Colchicine for secondary prevention of ischaemic stroke and atherosclerotic events: a meta-analysis of randomised trials

\ua9 2024 The Authors. Background: Guidelines recommend low-dose colchicine for secondary prevention in cardiovascular disease, but uncertainty remains concerning its efficacy for stroke, efficacy in key subgroups and about uncommon but serious safety outcomes. Methods: In this trial-level meta-analysis, we searched bibliographic databases and trial registries form inception to May 16, 2024. We included randomised trials of colchicine for secondary prevention of ischaemic stroke and major adverse cardiovascular events (MACE: ischaemic stroke, myocardial infarction, coronary revascularisation, or cardiovascular death). Secondary outcomes were serious safety outcomes and mortality. A fixed-effect inverse-variance model was used to generate a pooled estimate of relative risk (RR) with 95% confidence intervals (CI). This study is registered with PROSPERO, CRD42024540320. Findings: Six trials involving 14,934 patients with prior stroke or coronary disease were included. In all patients, colchicine compared with placebo or no colchicine reduced the risk for ischaemic stroke by 27% (132 [1.8%] events versus 186 [2.5%] events, RR 0.73 [95% CI 0.58–0.90]) and MACE by 27% (505 [6.8%] events versus 693 [9.4%] events, with RR 0.73 [0.65–0.81]). Efficacy was consistent in key subgroups (females versus males, age below versus above 70, with versus without diabetes, statin versus non-statin users). Colchicine was not associated with an increase in serious safety outcomes: hospitalisation for pneumonia (109 [1.5%] versus 106 [1.5%], RR 0.99 [0.76–1.30]), cancer (247 [3.5%] versus 255 [3.6%], RR 0.97 [0.82–1.15]), and gastro-intestinal events (153 [2.1%] versus 135 [1.9%]), RR 1.15 [0.91–1.44]. There was no difference in all-cause death (201 [2.7%] versus 181 [2.4%], RR 1.09 [0.89–1.33]), cardiovascular death (70 [0.9%] versus 80 [1.1%], RR 0.89 [0.65–1.23]), or non-cardiovascular death (131 [1.8%] versus 101 [1.4%], RR 1.26 [0.98–1.64]). Interpretation: In patients with prior stroke or coronary disease, colchicine reduced ischaemic stroke and MACE, with consistent treatment effect in key subgroups, and did not increase serious safety events or death. Funding: There was no funding source for this study

Theoretical description of hydrogen bonding in oxalic acid dimer and trimer based on the combined extended-transition-state energy decomposition analysis and natural orbitals for chemical valence (ETS-NOCV)

In the present study we have analyzed hydrogen bonding in dimer and trimer of oxalic acid, based on a recently proposed charge and energy decomposition scheme (ETS-NOCV). In the case of a dimer, two conformations, α and β, were considered. The deformation density contributions originating from NOCV’s revealed that the formation of hydrogen bonding is associated with the electronic charge deformation in both the σ—(Δρσ) and π-networks (Δρπ). It was demonstrated that σ-donation is realized by electron transfer from the lone pair of oxygen on one monomer into the empty \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$\rho_{H - O}^*$$\end{document} orbital of the second oxalic acid fragment. In addition, a covalent contribution is observed by the density transfer from hydrogen of H-O group in one oxalic acid monomer to the oxygen atom of the second fragment. The resonance assisted component (Δρπ), is based on the transfer of electron density from the π—orbital localized on the oxygen of OH on one oxalic acid monomer to the oxygen atom of the other fragment. ETS-NOCV allowed to conclude that the σ(O---HO) component is roughly eight times as important as π (RAHB) contribution in terms of energetic estimation. The electrostatic factor (ΔEelstat) is equally as important as orbital interaction term (ΔEorb). Finally, comparing β-dimer of oxalic acid with trimer we found practically no difference concerning each of the O---HO bonds, neither qualitative nor quantitative

An exceptional horizontal gene transfer in plastids: gene replacement by a distant bacterial paralog and evidence that haptophyte and cryptophyte plastids are sisters

BACKGROUND: Horizontal gene transfer (HGT) to the plant mitochondrial genome has recently been shown to occur at a surprisingly high rate; however, little evidence has been found for HGT to the plastid genome, despite extensive sequencing. In this study, we analyzed all genes from sequenced plastid genomes to unearth any neglected cases of HGT and to obtain a measure of the overall extent of HGT to the plastid. RESULTS: Although several genes gave strongly supported conflicting trees under certain conditions, we are confident of HGT in only a single case beyond the rubisco HGT already reported. Most of the conflicts involved near neighbors connected by long branches (e.g. red algae and their secondary hosts), where phylogenetic methods are prone to mislead. However, three genes – clpP, ycf2, and rpl36 – provided strong support for taxa moving far from their organismal position. Further taxon sampling of clpP and ycf2 resulted in rejection of HGT due to long-branch attraction and a serious error in the published plastid genome sequence of Oenothera elata, respectively. A single new case, a bacterial rpl36 gene transferred into the ancestor of the cryptophyte and haptophyte plastids, appears to be a true HGT event. Interestingly, this rpl36 gene is a distantly related paralog of the rpl36 type found in other plastids and most eubacteria. Moreover, the transferred gene has physically replaced the native rpl36 gene, yet flanking genes and intergenic regions show no sign of HGT. This suggests that gene replacement somehow occurred by recombination at the very ends of rpl36, without the level and length of similarity normally expected to support recombination. CONCLUSION: The rpl36 HGT discovered in this study is of considerable interest in terms of both molecular mechanism and phylogeny. The plastid acquisition of a bacterial rpl36 gene via HGT provides the first strong evidence for a sister-group relationship between haptophyte and cryptophyte plastids to the exclusion of heterokont and alveolate plastids. Moreover, the bacterial gene has replaced the native plastid rpl36 gene by an uncertain mechanism that appears inconsistent with existing models for the recombinational basis of gene conversion

Rotor-vibrator couplings in partially deuterated toluenes

Fluorescence excitation spectra covering the origin–band region of the two partially methyl-deuterated toluenes (α-deuterotoluene, C<SUB>6</SUB>H<SUB>5</SUB>CH<SUB>2</SUB>D and α-dideuterotoluene, C<SUB>6</SUB>H<SUB>5</SUB>CHD<SUB>2</SUB>) are reported. The spectra, observed in a cold supersonic beam, show transitions between low methyl–rotor levels, and are analyzed in terms of vibrationally adiabatic torsional potentials with two-, four-, and sixfold periodicity. To interpret the resulting potential parameters, ab initio vibrational force field calculations are carried out at the four stationary structures of each isotopomer. The calculations yield accurate values for the adiabatic torsional barriers and qualitatively correct results for the vibrationally adiabatic potentials. Specifically, they show that the twofold potential term dominates in the partially methyl-deuterated isotopomers and that this component has the same magnitude but opposite sign in the mono- and dideuterocompounds. The potential parameters are interpreted in terms of nonbonded interactions between a CH bond of the methyl group and the phenyl ring; specifically, they represent the difference between the interactions of a methyl-CH and a methyl-CD bond with the ortho-CH bonds of the phenyl ring. Modeling of this interaction as a function of H–H separation in terms of a simple analytical expression shows that the repulsive potential is very soft and that individual H–H interactions are of the same order of magnitude as vibrational frequencies

Information, Credit Risk, Lender Specialization and Loan Pricing: Evidence from the DIP Financing Market

Bank loans, Financial intermediation, Debtor in possession financing, Loan contracting, Lending specialization, Loan pricing, Information effects, Credit risk, Chapter 11, G21, G33,