Safety and immunogenicity of a chimpanzee adenovirus-vectored Ebola vaccine in healthy adults: a randomised, double-blind, placebo-controlled, dose-finding, phase 1/2a study.

BACKGROUND: The ongoing Ebola outbreak led to accelerated efforts to test vaccine candidates. On the basis of a request by WHO, we aimed to assess the safety and immunogenicity of the monovalent, recombinant, chimpanzee adenovirus type-3 vector-based Ebola Zaire vaccine (ChAd3-EBO-Z). METHODS: We did this randomised, double-blind, placebo-controlled, dose-finding, phase 1/2a trial at the Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland. Participants (aged 18-65 years) were randomly assigned (2:2:1), via two computer-generated randomisation lists for individuals potentially deployed in endemic areas and those not deployed, to receive a single intramuscular dose of high-dose vaccine (5 × 10(10) viral particles), low-dose vaccine (2·5 × 10(10) viral particles), or placebo. Deployed participants were allocated to only the vaccine groups. Group allocation was concealed from non-deployed participants, investigators, and outcome assessors. The safety evaluation was not masked for potentially deployed participants, who were therefore not included in the safety analysis for comparison between the vaccine doses and placebo, but were pooled with the non-deployed group to compare immunogenicity. The main objectives were safety and immunogenicity of ChAd3-EBO-Z. We did analysis by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT02289027. FINDINGS: Between Oct 24, 2014, and June 22, 2015, we randomly assigned 120 participants, of whom 18 (15%) were potentially deployed and 102 (85%) were non-deployed, to receive high-dose vaccine (n=49), low-dose vaccine (n=51), or placebo (n=20). Participants were followed up for 6 months. No vaccine-related serious adverse events were reported. We recorded local adverse events in 30 (75%) of 40 participants in the high-dose group, 33 (79%) of 42 participants in the low-dose group, and five (25%) of 20 participants in the placebo group. Fatigue or malaise was the most common systemic adverse event, reported in 25 (62%) participants in the high-dose group, 25 (60%) participants in the low-dose group, and five (25%) participants in the placebo group, followed by headache, reported in 23 (57%), 25 (60%), and three (15%) participants, respectively. Fever occurred 24 h after injection in 12 (30%) participants in the high-dose group and 11 (26%) participants in the low-dose group versus one (5%) participant in the placebo group. Geometric mean concentrations of IgG antibodies against Ebola glycoprotein peaked on day 28 at 51 μg/mL (95% CI 41·1-63·3) in the high-dose group, 44·9 μg/mL (25·8-56·3) in the low-dose group, and 5·2 μg/mL (3·5-7·6) in the placebo group, with respective response rates of 96% (95% CI 85·7-99·5), 96% (86·5-99·5), and 5% (0·1-24·9). Geometric mean concentrations decreased by day 180 to 25·5 μg/mL (95% CI 20·6-31·5) in the high-dose group, 22·1 μg/mL (19·3-28·6) in the low-dose group, and 3·2 μg/mL (2·4-4·9) in the placebo group. 28 (57%) participants given high-dose vaccine and 31 (61%) participants given low-dose vaccine developed glycoprotein-specific CD4 cell responses, and 33 (67%) and 35 (69%), respectively, developed CD8 responses. INTERPRETATION: ChAd3-EBO-Z was safe and well tolerated, although mild to moderate systemic adverse events were common. A single dose was immunogenic in almost all vaccine recipients. Antibody responses were still significantly present at 6 months. There was no significant difference between doses for safety and immunogenicity outcomes. This acceptable safety profile provides a reliable basis to proceed with phase 2 and phase 3 efficacy trials in Africa. FUNDING: Swiss State Secretariat for Education, Research and Innovation (SERI), through the EU Horizon 2020 Research and Innovation Programme

Data-Informed Lifetime Reliability Prediction for Offshore Wind Farms

This is the author accepted manuscript. The final version is available from IEEE via the DOI in this recordOffshore wind operation and maintenance (O&M) costs can reach up to 1/3 of the overall project costs. In order to accelerate the deployment of these clean energy assets, costs need to come down. This requires, a good understanding of the different operations along with a robust planning, maintenance and monitoring strategy. Asset management tools have been developed, which require reliability inputs, able to estimate the lifetime operational expenditure (OPEX) and optimize the maintenance strategies for the assets. The lack of large datasets with offshore wind failure rate data in the literature increases the uncertainty in the estimations made by those tools. This paper aims to compare whether the publicly available data could provide an accurate information of the lifetime reliability predictions of the assets. It initially uses a generic average failure rate, taken from literature to model the wind farm; as most wind farm developers will not have any detailed understanding of the reliability of the asset prior to construction. It then uses a more detailed, turbine-specific model, taking into account reliability data from an operational wind farm. Results show a small overall difference when the model uses the data-informed parameters, by up to 0.4% in the overall availability. Moreover, it is shown that the use of generic values can create more pessimistic results compared to the data-informed data. The results of the paper are of interest to offshore wind farm developers and operators aiming to improve their lifetime reliability estimations and reduce the O&M costs of the offshore wind farms.Energy Technology InstituteEngineering and Physical Sciences Research Council (EPSRC)EDF Energ

L’intégration au quotidien : les représentations des enseignantes et des enseignants au sein d’un établissement scolaire

Entre l’intention de mettre en œuvre une politique d’intégration au sein d’un établissement et la perception de celle-ci par les enseignant-e-s, il y a un écart dont il est important de prendre la mesure. En effet, c’est bien dans le vécu des enseignant-e-s que la réussite ou non d’un projet d’intégration ou d’inclu- sion se joue et il est essentiel que le pilotage de l’école passe par une meilleu- re connaissance des représentations de ses acteurs. Notre étude, inscrite dans la réalité d’un établissement scolaire primaire et secondaire, vise à mettre en évidence ces représentations et à les porter en regard des travaux de recherches menés sur la thématique de l’intégration et de l’inclusion. De cette confrontation naissent de nouvelles pistes d’accompa- gnement des enseignant-e-s dans ce défi quotidien qui est de maintenir ou intégrer des élèves en grande difficulté au sein d’une classe ordinaire

Utiles explicaciones sobre los seguros de vida

Rúst

Iterated racing algorithm for simulation-optimisation of maintenance planning.

The purpose of this paper is two fold. First, we present a set of benchmark problems for maintenance optimisation called VMELight. This model allows the user to define the number of components in the system to maintain and a number of customisable parameters such as the failure distribution of the components, the spare part stock level and every costs associated with the preventive and corrective maintenances, unavailability and spare parts. From this model, we create a benchmark of 175 optimisation problems across different dimensions. This benchmark allows us to test the idea of using an iterated racing algorithm called IRACE based on the Friedman statistical test, to reduce the number of simulations needed to compare solutions in the population.We assess different population size and truncation rate to show that those parameters can have a strong influence on the performance of the algorithm

What crowding can tell us about object representations

In crowding, perception of a target usually deteriorates when flanking elements are presented next to the target. Surprisingly, adding further flankers can lead to a release from crowding. In previous work we showed that, for example, vernier offset discrimination at 9� of eccentricity deteriorated when a vernier was embedded in a square. Adding further squares improved performance. The more squares presented, the better the performance, extending across 20� of the visual field. Here, we show that very similar results hold true for shapes other than squares, including unfamiliar, irregular shapes. Hence, uncrowding is not restricted to simple and familiar shapes. Our results provoke the question of whether any type of shape is represented at any location in the visual field. Moreover, small changes in the orientation of the flanking shapes led to strong increases in crowding strength. Hence, highly specific shape-specific interactions across large parts of the visual field determine vernier acuity

What crowding can tell us about object representations

Peer reviewedPublisher PD

Axonal regeneration is compromised in NFH-LacZ transgenic mice but not in NFH-GFP mice

To investigate neurofilament (NF) dynamics during the cytoskeleton reorganization in regenerating axons, and their electrophysiological and histological consequences, we used two transgenic lines of mice: neurofilament high (NFH)-LacZ and NFH-green fluorescent protein (GFP). In NFH-LacZ mice, NFs are retained in cell bodies and deficient in axons (Eyer and Peterson, 1994), while in NFH-GFP mice the fluorescent fusion protein is normally transported along axons (Letournel et al., 2006). Following a crush of the sciatic nerve, conduction recovery in NFH-GFP mice is similar to wild-type (wt) mice, but it is reduced in NFH-LacZ mice. Moreover, changes of axonal calibres following regeneration are similar between NFH-GFP and wt mice, but they are systematically reduced in NFH-LacZ mice. Finally, the axonal transport of NFH-GFP fusion protein and NFs is re-initiated after the crush as evidenced by the fluorescent and immunolabelling of axons distal from the crushed point, but NFs and the fusion protein are not transported along axons during regeneration in NFH-LacZ mice. Together, these results argue that the absence of axonal NFs in NFH-LacZ mice compromises the axonal regeneration, and that the NFH-GFP reporter fusion protein represents an efficient model to evaluate the NF dynamics during axonal regeneration