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Lisa Burback,1,2 Christine Forner,3 Olga Karolina Winkler,1 Huda F Al-Shamali,1 Yahya Ayoub,1 Jacquelyn Paquet,1 Myah Verghese4 1Department of Psychiatry, University of Alberta, Edmonton, Alberta, Canada; 2Neuroscience and Mental Health Institute (NMHI), University of Alberta, Edmonton, Alberta, Canada; 3Associated Counseling, Calgary, Alberta, Canada; 4Department of Neuroscience, University of Alberta, Edmonton, Alberta, CanadaCorrespondence: Lisa Burback, Department of Psychiatry, University of Alberta, 4-142A Katz Group Centre for Research, 11315 - 87 Ave NW, Edmonton, AB, T6G 2H5, Canada, Tel +1 780 342 5635, Fax +1 780 342 5230, Email burback@ualberta.caPurpose: Dissociation is a necessary part of our threat response system, common to all animal species, normally temporarily activated under conditions of extreme or inescapable threat. Pathological dissociation, however, continues to occur after the initial threat has passed, in response to reminders or inaccessibility of safety and security. Present across the spectrum of psychiatric diagnoses, recurrent dissociative symptoms are linked to severe trauma exposure, insecure attachment, treatment non-response, and maladaptive coping behaviors such as substance use, suicidality, and self-harm. However, empirical studies testing treatments specific to dissociative processes remain scarce. This narrative review summarizes existing studies and provides theoretical, neurobiological, and evolutionary perspectives on dissociative processes and treatments for pathological dissociation.Methods: A systematic search of five databases (MEDLINE, EMBASE, APA PsycINFO, CINAHL plus, Scopus) was conducted on April 13, 2023. Peer-reviewed clinical studies with adult participants, assessing intervention effects on dissociative symptoms, were included. Results were thematically analyzed and summarized.Results: Sixty-nine studies were identified, mainly focused on posttraumatic stress disorder, trauma-exposed populations, and borderline personality disorder. Psychotherapy was studied in 72.5% of studies; other interventions included medications and neurostimulation. The majority reported positive outcomes, despite the heterogeneous spectrum of interventions. However, treatment of dissociative symptoms was the primary objective in only a minority.&#x00A0Conclusion: Pathological dissociation is a complex phenomenon involving brain and body systems designed for perceiving and responding to severe threats, requiring an individualized approach. A literature is emerging regarding potentially evidence-based treatments to help those impacted by recurrent dissociative symptoms. When contextualized within a neurobiological and evolutionary perspective, these treatments can be understood as facilitating an internal and/or relational sense of safety, resulting in symptom reduction. Further studies are needed to explore effective treatments for dissociative symptoms.Keywords: derealization, depersonalization, posttraumatic stress disorder, psychotherapy, psychopharmacology, transcranial magnetic stimulation

Intermediate-risk pulmonary embolism (PE) has variable outcomes. Current risk stratification models lack the positive predictive value to identify patients at highest risk of PE-related mortality. We identified intermediate-risk PE patients who underwent catheter-based interventions and right heart catheterization (RHC) and identified those with low cardiac index (CI < 2.2 L/min/m 2 ). We utilized regression models to identify echocardiographic predictors of low CI and Kaplan Meier curve to evaluate PE-related mortality when stratified by the echocardiographic predictor. Of 174 intermediate-risk PE patients, 41 underwent RHC. Within this cohort, 46.3% had low CI. Univariable linear regression identified right ventricular outflow tract velocity time integral (RVOT VTI), right/left ventricular ratio, S prime, inferior vena cava diameter, and pulmonary artery systolic pressure as potential predictors of low CI. Multivariable linear regression identified RVOT VTI as significant predictor of low CI (β coefficient 0.124, 95% confidence interval [CI]: 0.01-0.24, P = .034). Right ventricular outflow tract velocity time integral

Abstract Background The respiratory tract epithelium is a critical environmental interface that regulates inflammation. In chronic infectious airway diseases, pathogens may permanently colonize normally sterile luminal environments. Host-pathogen interactions determine the intensity of inflammation and thus, rates of tissue injury. Although many cells become refractory to stimulation by pathogen products, it is unknown whether the airway epithelium becomes either tolerant or hypersensitive in the setting of chronic infection. Our goals were to characterize the response of well-differentiated primary human tracheobronchial epithelial cells to Pseudomonas aeruginosa, to understand whether repeated exposure induced tolerance and, if so, to explore the mechanism(s). Methods The apical surface of well-differentiated primary human tracheobronchial epithelial cell cultures was repetitively challenged with Pseudomonas aeruginosa culture filtrates or the bacterial media control. Toxicity, cytokine production, signal transduction events and specific effects of dominant negative forms of signaling molecules were examined. Additional experiments included using IL-1β and TNFα as challenge agents, and performing comparative studies with a novel airway epithelial cell line. Results An initial challenge of the apical surface of polarized human airway epithelial cells with Pseudomonas aeruginosa culture filtrates induced phosphorylation of IRAK1, JNK, p38, and ERK, caused degradation of IκBα, generation of NF-κB and AP-1 transcription factor activity, and resulted in IL-8 secretion, consistent with activation of the Toll-like receptor signal transduction pathway. These responses were strongly attenuated following a second Pseudomonas aeruginosa, or IL-1β, but not TNFα, challenge. Tolerance was associated with decreased IRAK1 protein content and kinase activity and dominant negative IRAK1 inhibited Pseudomonas aeruginosa -stimulated NF-κB transcriptional activity. Conclusion The airway epithelial cell response to Pseudomonas aeruginosa entails adaptation and tolerance likely mediated, in part, by down-regulation of IRAK1.