138 research outputs found
EFFICACY OF ALIROCUMAB IN 1,191 PATIENTS WITH A WIDE SPECTRUM OF MUTATIONS IN GENES CAUSATIVE FOR FAMILIAL HYPERCHOLESTEROLEMIA
No full textBackground: Next Generation Sequencing was performed to examine treatment response with alirocumab in patients carrying one or
more causative mutation(s) in five familial hypercholesterolemia (FH) genes.
Methods: From 6 clinical trials of alirocumab (one Phase 2, five Phase 3), 1191 patients with elevated LDL-C and phenotypic FH (including
758 treated with alirocumab) were sequenced for mutations using the SEQPRO LIPO platform in LDL receptor (LDLR), apolipoprotein B
(APOB), PCSK9 (PCSK9), LDL receptor adaptor protein 1 (LDLRAP1), and signal-transducing adaptor protein 1 (STAP1) genes. New
mutations were confirmed by Sanger sequencing and MLPA analysis in case of large gene rearrangements in the original DNA samples.
Results: In total, 387 patients (32%) and 438 (37%) had single receptor defective and receptor negative mutations in LDLR, respectively;
46 (4%) had single mutations in APOB; 8 (0.7%) had single gain-of-function mutations in PCSK9; 2 (0.17%) were homozygous
for mutations in LDRAP1; 6 (0.5%) were double heterozygotes for mutations in both APOB and LDLR; 10 (0.8%) were compound
heterozygotes in LDLR; 1 (0.08%) was a double heterozygote for mutations in LDLR and PCSK9; 293 (25%) had no identifiable causative
mutation in any of the genes investigated. LDL-C reduction with alirocumab at week 12 was generally similar across background FH
mutations: LDLR defective heterozygotes -51.8% (N=231), LDLR negative heterozygotes -50.2% (N=289); APOB heterozygotes -45.5%
(N=26); PCSK9 heterozygotes -53.3% (N=5); subjects with no identifiable mutation -51.0% (N=171). A similar large decrease in LDL-C
was also seen in the 3 double heterozygotes (LDLR, APOB, -49.2%) and 6 potentially compound heterozygous (LDLR, -48.0%) patients.
Overall rates of TEAEs were similar for alirocumab vs controls, with a higher rate of injection site reactions with alirocumab.
Conclusions: In this large cohort of FH patients, individuals with a wide spectrum of mutations in genes causative for FH responded
substantially to alirocumab treatment. LDL-C-lowering activity by alirocumab in compound heterozygotes and double heterozygotes is likely
attributable to the presence of at least one partially functional allele
Art and the artist in the literary works of Elsa Triolet
No full textThis thesis takes a representative selection of Triolet's works to study the themes of writing and creativity as they are presented in the novels. These are all portraits of artists and the accounts of the search for a synthesis of aesthetic freedom and ethical responsibility. It considers Triolet's importance as a foreign writer, adopting a new creative language to be adopted by a different cultural
environment, to be essential in understanding her importance to the French literary tradition. By emphasising her formative years in the avant-garde circles of prerevolutionary Russia, my study demonstrates her considerable contribution to the meeting of Russian and French aesthetic theories. I extend this with close textual
readings of certain works to demonstrate her techniques in novelistic construction which reveal many Formalist practices before Formalist works in translation made
their official influence on creative methods.
The introduction considers the reasons for Triolet's neglect as a writer. It then considers various contemporary and recent critical appraisals which indicate
the interest she has received until present and which allow me to define my own critical approach. Part One traces Triolet's literary evolution from her formative
years in Russia, through exile to her first publications in Russian. It then considers her insertion into French literary activity, and her association with the schools of
socialist realism and the "nouveau roman".
Part Two examines two traditional novels which portray the creative and metaphorical roles of the artist and his work, showing the constant conflict between private and public lives. In Part Three, I show how aspects of novelistic
traditionalism are gradually foregrounded so that the work develops a dual-sided character where it both narrates and examines the processes of its own narration. In Part Four, this move to highly self-conscious aesthetics demonstrates an idiosyncratic exploration of new paths for the novel that bring visual, auditive and cinematographic media into the traditional domain of written art. Accompanying
the very post-modernist experimentation, I show how this research within the novel into the novel's own future has an ethical and redemptive purpose whose final conclusion is that creativity and human freedom are inexorably interwoven
Effect of gentle stroking and vocalization on behaviour, mucosal immunity and upper respiratory disease in anxious shelter cats
No full textEmotional, behavioural, and health benefits of gentle stroking and vocalizations, otherwise known as gentling, have been documented for several species, but little is known about the effect of gentling on cats in stressful situations. In this study, 139 cats rated as anxious upon admission to an animal shelter were allocated to either a Gentled or Control group. Cats were gentled four times daily for 10min over a period of 10 days, with the aid of a tool for cats that were too aggressive to handle. The cats' mood, or persistent emotional state, was rated daily for 10 d as Anxious, Frustrated or Content. Gentled cats were less likely to have negatively valenced moods (Anxious or Frustrated) than Control cats (Incidence Rate Ratio [IRR]=0.61 CI 0.42-0.88, P=0.007). Total secretory immunoglobulin A (S-IgA) was quantified from faeces by enzyme-linked immunosorbent assay. Gentled cats had increased S-IgA (6.9±0.7logμg/g) compared to Control cats (5.9±0.5logμg/g) (
Experimental and Modeling Investigation of Unsaturated Solute Transport with Water-Table Fluctuation
No full textCorresponding author: [email protected] audienceWe studied the transport of a nonreactive tracer in an unconsolidated weathered granite column under steady-state flow and transient flow induced by water-table fluctuation in the bottom half of the column. Experiments reproducing one-dimensional vertical flow and tracer transport were performed at two infiltration rates, 12 and 22 mm h–1. Breakthrough data were used (i) to compare tracer dispersion under steady-state and transient flow, (ii) to analyze the mechanisms responsible for tracer transport under both flow conditions, and (iii) to test the ability of existing transport models to reproduce observed breakthrough curves (BTCs). The BTCs under steady-state flow are typical of physical nonequilibrium transport in a dual-porosity medium. The shapes of BTCs under transient flow are less common, showing multiple peaks. The spreading of the tracer was one order of magnitude greater under transient flow than under steady-state flow. We attribute the multiple-peak shape of BTCs and the greater spreading under transient flow to rapid convection in a rapid mobile domain. Diffusion and advection could account for tracer exchanges between the slow mobile domain, which is active during unsaturated water flow, and the rapid mobile domain, which becomes active as soon as the pore space is fully saturated. Water flow was simulated with the Richards equation using HYDRUS-1D. A mobile–immobile transport model coupled to the Richards equation reproduced the BTCs satisfactorily under steady-state flow at both infiltration rates; however, it was unable to reproduce the multiple peaks of tracer concentrationse under a fluctuating water-table regime
Reactivity of aluminum sulfate and silica in molten alkalimetal sulfates in order to prepare mullite
No full textWith the aim of preparing mullite, reactions between aluminum sulfate and silica in appropriate proportions and molten sulfate media M2SO4 (M=Na and/or K) were performed at different temperatures. The powders obtained were characterized by XRD, FT-IR, SEM and TEM. The reactivity was the same in Na2SO4 and (K,Na)2SO4 media. The best results in terms of yield (98.3%) and weight of mullite produced (95%) were obtained in Na2SO4 at 950 °C. The mullite phase exhibits an acicular morphology (75×0.75 μm) and a specific surface area close to 20 m2/g. In K2SO4 medium, a potassium alumino silicate is formed as well as mullite
Descriptive epidemiology of upper respiratory disease and associated risk factors in cats in an animal shelter in coastal western Canada
No full textWe examined 250 cats at an animal shelter in the coastal temperate region of Canada to determine whether age, source, gender, and sterilization status influenced risk of shedding at intake, transmission of infection, and development of clinical upper respiratory disease (URD). On admission, 28% of the cats were positive for 1 or more infectious agent related to URD; 21% were carriers of Mycoplasma felis and 0.05). Viral and bacterial shedding increased by 9% and 11%, respectively, over 3 sampling times (days 1, 4, and 10). Over 40 days after admission, the cumulative probability of developing URD was 2.2 times greater for stray than owner-surrendered cats (P = 0.02) and 0.5 times as great for neutered cats as for intact cats (P = 0.03). Cats that were shedding at intake were 2.6 times more likely to develop URD than were non-carriers (
Corrigendum to “Efficacy of alirocumab in 1191 patients with a wide spectrum of mutations in genes causative for familial hypercholesterolemia” J Clin Lipidol 11 (2017) 1338-1346 (Journal of Clinical Lipidology (2017) 11(6) (1338–1346.e7), (S1933287417304415), (10.1016/j.jacl.2017.08.016))
No full textThe authors regret that the row labels for the following data in Table 1 were transposed: ApoB and non-HDL-C; and TG and Lp(a). The authors would like to apologise for any inconvenience caused
First measurement of Xi(0)(c) production in pp collisions at root s=7 TeV
No full textThe production of the charm-strange baryon Xi(0)(c) is measured for the first time at the LHC via its semileptonic decay into e(+) Xi(-) nu(e) in ppcollisions at root s = 7 TeV with the ALICE detector. The transverse momentum ( p(T)) differential cross section multiplied by the branching ratio is presented in the interval 1 < p(T)< 8 GeV/c at mid-rapidity, vertical bar y vertical bar < 0.5. The transverse momentum dependence of the Xi(0)(c) baryon production relative to the D-0 meson production is compared to predictions of event generators with various tunes of the hadronisation mechanism, which are found to underestimate the measured cross-section ratio. (C) 2018 The Author(s). Published by Elsevier B.V
Author Correction: Trained immunity, tolerance, priming and differentiation: distinct immunological processes
No full textIn the version of this article initially published, author Raphael Duivenvoorden’s last name was spelt incorrectly as Duivenwoorden. The error has been corrected in the HTML and PDF versions of the article
Alirocumab efficacy in patients with double heterozygous, compound heterozygous, or homozygous familial hypercholesterolemia
No full textMutations in the genes for the low-density lipoprotein receptor (LDLR), apolipoprotein B, and proprotein convertase subtilisin/kexin type 9 have been reported to cause heterozygous and homozygous familial hypercholesterolemia (FH). The objective is to examine the influence of double heterozygous, compound heterozygous, or homozygous mutations underlying FH on the efficacy of alirocumab. Patients from 6 alirocumab trials with elevated low-density lipoprotein cholesterol (LDL-C) and FH diagnosis were sequenced for mutations in the LDLR, apolipoprotein B, proprotein convertase subtilisin/kexin type 9, LDLR adaptor protein 1 (LDLRAP1), and signal-transducing adaptor protein 1 genes. The efficacy of alirocumab was examined in patients who had double heterozygous, compound heterozygous, or homozygous mutations. Of 1191 patients sequenced, 20 patients were double heterozygotes (n = 7), compound heterozygotes (n = 10), or homozygotes (n = 3). Mean baseline LDL-C levels were similar between patients treated with alirocumab (n = 11; 198 mg/dL) vs placebo (n = 9; 189 mg/dL). All patients treated with alirocumab 75/150 or 150 mg every 2 weeks had an LDL-C reduction of ≥15% at either week 12 or 24. At week 12, 1 patient had an increase of 7.1% in LDL-C, whereas in others, LDL-C was reduced by 21.7% to 63.9% (corresponding to 39-114 mg/dL absolute reduction from baseline). At week 24, LDL-C was reduced in all patients by 8.8% to 65.1% (10-165 mg/dL absolute reduction from baseline). Alirocumab was generally well tolerated in the 6 trials. Clinically meaningful LDL-C-lowering activity was observed in patients receiving alirocumab who were double heterozygous, compound heterozygous, or homozygous for genes that are causative for F
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