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Early-life adversity (ELA) is a major predictor of psychopathology, and is thought to increase lifetime risk by epigenetically regulating the genome. Here, focusing on the lateral amygdala, a major brain site for emotional homeostasis, we describe molecular cross-talk among multiple mechanisms of genomic regulation, including 6 histone marks and DNA methylation, and the transcriptome, in subjects with a history of ELA and controls. In the healthy brain tissue, we first uncover interactions between different histone marks and non-CG methylation in the CAC context. Additionally, we find that ELA associates with methylomic changes that are as frequent in the CAC as in the canonical CG context, while these two forms of plasticity occur in sharply distinct genomic regions, features, and chromatin states. Combining these multiple data indicates that immune-related and small GTPase signaling pathways are most consistently impaired in the amygdala of ELA individuals. Overall, this work provides insights into genomic brain regulation as a function of early-life experience.

Introduction: Excessive prescribing after surgery has contributed to a public health crisis of opioid addiction and overdose in North America. However, the value of prescribing opioids to manage postoperative pain after surgical discharge remains unclear. We propose a systematic review and meta-analysis to assess the extent to which opioid analgesia impact postoperative pain intensity and adverse events in comparison to opioid-free analgesia in patients discharged after surgery., Methods and Analysis: Major electronic databases (MEDLINE, Embase, Cochrane Library, Scopus, AMED, BIOSIS, CINAHL and PsycINFO) will be searched for multi-dose randomised-trials examining the comparative effectiveness of opioid versus opioid-free analgesia after surgical discharge. Studies published from January 1990 to July 2019 will be targeted, with no language restrictions. The search will be re-run before manuscript submission to include most recent literature. We will consider studies involving patients undergoing minor and major surgery. Teams of reviewers will, independently and in duplicate, assess eligibility, extract data and evaluate risk of bias. Our main outcomes of interest are pain intensity and postoperative vomiting. Study results will be pooled using random effects models. When trials report outcomes for a common domain (eg, pain intensity) using different scales, we will convert effect sizes to a common standard metric (eg, Visual Analogue Scale). Minimally important clinical differences reported in previous literature will be considered when interpreting results. Subgroup analyses defined a priori will be conducted to explore heterogeneity. Risk of bias will be assessed according to the Cochrane Collaboration's Risk of Bias Tool 2.0. The quality of evidence for all outcomes will be evaluated using the GRADE rating system., Ethics and Dissemination: Ethical approval is not required since this is a systematic review of published studies. Our results will be published in a peer-reviewed journal and presented at relevant conferences. Further knowledge dissemination will be sought via public and patient organisations focussed on pain and opioid-related harms., Competing Interests: Competing interests: JF has received grants from Merck and personal fees for consulting from Shionogi. LF has received grants from Merck and Johnson & Johnson., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)