Conception de VCOs 15 GHz à très faible bruit de phase intégrés sur technologie BiCMOS SiGe 0,25μm

National audienceCe papier présente les résultats issus de l'étude de deux topologies d'oscillateurs contrôlés en tension entièrement intégrés sur une technologie BiCMOS SiGe:C 0,25μm, développée par NXP Semiconductors (QUBiC4X). La principale caractéristique analysée porte sur les performances en terme de bruit de phase. Les topologies retenues sont des architectures reconnues comme étant parmi les plus performantes dans les bandes L ou S. Il nous a donc semblé intéressant d'évaluer leurs performances dans la bande Ku pour laquelle les technologies III-V sont généralement utilisées

Effect of Evobrutinib on Slowly Expanding Lesion Volume in Relapsing Multiple Sclerosis: A Post Hoc Analysis of a Phase 2 Trial

Evobrutinib; Lesion; Relapsing multiple sclerosisEvobrutini; Lesión; Esclerosis múltiple recurrenteEvobrutinib; Lesió; Esclerosi múltiple recurrentBackground and Objectives Chronic active lesions (CALs) are demyelinated multiple sclerosis (MS) lesions with ongoing microglia/macrophage activity, resulting in irreversible neuronal damage and axonal loss. Evobrutinib is a highly selective, covalent, CNS-penetrant, Bruton tyrosine kinase inhibitor. This post hoc analysis evaluated the effect of evobrutinib on slowly expanding lesion (SEL) volume, an MRI marker of CALs, assessed baseline–week 48 in a phase 2, double-blind, randomized trial (NCT02975349) in relapsing MS (RMS). Methods In the 48-week, double-blind trial, adult patients received evobrutinib (25 mg once daily [QD], 75 mg QD, or 75 mg twice daily [BID]), placebo (switched to evobrutinib 25 mg QD after week 24), or open-label dimethyl fumarate (DMF) 240 mg BID. SELs were defined as slowly and consistently radially expanding areas of preexisting T2 lesions of ≥10 contiguous voxels (∼30 mm3) over time. SELs were identified by MRI and assessed by the Jacobian determinant of the nonlinear deformation from baseline to week 48. SEL volume analysis, stratified by baseline T2 lesion volume tertiles, was based on week 48/end-of-treatment status (completers/non-completers). Treatment effect was analyzed using the stratified Hodges-Lehmann estimate of shift in distribution and stratified Wilcoxon rank-sum test. Comparisons of evobrutinib and DMF vs placebo/evobrutinib 25 mg QD were made. Subgroup analyses used pooled treatment groups (evobrutinib high dose [75 mg QD/BID] vs low dose [placebo/evobrutinib 25 mg QD]). Results The SEL analysis set included 223 patients (mean [SD] age: 42.4 [10.7] years; 69.3% female; 87.4% relapsing/remitting MS). Mean (SD) SEL volume was 2,099 (2,981.0) mm3 with evobrutinib 75 mg BID vs 2,681 (3,624.2) mm3 with placebo/evobrutinib 25 mg QD. Median number of SELs/patient ranged from 7 to 11 across treatments. SEL volume decreased with increasing evobrutinib dose vs placebo/evobrutinib 25 mg QD, and no difference with DMF vs placebo/evobrutinib 25 mg QD was noted. SEL volume significantly decreased with evobrutinib 75 mg BID vs placebo/evobrutinib 25 mg QD (−474.5 mm3 [−1,098.0 to −3.0], p = 0.047) and vs DMF (−711.6 [−1,290.0 to −149.0], p = 0.011). SEL volume was significantly reduced for evobrutinib high vs low dose within baseline Expanded Disability Status Scale ≥3.5 and longer disease duration (≥8.5 years) subgroups. Discussion Evobrutinib reduced SEL volume in a dose-dependent manner in RMS, with a significant reduction with evobrutinib 75 mg BID. This is evident that evobrutinib affects brain lesions associated with chronic inflammation and tissue loss. Trial Registration Information ClinicalTrials.gov number: NCT02975349. Submitted to ClinicalTrials.gov on November 29, 2016. First patient enrolled: March 7, 2017. Classification of Evidence This study provides Class II evidence that evobrutinib reduces the volume of SELs assessed on MRI comparing baseline with week 48, in patients with RMS.The trial was sponsored by the healthcare business of Merck KGaA, Darmstadt, Germany (CrossRef Funder ID: 10.13039/100009945)

Pharmacodynamic biomarkers of long-term interferon beta-1a therapy in REFLEX and REFLEXION.

Abstract This post-hoc analysis evaluated candidate biomarkers of long-term efficacy of subcutaneous interferon beta-1a (sc IFN β-1a) in REFLEX/REFLEXION studies of clinically isolated syndrome. Samples from 507 REFLEX and 287 REFLEXION study participants were analyzed. All investigated biomarkers were significantly upregulated 1.5–4-fold in response to sc IFN β-1a treatment versus baseline (p ≤ 0.008). The validity of MX1, 2'5'OAS, and IL-1RA as biomarkers of response to sc IFN β-1a was confirmed in this large patient cohort, with biomarkers consistently upregulated in a dose-dependent manner. Neopterin, TRAIL, and IP-10 were confirmed as biomarkers associated with long-term sc IFN β-1a treatment efficacy over 5 years

Antibody response to SARS-CoV-2 vaccines in patients with relapsing multiple sclerosis treated with evobrutinib: A Bruton\u27s tyrosine kinase inhibitor

BACKGROUND: Evobrutinib is an oral, central nervous system (CNS)-penetrant and highly selective covalent Bruton\u27s tyrosine kinase inhibitor under clinical development for patients with relapsing multiple sclerosis (RMS). OBJECTIVE: To investigate the effect of evobrutinib on immune responses in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccinated patients with RMS from a Phase II trial (NCT02975349). METHODS: A RESULTS: In the vaccinated subgroup, mean/minimum evobrutinib exposure pre-vaccination was 105.2/88.7 weeks. In total, 43 of 45 patients developed/increased S1/S2 IgG antibody levels post-vaccination; one patient\u27s antibody response remained negative post-vaccination and the other had antibody levels above the upper limit of detection, both pre- and post-vaccination. Most patients ( CONCLUSION: These results suggest evobrutinib, an investigational drug with therapeutic potential for patients with RMS, acts as an immunomodulator, that is, it inhibits aberrant immune cell responses in patients with RMS, while responsiveness to foreig

Efficacy and Safety Results After \u3e35 Years of Treatment With the Bruton’s Tyrosine Kinase Inhibitor Evobrutinib in Relapsing Multiple Sclerosis: Long-Term Follow-Up of a Phase II Randomised Clinical Trial With a Cerebrospinal Fluid Sub-Study

BACKGROUND: Evobrutinib - an oral, central nervous system (CNS)-penetrant, and highly selective Bruton\u27s tyrosine kinase inhibitor - has shown efficacy in a 48-week, double-blind, Phase II trial in patients with relapsing MS. OBJECTIVE: Report results of the Phase II open-label extension (OLE; up to week 192 from randomisation) and a cerebrospinal fluid (CSF) sub-study. METHODS: In the 48-week double-blind period (DBP), patients received evobrutinib 25 mg once-daily, 75 mg once-daily, 75 mg twice-daily or placebo (switched to evobrutinib 25 mg once-daily after week 24). Patients could then enter the OLE, receiving evobrutinib 75 mg once-daily (mean (± standard deviation (SD)) duration = 50.6 weeks (±6.0)) before switching to 75 mg twice-daily. RESULTS: Of 164 evobrutinib-treated patients who entered the OLE, 128 (78.0%) completed ⩾192 weeks of treatment. Patients receiving DBP evobrutinib 75 mg twice-daily: annualised relapse rate at week 48 (0.11 (95% confidence interval (CI) = 0.04-0.25)) was maintained with the OLE twice-daily dose up to week 192 (0.11 (0.05-0.22)); Expanded Disability Status Scale score remained stable; serum neurofilament light chain fell to levels like a non-MS population ( CONCLUSION: Long-term evobrutinib treatment was well tolerated and associated with a sustained low level of disease activity. Evobrutinib was present in CSF at concentrations similar to plasma

Mobilise-D insights to estimate real-world walking speed in multiple conditions with a wearable device

This study aimed to validate a wearable device’s walking speed estimation pipeline, considering complexity, speed, and walking bout duration. The goal was to provide recommendations on the use of wearable devices for real-world mobility analysis. Participants with Parkinson’s Disease, Multiple Sclerosis, Proximal Femoral Fracture, Chronic Obstructive Pulmonary Disease, Congestive Heart Failure, and healthy older adults (n = 97) were monitored in the laboratory and the real-world (2.5 h), using a lower back wearable device. Two walking speed estimation pipelines were validated across 4408/1298 (2.5 h/laboratory) detected walking bouts, compared to 4620/1365 bouts detected by a multi-sensor reference system. In the laboratory, the mean absolute error (MAE) and mean relative error (MRE) for walking speed estimation ranged from 0.06 to 0.12 m/s and − 2.1 to 14.4%, with ICCs (Intraclass correlation coefficients) between good (0.79) and excellent (0.91). Real-world MAE ranged from 0.09 to 0.13, MARE from 1.3 to 22.7%, with ICCs indicating moderate (0.57) to good (0.88) agreement. Lower errors were observed for cohorts without major gait impairments, less complex tasks, and longer walking bouts. The analytical pipelines demonstrated moderate to good accuracy in estimating walking speed. Accuracy depended on confounding factors, emphasizing the need for robust technical validation before clinical application. Trial registration: ISRCTN – 12246987