There was agreement at the workshop on the fact that selection of dose for phase III is an estimation problem and should not be addressed via hypothesis testing. Dose selection for phase III trials should be informed by well-designed dose-finding studies; however, the specific choice of method(s) will depend on several aspects and it is not possible to recommend a generalized decision tree. There are many valuable methods available, the methods are not mutually exclusive, and they should be used in conjunction to ensure a scientifically rigorous understanding of the dosing rationale

The MCRA toolbox of models and data to support chemical mixture risk assessment

A model and data toolbox is presented to assess risks from combined exposure to multiple chemicals using probabilistic methods. The Monte Carlo Risk Assessment (MCRA) toolbox, also known as the EuroMix toolbox, has more than 40 modules addressing all areas of risk assessment, and includes a data repository with data collected in the EuroMix project. This paper gives an introduction to the toolbox and illustrates its use with examples from the EuroMix project. The toolbox can be used for hazard identification, hazard characterisation, exposure assessment and risk characterisation. Examples for hazard identification are selection of substances relevant for a specific adverse outcome based on adverse outcome pathways and QSAR models. Examples for hazard characterisation are calculation of benchmark doses and relative potency factors with uncertainty from dose response data, and use of kinetic models to perform in vitro to in vivo extrapolation. Examples for exposure assessment are assessing cumulative exposure at external or internal level, where the latter option is needed when dietary and non-dietary routes have to be aggregated. Finally, risk characterisation is illustrated by calculation and display of the margin of exposure for single substances and for the cumulation, including uncertainties derived from exposure and hazard characterisation estimates.</p

COVID-19 vaccine-readiness for anti-CD20-depleting therapy in autoimmune diseases

Although most autoimmune diseases are considered to be CD4 T cell- or antibody-mediated, many respond to CD20-depleting antibodies that have limited influence on CD4 and plasma cells. This includes rituximab, oblinutuzumab and ofatumumab that are used in cancer, rheumatoid arthritis and off-label in a large number of other autoimmunities and ocrelizumab in multiple sclerosis. Recently, the COVID-19 pandemic created concerns about immunosuppression in autoimmunity, leading to cessation or a delay in immunotherapy treatments. However, based on the known and emerging biology of autoimmunity and COVID-19, it was hypothesised that while B cell depletion should not necessarily expose people to severe SARS-CoV-2-related issues, it may inhibit protective immunity following infection and vaccination. As such, drug-induced B cell subset inhibition, that controls at least some autoimmunities, would not influence innate and CD8 T cell responses, which are central to SARS-CoV-2 elimination, nor the hypercoagulation and innate inflammation causing severe morbidity. This is supported clinically, as the majority of SARS-CoV-2-infected, CD20-depleted people with autoimmunity have recovered. However, protective neutralizing antibody and vaccination responses are predicted to be blunted until naive B cells repopulate, based on B cell repopulation kinetics and vaccination responses, from published rituximab and unpublished ocrelizumab (NCT00676715, NCT02545868) trial data, shown here. This suggests that it may be possible to undertake dose interruption to maintain inflammatory disease control, while allowing effective vaccination against SARS-CoV-29, if and when an effective vaccine is available

Erratum: The solar orbiter radio and plasma waves (RPW) instrument (Astronomy and Astrophysics (2020) 642 (A12) DOI: 10.1051/0004-6361/201936214)

The erratum concerns Fig. 9 entitled "Antenna radio-electrical properties" for which some of the parameters are not correct. The new figure with new parameters is provided in Fig. 1 of this corrigendum. Fig. 1. Corrected Antenna radio-electrical properties. (Figure Presented)

La modélisation intégrée de la production de sédiments après l'incendie du bassin versant du Rimbaud (Var, France)

An hydrosedimentologic model, called ETC, which deals with erosion using an hydrologic approach, was developed. Its objective is to predict erosion and sediment yield within mountainous mediterranean catchments. The erosion and sediment yield component was validated on Rimbaud basin. Before Rimbaud forest fire, only rain and liquid discharge were registered. Upon an experimental plot, whose area was 75 m2, located in the upper part of the catchment, erosion was measured. The next months before the forest fire, the hydrological and erosive processes were strongly disturbed. An automatic sampler was set up at Rimbaud gauging station and provided transited sediment concentrations. Validation results were quite promising. / Le bassin versant du Rimbaud a été dévasté à 84 % de sa surface par l'incendie d'août 1990. Dans les mois qui ont suivi, les processus hydrologiques et érosifs ont été fortement pertubés. Des observations spécifiques de l'érosion ont été conduites (MARTIN C. et al., 1993) : une parcelle de 75 m2, située dans le haut du bassin, a fait l'objet de mesures ; un préleveur d'échantillons est venu compléter le dispositif préexistant à la station de jaugeage afin de connaître le débit solide en suspension ; les dépôts dans le lit et à l'amont immédiat de la station ont été estimés sommairement par topographie. Cette situation offrait l'opportunité de valider le modèle ETC au travers de la reconstitution des premières crues de l'automne 1990

Development of a physiologically based toxicokinetic model for butadiene and four major metabolites in humans : global sensivity analysis for experimental design issues

International audience1,3-Butadiene (BD) is metabolized in humans and rodents to mutagenic and carcinogenic species. Our previous work has focused on developing a physiologically based toxicokinetic (PBTK) model for BD to estimate its metabolic rate to 1,2-epoxy-3-butene (EB), using exhaled breath BD concentrations in human volunteers exposed by inhalation. In this paper, we extend our BD model to describe the kinetics of its four major metabolites EB, 1,2:3,4-diepoxybutane (DEB), 3-butene-1,2-diol (BDD), and 3,4-epoxy-1,2-butanediol (EBD), and to test whether the extended model and experimental data (to be collected for BD and metabolites in humans) are together adequate to estimate the metabolic rate constants of each of the above chemicals. Global sensitivity analyses (GSA) were conducted to evaluate the relative importance of the model parameters on model outputs during the 20 min of exposure and the 40 min after exposure ended. All model parameters were studied together with various potentially measurable model outputs: concentrations of BD and EB in exhaled air, concentrations of BD and all metabolites in venous blood, and cumulated amounts of urinary metabolites excreted within 24 h. Our results show that pulmonary absorption of BD and subsequent distribution and metabolism in the well-perfused tissues compartment are the critical processes in the toxicokinetics of BD and metabolites. In particular, three parameters influence numerous outputs: the blood:air partition coefficient for BD, the metabolic rate of BD to EB, and the volume of the well-perfused tissues. Other influential parameters include other metabolic rates, some partition coefficients, and parameters driving the gas exchanges (in particular, for BD outputs). GSA shows that the impact of the metabolic rate of BD to EB on the BD concentrations in exhaled air is greatly increased if a few of the model's important parameters (such as the blood:air partition coefficient for BD) are measured experimentally. GSA also shows that all the transformation pathways described in the PBTK model may not be estimable if only data on the studied outputs are collected, and that data on a specific output for a chemical may not inform all the transformations involving that chemical. (C) 2007 Elsevier Ireland Ltd. All rights reserved

Observation of Intensified Lower Hybrid Noise in the Midlatitude Ionosphere

International audienceWe report DEMETER observations of strongly intensified electric noise at the lower hybrid frequency in the midlatitude ionosphere during the recovery phase of a magnetic storm. The spectrum of the noise is broadband and centered at the lower hybrid frequency, which is of a very unusual shape that suggests nonlinear interaction triggered by the injection of ring current ions into the ionosphere

Simulation de l'impact du couvert végétal sur le transport en masse des sédiments dans deux bassins méditerranéens, application du modèle Shetran

The EC finded DM2E project, completed in November 1994, was aimed at evaluating the role which vegetation cover and its degradation by natural and human means plays in determining hydrological, erosion and water quality regimes in areas undergoing desertification, with specific reference to Mediterranean Europe. As the Newcastle component of the work, the SHETRAN flow and sediment transport model was applied to the Rimbaud and Draix catchments situated in the South of France to investigate its ability to represent the impacts of vegetation changes on catchment sediment yield.Le projet DM2E financé par l'UE, achevé en novembre 1994, était destiné à évaluer le rôle que le couvert de végétation et sa dégradation par la nature et l'homme joue dans la définition des régimes de la qualité de l'eau, de l'érosion et des régimes hydrologiques dans des régions en voie de désertification en référence spécifique à l'Europe méditerranéenne. Composant de Newcastle de ce travail, le modèle de transport des sédiments et d'écoulement SHETRAN a été appliqué aux bassins hydrographiques de Rimbaud et de Draix situés dans le sud de la France pour étudier sa capacité à représenter les impacts des changements de la végétation sur le rendement des sédiments de captage