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Lisa M Einhorn,1 Padmaja Krishnan,2 Cassandra Poirier,3 Pablo Ingelmo4– 7 1Department of Anesthesiology, Division of Pediatrics, Duke University School of Medicine, Durham, NC, USA; 2Campbell University School of Osteopathic Medicine, Lillington, NC, USA; 3Department of Anesthesiology, University of British Columbia, Kelowna, BC, Canada; 4Edwards Family Interdisciplinary Center for Complex Pain, Montreal Children’s Hospital, McGill University Health Center, Montreal, QC, Canada; 5Research Institute, McGill University Health Center, Montreal, QC, Canada; 6Department of Anesthesia, McGill University, Montreal, QC, Canada; 7Alan Edwards Center for Research in Pain, Montreal, QC, CanadaCorrespondence: Lisa M Einhorn, Department of Anesthesiology, Division of Pediatrics, DUMC 3094, Durham, NC, 27710, USA, Tel +1 919 681-4487, Email Lisa.einhorn@duke.eduAbstract: Chronic postsurgical pain (CPSP) affects a significant proportion of children and adolescents after major surgery and is a detriment to both short- and long-term recovery outcomes. While clinical characteristics and psychosocial risk factors for developing CPSP in children and adults are well established in the literature, there has been little progress on the prevention and management of CPSP after pediatric surgery. Limited evidence to support current pharmacologic approaches suggests a fundamentally new paradigm must be considered by clinicians to both conceptualize and address this adverse complication. This narrative review provides a comprehensive evaluation of both the known and emerging mechanisms that support our current understanding of CPSP. Additionally, we discuss the importance of optimizing perioperative analgesic strategies to mitigate CPSP based on individual patient risks. We highlight the importance of postoperative pain trajectories to identify those most at risk for developing CPSP, the early referral to multi-disciplinary pain clinics for comprehensive evaluation and treatment of CPSP, and additional work needed to differentiate CPSP characteristics from other chronic pain syndromes in children. Finally, we recognize ongoing challenges associated with the universal implementation of available knowledge about pediatric CPSP into practically useful care plans for clinicians.Keywords: chronic postsurgical pain, pediatrics, perioperative care, pain management, secondary pain

Abstract. Introduction:. Mu opioid receptor gene (OPRM1) variant rs1799971 introduces a CpG site, which may influence DNA methylation (DNAm) and opioid/pain outcomes. Objectives:. In this nested analysis, we investigated both OPRM1 A118G genotype and promoter/immediate downstream blood DNAm sequencing data for associations with opioid effects and chronic postsurgical pain (CPSP) in a surgical cohort. Methods:. Prospectively recruited opioid naïve patients undergoing Nuss procedure or spinal fusion with rs1799971 genotypes (Illumina arrays), DNAm (next generation enzymatic methylation sequencing at Chr6:154,039,209-154,039,803) and outcomes—opioid analgesia (integrated opioid use + pain over postoperative days 0 and 1 normalized to surgery type), safety—respiratory depression (RD) in high opioid use groups, and CPSP (Numerical Rating Scale >3/10 2-12 months postsurgery)—were included. Linear and logistic regression were performed to test genetic and epigenetic associations, adjusted for sociodemographics, cell types, and analgesics. Results:. In this cohort (N = 112; 15.3 ± 2.0 years, 50% female, 83% White, 55% had CPSP, 13% had RD), DNAm at Chr6:154039216-154039217 was associated with CPSP (odds ratio [OR], 1.26; 95% confidence interval [CI], 1.00-1.57; P = 0.03), Chr6:154039661-154039662 with acute integrated pain (β = −20.9, 95% CI, −40.70 to −1.10, P = 0.04), Chr6:154039520-154039521 (OR, 1.49; 95% CI, 1.09-2.03; P = 0.01), and Chr6:154039571-154039572 (OR, 1.47; 95% CI, 1.08-2.01; P = 0.02) with RD. Significant CpG sites were located in Repressed Polycomb chromatin states. Genotype was not associated with DNAm or outcomes. Conclusion:. Our analyses support OPRM1 DNAm as predictors of acute and chronic pain/opioid outcomes in children after painful surgery. Study limitations included absent GG genotype, low sequencing coverage, and lack of correction for multiple testing.

Introduction Even with recent treatment advances, type 2 diabetes (T2D) remains poorly controlled for many patients, despite the best efforts to adhere to therapies and lifestyle modifications. Although estimates vary, studies indicate that in >10% of individuals with difficult-to-control T2D, hypercortisolism may be an underlying contributing cause. To better understand the prevalence of hypercortisolism and the impact of its treatment on T2D and associated comorbidities, we describe the two-part Hypercortisolism in Patients with Difficult to Control Type 2 Diabetes Despite Receiving Standard-of-Care Therapies: Prevalence and Treatment with Korlym® (Mifepristone) (CATALYST) trial.Methods and analysis In part 1, approximately 1000 participants with difficult-to-control T2D (haemoglobin A1c (HbA1c) 7.5%–11.5% despite multiple therapies) are screened with a 1 mg dexamethasone suppression test (DST). Those with post-DST cortisol >1.8 µg/dL and dexamethasone level ≥140 ng/dL are identified to have hypercortisolism (part 1 primary endpoint), have morning adrenocorticotropic hormone (ACTH) and dehydroepiandrosterone sulfate (DHEAS) measured and undergo a non-contrast adrenal CT scan. Those requiring evaluation for elevated ACTH are referred for care outside the study; those with ACTH and DHEAS in the range may advance to part 2, a randomised, double-blind, placebo-controlled trial to evaluate the impact of treating hypercortisolism with the competitive glucocorticoid receptor antagonist mifepristone (Korlym®). Participants are randomised 2:1 to mifepristone or placebo for 24 weeks, stratified by the presence/absence of an abnormal adrenal CT scan. Mifepristone is dosed at 300 mg once daily for 4 weeks, then 600 mg daily based on tolerability and clinical improvement, with an option to increase to 900 mg. The primary endpoint of part 2 assesses changes in HbA1c in participants with hypercortisolism with or without abnormal adrenal CT scan. Secondary endpoints include changes in antidiabetes medications, cortisol-related comorbidities and quality of life.Ethics and dissemination The study has been approved by Cleveland Clinic IRB (Cleveland, Ohio, USA) and Advarra IRB (Columbia, Maryland, USA). Findings will be presented at scientific meetings and published in peer-reviewed journals.Trial registration number NCT05772169.

Abstract Background The American College of Medical Genetics and Genomics (ACMG) recently published new tier-based carrier screening recommendations. While many pan-ethnic genetic disorders are well established, some genes carry pathogenic founder variants (PFVs) that are unique to specific ethnic groups. We aimed to demonstrate a community data-driven approach to creating a pan-ethnic carrier screening panel that meets the ACMG recommendations. Methods Exome sequencing data from 3061 Israeli individuals were analyzed. Machine learning determined ancestries. Frequencies of candidate pathogenic/likely pathogenic (P/LP) variants based on ClinVar and Franklin were calculated for each subpopulation based on the Franklin community platform and compared with existing screening panels. Candidate PFVs were manually curated through community members and the literature. Results The samples were automatically assigned to 13 ancestries. The largest number of samples was classified as Ashkenazi Jewish (n = 1011), followed by Muslim Arabs (n = 613). We detected one tier-2 and seven tier-3 variants that were not included in existing carrier screening panels for Ashkenazi Jewish or Muslim Arab ancestries. Five of these P/LP variants were supported by evidence from the Franklin community. Twenty additional variants were detected that are potentially pathogenic tier-2 or tier-3. Conclusions The community data-driven and sharing approaches facilitate generating inclusive and equitable ethnically based carrier screening panels. This approach identified new PFVs missing from currently available panels and highlighted variants that may require reclassification.