bluuebunny/crossref_metadata_2025_split huggingface dataset:
Once‐weekly dulaglutide 1.5 mg restores insulin secretion in response to intravenous glucose infusion
Authors: de la Peña Amparo , Loghin Corina , Cui Xuewei , Zhang Xin , Kapitza Christoph , Kelly Ronan P. 
Published: December 2016

AimsTo evaluate the effects of dulaglutide 1.5 mg on first‐ and second‐phase insulin secretion in response to an intravenous (i.v.) glucose bolus challenge, in subjects with type 2 diabetes mellitus (T2DM; primary objective) and in healthy subjects.Materials and methodsIn this randomized, double‐blind, placebo‐controlled, 2‐period crossover study, subjects received a single subcutaneous injection of dulaglutide 1.5 mg or placebo on day 1 of each period. On day 3, subjects underwent a 6‐hour insulin infusion, followed by an i.v. glucose bolus and a glucagon challenge during hyperglycaemia. Areas under the concentration–time curve and maximum concentrations for first‐ (AUC0
‐10 and Cmax0‐10) and second‐phase secretion (AUC10‐180 and Cmax10‐180) were calculated for insulin and C‐peptide. The glucose disappearance constant (Kg) and homeostasis model assessment of β‐cell function (HOMA‐β) were assessed.ResultsIn 20 subjects with T2DM, dulaglutide increased mean insulin AUC0‐10 by 7.92‐fold and Cmax0‐10 by 5.40‐fold vs placebo, and mean AUC10‐180 and Cmax10‐180 by 2.44‐ and 3.78‐ fold, respectively. In 10 healthy subjects, dulaglutide increased the mean insulin AUC0‐10 by 3.09‐fold and Cmax0‐10 by 2.96‐fold vs placebo, and mean AUC10‐180 and Cmax10‐180 by 2.04‐ and 4.15‐fold, respectively. The corresponding C‐peptide values also increased. Mean Kg and HOMA‐β were higher after dulaglutide compared with placebo.ConclusionsIn subjects with T2DM, a single dulaglutide 1.5‐mg dose restored the first‐phase insulin secretion in response to an i.v. glucose bolus, increased the second‐phase insulin response and enhanced β‐cell function.
Comparison of exposure response relationship of atrasentan between North American and Asian populations
Authors: Heerspink Hiddo J. L. , Makino Hirofumi , Andress Dennis , Brennan John J. , Correa‐Rotter Ricardo , Coll Blai , Davis Justin W. , Idler Ken , Kohan Donald E. , Liu Mohan , Perkovic Vlado , Remuzzi Giuseppe , Tobe Sheldon W. , Toto Robert , Parving Hans‐Henrik , de Zeeuw Dick 
Published: December 2016

AimsThe selective endothelin (ET) A receptor antagonist atrasentan has been shown to lower albuminuria in North American and Asian patients with type 2 diabetes and nephropathy. As drug responses to many drugs may differ between North American and Asian populations, we assessed the influence of geographical region on the albuminuria and fluid retention response to atrasentan.Materials and methodsTwo 12‐week double‐blind randomised controlled trials were performed with atrasentan 0.75 or 1.25 mg/d vs placebo in patients with type 2 diabetes and nephropathy. The efficacy endpoint was the percentage change in albuminuria. Bodyweight change, a proxy of fluid retention, was used as a safety endpoint. Pharmacodynamics were determined in Asians (N = 77) and North Americans (N = 134). Atrasentan plasma concentration was measured in 161 atrasentan‐treated patients.ResultsMean albuminuria reduction in Asian, compared to North American, patients was, respectively, −34.4% vs −26.3% for 0.75 mg/d (
P
= .44) and −48.0% vs −28.9% for 1.25 mg/d (
P
= .035). Bodyweight gain did not differ between North American and Asian populations. Atrasentan plasma concentrations were higher in Asians compared to North Americans and correlated with albuminuria response (7.2% albuminuria reduction per doubling atrasentan concentration;
P
= .024). Body surface area (β = −1.09 per m2;
P
< .001) and bilirubin, as a marker of hepatic organic anion transporter activity, (β = 0.69 per mg/dL increment;
P
= .010) were independent determinants of atrasentan plasma concentration; correction by body surface area and bilirubin left no significant difference in plasma concentration between Asian and North American populations.ConclusionThe higher exposure and albuminuria reduction of atrasentan in Asian patients is not associated with more fluid retention, suggesting that Asian patients are less sensitive to atrasentan‐induced sodium retention.
Efficacy and safety of dapagliflozin over 1 year as add‐on to insulin therapy in Japanese patients with type 2 diabetes: the DAISY (Dapagliflozin Added to patients under InSulin therapY) trial
Authors: Araki Eiichi , Onishi Yukiko , Asano Michiko , Kim Hyosung , Yajima Toshitaka 
Published: December 2016

AimsTo evaluate the efficacy and safety of dapagliflozin as add‐on to insulin in Japanese patients with type 2 diabetes.Materials and methodsInsulin‐treated Japanese patients were randomized to 5 mg dapagliflozin or placebo during a 16‐week double‐blind treatment period. Both groups then received dapagliflozin 5 or 10 mg (the dose was increased at or after week 24 if glycated haemoglobin [HbA1c] at the previous visit was >7.5%) during a 36‐week open‐label extension period. The exploratory efficacy endpoint was to assess the maintenance efficacy of 5/10 mg dapagliflozin + insulin over 52 weeks of treatment. Safety was assessed in terms of adverse events, laboratory variables and vital signs.ResultsThe changes in HbA1c from baseline to weeks 16 and 52 were −0.62% and −0.74%, respectively, in the dapagliflozin group, vs −0.08% and −0.83%, respectively, in the placebo–dapagliflozin group. Body weight decreased at both time points in the dapagliflozin group and after switching to open‐label dapagliflozin in the placebo–dapagliflozin group. The total insulin dose decreased slightly after starting dapagliflozin. Adverse events occurred in 82.9% and 71.7% of patients in the dapagliflozin and placebo–dapagliflozin groups, respectively. Hypoglycaemia occurred in 35.0% and 41.7% of patients in the dapagliflozin and placebo–dapagliflozin groups, respectively, but the incidence was not increased by use of dapagliflozin in either trial period. Genital/urinary tract infections, renal impairment/failure, volume depletion, fracture and hepatic disorders occurred in ≤5% of patients.ConclusionThis trial showed that administration of dapagliflozin as an add‐on to insulin therapy was effective, was well tolerated and had insulin‐sparing effects in Japanese patients with type 2 diabetes.
Similar pharmacokinetics and pharmacodynamics of rapid‐acting insulin lispro products SAR342434 and US‐ and EU‐approved Humalog in subjects with type 1 diabetes
Authors: Kapitza Christoph , Nowotny Irene , Lehmann Anne , Bergmann Karin , Rotthaeuser Baerbel , Nosek Leszek , Becker Reinhard H. A. 
Published: December 2016

AimTo compare the pharmacokinetics (PK) and pharmacodynamics (PD) of 3 rapid‐acting insulin lispro products: SAR342434 solution, United States (US)‐approved Humalog and European Union (EU)‐approved Humalog.MethodsIn a single‐centre, randomized, double‐blind, 3‐treatment, 3‐period, 6‐sequence, crossover, euglycaemic clamp study (NCT02273258), adult male subjects with type 1 diabetes were randomized to receive 0.3 U/kg of SAR342434 solution, US‐approved and EU‐approved Humalog under fasted conditions. PK and PD (glucose infusion rate [GIR]) were assessed up to 12 hours.ResultsOf the 30 subjects randomized, 28 completed all 3 treatment periods. Mean concentration and GIR vs time profiles were similar for all 3 products. Exposure (INS‐Cmax, INS‐AUClast and INS‐AUC) and activity (GIRmax and GIR‐AUC0‐12h) of SAR342434, US‐approved and EU‐approved Humalog were similar in all comparisons (point estimates of treatment ratios, 0.95‐1.03 for PK parameters and 1.00‐1.07 for PD parameters), with 90% confidence intervals for the ratios of geometric least squares means within the pre‐specified bioequivalence limit (0.80‐1.25) and no significant differences in time‐related parameters. Within‐subject variability of exposure and activity was low across the 3 clamps, indicating high day‐to‐day reproducibility in clamp performance, irrespective of the individual product. Adverse events were similar for all 3 products. No safety concerns were noted in vital signs or in laboratory and electrocardiogram data.ConclusionsThe results of this study demonstrate similarity in insulin lispro exposure profiles and PD activity of SAR342434 solution to both US‐ and EU‐approved Humalog, and between both US‐ and EU‐approved Humalog, supporting the use of SAR342434 solution for injection as a follow‐on product.
Susceptibility of Macrosiphum euphorbiae to the parasitoid Aphidius ervi: larval development depends on host aphid genotype
Authors: Clarke Hannah Victoria , Cullen Daniel , Hubbard Stephen Francis , Karley Alison Jane 
Published: December 2016

AbstractThe potato aphid, Macrosiphum euphorbiae Thomas (Hemiptera: Aphididae: Macrosiphini), is a common polyphagous aphid in Europe and North America. However, the factors influencing potato aphid dynamics and susceptibility to natural enemies are largely undescribed, particularly in relation to facultative endosymbiotic bacteria, which can provide protection against parasitism and disease in some aphid species. This study investigated whether potato aphid susceptibility to one of its principal natural enemies, the parasitoid Aphidius ervi Haliday (Hymenoptera: Braconidae: Aphidiinae), varied in relation to aphid genotype and/or endosymbiont presence. Parasitism and aphid fitness assays were conducted on clonal lineages of aphids, harbouring their natural endosymbiont infections, collected over 3 years from separate geographic locations. Parasitized aphids were dissected to quantify parasitoid oviposition, larval development, and mummification. Amongst the 19 clonal lines of M. euphorbiae tested, seven aphid genotypes were identified, and 11 lines harboured one or both of the facultative endosymbionts Hamiltonella defensa Moran et al. and Regiella insecticola Moran et al.; H. defensa infections were associated exclusively with two of the seven M. euphorbiae genotypes. Parasitism resistance was detected in clonal lines belonging to a single aphid genotype and resulted from failure of parasitoid eggs to develop into larvae rather than failure of the parasitoid to oviposit. Contrary with studies of several other aphid species, there was little evidence that H. defensa provided strong protection to M. euphorbiae from parasitism by A. ervi. Furthermore, there were no clear fitness costs to the aphid associated with parasitism resistance or with H. defensa infection. The two M. euphorbiae genotypes in which H. defensa occurred, which included the resistant genotype, exhibited faster development, higher survival, and greater fecundity than the other five aphid genotypes. These findings suggest that biological control of M. euphorbiae using A. ervi alone could exacerbate pest problems by selecting for the fittest parasitism‐resistant genotypes.
Rituximab in immune thrombocytopenia: gender, age, and response as predictors of long‐term response
Authors: Marangon Miriam , Vianelli Nicola , Palandri Francesca , Mazzucconi Maria Gabriella , Santoro Cristina , Barcellini Wilma , Fattizzo Bruno , Volpetti Stefano , Lucchini Elisa , Polverelli Nicola , Carpenedo Monica , Isola Miriam , Fanin Renato , Zaja Francesco 
Published: December 2016

AbstractObjectivesTo evaluate the efficacy of a salvage treatment with rituximab (RTX) in adults with primary immune thrombocytopenia (ITP), in terms of short‐term response and long‐term response (LTR, i.e., probability to achieve and maintain response) and to identify biological and clinical predictors of response.MethodsWe retrospectively evaluated the outcome of patients with primary ITP treated with standard dosage RTX (375 mg/m2 × 4) as salvage therapy in five Italian centers. One hundred and three patients, median age of 46 yr, were included. The median period of observation was 59 months.ResultsResponse (R) and complete response (CR) were documented in 57 (55%) and 37 (36%) patients, respectively. Patients younger than 40 yr had a higher probability to achieve CR (P = 0.025). Younger women (age < 40 yr) had a significantly higher probability to achieve R and CR (P = 0.039 and P = 0.009, respectively). The estimated LTR rate was 36% and 31% after 48 and 72 months, respectively; female sex (P = 0.033) and younger age (P = 0.021) were associated with better LTR. Younger women had the highest LTR rate (P = 0.006). Response duration was associated with the obtainment of CR after RTX (CR vs. partial response, P = 0.002).ConclusionsThe effect of RTX salvage treatment appears higher in younger women, with LTR rate possibly approaching that of splenectomy.
Intentionality, Constitution and Merleau‐Ponty's Concept of ‘The Flesh’
Authors: Apostolopoulos Dimitris 
Published: December 2016

AbstractSince Husserl, the task of developing an account of intentionality and constitution has been central to the phenomenological enterprise. Some of Merleau‐Ponty's descriptions of ‘the flesh’ suggest that he gives up on this task, or, more strongly, that the flesh is in principle incompatible with intentionality or constitution. I show that these remarks, as in Merleau‐Ponty's earlier writings, refer to the classical, early Husserlian interpretations of these concepts, and argue that the concept of the flesh can plausibly be understood to advance a refined account of intentionality and constitution. Instead of a first‐personal, unidirectional act or embodied motor project, intentionality is a latent openness to things, where the roles of subject and object are reversible. Whereas the view of constitution as meaning‐bestowal is untenable, the flesh has a constitutive role, which is supported by a ‘constitutional passivity’ from the subject. On this reading, Merleau‐Ponty's later work aims to develop basic tenets of his earlier thought, albeit at a critical distance, an attempt he thought was continuous with the central problems that Husserl claimed a phenomenological philosophy must grapple with, even if Merleau‐Ponty's answers to these problems are not Husserl's.
Population‐specific genotype x genotype x environment interactions in bacterial disease of early life stages of Pacific oyster larvae
Authors: Wendling Carolin C. , Fabritzek Armin G. , Wegner K. Mathias 
Published: December 2016

AbstractThe consequences of emerging marine diseases on the evolutionary trajectories of affected host populations in the marine realm are largely unexplored. Evolution in response to natural selection depends on the genetic variation of the traits under selection and the interaction of these traits with the environment (GxE). However, in the case of diseases, pathogen genotypes add another dimension to this interaction. Therefore, the study of disease resistance needs to be extended to the interaction of host genotype, pathogen genotype and environment (GxGxE). In this study, we used a full‐sib breeding design crossing two genetically differentiated populations of the Pacific oyster Crassostrea gigas (Thunberg, 1793), to determine the influence of host genotype, pathogen genotype and temperature on disease resistance. Based on a controlled infection experiment on two early life stages, that is, D‐larvae and Pediveliger larvae at elevated and ambient water temperatures, we estimated disease resistance to allopatric and sympatric Vibrio sp. by measuring survival and growth within and between genetically differentiated oyster populations. In both populations, survival was higher upon infection with sympatric Vibrio sp., indicating that disease resistance has a genetic basis and is dependent on host genotype. In addition, we observed a significant GxGxE effect in D‐larvae, where contrary to expectations, disease resistance was higher at warm than at cold temperatures. Using thermal reaction norms, we could further show that disease resistance is an environment dependent trait with high plasticity, which indicates the potential for a fast acclimatization to changing environmental conditions. These population‐specific reaction norms disappeared in hybrid crosses between both populations which demonstrates that admixture between genetically differentiated populations can influence GxGxE interactions on larger scales.
On the Relative Performance of Investment‐Grade Corporate Bonds with Differing Maturities
Authors: DeCosta Darrin , Leng Fei , Noronha Gregory 
Published: December 2016

AbstractWe find that short‐maturity investment‐grade corporate bonds perform better, controlling for risk differences, than similar bonds with longer maturities. Our results are at least partially attributable to insurance companies’ trading behavior and align with the preferred‐habitat theory of the term structure. We find that insurance‐company purchases create a strong demand for long‐term bonds and that their rebalancing activity results in sales of short‐term bonds. As documented by extant literature, such demand‐supply imbalance is not easily resolved by arbitrageurs or firms seeking to time the market with bond issuance.
Warming and provenance limit tree recruitment across and beyond the elevation range of subalpine forest
Authors: Kueppers Lara M. , Conlisk Erin , Castanha Cristina , Moyes Andrew B. , Germino Matthew J. , de Valpine Perry , Torn Margaret S. , Mitton Jeffry B. 
Published: December 2016

AbstractClimate niche models project that subalpine forest ranges will extend upslope with climate warming. These projections assume that the climate suitable for adult trees will be adequate for forest regeneration, ignoring climate requirements for seedling recruitment, a potential demographic bottleneck. Moreover, local genetic adaptation is expected to facilitate range expansion, with tree populations at the upper forest edge providing the seed best adapted to the alpine. Here, we test these expectations using a novel combination of common gardens, seeded with two widely distributed subalpine conifers, and climate manipulations replicated at three elevations. Infrared heaters raised temperatures in heated plots, but raised temperatures more in the forest than at or above treeline because strong winds at high elevation reduced heating efficiency. Watering increased season‐average soil moisture similarly across sites. Contrary to expectations, warming reduced Engelmann spruce recruitment at and above treeline, as well as in the forest. Warming reduced limber pine first‐year recruitment in the forest, but had no net effect on fourth‐year recruitment at any site. Watering during the snow‐free season alleviated some negative effects of warming, indicating that warming exacerbated water limitations. Contrary to expectations of local adaptation, low‐elevation seeds of both species initially recruited more strongly than high‐elevation seeds across the elevation gradient, although the low‐provenance advantage diminished by the fourth year for Engelmann spruce, likely due to small sample sizes. High‐ and low‐elevation provenances responded similarly to warming across sites for Engelmann spruce, but differently for limber pine. In the context of increasing tree mortality, lower recruitment at all elevations with warming, combined with lower quality, high‐provenance seed being most available for colonizing the alpine, portends range contraction for Engelmann spruce. The lower sensitivity of limber pine to warming indicates a potential for this species to become more important in subalpine forest communities in the coming centuries.
Can the agricultural AquaCrop model simulate water use and yield of a poplar short‐rotation coppice?
Authors: Horemans Joanna A. , Van Gaelen Hanne , Raes Dirk , Zenone Terenzio , Ceulemans Reinhart 
Published: December 2016

AbstractWe calibrated and evaluated the agricultural model AquaCrop for the simulation of water use and yield of a short‐rotation coppice (SRC) plantation with poplar (Populus) in East Flanders (Belgium) during the second and the third rotation (first 2 years only). Differences in crop development and growth during the course of the rotations were taken into account during the model calibration. Overall, the AquaCrop model showed good performance for the daily simulation of soil water content (R2 of 0.57–0.85), of green canopy cover (R2 > 0.87), of evapotranspiration (ET; R2 > 0.76), and of potential yield. The simulated, total yearly water use of the SRC ranged between 55% and 85% of the water use of a reference grass ecosystem calculated under the same environmental conditions. Crop transpiration was between 67% and 93% of total ET, with lower percentages in the first than in the second year of each rotation. The observed (dry mass) yield ranged from 6.61 to 14.76 Mg ha−1 yr−1. A yield gap of around 30% was observed between the second and the third rotation, as well as between simulated and observed yield during the third rotation. This could possibly be explained by the expansion of the understory (weed) layer; the relative cover of understory weeds was 22% in the third year of the third rotation. The agricultural AquaCrop model simulated total water use and potential yield of the operational SRC in a reliable way. As the plantation was extensively managed, potential effects of irrigation and/or fertilization on ET and on yield were not considered in this study.
A new graphical format to communicate treatment effects to patients—A web‐based randomized controlled trial
Authors: Kasper Jürgen , van de Roemer Adrian , Pöttgen Jana , Rahn Anne , Backhus Imke , Bay Yasemin , Köpke Sascha , Heesen Christoph 
Published: December 2016

AbstractObjectivePatients making treatment decisions require understandable evidence‐based information. However, evidence on graphical presentation of benefits and side‐effects of medical treatments is not conclusive. The study evaluated a new space‐saving format, CLARIFIG (clarifying risk figures), aiming to facilitate accuracy of comprehension.MethodsCLARIFIG displays groups of patients with and without treatment benefits as coloured sectors of a proportional bar graph representing in total 100 patients. Supplementary icons indicate the corresponding group's actual condition. The study used an application showing effects of immunotherapy intended to slow disease progression in multiple sclerosis (MS). In a four‐arm web‐based randomized controlled trial, CLARIFIG was compared to the reference standard, multifigure pictographs (MFP), regarding comprehension (primary outcome) and processing time. Both formats were presented as static and animated versions. People with MS were recruited through the website of the German MS society.ResultsSix hundred and eighty‐two patients were randomized and analysed for the primary end point. There were no differences in comprehension rates (MFPstatic=46%, CLARIFIGstatic=44%; P=.59; MFPanimated=23%, CLARIFIGanimated=30%; P=.134). Processing time for CLARIFIG was shorter only in the animated version (MFPstatic=162 seconds, CLARIFIGstatic=155 seconds; P=.653; MFPanimated=286 seconds, CLARIFIGanimated=189 seconds; P≤.001). However, both animated versions caused more wrong answers and longer processing time than static presentation (MFPstatic vs animated: P≤.001/.001, CLARIFIGstatic vs animated: P=.027/.017).ConclusionComprehension of the new format is comparable to MFP. CLARIFIG has the potential to simplify presentation in more complex contexts such as comparison of several treatment options in patient decision aids, but further studies are needed.