Effect of JAK Inhibition on the Induction of Proinflammatory HLA–DR+CD90+ Rheumatoid Arthritis Synovial Fibroblasts by Interferon-γ

OBJECTIVE: Findings from recent transcriptome analyses of the synovium of patients with rheumatoid arthritis (RA) have revealed that 15-fold expanded HLA–DR+CD90+ synovial fibroblasts potentially act as key mediators of inflammation. The reasons for the expansion of HLA–DR+CD90+ synovial fibroblasts are unclear, but genetic signatures indicate that interferon-γ (IFNγ) plays a central role in the generation of this fibroblast subset. The present study was undertaken to investigate the generation, function and therapeutically intended blockage of HLA–DR+CD90+ synovial fibroblasts. METHODS: We combined functional assays using primary human materials and focused bioinformatic analyses of mass cytometry and transcriptomics patient data sets. RESULTS: We detected enriched and activated Fcγ receptor type IIIa–positive (CD16+) NK cells in the synovial tissue from patients with active RA. Soluble immune complexes were recognized by CD16 in a newly described reporter cell model, a mechanism that could be contributing to the activation of natural killer (NK) cells in RA. In vitro, NK cell–derived IFNγ induced HLA–DR on CD90+ synovial fibroblasts, leading to an inflammatory, cytokine-secreting HLA–DR+CD90+ phenotype. HLA–DR+CD90+ synovial fibroblasts consecutively activated CD4+ T cells upon receptor crosslinking via superantigens. HLA–DR+CD90+ synovial fibroblasts also activated CD4+ T cells in the absence of superantigens, an effect that was initiated by NK cell–derived IFNγ and that was 4 times stronger in patients with RA compared to patients with osteoarthritis. Finally, JAK inhibition in synovial fibroblasts prevented HLA–DR induction and blocked proinflammatory signals to T cells. CONCLUSION: The HLA–DR+CD90+ phenotype represents an activation state of synovial fibroblasts during the process of inflammation in RA that can be induced by IFNγ, likely generated from infiltrating leukocytes such as activated NK cells. The induction of these proinflammatory, interleukin-6–producing, and likely antigen-presenting synovial fibroblasts can be targeted by JAK inhibition

Complementary medicine in Germany: a multi-centre cross-sectional survey on the usage by and the needs of patients hospitalized in university medical centers

BACKGROUND: The results of recent surveys indicate that more than 50% of the German population has experience with complementary and alternative medicine (CAM) or uses CAM regularly. This study investigated the CAM usage and CAM-related needs of hospitalized patients at university medical centres in the state of Baden-Württemberg, Germany. METHODS: A multi-centre, paper-based, pseudonymous survey was carried out by the members of the Academic Centre for Complementary and Integrative Medicine. Patients of all ages, regardless of sex, diagnosis and treatment, who were hospitalized in the Department of Cardiology, Gastroenterology, Oncology, Gynaecology or Surgery at the university medical centres in Freiburg, Heidelberg, Tübingen and Ulm were eligible for inclusion. RESULTS: Of the 1275 eligible patients, 67% (n = 854) consented to participate in the survey. Forty-eight percent of the study participants stated that they were currently using CAM. The most frequently used therapies were exercise (63%), herbal medicine (54%) and dietary supplements (53%). Only 16% of the patients discussed CAM usage with their attending physician. Half of the patients (48%) were interested in CAM consultations. More than 80% of the patients desired reliable CAM information and stated that physicians should be better informed about CAM. CONCLUSIONS: The frequency of CAM usage and the need for CAM counselling among hospitalized patients at university medical centres in Baden-Württemberg are high. To better meet patients’ needs, CAM research and physician education should be intensified. TRIAL REGISTRATION: German Clinical Trial register (DRKS00015445)

Overview of first Wendelstein 7-X high-performance operation

\u3cp\u3eThe optimized superconducting stellarator device Wendelstein 7-X (with major radius R = 5.5 m, minor radius a = 0.5 m, and 30 m3 plasma volume) restarted operation after the assembly of a graphite heat shield and 10 inertially cooled island divertor modules. This paper reports on the results from the first high-performance plasma operation. Glow discharge conditioning and ECRH conditioning discharges in helium turned out to be important for density and edge radiation control. Plasma densities of 1-4.5 × 10\u3csup\u3e19\u3c/sup\u3e m\u3csup\u3e-3\u3c/sup\u3e with central electron temperatures 5-10 keV were routinely achieved with hydrogen gas fueling, frequently terminated by a radiative collapse. In a first stage, plasma densities up to 1.4 × 10\u3csup\u3e20\u3c/sup\u3e m\u3csup\u3e-3\u3c/sup\u3e were reached with hydrogen pellet injection and helium gas fueling. Here, the ions are indirectly heated, and at a central density of 8 · 10\u3csup\u3e19\u3c/sup\u3e m\u3csup\u3e-3\u3c/sup\u3e a temperature of 3.4 keV with Te/Ti = 1 was transiently accomplished, which corresponds to nTi(0)TE = 6.4 × 10\u3csup\u3e19\u3c/sup\u3e keV s m\u3csup\u3e-3\u3c/sup\u3e with a peak diamagnetic energy of 1.1 MJ and volume-averaged normalized plasma pressure {B}= 1.2%. The routine access to high plasma densities was opened with boronization of the first wall. After boronization, the oxygen impurity content was reduced by a factor of 10, the carbon impurity content by a factor of 5. The reduced (edge) plasma radiation level gives routinely access to higher densities without radiation collapse, e.g. well above 1 × 1020 m\u3csup\u3e-2\u3c/sup\u3e line integrated density and Te = Ti = 2 keV central temperatures at moderate ECRH power. Both X2 and O2 mode ECRH schemes were successfully applied. Core turbulence was measured with a phase contrast imaging diagnostic and suppression of turbulence during pellet injection was observed.\u3c/p\u3

Confirmation of the topology of the Wendelstein 7-X magnetic field to better than 1:100,000

\u3cp\u3eFusion energy research has in the past 40 years focused primarily on the tokamak concept, but recent advances in plasma theory and computational power have led to renewed interest in stellarators. The largest and most sophisticated stellarator in the world, Wendelstein 7-X (W7-X), has just started operation, with the aim to show that the earlier weaknesses of this concept have been addressed successfully, and that the intrinsic advantages of the concept persist, also at plasma parameters approaching those of a future fusion power plant. Here we show the first physics results, obtained before plasma operation: that the carefully tailored topology of nested magnetic surfaces needed for good confinement is realized, and that the measured deviations are smaller than one part in 100,000. This is a significant step forward in stellarator research, since it shows that the complicated and delicate magnetic topology can be created and verified with the required accuracy.\u3c/p\u3

Erratum to:magnetic configuration effects on the Wendelstein 7-X stellarator (Nature Physics, (2018), 14, 8, (855-860), 10.1038/s41567-018-0141-9)

\u3cp\u3eIn the version of this Article originally published, A. Mollén’s affiliation was incorrectly denoted as number 10; it should have been 1. Throughout the Article, some technical problems in typesetting meant that the tilde symbol above b and one instance of a superscript 2 were too high to be visible; see the correction notice for details. Finally, the citation to ref. \u3csup\u3e35\u3c/sup\u3e on page one of the Supplementary Information was incorrect; it should have been to ref. 36. These issues have now been corrected.\u3c/p\u3

Magnetic configuration effects on the Wendelstein 7-X stellarator

\u3cp\u3e The two leading concepts for confining high-temperature fusion plasmas are the tokamak and the stellarator. Tokamaks are rotationally symmetric and use a large plasma current to achieve confinement, whereas stellarators are non-axisymmetric and employ three-dimensionally shaped magnetic field coils to twist the field and confine the plasma. As a result, the magnetic field of a stellarator needs to be carefully designed to minimize the collisional transport arising from poorly confined particle orbits, which would otherwise cause excessive power losses at high plasma temperatures. In addition, this type of transport leads to the appearance of a net toroidal plasma current, the so-called bootstrap current. Here, we analyse results from the first experimental campaign of the Wendelstein 7-X stellarator, showing that its magnetic-field design allows good control of bootstrap currents and collisional transport. The energy confinement time is among the best ever achieved in stellarators, both in absolute figures (τ \u3csub\u3eE\u3c/sub\u3e > 100 ms) and relative to the stellarator confinement scaling. The bootstrap current responds as predicted to changes in the magnetic mirror ratio. These initial experiments confirm several theoretically predicted properties of Wendelstein 7-X plasmas, and already indicate consistency with optimization measures. \u3c/p\u3