Trap-integrated fluorescence detection with silicon photomultipliers for sympathetic laser cooling in a cryogenic Penning trap.

We present a fluorescence-detection system for laser-cooled 9Be+ ions based on silicon photomultipliers (SiPMs) operated at 4 K and integrated into our cryogenic 1.9 T multi-Penning-trap system. Our approach enables fluorescence detection in a hermetically sealed cryogenic Penning-trap chamber with limited optical access, where state-of-the-art detection using a telescope and photomultipliers at room temperature would be extremely difficult. We characterize the properties of the SiPM in a cryocooler at 4 K, where we measure a dark count rate below 1 s-1 and a detection efficiency of 2.5(3)%. We further discuss the design of our cryogenic fluorescence-detection trap and analyze the performance of our detection system by fluorescence spectroscopy of 9Be+ ion clouds during several runs of our sympathetic laser-cooling experiment.

BASE-STEP: A transportable antiproton reservoir for fundamental interaction studies.

Currently, the world's only source of low-energy antiprotons is the AD/ELENA facility located at CERN. To date, all precision measurements on single antiprotons have been conducted at this facility and provide stringent tests of fundamental interactions and their symmetries. However, magnetic field fluctuations from the facility operation limit the precision of upcoming measurements. To overcome this limitation, we have designed the transportable antiproton trap system BASE-STEP to relocate antiprotons to laboratories with a calm magnetic environment. We anticipate that the transportable antiproton trap will facilitate enhanced tests of charge, parity, and time-reversal invariance with antiprotons and provide new experimental possibilities of using transported antiprotons and other accelerator-produced exotic ions. We present here the technical design of the transportable trap system. This includes the transportable superconducting magnet, the cryogenic inlay consisting of the trap stack and detection systems, and the differential pumping section to suppress the residual gas flow into the cryogenic trap chamber.

Ultra-thin polymer foil cryogenic window for antiproton deceleration and storage.

We present the design and characterization of a cryogenic window based on an ultra-thin aluminized biaxially oriented polyethylene terephthalate foil at T < 10 K, which can withstand a pressure difference larger than 1 bar at a leak rate <1×10-9 mbar l/s. Its thickness of ∼1.7 µm makes it transparent to various types of particles over a broad energy range. To optimize the transfer of 100 keV antiprotons through the window, we tested the degrading properties of different aluminum coated polymer foils of thicknesses between 900 and 2160 nm, concluding that 1760 nm foil decelerates antiprotons to an average energy of 5 keV. We have also explicitly studied the permeation as a function of coating thickness and temperature and have performed extensive thermal and mechanical endurance and stress tests. Our final design integrated into the experiment has an effective open surface consisting of seven holes with a diameter of 1 mm and will transmit up to 2.5% of the injected 100 keV antiproton beam delivered by the Antiproton Decelerator and Extra Low ENergy Antiproton ring facility of CERN.

BASE-high-precision comparisons of the fundamental properties of protons and antiprotons.

Abstract: The BASE collaboration at the antiproton decelerator/ELENA facility of CERN compares the fundamental properties of protons and antiprotons with ultra-high precision. Using advanced Penning trap systems, we have measured the proton and antiproton magnetic moments with fractional uncertainties of 300 parts in a trillion (p.p.t.) and 1.5 parts in a billion (p.p.b.), respectively. The combined measurements improve the resolution of the previous best test in that sector by more than a factor of 3000. Very recently, we have compared the antiproton/proton charge-to-mass ratios with a fractional precision of 16 p.p.t., which improved the previous best measurement by a factor of 4.3. These results allowed us also to perform a differential matter/antimatter clock comparison test to limits better than 3%. Our measurements enable us to set limits on 22 coefficients of CPT- and Lorentz-violating standard model extensions (SME) and to search for potentially asymmetric interactions between antimatter and dark matter. In this article, we review some of the recent achievements and outline recent progress towards a planned improved measurement of the antiproton magnetic moment with an at least tenfold improved fractional accuracy.

A high-Q superconducting toroidal medium frequency detection system with a capacitively adjustable frequency range >180 kHz.

We describe a newly developed polytetrafluoroethylene/copper capacitor driven by a cryogenic piezoelectric slip-stick stage and demonstrate with the chosen layout cryogenic capacitance tuning of ≈60 pF at ≈10 pF background capacitance. Connected to a highly sensitive superconducting toroidal LC circuit, we demonstrate tuning of the resonant frequency between 345 and 685 kHz, at quality factors Q > 100 000. Connected to a cryogenic ultra low noise amplifier, a frequency tuning range between 520 and 710 kHz is reached, while quality factors Q > 86 000 are achieved. This new device can be used as a versatile image current detector in high-precision Penning-trap experiments or as an LC-circuit-based haloscope detector to search for the conversion of axion-like dark matter to radio-frequency photons. This new development increases the sensitive detection bandwidth of our axion haloscope by a factor of ≈1000.

A 16-parts-per-trillion measurement of the antiproton-to-proton charge-mass ratio.

The standard model of particle physics is both incredibly successful and glaringly incomplete. Among the questions left open is the striking imbalance of matter and antimatter in the observable universe1, which inspires experiments to compare the fundamental properties of matter/antimatter conjugates with high precision2-5. Our experiments deal with direct investigations of the fundamental properties of protons and antiprotons, performing spectroscopy in advanced cryogenic Penning trap systems6. For instance, we previously compared the proton/antiproton magnetic moments with 1.5 parts per billion fractional precision7,8, which improved upon previous best measurements9 by a factor of greater than 3,000. Here we report on a new comparison of the proton/antiproton charge-to-mass ratios with a fractional uncertainty of 16 parts per trillion. Our result is based on the combination of four independent long-term studies, recorded in a total time span of 1.5 years. We use different measurement methods and experimental set-ups incorporating different systematic effects. The final result, [Formula: see text], is consistent with the fundamental charge-parity-time reversal invariance, and improves the precision of our previous best measurement6 by a factor of 4.3. The measurement tests the standard model at an energy scale of 1.96 × 10-27 gigaelectronvolts (confidence level 0.68), and improves ten coefficients of the standard model extension10. Our cyclotron clock study also constrains hypothetical interactions mediating violations of the clock weak equivalence principle (WEPcc) for antimatter to less than 1.8 × 10-7, and enables the first differential test of the WEPcc using antiprotons11. From this interpretation we constrain the differential WEPcc-violating coefficient to less than 0.030.

Increased Serum Levels of soluble ST2 as a Predictor of Disease Progression in Systemic Sclerosis.

OBJECTIVE: Interleukin-33 (IL-33) has been investigated as a mediator in the pathogenesis of fibrosis in lung, liver, and heart. There is accumulating evidence for the involvement of the IL-33/IL-33 receptor ST2L signalling pathway in systemic sclerosis (SSc). Little is known about the role of serum sST2 in SSc, which is the subject of the present investigation. METHOD: Serum levels of sST2 were measured in 49 patients with SSc, recruited prospectively between November 2017 and March 2019. Patients were divided into those with progressive and those with stable disease. Receiver operating characteristics (ROC) curve analysis was applied to study sST2 as a marker for identifying patients with progressive disease. We used multivariate logistic regression analysis to evaluate the predictive value of sST2 for progressive disease after adjustment for potential confounding factors. RESULTS: Serum sST2 levels in patients with progressive disease were significantly elevated compared with patients with stable disease (mean ± sem: 50.4 ± 4.7 ng/mL vs 29.2 ± 2.97 ng/mL, p < 0.001). ROC curve analysis identified an sST2 cut-off value of 37.8 ng/mL as optimal for discriminating patients with progressive disease from those with stable disease (sensitivity 80.0%, specificity 79.3%, area under the curve 0.80). After controlling for potential confounding factors (age, gender, C-reactive protein, pro-brain natriuretic peptide, and sum of internal medicine comorbidities), sST2 remained predictive of progressive disease (odds ratio 1.070, 95% confidence interval 1.017-1.126, p < 0.009). CONCLUSION: In the present study, sST2 serum levels were predictive of disease progression in patients with SSc.

Sympathetic cooling of a trapped proton mediated by an LC circuit.

Efficient cooling of trapped charged particles is essential to many fundamental physics experiments1,2, to high-precision metrology3,4 and to quantum technology5,6. Until now, sympathetic cooling has required close-range Coulomb interactions7,8, but there has been a sustained desire to bring laser-cooling techniques to particles in macroscopically separated traps5,9,10, extending quantum control techniques to previously inaccessible particles such as highly charged ions, molecular ions and antimatter. Here we demonstrate sympathetic cooling of a single proton using laser-cooled Be+ ions in spatially separated Penning traps. The traps are connected by a superconducting LC circuit that enables energy exchange over a distance of 9 cm. We also demonstrate the cooling of a resonant mode of a macroscopic LC circuit with laser-cooled ions and sympathetic cooling of an individually trapped proton, reaching temperatures far below the environmental temperature. Notably, as this technique uses only image-current interactions, it can be easily applied to an experiment with antiprotons1, facilitating improved precision in matter-antimatter comparisons11 and dark matter searches12,13.

[Novel revision of the training regulations for German physicians-Consequences for trainees and trainers in rheumatology]. / Neue Musterweiterbildungsordnung ­ Konsequenzen für die Weiterzubildenden und die Weiterbilder in der Rheumatologie.

Rheumatology training is reorganized with the implementation of the revision of the training regulations for German physicians (MWBO) to become a specialist in internal medicine and rheumatology. This article focusses on novel aspects including far-reaching waiver of reference numbers, the professionally recommended training plan, the e­logbook, the regulation of specific training periods and the requirement of reapplication for the training authorization in addition to the contents of training. These aspects involve direct consequences for trainees and trainers.

[Specialist training situation in rheumatology from a trainer's perspective]. / Weiterbildungssituation in der Rheumatologie aus Sicht der Weiterbilder.

This article focuses on the training situation of rheumatologists from the perspective of trainers regarding the existing and potentially increasing deficits of specialists for internal medicine and rheumatology. According to the new regulations defining the rheumatologist training, a substantial part of the training schedule is required to be completed in a hospital setting in order to become a specialist rheumatologist. In this context, the increased training capacity necessitates additional hospital training positions. In addition, the rheumatology residents desire a structured training program. Significantly, the work-life balance is an important factor to make working as a specialist for internal medicine and rheumatology more attractive.

Increased extracellular water measured by bioimpedance analysis and increased serum levels of atrial natriuretic peptide in polymyalgia rheumatica patients : Signs of volume overload.

BACKGROUND: Water retention is a typical feature of acute inflammatory episodes, chiefly implemented by the sympathetic nervous system (SNS) and the hypothalamic-pituitary-adrenal (HPA) axis. This is an important compensatory mechanism counteracting expected water loss, e.g., due to sweating. Both the SNS and HPA axis are activated in polymyalgia rheumatica (PMR). As retention mechanisms may similarly apply in this disease, we hypothesized increased water retention in PMR. METHODS: Using bioimpedance analysis body composition was investigated in 64 healthy controls and 32 treatment-naive PMR patients. All PMR patients satisfied the 2012 EULAR/ACR classification criteria for PMR. 32 PMR patients were tested before and after 7 days of glucocorticoid-based therapy. Serum levels of pro-atrial natriuretic peptide (proANP) were investigated in all PMR patients and 15 healthy controls. RESULTS: Extracellular water (ECW) was markedly higher in PMR patients than in controls (mean ± SD: 49.1 ± 6.0% versus 36.3 ± 2.5% of total body water, p < 0.001). Patients with PMR demonstrated significantly higher serum levels of proANP compared to controls. Even before glucocorticoid treatment was initiated, systolic and diastolic blood pressure were higher in PMR patients compared to controls. Extracellular water levels did not change in PMR patients upon 7 days of intensified treatment. CONCLUSION: This study demonstrated increased extracellular water and elevated serum levels of proANP as signs of fluid overload in patients with PMR. Volume changes are imprinted as long-lasting mechanisms as water distribution is not affected by short-term anti-inflammatory therapy.

The ASACUSA antihydrogen and hydrogen program: results and prospects.

The goal of the ASACUSA-CUSP collaboration at the Antiproton Decelerator of CERN is to measure the ground-state hyperfine splitting of antihydrogen using an atomic spectroscopy beamline. A milestone was achieved in 2012 through the detection of 80 antihydrogen atoms 2.7 m away from their production region. This was the first observation of 'cold' antihydrogen in a magnetic field free region. In parallel to the progress on the antihydrogen production, the spectroscopy beamline was tested with a source of hydrogen. This led to a measurement at a relative precision of 2.7×10-9 which constitutes the most precise measurement of the hydrogen hyperfine splitting in a beam. Further measurements with an upgraded hydrogen apparatus are motivated by CPT and Lorentz violation tests in the framework of the Standard Model Extension. Unlike for hydrogen, the antihydrogen experiment is complicated by the difficulty of synthesizing enough cold antiatoms in the ground state. The first antihydrogen quantum states scan at the entrance of the spectroscopy apparatus was realized in 2016 and is presented here. The prospects for a ppm measurement are also discussed.This article is part of the Theo Murphy meeting issue 'Antiproton physics in the ELENA era'.

[Efficacy and safety analysis of off-label treatment with biologics in autoinflammatory diseases : Experiences from a German registry (GRAID2)]. / Wirksamkeits- und Sicherheitsanalyse von Off-label-Biologikatherapien bei Patienten mit autoinflammatorischen Erkrankungen : Erfahrungen aus einem Deutschen Register (GRAID2).

OBJECTIVE: To evaluate the safety and efficacy of therapy with biologics in patients with autoinflammatory diseases (AIF) or macrophage activating syndrome (MAS) in a real-life setting in Germany. METHODS: The German Register of Autoimmune Diseases 2 (GRAID2) is a retrospective, non-interventional, multicenter registry collecting data from all patients with inflammatory rheumatic diseases refractory to conventional therapy and treated with initial off-label biologics between August 2006 and December 2013. Patients with MAS could be included without prior treatment with a biologic agent. RESULTS: Data from 26 patients with AIF and 5 with MAS were collected. Of the AIF patients 13 (50%) were diagnosed with adult onset Still's disease (AOSD), 6 (23%) with familial Mediterranean fever (FMF), 4 (15.4%) with tumor necrosis factor-associated periodic syndrome (TRAPS), 1 (3.8%) patient with cryopyrin-associated periodic syndrome (CAPS) and 2 (8%) with undifferentiated fever syndromes. The 5 MAS patients suffered from rheumatoid arthritis (RA) with chronic myeloid leukemia, systemic lupus erythematosus and in 2 cases AOSD. In 1 patient a chronic neurological disease was documented without further differentiaton. All patients with TRAPS were primarily treated with etanercept and all CAPS patients with canakinumab. The AOSD and FMF patients were treated with anakinra as the first line off-label biologic in 6 out of 13 and 5 out of 6 cases, respectively. The MAS patients responded very well or well to therapy in 40% and 60% had a moderate response. There were no non-responders. Within the group of AIF patients the physicians documented a very effective or effective treatment in 38.5%, a moderate response in 30.8% and no response in 30.7%. The tolerance was very good in 5 out of 5 of the MAS and in 92% of the AIF patients. CONCLUSION: The data of this retrospective register provide indications for an effective and safe treatment with off-label biologic medication in patients with AIF and MAS in daily practice.

[Virus-associated arthritis]. / Virusassoziierte Arthritiden.

Epidemiological studies suggest a viral etiology in approximately 1% of patients presenting with acute arthritis. The arthritogenic effect of viral infections may be related to viral invasion of synovial cells, the cellular and humoral immune response to viral antigens or by induction of autoimmunity. Viral arthritis can mimic rheumatoid arthritis by presenting as a symmetrical polyarticular disease often accompanied by a rash and influenza-like symptoms. Serological testing for pathogen-specific IgM and IgG antibodies is frequently performed for establishing a viral etiology of arthritis. Virus isolation from the joints or detection of viral nucleic acids in the synovium or synovial fluid is only rarely successful and does not always provide proof of a viral origin of arthritis. While viral arthritis in most cases is self-limiting, protracted disease can occur.

[Psoriatic arthritis : Drugs of the (near) future]. / Psoriasisarthritis : Medikamente der (nahen) Zukunft.

The treatment of psoriatic arthritis (PsA) necessitates different and highly effective treatment strategies due to the diverse clinical manifestations. Drugs that exhibit efficacy for most of the musculoskeletal (e.g. arthritis, dactylitis, enthesitis and spondyloarthritis) and extra-articular manifestations (e.g. skin and nail lesions) are therefore of special interest. This review presents a selection of drugs for the treatment of PsA, which might be available within the (near) future. Based on an improved understanding of the pathopysiology of psoriasis as well as PsA, novel therapeutic approaches are under development. Results have already been obtained from phase 3 studies for tofacitinib, a Janus kinase inhibitor as well as for the antibodies brodalumab, bimekizumab and ABT-122 that inhibit the IL17-signaling pathway. The sphingolipid agonist ponesimod and the A3AR agonist CF101 represent "small molecules" similar to the Janus kinase inhibitors that will potentially extend the therapeutic options in the future.

[Evidence-based recommendations for diagnostics and treatment of gouty arthritis in the specialist sector : S2e guidelines of the German Society of Rheumatology in cooperation with the AWMF]. / Evidenzbasierte Empfehlung zur Diagnostik und Therapie der Gichtarthritis im fachärztlichen Sektor : S2e-Leitlinie der Deutschen Gesellschaft für Rheumatologie (DGRh) in Kooperation mit der AWMF.

Due to the increasing prevalence of gout, particularly in old age, the disease is becoming of increasing importance in Germany. Gout is one of the most common forms of recurrent inflammatory arthritis and is induced by the deposition of monosodium urate crystals in synovial fluid and other tissues. The principal goals of therapy in chronic gout are the symptomatic treatment of the acute joint inflammation and the causal treatment of the underlying metabolic cause, the hyperuricemia. Only a consistent and permanent reduction of the serum uric acid level ultimately results in an efficient avoidance of further gout attacks and therefore the prevention of structural damage. Due to an often inadequate treatment of gout, the target of healing the disease is often not achieved. A correct and timely diagnosis and adequate assessment of comorbidities associated with gout are, however, of substantial importance for patient and physician to achieve remission of the disease. In order to create a solid basis for a timely and effective treatment of affected patients, in 2016 the German Society of Rheumatology (DGRh) initiated the development of S2e guidelines on gouty arthritis for specialists. This article summarizes these S2e guidelines on the management of gouty arthritis in the specialist sector.

PCR analysis is superior to histology for diagnosis of Whipple's disease mimicking seronegative rheumatic diseases.

OBJECTIVES: The diagnosis of Whipple's disease (WD) is commonly confirmed by histology demonstrating Periodic Acid Schiff (PAS)-positive macrophages in the duodenal mucosa. Analysis of intestinal tissue or other specimens using polymerase chain reaction (PCR) is a more sensitive method. However, the relevance of positive PCR findings is still controversial. Therefore, we evaluated the relevance of histology and PCR findings to establishing the diagnosis of WD in a series of WD patients initially presenting with suspected rheumatic diseases. METHOD: Between 2006 and 2014, 20 patients with seronegative rheumatic diseases tested positive for Tropheryma whipplei (Tw) by PCR and/or histology and were enrolled in a retrospective analysis of the diagnostic value of both procedures. RESULTS: Seven of the 20 cases (35%) were diagnosed with 'classic' WD as indicated by PAS-positive macrophages. In the remaining 13 patients, the presence of Tw was detected by intestinal (n = 10) or synovial PCR analysis (n = 3). Two of the 20 patients (10%) with evidence of Tw did not respond to antibiotic therapy. They were not considered to suffer from WD. Therefore, relying only on histological findings of intestinal biopsies would have missed 11 (61%) of the 18 patients with WD in our cohort. In comparison, PCR of intestinal biopsies detected Tw-DNA in 14 (93%) of the 15 WD patients evaluated. Patients with a positive histology did not differ from PCR-positive patients with regard to sex, age, or duration of disease, but more often presented with gastrointestinal symptoms. CONCLUSIONS: A substantial number of WD patients present without typical intestinal histology findings. Additional PCR analysis of intestinal tissue or synovial fluid increased the sensitivity of the diagnostic evaluation and should be considered particularly in patients presenting with atypical seronegative rheumatic diseases and a high-risk profile for WD.

Brain-derived neurotrophic factor increase during treatment in severe mental illness inpatients.

Meta-analytical evidence suggests that brain-derived neurotrophic factor (BDNF) is altered in various psychiatric disorders. However, meta-analyses may be hampered by the heterogeneity of BDNF assays, lack of BDNF standard values and heterogeneity among the populations included in the studies. To address these issues, our study aimed to test, in a 'true-to-life' setting, the hypothesis that the serum BDNF level is nonspecifically reduced in acute severe mental illness (SMI) patients and increases during inpatient treatment. Consecutive samples of 236 inpatients with SMI and 100 healthy controls were recruited. SMI includes schizophrenia and severe mood disorders, and is characterized in the sample by the presence of at least 2 years of psychiatric treatment and disability. Generalized estimating equations were used to analyze BDNF serum levels at admission and upon discharge controlled by confounding factors. BDNF levels increased significantly between admission and discharge in SMI patients. BDNF levels showed significant reductions compared with controls both at admission and upon discharge. In addition, BDNF levels showed no difference among SMI patient diagnostic subgroups (unipolar depression, bipolar depression, schizophrenia and manic episode). The increase but non-restoration of BDNF levels, even with the general acute improvement of clinical scores, may reflect the progression of the disorder characteristically seen in these patients. BDNF levels could be considered as a marker for the presence of a nonspecific psychiatric disorder and possibly a transdiagnostic and nonspecific marker of disease activity.