Effect of oral calcium loading on intact PTH and calcitriol in idiopathic renal calcium stone formers and healthy controls

The calciuric response after an oral calcium load (l000 mg elemental calcium together with a standard breakfast) was studied in 13 healthy male controls and 21 recurrent idiopathic renal calcium stone formers, 12 with hypercalciuria (UCa×V>7.50 mmol/24 h) and nine with normocalciuria. In controls, serum 1,25(OH)2 vitamin D3 (calcitriol) remained unchanged 6 h after oral calcium load (50.6±5.1 versus 50.9±5.0 pg/ml), whereas it tended to increase in hypercalciuric (from 53.6±3.2 to 60.6±5.4 pg/ml, P=0.182) and fell in normocalciuric stone formers (from 45.9±2.6 to 38.1±3.3 pg/ml, P=0.011). The total amount of urinary calcium excreted after OCL was 2.50±0.20 mmol in controls, 2.27±0.27 mmol in normocalciuric and 3.62±0.32 mmol in hypercalciuric stone formers (P=0.005 versus controls and normocalciuric stone formers respectively); it positively correlated with serum calcitriol 6 h after calcium load (r=0.392, P=0.024). Maximum increase in urinary calcium excretion rate, δCa-Emax, was inversely related to intact PTH levels in the first 4 h after calcium load, i.e. more pronounced PTH suppression predicted a steeper increase in urinary calcium excretion rate. Twenty-four-hour urine calcium excretion rate was inversely related to the ratio of δ calcitriol/δPTHmax after calcium load (r=−0.653, P=0.0001), indicating that an abnormally up-regulated synthesis of calcitriol and consecutive relative PTH suppression induce hypercalciuria. Finally, late absorption of calcium as suggested by maximum urinary calcium excretion beyond 4 h after oral calcium load was as rare in hypercalciuric stone formers (2 of 12) as in controls (1 of 13) and did not occur in normocalciuric stone former

Virtual reality rehabilitation system for neuropathic pain and motor dysfunction in spinal cord injury patients

Spinal cord injury (SCI) causes both lower limb motor dysfunction and associated neuropathic pain. Although these two conditions share related cortical mechanisms, different interventions are currently used to treat each condition. With intensive training using entertaining virtual reality (VR) scenarios, it may be possible to reshape cortical networks thereby reducing neuropathic pain and improving motor function. We have created the first VR training system combining action observation and execution addressing lower limb function in incomplete SCI (iSCI) patients. A particular feature of the system is the use of size-adjustable shoes with integrated motion sensors. A pilot single-case clinical study is currently being conducted on six iSCI patients. Two patients tested to date were highly motivated to perform and reported improved physical well-being. They improved in playing skill and in controlling the virtual lower limbs. There were post-intervention indications of neuropathic pain decrease, muscle strength increase, faster walking speed and improved performance on items relevant for ambulation. In addition functional MRI before and after treatment revealed a decreased activation pattern. We interpret this result as an improvement of neuronal synergies for this task. These results suggest that our VR system may be beneficial for both reducing neuropathic pain and improving motor function in iSCI patients

The evolution and storage of primitive melts in the Eastern Volcanic Zone of Iceland: the 10 ka Grímsvötn tephra series (i.e. the Saksunarvatn ash)

Major, trace and volatile elements were measured in a suite of primitive macrocrysts and melt inclusions from the thickest layer of the 10 ka Grímsvötn tephra series (i.e. Saksunarvatn ash) at Lake Hvítárvatn in central Iceland. In the absence of primitive tholeiitic eruptions (MgO > 7 wt.%) within the Eastern Volcanic Zone (EVZ) of Iceland, these crystal and inclusion compositions provide an important insight into magmatic processes in this volcanically productive region. Matrix glass compositions show strong similarities with glass compositions from the AD 1783–84 Laki eruption, confirming the affinity of the tephra series with the Grímsvötn volcanic system. Macrocrysts can be divided into a primitive assemblage of zoned macrocryst cores (An_78–An_92, Mg#_cpx = 82–87, Fo_79.5–Fo_87) and an evolved assemblage consisting of unzoned macrocrysts and the rims of zoned macrocrysts (An_60–An_68, Mg#_cpx = 71–78, Fo_70–Fo_76). Although the evolved assemblage is close to being in equilibrium with the matrix glass, trace element disequilibrium between primitive and evolved assemblages indicates that they were derived from different distributions of mantle melt compositions. Juxtaposition of disequilibrium assemblages probably occurred during disaggregation of incompatible trace element-depleted mushes (mean La/Yb_melt = 2.1) into aphyric and incompatible trace element-enriched liquids (La/Yb_melt = 3.6) shortly before the growth of the evolved macrocryst assemblage. Post-entrapment modification of plagioclase-hosted melt inclusions has been minimal and high-Mg# inclusions record differentiation and mixing of compositionally variable mantle melts that are amongst the most primitive liquids known from the EVZ. Coupled high field strength element (HFSE) depletion and incompatible trace element enrichment in a subset of primitive plagioclase-hosted melt inclusions can be accounted for by inclusion formation following plagioclase dissolution driven by interaction with plagioclase-undersaturated melts. Thermobarometric calculations indicate that final crystal-melt equilibration within the evolved assemblage occurred at ~1140°C and 0.0–1.5 kbar. Considering the large volume of the erupted tephra and textural evidence for rapid crystallisation of the evolved assemblage, 0.0–1.5 kbar is considered unlikely to represent a pressure of long-term magma accumulation and storage. Multiple thermometers indicate that the primitive assemblage crystallised at high temperatures of 1240–1300°C. Different barometers, however, return markedly different crystallisation depth estimates. Raw clinopyroxene-melt pressures of 5.5–7.5 kbar conflict with apparent melt inclusion entrapment pressures of 1.4 kbar. After applying a correction derived from published experimental data, clinopyroxene-melt equilibria return mid-crustal pressures of 4±1.5 kbar, which are consistent with pressures estimated from the major element content of primitive melt inclusions. Long-term storage of primitive magmas in the mid-crust implies that low CO_2 concentrations measured in primitive plagioclase-hosted inclusions (262–800 ppm) result from post-entrapment CO_2 loss during transport through the shallow crust. In order to reconstruct basaltic plumbing system geometries from petrological data with greater confidence, mineral-melt equilibrium models require refinement at pressures of magma storage in Iceland. Further basalt phase equilibria experiments are thus needed within the crucial 1–7 kbar range.D.A.N. was supported by a Natural Environment Research Council studentship (NE/1528277/1) at the start of this project. SIMS analyses were supported by Natural Environment Research Council Ion Microprobe Facility award (IMF508/1013).This is the final version of the article. It first appeared from Springer via http://dx.doi.org/10.1007/s00410-015-1170-

Clinical outcomes in patients with systemic lupus erythematosus treated with belimumab in clinical practice settings: a retrospective analysis of results from the OBSErve study in Switzerland

AIMS OF THE STUDY To describe patterns of systemic lupus erythematosus (SLE) care and the clinical effectiveness of belimumab plus standard of care therapy in a real-world clinical setting in Switzerland. METHODS This multicentre, observational, retrospective cohort study included adults with SLE who initiated belimumab as part of their usual care at least six months before data analysis. The primary outcome was the overall clinical response, assessed by a physician on a Physician’s Global Assessment-like scale, to six months’ treatment with belimumab. Secondary outcomes included improvement in disease activity, SLE manifestations and changes in corticosteroid use. RESULTS 53 patients (81% female) from three hospitals were included. At index (belimumab initiation), 23 patients (43%) had mild, 23 (43%) had moderate, and 7 (13%) had severe SLE. Overall improvement in disease activity in patients receiving belimumab was: ≥80% in 6 patients (11%), ≥50% in 12 (23%), ≥20% in 31 (58%), <20% in 13 (25%), and no improvement in 9 (17%). Mean Safety of Estrogens in Lupus Erythematosus National Assessment-SLE Disease Activity Index score decreased from 8.0 at index to 3.6 at six months post index in the 27 patients assessed. In addition, a ≥50% improvement in arthritis, fatigue, rash, low complement (C3, C4 or total haemolytic complement activity), and anti-double-stranded deoxyribonucleic acid antibody levels was experienced six months post index by 10 (38%), 3 (16%), 6 (38%), 2 (12%) and 4 (16%) patients who presented the manifestations at index respectively. At index, 41 patients (77%) received oral corticosteroids at a mean dose of 11.6 mg/day, which decreased to 5.9 mg/day at six months post index. Of the 31 patients receiving a high dose of corticosteroids (≥7.5 mg/day) at index, 18 required <7.5 mg/day and a further two discontinued corticosteroids at six months post index. CONCLUSIONS This study provides real-world insight into belimumab use in clinical practice in Switzerland. In line with findings from other countries, Swiss patients with SLE who received belimumab demonstrated clinical and serological improvements in SLE and a reduction in corticosteroid use after six months of treatment

3 years of liraglutide versus placebo for type 2 diabetes risk reduction and weight management in individuals with prediabetes: a randomised, double-blind trial

Background Liraglutide 3\ub70 mg was shown to reduce bodyweight and improve glucose metabolism after the 56-week period of this trial, one of four trials in the SCALE programme. In the 3-year assessment of the SCALE Obesity and Prediabetes trial we aimed to evaluate the proportion of individuals with prediabetes who were diagnosed with type 2 diabetes. Methods In this randomised, double-blind, placebo-controlled trial, adults with prediabetes and a body-mass index of at least 30 kg/m2, or at least 27 kg/m2 with comorbidities, were randomised 2:1, using a telephone or web-based system, to once-daily subcutaneous liraglutide 3\ub70 mg or matched placebo, as an adjunct to a reduced-calorie diet and increased physical activity. Time to diabetes onset by 160 weeks was the primary outcome, evaluated in all randomised treated individuals with at least one post-baseline assessment. The trial was conducted at 191 clinical research sites in 27 countries and is registered with ClinicalTrials.gov, number NCT01272219. Findings The study ran between June 1, 2011, and March 2, 2015. We randomly assigned 2254 patients to receive liraglutide (n=1505) or placebo (n=749). 1128 (50%) participants completed the study up to week 160, after withdrawal of 714 (47%) participants in the liraglutide group and 412 (55%) participants in the placebo group. By week 160, 26 (2%) of 1472 individuals in the liraglutide group versus 46 (6%) of 738 in the placebo group were diagnosed with diabetes while on treatment. The mean time from randomisation to diagnosis was 99 (SD 47) weeks for the 26 individuals in the liraglutide group versus 87 (47) weeks for the 46 individuals in the placebo group. Taking the different diagnosis frequencies between the treatment groups into account, the time to onset of diabetes over 160 weeks among all randomised individuals was 2\ub77 times longer with liraglutide than with placebo (95% CI 1\ub79 to 3\ub79, p<0\ub70001), corresponding with a hazard ratio of 0\ub721 (95% CI 0\ub713\u20130\ub734). Liraglutide induced greater weight loss than placebo at week 160 (\u20136\ub71 [SD 7\ub73] vs 121\ub79% [6\ub73]; estimated treatment difference 124\ub73%, 95% CI 124\ub79 to 123\ub77, p<0\ub70001). Serious adverse events were reported by 227 (15%) of 1501 randomised treated individuals in the liraglutide group versus 96 (13%) of 747 individuals in the placebo group. Interpretation In this trial, we provide results for 3 years of treatment, with the limitation that withdrawn individuals were not followed up after discontinuation. Liraglutide 3\ub70 mg might provide health benefits in terms of reduced risk of diabetes in individuals with obesity and prediabetes. Funding Novo Nordisk, Denmark

Immunity, Inflammation and Airway Dysfunction in Elite Cross-Country Skiers and Ice Hockey Players: A Systematic Review

Strenuous exercise in elite sports impacts the immune system, leading to high rates of upper respiratory tract infections and airway dysfunction, such as asthma and exercise-induced bronchoconstriction (EIB). Cross-country (XC) skiers and ice hockey (IH) players are particularly affected due to their training environments and sports disciplines. This systematic review (SR) evaluates immune and inflammatory responses and the risk of developing airway dysfunction in these athletes. Original articles focusing on immune response, systemic inflammation, and airway dysfunction in competitive XC skiers and IH players were retrieved from MEDLINE/Ovid, EMBASE, and the Cochrane Library. Risk of bias was assessed using the Cochrane Risk of Bias Tool. Of 3582 studies screened, 50 met the inclusion criteria. Both elite XC skiers and IH players exhibit increased cortisol levels and altered systemic immune cell compositions in response to training and competition. Both groups show neutrophilic or mixed neutrophilic/eosinophilic airway inflammation, in contrast to the primarily eosinophilic inflammation associated with allergic asthma. Both XC skiers (27%) and IH players (14%) had a high prevalence of physician-diagnosed asthma. This SR highlights the notable burden of airway dysfunction in elite winter athletes, with elevated rates of asthma and EIB. The observed inflammatory patterns support the concept of a “sport asthma” endotype, which may be a result of chronic exposure to cold, dry air. Effective management may benefit from refined diagnostic criteria, the identification of specific biomarkers, and tailored prevention and treatment strategies for asthma and EIB

Development of SRF Cavity Tuners for CERN

Superconducting RF cavity developments are currently on-going for new accelerator projects at CERN such as HIE ISOLDE and HL-LHC. Mechanical RF tuning systems are required to compensate cavity frequency shifts of the cavities due to temperature, mechanical, pressure and RF effects on the cavity geometry. A rich history and experience is available for such mechanical tuners developed for existing RF cavities. Design constraints in the context of HIE ISOLDE and HL-LHC such as required resolution, space limitation, reliability and maintainability have led to new concepts in the tuning mechanisms. This paper will discuss such new approaches, their performances and planned developments

Isotopic measurements in water vapor, precipitation, and seawater during EUREC4^4A

n early 2020, an international team set out to investigate trade-wind cumulus clouds and their coupling to the large-scale circulation through the field campaign EUREC$^4$A: ElUcidating the RolE of Clouds-Circulation Coupling in ClimAte. Focused on the western tropical Atlantic near Barbados, EUREC$^4$A deployed a number of innovative observational strategies, including a large network of water isotopic measurements collectively known as EUREC$^4$A-iso, to study the tropical shallow convective environment. The goal of the isotopic measurements was to elucidate processes that regulate the hydroclimate state – for example, by identifying moisture sources, quantifying mixing between atmospheric layers, characterizing the microphysics that influence the formation and persistence of clouds and precipitation, and providing an extra constraint in the evaluation of numerical simulations. During the field experiment, researchers deployed seven water vapor isotopic analyzers on two aircraft, on three ships, and at the Barbados Cloud Observatory (BCO). Precipitation was collected for isotopic analysis at the BCO and from aboard four ships. In addition, three ships collected seawater for isotopic analysis. All told, the in situ data span the period 5 January–22 February 2020 and cover the approximate area 6 to 16° N and 50 to 60° W, with water vapor isotope ratios measured from a few meters above sea level to the mid-free troposphere and seawater samples spanning the ocean surface to several kilometers depth. This paper describes the full EUREC$^4$A isotopic in situ data collection – providing extensive information about sampling strategies and data uncertainties – and also guides readers to complementary remotely sensed water vapor isotope ratios. All field data have been made publicly available even if they are affected by known biases, as is the case for high-altitude aircraft measurements, one of the two BCO ground-based water vapor time series, and select rain and seawater samples from the ships. Publication of these data reflects a desire to promote dialogue around improving water isotope measurement strategies for the future. The remaining, high-quality data create unprecedented opportunities to close water isotopic budgets and evaluate water fluxes and their influence on cloudiness in the trade-wind environment. The full list of dataset DOIs and notes on data quality flags are provided in Table 3 of Sect. 5 (“Data availability”)

A phase 3 randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of sarilumab in patients with giant cell arteritis

Background Giant cell arteritis (GCA) is primarily treated with glucocorticoids (GCs), which have substantial toxicity. Tocilizumab, an interleukin-6-receptor inhibitor (IL-6Ri), showed beneficial effects in GCA, leading to its approval. This study investigated the efficacy and safety of sarilumab (another IL-6Ri) in GCA. Methods This Phase 3, double-blind study comprised a 52-week treatment period and a 24-week follow-up phase. Eligible GCA patients were randomized to receive sarilumab 200 mg (SAR200 + 26W) or 150 mg (SAR150 + 26W) with a 26-week GC taper, or placebo with a 52-week (PBO + 52W) or 26-week (PBO + 26W) GC taper. The primary efficacy endpoint was sustained remission (SR) at week 52. Additional endpoints were SR at week 24, cumulative GC dose, and safety. The study was discontinued prematurely due to protracted recruitment timelines, because of the impact of COVID-19. Therefore, only descriptive statistics were summarized. Results Of the planned 360 subjects, only 83 were randomized and 36 were included in the week 52 analysis. At week 52, 46% (n = 6/13) of patients in SAR200 + 26W, 43% (n = 3/7) in SAR150 + 26W, 30% (n = 3/10) in PBO + 52W, and 0 (n = 0/6) in PBO + 26W taper groups achieved SR. Sensitivity analyses, excluding acute-phase reactants from the SR definition, showed similar results for SAR groups, but 60% (n = 6/10) in PBO + 52W and 17% (n = 1/6) in PBO + 26W taper groups achieved SR at week 52. Similar findings were noted at week 24. The proportions of patients who adhered to GC taper from week 12 through week 52 in each group were as follows: 46% (n = 6/13, SAR200 + 26W), 43% (n = 3/7, SAR150 + 26W), 60% (n = 6/10, PBO + 52W), and 33% (n = 2/6, PBO + 26W). The median actual cumulative GC dose received in the SAR200 + 26W group was lower than other groups. Most patients (80–100%) experienced treatment-emergent adverse events, with similar incidences reported across groups. Conclusions Owing to the small sample size due to the early termination, it is difficult to draw clear conclusions from this study. There were no unexpected safety findings. Trial registration ClinicalTrials.gov NCT03600805. Registered on July 26, 2018