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Quantitative tracking of inflammatory activity at the peak and trough plasma levels of tofacitinib, a Janus kinase inhibitor, via in vivo 18F‐FDG PET

PurposeTo assess the capability of in vivo positron emission tomography (PET) using 18 F-fluorodeoxyglucose (18 F-FDG) to quantify changes in inflammatory activity in response to tofacitinib, a Janus kinase (JAK) inhibitor, over a timeframe of a few hours to few days in a preclinical model of rheumatoid arthritis (RA).MethodsTwenty-four mice with collagen-induced arthritis in the following groups were assessed: Group 1, where the changes in PET measures for the extremity joints were evaluated at the peak and trough plasma drug levels after administration of a single dose of tofacitinib (4 hours apart); Group 2, where joint PET measures were assessed before treatment and after 6 days of administration of a daily dose of tofacitinib; and group 3 (controls), where joint PET measures were derived from the same mice, 6 days apart.ResultsAt about peak plasma levels of the drug after a single tofacitinib administration, there was a reduction in PET measures compared to pretreatment values, suggesting decreased inflammatory activity. These measures were equivalent to those obtained after 6 days of daily dosing by tofacitinib. However, PET measures at trough plasma levels of the drug from tofacitinib administration were significantly higher than those at peak plasma drug levels and equivalent to pretreatment measures. There were insignificant changes in PET measures for the control animals.Conclusion18 F-FDG PET can detect changes in inflammatory activity occurring in response to the JAK inhibitor tofacitinib: (a) during peak and trough plasma drug levels, that is within mere hours of treatment; and (b) over a span of days

CMS Technical design report for the Muon Endcap GEM upgrade

This report describes both the technical design and the expected performance of the Phase-II upgrade, using Gas Electron Multiplier (GEM) detectors, of the first endcap station of the CMS muon system. The upgrade is targeted for the second long shutdown of the CERN LHC and is designed to improve the muon trigger and tracking performance at high luminosity. The GEM detectors will add redundancy to the muon system in the 1.6 < |η| < 2.2 pseudorapidity region, where the amount of detection layers is lowest while the background rates are highest and the bending of the muon trajectories due to the CMS magnetic field is small. GEM detectors have been identified as a suitable technology to operate in the high radiation environment present in that region. The first muon endcap station will be instrumented with a double layer of triple-GEM chambers in the 1.6 < |η| < 2.2 region. The detector front-end electronics uses the custom designed VFAT3 chip to provide both fast input for the level-1 muon trigger and full granularity information for offline muon reconstruction. This document describes the design of detectors, electronics, and services. The expected performance of the upgraded muon system is discussed in the context of several benchmark physics channels. The document also presents the plan - including the project schedule, cost, and organization - for the detector construction, testing, and integration into the CMS detector