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

The CERN PS multi-turn extraction based on beam splittting in stable islands of transverse phase space: Design Report

Since 2001 considerable effort has been devoted to the study of a possible replacement of the continuous-transfer extraction mode from the PS to the SPS. Such an approach, called Multi-Turn Extraction (MTE), is based on capture of the beam inside stable islands of transverse phase space, generated by sextupoles and octupoles, thanks to a properly chosen tune variation. Both numerical simulations and measurements with beam were performed to understand the properties of this new extraction mode. The experimental study was completed at the end of 2004 and by the end of 2005 a scheme to implement this novel approach in the PS machine was defined and its performance assessed. This design report presents the outcome of the studies undertaken both in terms of technical issues as well as of resources necessary to implement the proposed scheme

Installation and Hardware commissioning of the Multi-Turn extraction at the CERN proton synchrotron

The implementation of the new Multi-Turn Extraction (MTE) at the CERN Proton Synchrotron required major hardware changes for the nearly 50-year old accelerator. The installation of new Pulse Forming Networks (PFN) and refurbished kicker magnets for the extraction, new sextupole and octupole magnets, new power converters, together with an in-depth review of the machine aperture leading to the design of new vacuum chambers was required. As a result, a heavy programme of interventions had to be scheduled during the winter shut-down 2007-8. The newly installed hardware and its commissioning is presented and discussed in details

The CODE ambiguity-fixed clock and phase bias analysis products: generation, properties, and performance

The generation and use of GNSS analysis products that allowparticularly for the needs of single-receiver applicationsprecise point positioning with ambiguity resolution (PPP-AR) are becoming more and more popular. A general uncertainty concerns the question on how the necessary phase bias information should be provided to the PPP-AR user. Until now, each AR-enabling clock/bias representation method had its own practice to provide the necessary bias information. We have generalized the observable-specific signal bias (OSB) representation, as introduced in Villiger (J Geod 93:14871500, 2019) originally exclusively for pseudorange measurements, to carrier phase measurements. The existing common clock (CC) approach has been extended in a way that OSBs allowing for flexible signal and frequency handling between multiple GNSS become possible. Advantages of the proposed OSB-based PPP-AR approach are: GNSS biases can be provided in a consistent way for phase and code measurements and it is capable of multi-GNSS and suitable for standardization. This new, extended PPP-AR approach has been implemented by the Center for Orbit Determination in Europe (CODE). CODE clock products that adhere to the integer-cycle property have been submitted to the International GNSS Service (IGS) since mid of 2018 for three analysis lines: Rapid, Final, and MGEX (Multi-GNSS Extension). Ambiguity fixing is performed not only for GPS but also for Galileo. The integer-cycle property of between-satellite clock differences is of fundamental importance when comparing satellite clock estimates among various analysis lines, or at day boundaries. Both kinds of comparisons could be exploited at a very high level of consistency. Any retrieved comparison essentially indicated a standard deviation for between-satellite clocks from CODE of the order of 5 ps (1.5 mm in range). Finally, the integer-cycle property that may be recovered between the CODE Final clock and the accompanying bias product of consecutive daily sessions (using clock estimates additionally provided for the second midnight epoch) allows us to deduce GPS satellite clock and phase bias information that is consistent and continuous with respect to carrier phase observation data over two, three, or, in principle, yet more days. Phase-based clock densification from initially estimated integer-cycle-conform clock corrections at intervals of 300 s to 30 s (5 s in case of our Final clock product) is a matter of particular interest. Based on direct product comparisons and GRACE K-band ranging (KBR) data analysis, the quality of accordingly densified clock corrections could be confirmed to be on a level similar to that of of “anchor” (300s) clock corrections

Modelling crop hail damage footprints with single-polarization radar: the roles of spatial resolution, hail intensity, and cropland density

Hail represents a major threat to agriculture in Switzerland, and assessments of current and future hail risk are of paramount importance for decision-making in the insurance industry and the agricultural sector. However, relating observational information on hail with crop-specific damage is challenging. Here, we build and systematically assess an open-source model to predict hail damage footprints for field crops (wheat, maize, barley, rapeseed) and grapevine from the operational radar product Maximum Expected Severe Hail Size (MESHS) at different spatial resolutions. To this end, we combine the radar information with detailed geospatial information on agricultural land use and geo-referenced damage data from a crop insurer for 12 recent hail events in Switzerland. We find that for field crops model skill gradually increases when the spatial resolution is reduced from 1 km down to 8 km. For even lower resolutions, the skill is diminished again. In contrast, for grapevine, decreasing model resolution below 1 km tends to reduce skill, which is attributed to the different spatial distribution of field crops and grapevine in the landscape. It is shown that identifying a suitable MESHS thresholds to model damage footprints always involves trade-offs. For the lowest possible MESHS threshold (20 mm) the model predicts damage about twice as often as observed (high frequency bias and false alarm ratio), but it also has a high probability of detection (80 %). The frequency bias decreases for larger thresholds and reaches an optimal value close to 1 for MESHS thresholds of 30–40 mm. However, this comes at the cost of a substantially lower probability of detection (around 50 %), while overall model skill, as measured by the Heidke skill score (HSS), remains largely unchanged (0.41–0.44). We argue that, ultimately, the best threshold therefore depends on the relative costs of a false alarm versus a missed event. Finally, the frequency of false alarms is substantially reduced and skill is improved (HSS = 0.54) when only areas with high cropland density are considered. Results from this simple, open-source model show that modelling of hail damage footprints to crops from single-polarization radar in Switzerland is skilful and is best done at 8 km resolution for field crops and 1 km for grapevine.</p

Co-current Filtrate Flow in Tff Perfusion Processes: Decoupling Transmembrane Pressure from Crossflow to Improve Product Sieving

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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-

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