Albiglutide and cardiovascular outcomes in patients with type 2 diabetes and cardiovascular disease (Harmony Outcomes): a double-blind, randomised placebo-controlled trial

Background: Glucagon-like peptide 1 receptor agonists differ in chemical structure, duration of action, and in their effects on clinical outcomes. The cardiovascular effects of once-weekly albiglutide in type 2 diabetes are unknown. We aimed to determine the safety and efficacy of albiglutide in preventing cardiovascular death, myocardial infarction, or stroke. Methods: We did a double-blind, randomised, placebo-controlled trial in 610 sites across 28 countries. We randomly assigned patients aged 40 years and older with type 2 diabetes and cardiovascular disease (at a 1:1 ratio) to groups that either received a subcutaneous injection of albiglutide (30–50 mg, based on glycaemic response and tolerability) or of a matched volume of placebo once a week, in addition to their standard care. Investigators used an interactive voice or web response system to obtain treatment assignment, and patients and all study investigators were masked to their treatment allocation. We hypothesised that albiglutide would be non-inferior to placebo for the primary outcome of the first occurrence of cardiovascular death, myocardial infarction, or stroke, which was assessed in the intention-to-treat population. If non-inferiority was confirmed by an upper limit of the 95% CI for a hazard ratio of less than 1·30, closed testing for superiority was prespecified. This study is registered with ClinicalTrials.gov, number NCT02465515. Findings: Patients were screened between July 1, 2015, and Nov 24, 2016. 10 793 patients were screened and 9463 participants were enrolled and randomly assigned to groups: 4731 patients were assigned to receive albiglutide and 4732 patients to receive placebo. On Nov 8, 2017, it was determined that 611 primary endpoints and a median follow-up of at least 1·5 years had accrued, and participants returned for a final visit and discontinuation from study treatment; the last patient visit was on March 12, 2018. These 9463 patients, the intention-to-treat population, were evaluated for a median duration of 1·6 years and were assessed for the primary outcome. The primary composite outcome occurred in 338 (7%) of 4731 patients at an incidence rate of 4·6 events per 100 person-years in the albiglutide group and in 428 (9%) of 4732 patients at an incidence rate of 5·9 events per 100 person-years in the placebo group (hazard ratio 0·78, 95% CI 0·68–0·90), which indicated that albiglutide was superior to placebo (p<0·0001 for non-inferiority; p=0·0006 for superiority). The incidence of acute pancreatitis (ten patients in the albiglutide group and seven patients in the placebo group), pancreatic cancer (six patients in the albiglutide group and five patients in the placebo group), medullary thyroid carcinoma (zero patients in both groups), and other serious adverse events did not differ between the two groups. There were three (<1%) deaths in the placebo group that were assessed by investigators, who were masked to study drug assignment, to be treatment-related and two (<1%) deaths in the albiglutide group. Interpretation: In patients with type 2 diabetes and cardiovascular disease, albiglutide was superior to placebo with respect to major adverse cardiovascular events. Evidence-based glucagon-like peptide 1 receptor agonists should therefore be considered as part of a comprehensive strategy to reduce the risk of cardiovascular events in patients with type 2 diabetes. Funding: GlaxoSmithKline

Collins and Sivers asymmetries in muonproduction of pions and kaons off transversely polarised protons

Measurements of the Collins and Sivers asymmetries for charged pions and charged and neutral kaons produced in semi-inclusive deep-inelastic scattering of high energy muons off transversely polarised protons are presented. The results were obtained using all the available COMPASS proton data, which were taken in the years 2007 and 2010. The Collins asymmetries exhibit in the valence region a non-zero signal for pions and there are hints of non-zero signal also for kaons. The Sivers asymmetries are found to be positive for positive pions and kaons and compatible with zero otherwise. © 2015

Cyst Nematode Parasitism of Arabidopsis thaliana Is Inhibited by Salicylic Acid (SA) and Elicits Uncoupled SA-Independent Pathogenesis-Related Gene Expression in Roots

Compatible plant–nematode interactions involve the formation of an elaborate feeding site within the host root that requires the evasion of plant defense mechanisms by the parasite. Little is known regarding plant defense signaling pathways that limit nematode parasitism during a compatible interaction. Therefore, we utilized Arabidopsis thalianamutants perturbed in salicylic acid (SA) biosynthesis or signal transduction to investigate the role of SA in inhibiting parasitism by the beet cyst nematode Heterodera schachtii. We determined that SA-deficient mutants (sid2-1, pad4-1, and NahG) exhibited increased susceptibility to H. schachtii. In contrast, SA-treated wild-type plants showed decreased H. schachtii susceptibility. The npr1-2 and npr1-3 mutants, which are impaired in SA signaling, also showed increased susceptibility to H. schachtii, whereas the npr1-suppressor mutation sni1 showed decreased susceptibility. Constitutive pathogenesis-related (PR) gene-expressing mutants (cpr1 and cpr6) did not show altered susceptibility to H. schachtii; however, constitutive PR gene expression was restricted to cpr1 shoots with wild-type levels of PR-1 transcript present in cpr1 roots. Furthermore, we determined that H. schachtii infection elicits SA-independent PR-2 and PR-5 induction in wild-type roots, while PR-1 transcript and total SA levels remained unaltered. This was in contrast to shoots of infected plants where PR-1 transcript abundance and total SA levels were elevated. We conclude that SA acts via NPR1 to inhibit nematode parasitism which, in turn, is negatively regulated by SNI1. Our results show an inverse correlation between root basal PR-1 expression and plant susceptibility to H. schachtii and suggest that successful cyst nematode parasitism may involve a local suppression of SA signaling in roots.This article is published as Wubben, Martin John Evers, Jing Jin, and Thomas Josef Baum. "Cyst nematode parasitism of Arabidopsis thaliana is inhibited by salicylic acid (SA) and elicits uncoupled SA-independent pathogenesis-related gene expression in roots." Molecular Plant-Microbe Interactions 21, no. 4 (2008): 424-432, doi: 10.1094/MPMI-21-4-0424.</p

HIGH RESOLUTION INFRARED MEASUREMENTS ON HSOH

{G. Winnewisser, F. Lewen, S. Thorwirth, M. Behnke, J. Hahn, J. Gauss, E. Herbst, {\em J. Chem. Phys.\/{H. Pickett, {\em J. Mol. Spectrosc. \/Author Institution: I. Physikalisches Institut, Universitat zu Koln, 50937 Koln, Germany; Institut fur Anorganische Chemie, Universitat zu Koln, 50937 Koln, Germany; Bergische Universitat, FB C - Anorganische Chemie, 42097 Wuppertal, GermanyWe report the first high resolution infrared measurements on oxadisulfane, HSOH. The molecule is non planar with a simple skew chain structure analogues to the kin molecules hydrogenperoxide, HOOH, and hydrogendisulfane, HSSH.\\ In 2001 Behnke et al.$^{a}$ synthesized HSOH by flash vacuum pyrolysis of di-{\it tert}-butyl sulfoxide in amounts which are sufficient for gas phase detection. Winnewisser et al.} {\bf 9} (2003) 5501--5510} recorded the pure rotation-torsional spectra of HSOH in gas phase at high resolution using the Cologne Terahertz Spectrometer. The ground state molecular constants have been obtained with high accuracy.\\ Recently we extended our studies into the mid infrared region. We recorded spectra between 380 and 1400 cm$^{-1}$ and between 1850 and 3800 cm$^{-1}$ by using a Fourier transform spectrometer. We undoubtedly detected the O-H stretching vibration at about 3625.5 cm$^{-1}$ and we assigned almost 1500 lines to this fundamental vibrational mode. According to the orientation of the vibrational dipole moment, HSOH displays strong {\it a}-type and {\it c}-type transitions in the spectrum of the O-H stretching mode but no {\it b}-type transitions.\\ We have used Pickett's program} {\bf 148} (1991) 371--377} to fit more than 1300 transitions by employing a Watson Hamiltonian in S reduction. The ground state constants were fixed to the values achieved from our microwave experiment. We obtained rotational constants {\it A}, {\it B}, {\it C}, {\it D$_J$}, {\it D$_{JK}$}, {\it D$_K$}, {\it d$_1$}, {\it d$_2$}, and {\it H$_J$} for the first vibrational exited state and determined the position of the band origin at 3625,49917(20) cm$^{-1}$.\

Gas-phase detection of HSOD and empirical equilibrium structure of oxadisulfane

Abstract We present the first gas phase spectra of singly deuterated oxadisulfane, HSOD, in its vibrational ground state. More than 100 transitions have been recorded with highest frequency accuracy using the Cologne Terahertz Spectrometer. The molecular parameters derived from a least squares fit analysis proof HSOD to be an almost accidental symmetric prolate top molecule with an asymmetry parameter kZK0.9985. Spectra of c-type and weaker b-type transitions have been recorded in the range from 716 to 772 GHz. The ratio of the dipole moments m c /m b Z2.4(3) has been derived from measured line intensities. The c-type transitions are split by the tunneling motion of a hindered internal rotation, whereas b-type transitions show no splitting within the Doppler limited line profiles. We derived the equilibrium molecular structure of oxadisulfane, HSOH, from experimental values of the rotational constants A 0 , B 0 , and C 0 of HSOH, H 34 SOH, DSOD, and HSOD. The equilibrium rotational constants A e , B e , and C e were derived by taking vibration-rotation interaction constants a r obtained from high-level ab initio calculations into account.

TU-Spektrum 'Sonderausgabe Auto & Verkehr' 2004, Magazin der Technischen Universität Chemnitz

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