Synthetic Mirnov diagnostic for the validation of experimental observations.

A synthetic Mirnov diagnostic has been developed to investigate the capabilities and limitations of an arrangement of Mirnov coils in terms of a mode analysis. Eight test cases have been developed, with different coil arrangements and magnetic field configurations. Three of those cases are experimental configurations of the stellarator Wendelstein 7-X. It is observed that, for a high triangularity of the flux surfaces, the arrangement of the coils plays a significant role in the exact determination of the poloidal mode number. For the mode analysis, torus and magnetic coordinates have been used. In most cases, the reconstruction of the poloidal mode number of a prescribed mode was found to be more accurate in magnetic coordinates. As an application, the signal of an Alfvén eigenmode, which has been calculated with a three-dimensional magnetohydrodynamics code, is compared to experimental observations at Wendelstein 7-X. For the chosen example, the calculated and measured mode spectra agree very well and additional information on the toroidal mode number and localization of the mode has been inferred.

Thoracic spine X-ray examination of patients with back pain using different breathing technique and exposure times - A diagnostic study.

INTRODUCTION: The breathing and suspended inspiration techniques are often used interchangeably for spine X-ray examinations. However, these techniques are not always adequately supported by clinical evidence. This study aimed to determine the two techniques' diagnostic value and adverse image outcomes. METHODS: A total of 400 participants were examined on a Siemens Ysio Max system and randomized into four examination groups: suspended inspiration or breathing techniques with exposure times of 1, 2, and 3.2 s, respectively. Two consultant radiologists conducted the evaluation of the X-ray images. If disagreement was present, the radiologists collaboratively reviewed the X-ray images until a consensus was reached. RESULTS: The final 394 study population comprised 275 women and 119 men with a mean age of 64 years (range:18-96 years). The proportions of visually sharp reproduction of the endplates and trabecular structures did not differ significantly with regards to differences in exposure times between groups. The breathing technique groups had significantly higher proportions of blurring and motion artifacts (p < 0.001). However, adverse image outcomes (motions artifacts) were significantly lower in the 1-s exposure group. CONCLUSIONS: The suspended inspiration and breathing techniques performed equally well regarding visually sharp reproduction. However, the suspended inspiration technique was superior to the breathing technique. regarding adverse image outcomes, although the latter could be improved by using a shorter exposure time. IMPLICATIONS FOR PRACTICE: The suspended inspiration and breathing technique appeared to perform at equal diagnostic levels. The suspended inspiration technique should be preferred due to its reduced risk of adverse image outcomes. However, the risk could also be reduced using a short exposure time with the breathing technique.

Effect of initiating biologics compared to intensifying conventional DMARDs on clinical and MRI outcomes in established rheumatoid arthritis patients in clinical remission: Secondary analyses of the IMAGINE-RA trial.

OBJECTIVES: To compare the effect of treat-to-target-based escalations in conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) and biologics on clinical disease activity and magnetic resonance imaging (MRI) inflammation in a rheumatoid arthritis (RA) cohort in clinical remission. METHOD: One-hundred patients with established RA, Disease Activity Score based on 28-joint count-C-reactive protein (DAS28-CRP) < 3.2, and no swollen joints (hereafter referred to as 'in clinical remission') who received csDMARDs underwent clinical evaluation and MRI of the wrist and second to fifth metacarpophalangeal joints every 4 months. They followed a 2 year MRI treatment strategy targeting DAS28-CRP ≤ 3.2, no swollen joints, and absence of MRI osteitis, with predefined algorithmic treatment escalation: first: increase in csDMARDs; second: adding a biologic; third: switch biologic. MRI osteitis and Health Assessment Questionnaire (HAQ) (co-primary outcomes) and MRI combined inflammation and Simplified Disease Activity Index (SDAI) (key secondary outcomes) were assessed 4 months after treatment change and expressed as estimates of group differences. Statistical analyses were based on the intention-to-treat population analysed using repeated-measures mixed models. RESULTS: Escalation to first biologic compared to csDMARD escalation more effectively reduced MRI osteitis (difference between least squares means 1.8, 95% confidence interval 1.0-2.6), HAQ score (0.08, 0.03-0.1), MRI combined inflammation (2.5, 0.9-4.1), and SDAI scores (2.7, 1.9-3.5). CONCLUSIONS: Treat-to-target-based treatment escalations to biologics compared to escalation in csDMARDs more effectively improved MRI inflammation, physical function, and clinical disease activity in patients with established RA in clinical remission. Treatment escalation in RA patients in clinical remission reduces clinical and MRI-assessed disease activity. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT01656278.

Demonstration of reduced neoclassical energy transport in Wendelstein 7-X.

Research on magnetic confinement of high-temperature plasmas has the ultimate goal of harnessing nuclear fusion for the production of electricity. Although the tokamak1 is the leading toroidal magnetic-confinement concept, it is not without shortcomings and the fusion community has therefore also pursued alternative concepts such as the stellarator. Unlike axisymmetric tokamaks, stellarators possess a three-dimensional (3D) magnetic field geometry. The availability of this additional dimension opens up an extensive configuration space for computational optimization of both the field geometry itself and the current-carrying coils that produce it. Such an optimization was undertaken in designing Wendelstein 7-X (W7-X)2, a large helical-axis advanced stellarator (HELIAS), which began operation in 2015 at Greifswald, Germany. A major drawback of 3D magnetic field geometry, however, is that it introduces a strong temperature dependence into the stellarator's non-turbulent 'neoclassical' energy transport. Indeed, such energy losses will become prohibitive in high-temperature reactor plasmas unless a strong reduction of the geometrical factor associated with this transport can be achieved; such a reduction was therefore a principal goal of the design of W7-X. In spite of the modest heating power currently available, W7-X has already been able to achieve high-temperature plasma conditions during its 2017 and 2018 experimental campaigns, producing record values of the fusion triple product for such stellarator plasmas3,4. The triple product of plasma density, ion temperature and energy confinement time is used in fusion research as a figure of merit, as it must attain a certain threshold value before net-energy-producing operation of a reactor becomes possible1,5. Here we demonstrate that such record values provide evidence for reduced neoclassical energy transport in W7-X, as the plasma profiles that produced these results could not have been obtained in stellarators lacking a comparably high level of neoclassical optimization.

Prediction of clinical diagnosis of Alzheimer's disease, vascular, mixed, and all-cause dementia by a polygenic risk score and APOE status in a community-based cohort prospectively followed over 17 years.

The strongest genetic risk factor for Alzheimer's disease (AD) is the ε4 allele of Apolipoprotein E (APOE) and recent genome-wide association meta-analyses have confirmed additional associated genetic loci with smaller effects. The aim of this study was to investigate the ability of an AD polygenic risk score (PRS) and APOE status to predict clinical diagnosis of AD, vascular (VD), mixed (MD), and all-cause dementia in a community-based cohort prospectively followed over 17 years and secondarily across age, sex, and education strata. A PRS encompassing genetic variants reaching genome-wide significant associations to AD (excluding APOE) from the most recent genome-wide association meta-analysis data was calculated and APOE status was determined in 5203 participants. During follow-up, 103, 111, 58, and 359 participants were diagnosed with AD, VD, MD, and all-cause dementia, respectively. Prediction ability of AD, VD, MD, and all-cause dementia by the PRS and APOE was assessed by multiple logistic regression and receiver operating characteristic curve analyses. The PRS per standard deviation increase in score and APOE4 positivity (≥1 ε4 allele) were significantly associated with greater odds of AD (OR, 95% CI: PRS: 1.70, 1.45-1.99; APOE4: 3.34, 2.24-4.99) and AD prediction accuracy was significantly improved when adding the PRS to a base model of age, sex, and education (ASE) (c-statistics: ASE, 0.772; ASE + PRS, 0.810). The PRS enriched the ability of APOE to discern AD with stronger associations than to VD, MD, or all-cause dementia in a prospective community-based cohort.

Nitrogen depletion enhances endodermal suberization without restricting transporter-mediated root NO3- influx.

Roots vary their permeability to aid radial transport of solutes towards xylem vessels in response to nutritional cues. Nitrogen (N) depletion was previously shown to induce early suberization of endodermal cell walls and reduce hydraulic conductivity of barley roots suggesting reduced apoplastic transport of ions (Armand et al., 2019). Suberization may also limit transcellular ion movement by blocking access to transporters (Barberon et al., 2016). The aim of this study was to confirm that N depletion induced suberization in the roots of barley and demonstrate that this was a specific effect in response to NO3- depletion. Furthermore, in roots with early and enhanced suberization, we assessed their ability for transporter-mediated NO3- influx. N depletion induced lateral root elongation and early and enhanced endodermal suberization of the seminal root of each genotype. Both root to shoot NO3- translocation and net N uptake was half that of plants supplied with steady-state NO3-. Genes with predicted functions in suberin synthesis (HvHORST) and NO3- transport (HvNRT2.2) were induced under N-deplete conditions. N-deplete roots had a higher capacity for high-affinity NO3- influx in early suberized roots than under optimal NO3-. In conclusion, NO3- depletion induced early and enhanced suberization in the roots of barley, however, suberization did not restrict transcellular NO3- transport.

First Observation of a Stable Highly Dissipative Divertor Plasma Regime on the Wendelstein 7-X Stellarator.

For the first time, the optimized stellarator Wendelstein 7-X has operated with an island divertor. An operation regime in hydrogen was found in which the total plasma radiation approached the absorbed heating power without noticeable loss of stored energy. The divertor thermography recorded simultaneously a strong reduction of the heat load on all divertor targets, indicating almost complete power detachment. This operation regime was stably sustained over several energy confinement times until the preprogrammed end of the discharge. The plasma radiation is mainly due to oxygen and is located at the plasma edge. This plasma scenario is reproducible and robust at various heating powers, plasma densities, and gas fueling locations. These experimental results show that the island divertor concept actually works and displays good power dissipation potential, producing a promising exhaust concept for the stellarator reactor line.

Inference of temperature and density profiles via forward modeling of an x-ray imaging crystal spectrometer within the Minerva Bayesian analysis framework.

At the Wendelstein 7-X stellarator, the X-ray imaging crystal spectrometer provides line integrated measurements of ion and electron temperatures, plasma flows, as well as impurity densities from a spectroscopic analysis of tracer impurity radiation. In order to infer the actual profiles from line integrated data, a forward modeling approach has been developed within the Minerva Bayesian analysis framework. In this framework, the inversion is realized on the basis of a complete forward model of the diagnostic, including error propagation and utilizing Gaussian processes for generation and inference of arbitrary shaped plasma parameter profiles. For modeling of line integrated data as measured by the detector, the installation geometry of the spectrometer, imaging properties of the crystal, and Gaussian detection noise are considered. The inversion of line integrated data is achieved using the maximum posterior method for plasma parameter profile inference and a Markov chain Monte Carlo sampling of the posterior distribution for calculating uncertainties of the inference process. The inversion method shows a correct and reliable inference of temperature and impurity density profiles from synthesized data within the estimated uncertainties along the whole plasma radius. The application to measured data yields a good match of derived electron temperature profiles to data of the Thomson scattering diagnostic for central electron temperatures between 2 and 5 keV using argon impurities.

Plasma impurities observed by a pulse height analysis diagnostic during the divertor campaign of the Wendelstein 7-X stellarator.

The paper reports on the optimization process of the soft X-ray pulse height analyzer installed on the Wendelstein 7-X (W7-X) stellarator. It is a 3-channel system that records X-ray spectra in the range from 0.6 to 19.6 keV. X-ray spectra, with a temporal and spatial resolution of 100 ms and 2.5 cm (depending on selected slit sizes), respectively, are line integrated along a line-of-sight that crosses near to the plasma center. In the second W7-X operation phase with a carbon test divertor unit, light impurities, e.g., carbon and oxygen, were observed as well as mid- to high-Z elements, e.g., sulfur, chlorine, chromium, manganese, iron, and nickel. In addition, X-ray lines from several tracer elements have been observed after the laser blow-off injection of different impurities, e.g., silicon, titanium, and iron, and during discharges with prefill or a gas puff of neon or argon. These measurements were achieved by optimizing light absorber-foil selection, which defines the detected energy range, and remotely controlled pinhole size, which defines photon flux. The identification of X-ray lines was confirmed by other spectroscopic diagnostics, e.g., by the High-Efficiency XUV Overview Spectrometer, HEXOS, and high-resolution X-ray imaging spectrometer, HR-XIS.

Design, capabilities, and first results of the new laser blow-off system on Wendelstein 7-X.

We present a detailed overview and first results of the new laser blow-off system on the stellarator Wendelstein 7-X. The system allows impurity transport studies by the repetitive and controlled injection of different tracer ions into the plasma edge. A Nd:YAG laser is used to ablate a thin metal film, coated on a glass plate, with a repetition rate of up to 20 Hz. A remote-controlled adjustable optical system allows the variation of the laser spot diameter and enables the spot positioning to non-ablated areas on the target between laser pulses. During first experiments, clear spectral lines from higher ionization stages of the tracer ions have been observed in the X-ray to the extreme ultraviolet spectral range. The temporal behavior of the measured emission allows the estimate of transport properties, e.g., impurity transport times in the order of 100 ms. Although the strong injection of impurities is well detectable, the global plasma parameters are barely changed.

A genome-wide association study identifies risk loci for childhood acute lymphoblastic leukemia at 10q26.13 and 12q23.1.

Genome-wide association studies (GWASs) have shown that common genetic variation contributes to the heritable risk of childhood acute lymphoblastic leukemia (ALL). To identify new susceptibility loci for the largest subtype of ALL, B-cell precursor ALL (BCP-ALL), we conducted a meta-analysis of two GWASs with imputation using 1000 Genomes and UK10K Project data as reference (totaling 1658 cases and 7224 controls). After genotyping an additional 2525 cases and 3575 controls, we identify new susceptibility loci for BCP-ALL mapping to 10q26.13 (rs35837782, LHPP, P=1.38 × 10-11) and 12q23.1 (rs4762284, ELK3, P=8.41 × 10-9). We also provide confirmatory evidence for the existence of independent risk loci at 9p21.3, but show that the association marked by rs77728904 can be accounted for by linkage disequilibrium with the rare high-impact CDKN2A p.Ala148Thr variant rs3731249. Our data provide further insights into genetic susceptibility to ALL and its biology.

Effect of a treat-to-target strategy based on methotrexate and intra-articular betamethasone with or without additional cyclosporin on MRI-assessed synovitis, osteitis, tenosynovitis, bone erosion, and joint space narrowing in early rheumatoid arthritis: results from a 2-year randomized double-blind placebo-controlled trial (CIMESTRA).

OBJECTIVES: To investigate whether a treat-to-target strategy based on methotrexate (MTX) and intra-articular (IA) betamethasone suppresses magnetic resonance imaging (MRI)-determined measures of disease activity and reduces joint destruction in early rheumatoid arthritis (eRA) patients, and to investigate whether concomitant cyclosporin A (CyA) provides an additional effect. METHOD: In the 2-year randomized, double-blind, treat-to-target trial CIMESTRA, 160 patients with eRA (< 6 months) were randomized to MTX, intra-articular betamethasone and CyA, or placebo CyA. A total of 129 patients participated in the MRI substudy, and had contrast-enhanced MR images of the non-dominant hand at months 0, 6, 12, and 24. MR images were evaluated for osteitis, synovitis, tenosynovitis, bone erosion, and joint space narrowing (JSN), using validated scoring methods. RESULTS: Significant reductions were seen at 6 months in all inflammatory parameters [synovitis, mean change -1.6 (p < 0.001, Wilcoxon), tenosynovitis, -3.5 (p < 0.001), and osteitis, -1.3 (p < 0.05)] and at 12/24 months in synovitis and tenosynovitis [-1.6/-2.2 and -3.6/-3.8, respectively; all p < 0.001]. MRI signs of inflammation were not fully eliminated, and increases in erosion and JSN scores were observed at 6 months [0.4 (p < 0.01)/0.1 (p < 0.05)], 12 months [0.8 (p < 0.001)/0.3 (p < 0.01)], and 24 months [1.0 (p < 0.001)/0.4 (p < 0.001)]. Clinical measures decreased significantly (p < 0.001) at all time points. There were no consistent statistically significant differences between treatment groups. CONCLUSIONS: In this eRA treat-to-target trial, MTX and intra-articular glucocorticoids markedly reduced, but did not eliminate, MRI osteitis, synovitis, and tenosynovitis. Accordingly, minimal but statistically significant increases in bone erosion and JSN were observed. No additional effect of CyA was demonstrated.

1H-MRS measured ectopic fat in liver and muscle is associated with the metabolic syndrome in Danish girls but not in boys with overweight and obesity.

BACKGROUND: The metabolic syndrome (MetS) is a complication to overweight and obesity, which can be observed already in childhood. Ectopic lipid accumulation in muscle and liver has been shown to associate with the development of insulin resistance and dyslipidemia. Thus, the interaction between MetS and ectopic fat may offer clinical relevance. OBJECTIVES: To investigate the prevalence of MetS, or components hereof, and ectopic fat accumulation in liver and skeletal muscle tissue in children, as well as interactions between these. METHODS: Two-hundred-and-sixteen children and adolescents (95 boys) with overweight/obesity were investigated, as well as 47 controls (22 boys) with normal weight. The assessments included anthropometry, fasting blood biochemistry and blood pressure measurements. Liver and muscle lipid contents were assessed by proton magnetic resonance spectroscopy. RESULTS: We observed an odds ratio in girls with overweight/obesity of 12.2 (95% confidence interval: [3.8; 49.0]) for exhibiting MetS when hepatic steatosis was present, whereas no association was observed in boys with overweight/obesity (odds ratio 0.7 [0.2; 2.7]). The odds ratio of exhibiting MetS in the presence of muscular steatosis was 3.5 [1.4; 9.5] in girls with overweight/obesity and 1.0 [0.2; 5.6] in boys with overweight/obesity. Similar results were seen for girls with overweight/obesity exhibiting concurrent hepatic and muscular steatoses. CONCLUSION: Hepatic and muscular steatoses were associated with MetS among girls, but not among boys with overweight/obesity.

Amino acid supplementation is anabolic during the acute phase of endotoxin-induced inflammation: A human randomized crossover trial.

BACKGROUND & AIMS: Inflammation is catabolic and causes muscle loss. It is unknown if amino acid supplementation reverses these effects during the acute phase of inflammation. The aim was to test whether amino acid supplementation counteracts endotoxin-induced catabolism. METHODS: Eight young, healthy, lean males were investigated three times in randomized order: (i) normal conditions (Placebo), (ii) endotoxemia (LPS), and (iii) endotoxemia with amino acid supplementation (LPS + A). Protein kinetics were determined using phenylalanine, tyrosine, and urea tracers. Each study day consisted of a four-hour non-insulin stimulated period and a two-hour hyperinsulinemic euglycemic clamp period. Muscle biopsies were collected once each period. RESULTS: Endotoxin administration created a significant inflammatory response (cytokines, hormones, and vital parameters) without significant differences between LPS and LPS + A. Whole body protein breakdown was elevated during LPS compared with Placebo and LPS + A (p < 0.05). Whole body protein synthesis was higher during LPS + A than both Placebo and LPS (p < 0.003). Furthermore, protein synthesis was higher during LPS than during Placebo (p < 0.02). Net muscle phenylalanine release was markedly decreased during LPS + A (p < 0.004), even though muscle protein synthesis and breakdown rates did not differ significantly between interventions. LPS + A increased mammalian target of rapamycin (mTOR) phosphorylation (p < 0.05) and eukaryotic translation factor 4E-binding protein 1 (4EBP1) phosphorylation (p = 0.007) without activating AMPK or affecting insulin signaling through Akt. During insulin stimulation net muscle phenylalanine release and protein degradation were further reduced. CONCLUSIONS: Amino acid supplementation in the acute phase of inflammation reduces whole body and muscle protein loss, and this effect is associated with activation of mTOR and downstream signaling to protein synthesis through mTORC1, suggesting a therapeutic role for intravenous amino acids in inflammatory states. CLINICAL TRIAL REGISTRY: The Central Denmark Region Ethics Commitee (1-10-71-410-12) www.clinicaltrials.gov (identification number NCT01705782).

Resolving structural transitions in spherical dust clusters.

Finite systems in confining potentials are known to undergo structural transitions similar to phase transitions. However, these systems are inhomogeneous, and their "melting" point may depend on the position in the trap and vary with the particle number. Focusing on three-dimensional Coulomb systems in a harmonic trap a rich physics is revealed: in addition to radial melting we demonstrate the existence of intrashell disordering and intershell angular melting. Our analysis takes advantage of a novel melting criterion that is based on the spatial two- and three-particle distribution functions and the associated reduced entropy which can be directly measured in complex plasma experiments.

Status of the diagnostics development for the first operation phase of the stellarator Wendelstein 7-X.

An overview of the diagnostics which are essential for the first operational phase of Wendelstein 7-X and the set of diagnostics expected to be ready for operation at this time are presented. The ongoing investigations of how to cope with high levels of stray Electron Cyclotron Resonance Heating (ECRH) radiation in the ultraviolet (UV)/visible/infrared (IR) optical diagnostics are described.