Natalizumab treatment shows low cumulative probabilities of confirmed disability worsening to EDSS milestones in the long-term setting.

Abstract Background Though the Expanded Disability Status Scale (EDSS) is commonly used to assess disability level in relapsing-remitting multiple sclerosis (RRMS), the criteria defining disability progression are used for patients with a wide range of baseline levels of disability in relatively short-term trials. As a result, not all EDSS changes carry the same weight in terms of future disability, and treatment benefits such as decreased risk of reaching particular disability milestones may not be reliably captured. The objectives of this analysis are to assess the probability of confirmed disability worsening to specific EDSS milestones (i.e., EDSS scores ≥3.0, ≥4.0, or ≥6.0) at 288 weeks in the Tysabri Observational Program (TOP) and to examine the impact of relapses occurring during natalizumab therapy in TOP patients who had received natalizumab for ≥24 months. Methods TOP is an ongoing, open-label, observational, prospective study of patients with RRMS in clinical practice. Enrolled patients were naive to natalizumab at treatment initiation or had received ≤3 doses at the time of enrollment. Intravenous natalizumab (300 mg) infusions were given every 4 weeks, and the EDSS was assessed at baseline and every 24 weeks during treatment. Results Of the 4161 patients enrolled in TOP with follow-up of at least 24 months, 3253 patients with available baseline EDSS scores had continued natalizumab treatment and 908 had discontinued (5.4% due to a reported lack of efficacy and 16.4% for other reasons) at the 24-month time point. Those who discontinued due to lack of efficacy had higher baseline EDSS scores (median 4.5 vs. 3.5), higher on-treatment relapse rates (0.82 vs. 0.23), and higher cumulative probabilities of EDSS worsening (16% vs. 9%) at 24 months than those completing therapy. Among 24-month completers, after approximately 5.5 years of natalizumab treatment, the cumulative probabilities of confirmed EDSS worsening by 1.0 and 2.0 points were 18.5% and 7.9%, respectively (24-week confirmation), and 13.5% and 5.3%, respectively (48-week confirmation). The risks of 24- and 48-week confirmed EDSS worsening were significantly higher in patients with on-treatment relapses than in those without relapses. An analysis of time to specific EDSS milestones showed that the probabilities of 48-week confirmed transition from EDSS scores of 0.0–2.0 to ≥3.0, 2.0–3.0 to ≥4.0, and 4.0–5.0 to ≥6.0 at week 288 in TOP were 11.1%, 11.8%, and 9.5%, respectively, with lower probabilities observed among patients without on-treatment relapses (8.1%, 8.4%, and 5.7%, respectively). Conclusions In TOP patients with a median (range) baseline EDSS score of 3.5 (0.0–9.5) who completed 24 months of natalizumab treatment, the rate of 48-week confirmed disability worsening events was below 15%; after approximately 5.5 years of natalizumab treatment, 86.5% and 94.7% of patients did not have EDSS score increases of ≥1.0 or ≥2.0 points, respectively. The presence of relapses was associated with higher rates of overall disability worsening. These results were confirmed by assessing transition to EDSS milestones. Lower rates of overall 48-week confirmed EDSS worsening and of transitioning from EDSS score 4.0–5.0 to ≥6.0 in the absence of relapses suggest that relapses remain a significant driver of disability worsening and that on-treatment relapses in natalizumab-treated patients are of prognostic importance

Caractérisation physiopathologique, moléculaire et métabolique de la jonction neuromusculaire et du nerf périphérique après lésion du système nerveux central

Une lésion du SNC occasionne par le biais d'une dénervation trans-synaptique la survenue d'un handicap fonctionnel majeur découlant à la fois du déficit sensitivo-moteur engendré par les dégâts neuronaux primitifs, mais aussi d'une spasticité de déafférentation et d'une amyotrophie qu'il est bien difficile, conceptuellement, d'attribuer seulement à une sous-utilisation musculaire. Ce travail a permis d'incriminer des dysfonctionnements morphologiques et métaboliques précoces survenant dans les nerfs périphériques et muscles sous-jacents à une lésion du SNC, dysfonctionnements qui pourraient, en partie, expliquer certains mécanismes d'adaptation de l'organisme en réponse à la dénervation trans-synaptique. Nous avons montré que ces mécanismes seraient sous-tendus par l'existence de circuits intra-spinaux d'une part, et par le rôle potentiel de signalisation intracellulaire neuronal des isoformes de la pompe à sodium d'autre part. Nous avons également observé des modifications précoces du métabolisme énergétique lipidique impliquant particulièrement les acides gras poly-insaturés dont la participation serait directement au coeur des mécanismes de réparation neuronale. Les perspectives de recherche se dégageant de cette étude sont multiples et pourraient nous amener à élargir notre approche métabolique à un regard résolument tourné vers la fonction et la programmation motrice. De telles ambitions restent à la hauteur du challenge laissé quasiment intact par ces travaux de nature exploratoires.POITIERS-BU Médecine pharmacie (861942103) / SudocSudocFranceF

Amplification de puissance en technologie GaN en classe B exacte avec la technique de suivi d'enveloppe appliquée sur la grille

National audienceCe travail concerne l'amélioration de la linéarité d'un amplificateur10W en bande S en technologie GaN, polarisé en classe B exacte (IDSQ=0mA) en utilisant la technique de suivi d'enveloppe sur la grille. Un traitement simple de l'enveloppe du signal RF d'entrée est appliqué pour obtenir une tension de polarisation qui est remontée au-dessus du point de pincement lorsque la puissance instantanée du signal d'entrée RF est faible. Cette technique permet une amélioration de la linéarité de l'amplificateur de puissance avec un très faible impact sur le rendement en puissance ajoutée. Dans cet article, un gain de près de 6 dB de l'ACPR pour un signal 16-QAM 2MSymb / s à 2,5 GHz a été expérimentalement obtenu. Enfin, un prototype de circuit de gestion de la polarisation dynamique de grille à base d'amplificateurs opérationnels rapides a été développé et est présenté

A 20W ka-band radial solid-state power amplifier with 20% associated power-added efficiency

International audienceThis paper presents a high power and high efficiency Ka-band Solid-State Power Amplifier based on the uses of an efficient radial power-combining structure for space applications. This design was validated by the measurement of a 16-way divider/combiner and the characterization of a 16-way High Power Amplifier. Based on the use of 1.3W elementary amplifier modules, the radial HPA delivers an output power higher than 20W with an associated Power-Added Efficiency close to 20% from 35.3GHz to 36.5GHz. The loss of the radial combiner was measured at around 0.3dB. The HPA volume is equivalent to a cylinder of 20cm diameter and 7cm height

High Efficiency Class-B power amplifier with dynamic gate biasing for improved linearity

International audienc

Phase compensation technique in a radial divider/combiner structure

International audienceThe paper presents an efficient technique to compensate for phase dispersion of the elementary power amplifiers in a radial power divider/combiner. A power combiner structure is very sensitive to the phase mismatch between ways which cause degradation of the power combining efficiency. The technique is applied to a 16-way divider/combiner designed for Solid State Power Amplifiers in the K band. The 16-way structure consists of a radial non-resonant cavity connected to 8 peripheral rectangular waveguides with two waveguide-to-microstrip transitions inserted in each peripheral waveguide. Each individual way can be adjusted separately by mechanical sliding of the tray that supports the amplification module. The phase compensation technique was validated with a passive 16-way divider/combiner using trays with different lengths of the microstrip lines to simulate phase mismatch between ways. Finally, a 2-way active module with two combined MMICs has also been tested with 33 dBm output power at 19 GHz

Formation of Nup98-containing nuclear bodies in HeLa sublines is linked to genomic rearrangements affecting chromosome 11.

International audienc

Molecular karyotyping in human constitutional cytogenetics

International audienc