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Posttraumatic stress disorder (PTSD) is a heritable (h 2  = 24-71%) psychiatric illness. Copy number variation (CNV) is a form of rare genetic variation that has been implicated in the etiology of psychiatric disorders, but no large-scale investigation of CNV in PTSD has been performed. We present an association study of CNV burden and PTSD symptoms in a sample of 114,383 participants (13,036 cases and 101,347 controls) of European ancestry. CNVs were called using two calling algorithms and intersected to a consensus set. Quality control was performed to remove strong outlier samples. CNVs were examined for association with PTSD within each cohort using linear or logistic regression analysis adjusted for population structure and CNV quality metrics, then inverse variance weighted meta-analyzed across cohorts. We examined the genome-wide total span of CNVs, enrichment of CNVs within specified gene-sets, and CNVs overlapping individual genes and implicated neurodevelopmental regions. The total distance covered by deletions crossing over known neurodevelopmental CNV regions was significant (beta = 0.029, SE = 0.005, P = 6.3 × 10 -8 ). The genome-wide neurodevelopmental CNV burden identified explains 0.034% of the variation in PTSD symptoms. The 15q11.2 BP1-BP2 microdeletion region was significantly associated with PTSD (beta = 0.0206, SE = 0.0056, P = 0.0002). No individual significant genes interrupted by CNV were identified. 22 gene pathways related to the function of the nervous system and brain were significant in pathway analysis (FDR q < 0.05), but these associations were not significant once NDD regions were removed. A larger sample size, better detection methods, and annotated resources of CNV are needed to explore this relationship further., (© 2022. The Author(s).)

Importance: Direct oral anticoagulant (DOAC)-associated intracranial hemorrhage (ICH) has high morbidity and mortality. The safety and outcome data of DOAC reversal agents in ICH are limited., Objective: To evaluate the safety and outcomes of DOAC reversal agents among patients with ICH., Data Sources: PubMed, MEDLINE, The Cochrane Library, Embase, EBSCO, Web of Science, and CINAHL databases were searched from inception through April 29, 2022., Study Selection: The eligibility criteria were (1) adult patients (age ≥18 years) with ICH receiving treatment with a DOAC, (2) reversal of DOAC, and (3) reported safety and anticoagulation reversal outcomes. All nonhuman studies and case reports, studies evaluating patients with ischemic stroke requiring anticoagulation reversal or different dosing regimens of DOAC reversal agents, and mixed study groups with DOAC and warfarin were excluded., Data Extraction and Synthesis: Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines were used for abstracting data and assessing data quality and validity. Two reviewers independently selected the studies and abstracted data. Data were pooled using the random-effects model., Main Outcomes and Measures: The primary outcome was proportion with anticoagulation reversed. The primary safety end points were all-cause mortality and thromboembolic events after the reversal agent., Results: A total of 36 studies met criteria for inclusion, with a total of 1832 patients (967 receiving 4-factor prothrombin complex concentrate [4F-PCC]; 525, andexanet alfa [AA]; 340, idarucizumab). The mean age was 76 (range, 68-83) years, and 57% were men. For 4F-PCC, anticoagulation reversal was 77% (95% CI, 72%-82%; I2 = 55%); all-cause mortality, 26% (95% CI, 20%-32%; I2 = 68%), and thromboembolic events, 8% (95% CI, 5%-12%; I2 = 41%). For AA, anticoagulation reversal was 75% (95% CI, 67%-81%; I2 = 48%); all-cause mortality, 24% (95% CI, 16%-34%; I2 = 73%), and thromboembolic events, 14% (95% CI, 10%-19%; I2 = 16%). Idarucizumab for reversal of dabigatran had an anticoagulation reversal rate of 82% (95% CI, 55%-95%; I2 = 41%), all-cause mortality, 11% (95% CI, 8%-15%, I2 = 0%), and thromboembolic events, 5% (95% CI, 3%-8%; I2 = 0%). A direct retrospective comparison of 4F-PCC and AA showed no differences in anticoagulation reversal, proportional mortality, or thromboembolic events., Conclusions and Relevance: In the absence of randomized clinical comparison trials, the overall anticoagulation reversal, mortality, and thromboembolic event rates in this systematic review and meta-analysis appeared similar among available DOAC reversal agents for managing ICH. Cost, institutional formulary status, and availability may restrict reversal agent choice, particularly in small community hospitals.

Interleukin-2 (IL-2) is a hormone of the immune system responsible for control of the proliferation and cytotoxicity of T lymphocytes and natural killer cells as well as the proliferation of B lymphocytes. Recombinant IL-2 has been only minimally to modestly successfully to date in the treatment of cancer and infectious diseases, largely because the drug is associated with toxicity and a narrow therapeutic index. Quantitative measurement of IL-2 can be quickly done by enzyme immunoassay. IL-2 bioassay provides an index of biologically active cytokine. IL-2 action and pharmacokinetics can be understood in the context of the effect IL-2 on high (alpha, beta, gamma trimer) vs intermediate (alpha, beta) vs low (beta only or alpha only) affinity IL-2 receptors on various cells of the immune system. IL-2 undergoes rapid renal elimination. The route of administration is important to determine the provision of sustained drug concentrations adequate to support the proliferation and cytotoxicity of immune cells. When IL-2 is given intravenously it has rapid elimination pharmacokinetics with an initial elimination half-life and terminal elimination half-life (t1/2 beta) of 6 to 12 minutes and 40 to 80 minutes, respectively. Subcutaneous or intramuscular administration of IL-2 results in sustained systemic absorption and approximately 30% of the injected dose is absorbed. Because IL-2 is less rapidly cleared from the site of intracavitary injection, when the drug is given by these less traditional routes (e.g. intraperitoneal, intrapleural, intrathecal, intraventricular, intravesicular, and inhalational administration) sustained local IL-2 activity can result. In some cases this has resulted in an improved therapeutic index compared with that resulting after administration of the drug by high dose intravenous bolus or continuous infusion. Depot IL-2 preparations may offer more convenient administration (e.g. t1/2 beta of polyethylene glycolated IL-2 is approximately 10-fold higher than that of recombinant IL-2) or more favourable biodistribution (e.g. IL-2 liposomes are more potent against lung metastases) compared with IL-2 administered by more conventional routes. An understanding of IL-2 clinical pharmacokinetics in relation to immunobiology of this central cytokine should lead to less toxicity and more effective clinical use.