Precision medicine and adverse drug reactions related to cardiovascular drugs

Cardiovascular disease remains the leading global cause of death. Early intervention, with lifestyle advice alongside appropriate medical therapies, is fundamental to reduce patient mortality among high-risk individuals. For those who live with the daily challenges of cardiovascular disease, pharmacological management aims to relieve symptoms and prevent disease progression. Despite best efforts, prescription drugs are not without their adverse effects, which can cause significant patient morbidity and consequential economic burden for healthcare systems. Patients with cardiovascular diseases are often among the most vulnerable to adverse drug reactions due to multiple co-morbidities and advanced age. Examining a patient’s genome to assess for variants that may alter drug efficacy and susceptibility to adverse reactions underpins pharmacogenomics. This strategy is increasingly being implemented in clinical cardiology to tailor patient therapies. The identification of specific variants associated with adverse drug effects aims to predict those at greatest risk of harm, allowing alternative therapies to be given. This review will explore current guidance available for pharmacogenomic-based prescribing as well as exploring the potential implementation of genetic risk scores to tailor treatment. The benefits of large databases and electronic health records will be discussed to help facilitate the integration of pharmacogenomics into primary care, the heartland of prescribing

Interspecific analysis of diurnal gene regulation in panicoid grasses identifies known and novel regulatory motifs

Background: The circadian clock drives endogenous 24-h rhythms that allow organisms to adapt and prepare for predictable and repeated changes in their environment throughout the day-night (diurnal) cycle. Many components of the circadian clock in Arabidopsis thaliana have been functionally characterized, but comparatively little is known about circadian clocks in grass species including major crops like maize and sorghum. Results: Comparative research based on protein homology and diurnal gene expression patterns suggests the function of some predicted clock components in grasses is conserved with their Arabidopsis counterparts, while others have diverged in function. Our analysis of diurnal gene expression in three panicoid grasses sorghum, maize, and foxtail millet revealed conserved and divergent evolution of expression for core circadian clock genes and for the overall transcriptome. We find that several classes of core circadian clock genes in these grasses differ in copy number compared to Arabidopsis, but mostly exhibit conservation of both protein sequence and diurnal expression pattern with the notable exception of maize paralogous genes. We predict conserved cis-regulatory motifs shared between maize, sorghum, and foxtail millet through identification of diurnal co-expression clusters for a subset of 27,196 orthologous syntenic genes. In this analysis, a Cochran– Mantel–Haenszel based method to control for background variation identified significant enrichment for both expected and novel 6–8 nucleotide motifs in the promoter regions of genes with shared diurnal regulation predicted to function in common physiological activities. Conclusions: This study illustrates the divergence and conservation of circadian clocks and diurnal regulatory networks across syntenic orthologous genes in panacoid grass species. Further, conserved local regulatory sequences contribute to the architecture of these diurnal regulatory networks that produce conserved patterns of diurnal gene expression

Universality of the Ising Model on Sphere-like Lattices

We study the 2D Ising model on three different types of lattices that are topologically equivalent to spheres. The geometrical shapes are reminiscent of the surface of a pillow, a 3D cube and a sphere, respectively. Systems of volumes ranging up to O($10^5$) sites are simulated and finite size scaling is analyzed. The partition function zeros and the values of various cumulants at their respective peak positions are determined and they agree with the scaling behavior expected from universality with the Onsager solution on the torus ($\nu=1$). For the pseudocritical values of the coupling we find significant anomalies indicating a shift exponent $\neq 1$ for sphere-like lattice topology.Comment: 24 pages, LaTeX, 8 figure

A 4-unit-cell superstructure in optimally doped YBa2Cu3O6.92 superconductor

Using high-energy diffraction we show that a 4-unit-cell superstructure, q0=(1/4,0,0), along the shorter Cu-Cu bonds coexists with superconductivity in optimally doped YBCO. A complex set of anisotropic atomic displacements on neighboring CuO chain planes, BaO planes, and CuO2 planes, respectively, correlated over ~3-6 unit cells gives rise to diffuse superlattice peaks. Our observations are consistent with the presence of Ortho-IV nanodomains containing these displacements.Comment: Corrected typo in abstrac

Lineage Switch Macrophages Can Present Antigen

Recent reports of “lineage switching” from a lymphoid to macrophage phenotype have left unresolved the question of whether such cells are functional macrophages or nonfunctional products of differentiation gone awry. This study demonstrates that several “macrophage-like” cell lines derived from v-Ha-ras-transformed pre-B cells have gained the capacity to effectively present antigen in MHC-restricted fashion. Using an assay involving the cocultivation of putative antigen-presenting cells with chicken ovalbumin (cOVA) and a cOVA-specific T-cell hybridoma, “lineage switch” cell lines were found to present antigen as effectively as macrophage-containing peritoneal exudates. Neither the original pre-B-cell precursors nor B-cell lymphomas derived from them present antigen. Thus, we have demonstrated that these “lineage switch” macrophages are capable of antigen presentation, a mature differentiated function. While gaining macrophage characteristics, these cells have also rearranged their kappa light-chain immunoglobulin locus, suggesting that macrophage differentiation and immunoglobulin rearrangement are not mutually exclusive processes. The existence of both lymphoid and myeloid characteristics in a cell fully capable of antigen presentation suggests greater plasticity in hematopoietic lineage commitment than conventionally thought to be the case

Genetic and pharmacological relationship between P-Glycoprotein and increased cardiovascular risk associated with clarithromycin prescription:An Epidemiological and Genomic Population-Based Cohort Study in Scotland, UK

BackgroundThere are conflicting reports regarding the association of the macrolide antibiotic clarithromycin with cardiovascular (CV) events. A possible explanation may be that this risk is partly mediated through drug-drug interactions and only evident in at-risk populations. To the best of our knowledge, no studies have examined whether this association might be mediated via P-glycoprotein (P-gp), a major pathway for clarithromycin metabolism. The aim of this study was to examine CV risk following prescription of clarithromycin versus amoxicillin and in particular, the association with P-gp, a major pathway for clarithromycin metabolism.Methods and findingsWe conducted an observational cohort study of patients prescribed clarithromycin or amoxicillin in the community in Tayside, Scotland (population approximately 400,000) between 1 January 2004 and 31 December 2014 and a genomic observational cohort study evaluating genotyped patients from the Genetics of Diabetes Audit and Research Tayside Scotland (GoDARTS) study, a longitudinal cohort study of 18,306 individuals with and without type 2 diabetes recruited between 1 December 1988 and 31 December 2015. Two single-nucleotide polymorphisms associated with P-gp activity were evaluated (rs1045642 and rs1128503 -AA genotype associated with lowest P-gp activity). The primary outcome for both analyses was CV hospitalization following prescription of clarithromycin versus amoxicillin at 0-14 days, 15-30 days, and 30 days to 1 year. In the observational cohort study, we calculated hazard ratios (HRs) adjusted for likelihood of receiving clarithromycin using inverse proportion of treatment weighting as a covariate, whereas in the pharmacogenomic study, HRs were adjusted for age, sex, history of myocardial infarction, and history of chronic obstructive pulmonary disease. The observational cohort study included 48,026 individuals with 205,227 discrete antibiotic prescribing episodes (34,074 clarithromycin, mean age 73 years, 42% male; 171,153 amoxicillin, mean age 74 years, 45% male). Clarithromycin use was significantly associated with increased risk of CV hospitalization compared with amoxicillin at both 0-14 days (HR 1.31; 95% CI 1.17-1.46, p ConclusionsIn this study, we observed that the increased risk of CV events with clarithromycin compared with amoxicillin was associated with an interaction with P-glycoprotein