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Long-term molecular changes in the brain resulting from blast exposure may be mediated by epigenetic changes, such as deoxyribonucleic acid (DNA) methylation, that regulate gene expression. Aberrant regulation of gene expression is associated with behavioral abnormalities, where DNA methylation bridges environmental signals to sustained changes in gene expression. We assessed DNA methylation changes in the brains of rats exposed to three 74.5 kPa blast overpressure events, conditions that have been associated with long-term anxiogenic manifestations weeks or months following the initial exposures. Rat frontal cortex eight months post-exposure was used for cell sorting of whole brain tissue into neurons and glia. We interrogated DNA methylation profiles in these cells using Expanded Reduced Representation Bisulfite Sequencing. We obtained data for millions of cytosines, showing distinct methylation profiles for neurons and glia and an increase in global methylation in neuronal versus glial cells ( p < 10 -7 ). We detected DNA methylation perturbations in blast overpressure-exposed animals, compared with sham blast controls, within 458 and 379 genes in neurons and glia, respectively. Differentially methylated neuronal genes showed enrichment in cell death and survival and nervous system development and function, including genes involved in transforming growth factor b and nitric oxide signaling. Functional validation via gene expression analysis of 30 differentially methylated neuronal and glial genes showed a 1.2 fold change in gene expression of the serotonin N-acetyltransferase gene (Aanat) in blast animals ( p < 0.05). These data provide the first genome-based evidence for changes in DNA methylation induced in response to multiple blast overpressure exposures. In particular, increased methylation and decreased gene expression were observed in the Aanat gene, which is involved in converting serotonin to the circadian hormone melatonin and is implicated in sleep disturbance and depression associated with traumatic brain injury.

Introduction Patients presenting for percutaneous coronary intervention (PCI) with acute coronary syndromes (ACS) often have overlapping bleeding and ischaemic risk factors that offset the long-term success of PCI and limit the post stenting therapeutic options. Aiming at improving outcomes following PCI, the Academic Research Consortium (ARC) recently published a set of major and minor criteria that identify, a priori, patients at high bleeding risk (HBR). Indeed, knowledge of these risk factors will help in optimization of pre-procedural therapy and minimization of post intervention complications. Nonetheless, the actual prevalence of these criteria among patients undergoing PCI for ACS is not well known. Purpose To determine the intersection and distribution of ARC-HBR major and minor criteria in a real-world ACS population presenting for PCI. Methods In this analysis, we included all patients who presented with ACS to a high-volume PCI centre from 2012 to 2017 and underwent PCI with 2nd generation drug-eluting stent (DES) implantation. Patients were then classified as HBR if they met ≥1 major or ≥2 minor criteria according to the ARC-HBR definition. Baseline clinical and procedural characteristics were extracted from each patient electronic health records. The most common exclusive intersections of ARC-HBR major and minor criteria were quantitatively visualized using an Upset Plot. Results Only 44.6% (n=2,717) of ACS patients (n=6,097) fulfilled the ARC-HBR definition. There were significant differences in baseline clinical characteristics between HBR and non-HBR groups: age (71.4±11.5 vs. 60.9±10.3 years, p&lt;0.001), females (40.7% vs. 25.5%, p&lt;0.001), cerebrovascular disease (19.5% vs. 3.9%, p&lt;0.001), and diabetes (55.4% vs. 42.1%, p&lt;0.001). The prevalence of active smoking, a major risk factor for bleeding, was higher in the non-HBR group (20.6% vs. 9.9%, p&lt;0.001). The most frequent major and minor criteria were severe anemia (n=1,072) and age ≥75 (n=1,264), respectively. The top five criteria intersections were: severe anemia (n=215), age ≥75 and moderate chronic kidney disease (CKD) (n=145); moderate CKD and mild anemia (n=142); age ≥75 and mild anemia (n=140); age ≥75, moderate CKD, and mild anemia (n=130) (Figure 1). Conclusion Among patients who have undergone PCI for ACS, a significant proportion of individuals fulfilled the ARC-HBR definition. Severe anemia was the most prevalent major criteria. Different combinations of minor criteria, mainly age ≥75, moderate CKD and mild anemia, represented the most common intersections. Figure 1 Funding Acknowledgement Type of funding source: None