350 research outputs found

    Methadone-induced mortality in the treatment of chronic pain: Role of QT prolongation

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    Methadone is increasingly prescribed for chronic pain, yet the associated mortality appears to be rising disproportionately relative to other opioid analgesics. We review the available evidence on methadone-associated mortality, and explore potential pharmacokinetic and pharmacodynamic explanations for its greater apparent lethality. While methadone shares properties of central nervous system and respiratory depression with other opioids, methadone is unique as a potent blocker of the delayed rectifier potassium ion channel (IKr). This results in QT-prolongation and torsade de pointes (TdP) in susceptible individuals. In some individuals with low serum protein binding of methadone, the extent of blockade is roughly comparable to that of sotalol, a potent QT-prolonging drug. Predicting an individual’s propensity for methadone-induced TdP is difficult at present given the inherent limitations of the QT interval as a risk-stratifier combined with the multifactorial nature of the arrhythmia. Consensus recommendations have recently been published to mitigate the risk of TdP until further studies better define the arrhythmia risk factors for methadone. Studies are needed to provide insights into the clinical covariates most likely to result in methadone-associated arrhythmia and to assess the feasibility of current risk mitigation strategies

    Central Powering of the Largest Lyman-alpha Nebula is Revealed by Polarized Radiation

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    High-redshift Lyman-alpha blobs are extended, luminous, but rare structures that appear to be associated with the highest peaks in the matter density of the Universe. Their energy output and morphology are similar to powerful radio galaxies, but the source of the luminosity is unclear. Some blobs are associated with ultraviolet or infrared bright galaxies, suggesting an extreme starburst event or accretion onto a central black hole. Another possibility is gas that is shock excited by supernovae. However some blobs are not associated with galaxies, and may instead be heated by gas falling into a dark matter halo. The polarization of the Ly-alpha emission can in principle distinguish between these options, but a previous attempt to detect this signature returned a null detection. Here we report on the detection of polarized Ly-alpha from the blob LAB1. Although the central region shows no measurable polarization, the polarized fraction (P) increases to ~20 per cent at a radius of 45 kpc, forming an almost complete polarized ring. The detection of polarized radiation is inconsistent with the in situ production of Ly-alpha photons, and we conclude that they must have been produced in the galaxies hosted within the nebula, and re-scattered by neutral hydrogen.Comment: Published in the August 18 issue of Nature. 1750 words, 3 figures, and full Supplementary Information. Version has not undergone proofing. Reduced and processed data products are available here: http://obswww.unige.ch/people/matthew.hayes/LymanAlpha/LabPol

    Pattern Transfer of Sub-10 nm Features via Tin-Containing Block Copolymers

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    Tin-containing block copolymers were investigated as materials for nanolithographic applications. Poly(4-trimethylstannylstyrene-block-styrene) (PSnS-PS) and poly(4-trimethylstannylstyrene-block-4-methoxystyrene) (PSnS-PMOST) synthesized by reversible addition–fragmentation chain transfer polymerization form lamellar domains with periodicities ranging from 18 to 34 nm. Thin film orientation control was achieved by thermal annealing between a neutral surface treatment and a top coat. Incorporation of tin into one block facilitates pattern transfer into SiO_2 via a two-step etch process utilizing oxidative and fluorine-based etch chemistries

    Evolution of opinions on social networks in the presence of competing committed groups

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    Public opinion is often affected by the presence of committed groups of individuals dedicated to competing points of view. Using a model of pairwise social influence, we study how the presence of such groups within social networks affects the outcome and the speed of evolution of the overall opinion on the network. Earlier work indicated that a single committed group within a dense social network can cause the entire network to quickly adopt the group's opinion (in times scaling logarithmically with the network size), so long as the committed group constitutes more than about 10% of the population (with the findings being qualitatively similar for sparse networks as well). Here we study the more general case of opinion evolution when two groups committed to distinct, competing opinions AA and BB, and constituting fractions pAp_A and pBp_B of the total population respectively, are present in the network. We show for stylized social networks (including Erd\H{o}s-R\'enyi random graphs and Barab\'asi-Albert scale-free networks) that the phase diagram of this system in parameter space (pA,pB)(p_A,p_B) consists of two regions, one where two stable steady-states coexist, and the remaining where only a single stable steady-state exists. These two regions are separated by two fold-bifurcation (spinodal) lines which meet tangentially and terminate at a cusp (critical point). We provide further insights to the phase diagram and to the nature of the underlying phase transitions by investigating the model on infinite (mean-field limit), finite complete graphs and finite sparse networks. For the latter case, we also derive the scaling exponent associated with the exponential growth of switching times as a function of the distance from the critical point.Comment: 23 pages: 15 pages + 7 figures (main text), 8 pages + 1 figure + 1 table (supplementary info

    Structure and properties of densified silica glass: characterizing the order within disorder

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    世界一構造秩序のあるガラスの合成と構造解析に成功 --ガラスの一見無秩序な構造の中に潜む秩序を抽出--. 京都大学プレスリリース. 2021-12-25.The broken symmetry in the atomic-scale ordering of glassy versus crystalline solids leads to a daunting challenge to provide suitable metrics for describing the order within disorder, especially on length scales beyond the nearest neighbor that are characterized by rich structural complexity. Here, we address this challenge for silica, a canonical network-forming glass, by using hot versus cold compression to (i) systematically increase the structural ordering after densification and (ii) prepare two glasses with the same high-density but contrasting structures. The structure was measured by high-energy X-ray and neutron diffraction, and atomistic models were generated that reproduce the experimental results. The vibrational and thermodynamic properties of the glasses were probed by using inelastic neutron scattering and calorimetry, respectively. Traditional measures of amorphous structures show relatively subtle changes upon compacting the glass. The method of persistent homology identifies, however, distinct features in the network topology that change as the initially open structure of the glass is collapsed. The results for the same high-density glasses show that the nature of structural disorder does impact the heat capacity and boson peak in the low-frequency dynamical spectra. Densification is discussed in terms of the loss of locally favored tetrahedral structures comprising oxygen-decorated SiSi4 tetrahedra

    Resequencing of genes for transforming growth factor β1 (TGFB1) type 1 and 2 receptors (TGFBR1, TGFBR2), and association analysis of variants with diabetic nephropathy

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    BACKGROUND: Diabetic nephropathy is the leading cause of end stage renal failure in the western world. There is substantial epidemiological evidence supporting a genetic predisposition to diabetic nephropathy, however the exact molecular mechanisms remain unknown. Transforming growth factor (TGFβ1) is a crucial mediator in the pathogenesis of diabetic nephropathy. METHODS: We investigated the role of five known single nucleotide polymorphisms (SNPs) in the TGFB1 gene for their association with diabetic nephropathy in an Irish, type 1 diabetic case (n = 272) control (n = 367) collection. The activity of TGFβ1 is facilitated by the action of type 1 and type 2 receptors, with both receptor genes (TGFBR1 and TGFBR2) shown to be upregulated in diabetic kidney disease. We therefore screened TGFBR1 and TGFBR2 genes for genomic variants using WAVE™ (dHPLC) technology and confirmed variants by direct capillary sequencing. Allele frequencies were determined in forty-eight healthy individuals. Data for all SNPs was assessed for Hardy Weinberg equilibrium, with genotypes and allele frequencies compared using the χ(2 )test for contingency tables. Patterns of linkage disequilibrium were established and common haplotypes estimated. RESULTS: Fifteen variants were identified in these genes, seven of which are novel, and putatively functional SNPs were subsequently genotyped using TaqMan™, Invader™ or Pyrosequencing(® )technology. No significant differences (p > 0.1) were found in genotype or allele distributions between cases and controls for any of the SNPs assessed. CONCLUSION: Our results suggest common variants in TGFB1, TGFBR1 and TGFBR2 genes do not strongly influence genetic susceptibility to diabetic nephropathy in an Irish Caucasian population
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