Posttraumatic Stress Disorder Symptomatology and Substance Use in an Outpatient Concurrent Disorders Sample.

OBJECTIVE: Posttraumatic stress disorder (PTSD) and substance use disorders (SUDs) present a complex and often severe clinical presentation within a concurrent disorders context. The objective of this study was to examine associations between PTSD symptoms and SUD outcomes to better understand the clinical phenomenon of comorbid PTSD and SUD. Multivariate statistical methods were used to test the hypothesis that elevated PTSD symptoms, both at the level of global severity and specific PTSD symptom clusters, are associated with greater substance use and related problems. METHODS: Data were collected from an intake assessment battery within a specialized concurrent disorders outpatient service in Hamilton, ON. The sample comprised 326 participants (mean age = 37.19, 45.4% female). Structural equation models examined associations between PTSD and alcohol, cannabis, and substance use frequency and problems, controlling for age and sex. Alcohol was ultimately dropped from the model due to non-significant bivariate associations. RESULTS: Higher global PTSD symptomatology was significantly associated with higher cannabis and other substance use frequency and related problems. Analyses using PTSD cluster scores showed higher scores for alterations in arousal were positively associated with cannabis-related problems, drug-related problems, and cannabis and other substance use frequency. Avoidance was significantly associated with cannabis frequency and cannabis-related problems. In general, effect sizes were small in magnitude, accounting for between 9% and 25% of variance. CONCLUSION: Significant cluster-level associations indicate the importance of specific PTSD symptoms (hyperarousal, avoidance) in relation to substance use when identifying therapeutic targets among individuals presenting with comorbid PTSD-SUD. This multivariate approach provides a higher resolution and potentially more clinically informative representation of the complex clinical presentation of PTSD and SUD in a concurrent disorder population and could guide the development of more effective treatment paths.

Measuring and understanding "quality of life" among emerging adults in a substance use program.

OBJECTIVE: This work focuses on understanding quality of life and evaluating a brief quality of life measure in an outpatient emerging adult (17-25 years of age) substance use program. METHOD: Mixed methods were used including: (a) psychometric evaluation of the adapted MyLifeTracker (MLT) based on assessments completed four times throughout treatment (n = 100) and (b) qualitative interviews with 12 emerging adults in the program. The study was codesigned, cofacilitated, and cointerpreted with emerging adults with lived experience. RESULTS: At intake, emerging adults reported quality of life scores of 3.7/10 on average and significantly improved (change M = 2.1 points, d = 0.86, p < .001) at the ∼12-week follow-up demonstrating program effects and sensitivity to change. Factor analysis suggested unidimensionality of the measure and internal consistency was high (ω = 0.81). MLT scores correlated in expected directions with other measures of quality of life, functioning, and mental health symptoms and demonstrated incremental validity in explaining variability in these measures over and above World Health Organization quality of life items. Emerging adults thought the five items (i.e., general well-being, day-to-day activities, relationships with friends, relationships with family, coping) generally captured the most important aspects of quality of life to them and had positive impressions regarding the use of this measure for measurement-based care. Other important aspects of quality of life included feeling a sense of meaning, purpose, motivation, and independence. CONCLUSION: Overall, the MLT demonstrated evidence of psychometric and content validity among emerging adults in substance use treatment. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Management of illicit substances in hospital: An evaluation of policy and procedure implementation.

Previous research has identified illicit substance use on hospital property as an ongoing concern, particularly in inpatient mental health units. This research, combined with concerns raised by healthcare providers, patients, and patients' families, resulted in one hospital in a medium-sized city in Canada enacting two internal strategies for the management of illicit substances on hospital property. The unit-based Green-Yellow-Red procedure employs environmental scanning and regular risk assessment to report the incidence rate of illicit substances suspected and/or found in the unit, to inform staff of the extent of necessary interventions which should ensue. The hospital-wide Management of Illicit Substances protocol includes ten steps which can be followed by any staff member who suspects they have found an illicit substance or related paraphernalia on hospital grounds. This paper discusses the creation and implementation of these two strategies, as well as associated challenges and outcomes of each. Overall, these strategies have effectively functioned to mitigate the potential dangers of exposure to illicit substances for staff and patients alike. These results stand to encourage other institutions to implement similar strategies in order to better manage situations in which illicit substances are suspected or discovered on hospital property.

Initial insights from a quality improvement initiative to develop an evidence-informed young adult substance use program.

High rates of substance misuse during emerging adulthood (~17-25 years of age, also referred to as young adulthood) require developmentally appropriate clinical programs. This article outlines: 1) the development of an evidence-informed young adult outpatient substance use program that takes a biopsychosocial patient-centred approach to care; 2) a quality improvement process and protocol; and 3) the patient characteristics of an initial cohort. Literature reviews, program reviews, environmental scans, and consultations with interested parties (including individuals with lived expertise) were used to develop the program. A 12-week measurement-based care program was developed comprising: 1) individual measurement-based care and motivational enhancement therapy sessions; 2) group programming focused on cognitive behavioural therapy, mindfulness, distress tolerance, and emotional regulation; 3) clinical consultations for diagnostic clarification and/or medication review; and 4) an independent Community Reinforcement Approach Family Training (CRAFT) group for loved ones. A measurement system was concurrently created to collect clinical and program evaluation data at six time points. In the first 21 months of the program, 152 young adults enrolled in the program (mean age = 21 years old, 47% female gender) primarily reporting treatment targets of cannabis (68%) and alcohol (63%) and almost all presenting with co-occurring mental health concerns (95%). The initial cohort who completed the program showed symptom improvements. Collectively, the program demonstrates the feasibility of developing an evidence-informed young adult substance use program using measurement-based care, but also the need for flexibility and ongoing monitoring to meet local needs.

Des taux élevés d'abus de substances durant la vie d'adulte émergente (~17­25 ans d'âge, aussi nommé jeune âge adulte) nécessitent des programmes cliniques appropriés au développement. Cet article présente: 1) le développement d'un programme fondé sur des données probantes sur l'utilisation de substances des jeunes patients ambulatoires qui adopte une approche biopsychosociale axée sur les patients; 2) un processus et un protocole d'amélioration de la qualité; et 3) les caractéristiques du patient d'une cohorte initiale. Les revues de la littérature, les examens de programme, les analyses de l'environnement, et les consultations avec les parties intéressées (notamment les personnes ayant une expertise vécue) ont servi à élaborer le programme. Un programme de soins de 12 semaines basés sur la mesure a été élaboré qui comprend: 1) ides soins individuels basés sur la mesure et des séances de thérapie d'amélioration de la motivation; 2) une programmation de groupe axée sur la thérapie cognitivo-comportementale, la pleine conscience, la tolérance à la détresse, et la régulation émotionnelle; 3) les consultations cliniques pour la clarification du diagnostic et/ou la revue des médicaments; et (4) un groupe indépendant d'Approche de renforcement communautaire Formation familiale (ARCFF) pour les êtres chers. Un système de mesure a été créé simultanément pour recueillir les données cliniques et d'évaluation du programme à six points dans le temps. Dans les 21 premiers mois du programme, 152 jeunes adultes s'y sont inscrits (âge moyen = 21 ans, 47 % de sexe féminin) et déclaraient principalement que les cibles du traitement étaient le cannabis (68 %) et l'alcool (63 %) et presque tous présentaient des problèmes de santé mentale co-occurrents (95 %). La cohorte initiale qui a terminé le programme présentait des améliorations des symptômes. Collectivement, le programme démontre la faisabilité de développer un programme d'utilisation de substances pour jeunes adultes fondé sur des données probantes et utilisant des soins basés sur la mesure, mais également le besoin de flexibilité et de surveillance constante pour répondre aux besoins locaux.

A temporal classifier predicts histopathology state and parses acute-chronic phasing in inflammatory bowel disease patients.

Previous studies have conducted time course characterization of murine colitis models through transcriptional profiling of differential expression. We characterize the transcriptional landscape of acute and chronic models of dextran sodium sulfate (DSS) and adoptive transfer (AT) colitis to derive temporal gene expression and splicing signatures in blood and colonic tissue in order to capture dynamics of colitis remission and relapse. We identify sub networks of patient-derived causal networks that are enriched in these temporal signatures to distinguish acute and chronic disease components within the broader molecular landscape of IBD. The interaction between the DSS phenotype and chronological time-point naturally defines parsimonious temporal gene expression and splicing signatures associated with acute and chronic phases disease (as opposed to ordinary time-specific differential expression/splicing). We show these expression and splicing signatures are largely orthogonal, i.e. affect different genetic bodies, and that using machine learning, signatures are predictive of histopathological measures from both blood and intestinal data in murine colitis models as well as an independent cohort of IBD patients. Through access to longitudinal multi-scale profiling from disease tissue in IBD patient cohorts, we can apply this machine learning pipeline to generation of direct patient temporal multimodal regulatory signatures for prediction of histopathological outcomes.

Perceptions of prevalence, consequences, and strategies for managing contraband substance use in an inpatient concurrent disorders program: A qualitative study of patient perspectives and survey of clinician perspectives.

Objective: Inpatient treatment programs for substance use disorders (SUDs) typically have an abstinence policy for patients, but unsanctioned substance use nonetheless takes place and can have significant negative clinical impacts. The current study sought to understand this problem from a patient perspective and to develop strategies for improved contraband substance management in an inpatient concurrent disorders sample. Methods: First, a qualitative study (n = 10; 60% female) was undertaken to ascertain perceived prevalence, impact, and patient-generated strategies. Second, an anonymous follow-up survey was conducted with unit staff clinicians to evaluate the suggested strategies. Results: Patients reported that contraband substance use was present and had significant negative consequences clinically. Recommendations from patients included more extensive urine drug screening, the use of drug-sniffing dogs, and direct contingencies for contraband use. Nineteen staff competed an anonymous follow-up questionnaire to evaluate the viability of these strategies, revealing variable perceptions of feasibility and effectiveness. Conclusion: These findings emphasize the adverse consequences of contraband substance use in addiction treatment programs and identify patient-preferred strategies for managing this challenge.

Novel antagonist antibody to TLR3 blocks poly(I:C)-induced inflammation in vivo and in vitro.

Toll-like receptor 3 (TLR3) binds and signals in response to dsRNA and poly(I:C), a synthetic double stranded RNA analog. Activation of TLR3 triggers innate responses that may play a protective or detrimental role in viral infections or in immune-mediated inflammatory diseases through amplification of inflammation. Two monoclonal antibodies, CNTO4685 (rat anti-mouse TLR3) and CNTO5429 (CDRs from CNTO4685 grafted onto a mouse IgG1 scaffold) were generated and characterized. These mAbs bind the extracellular domain of mouse TLR3, inhibit poly(I:C)-induced activation of HEK293T cells transfected with mTLR3, and reduce poly(I:C)-induced production of CCL2 and CXCL10 by primary mouse embryonic fibroblasts. CNTO5429 decreased serum IL-6 and TNFα levels post-intraperitoneal poly(I:C) administration, demonstrating in vivo activity. In summary, specific anti-mTLR3 mAbs have been generated to assess TLR3 antagonism in mouse models of inflammation.

Repeated exposure of house dust mite induces progressive airway inflammation in mice: Differential roles of CCL17 and IL-13.

We conducted a systematic evaluation of lung inflammation indued by repeated intranasal exposure (for 10 consecutive days) to a human aeroallergen, house dust mite (HDM) in BALB/c mice. Peak influx of neutrophils, monocytes/lymphocytes, and eosinophils was observed in bronchoalveolar lavage (BAL) on days 1, 7 and 11, respectively, and normalized to baseline by day 21. Peak elevations of Th2, myeloid-derived cytokines/chemokines and serum IgE were seen both in BAL and lung tissue homogenates between days 7 and 11, and declined thereafter; however, IL-33 levels remained elevated from day 7 to day 21. Airway hyperreactivity to inhaled methacholine was significantly increased by day 11 and decreased to baseline by day 21. The lung tissue showed perivascular and peribronchial cuffing, epithelial hypertrophy and hyperplasia and goblet cell formation in airways by day 11, and resolution by day 21. Levels of soluble collagen and tissue inhibitors of metalloproteinases (TIMP) also increased reflecting tissue remodeling in the lung. Microarray analysis demonstrated a significant time-dependent up-regulation of several genes including IL-33, CLCA3, CCL17, CD4, CD10, CD27, IL-13, Foxa3, IL-4, IL-10, and CD19, in BAL cells as well as the lung. Pre-treatment of HDM challenged mice with CCL17 and IL-13 antibodies reduced BAL cellularity, airway hyper-responsiveness (AHR), and histopathological changes. Notably, anti-IL-13, but not anti-CCL17 monoclonal antibodies (mAbs) reduced BAL neutrophilia while both mAbs attenuated eosinophilia. These results suggest that CCL17 has an overlapping, yet distinct profile versus IL-13 in the HDM model of pulmonary inflammation and potential for CCL17-based therapeutics in treating Th2 inflammation.

Long-term activation of TLR3 by poly(I:C) induces inflammation and impairs lung function in mice.

BACKGROUND: The immune mechanisms associated with infection-induced disease exacerbations in asthma and COPD are not fully understood. Toll-like receptor (TLR) 3 has an important role in recognition of double-stranded viral RNA, which leads to the production of various inflammatory mediators. Thus, an understanding of TLR3 activation should provide insight into the mechanisms underlying virus-induced exacerbations of pulmonary diseases. METHODS: TLR3 knock-out (KO) mice and C57B6 (WT) mice were intranasally administered repeated doses of the synthetic double stranded RNA analog poly(I:C). RESULTS: There was a significant increase in total cells, especially neutrophils, in BALF samples from poly(I:C)-treated mice. In addition, IL-6, CXCL10, JE, KC, mGCSF, CCL3, CCL5, and TNFalpha were up regulated. Histological analyses of the lungs revealed a cellular infiltrate in the interstitium and epithelial cell hypertrophy in small bronchioles. Associated with the pro-inflammatory effects of poly(I:C), the mice exhibited significant impairment of lung function both at baseline and in response to methacholine challenge as measured by whole body plethysmography and an invasive measure of airway resistance. Importantly, TLR3 KO mice were protected from poly(I:C)-induced changes in lung function at baseline, which correlated with milder inflammation in the lung, and significantly reduced epithelial cell hypertrophy. CONCLUSION: These findings demonstrate that TLR3 activation by poly(I:C) modulates the local inflammatory response in the lung and suggest a critical role of TLR3 activation in driving lung function impairment. Thus, TLR3 activation may be one mechanism through which viral infections contribute toward exacerbation of respiratory disease.

Carboxylic acid bioisosteres acylsulfonamides, acylsulfamides, and sulfonylureas as novel antagonists of the CXCR2 receptor.

A series of novel acylsulfonamide, acylsulfamide, and sulfonylurea bioisosteres of carboxylic acids were prepared as CXCR2 antagonists. Structure-activity relationships are reported for these series. One potent orally bioavailable inhibitor had excellent PK properties and was active in a lung injury model in hyperoxia-exposed newborn rats.

LC/MS/MS Profiling of Tissue Oxysterols and its Application in Dextran Sodium Sulphate Induced Mouse Colitis Models.

We have developed a workflow to extract, separate, and semi-quantify bioactive oxysterols from mouse colon tissues and fecal matters using solid- and liquid-phase extractions, enzymatic and chemical modifications, and stable-isotope dilution LC/MS/MS. The method was applied to a dextran sodium sulphate (DSS)-induced mouse colitis model, which revealed that one particular dihydroxycholesterol (diOHC), 7α,25-diOHC, was significantly elevated in both colon tissue and fecal matters of mice with colitis compared to that in naïve mice. The extent of 7α,25-diOHC elevation was positively correlated with colitis severity.

Loss of toll-like receptor 3 function improves glucose tolerance and reduces liver steatosis in obese mice.

OBJECTIVE: Emerging evidence suggests a link between innate immunity and development of type 2 diabetes mellitus (T2D); however, the molecular mechanisms linking them are not fully understood. Toll-like Receptor 3 (TLR3) is a pathogen pattern recognition receptor that recognizes the double-stranded RNA of microbial or mammalian origin and contributes to immune responses in the context of infections and chronic inflammation. The objective of this study was to determine whether TLR3 activity impacts insulin sensitivity and lipid metabolism. MATERIALS AND METHODS: Wild type (WT) and TLR3 knock-out (TLR3(-/-)) mice were fed a high fat diet (HFD) and submitted to glucose tolerance tests (GTTs) over a period of 33 weeks. In another study, the same group of mice was treated with a neutralizing monoclonal antibody (mAb) against mouse TLR3. RESULTS: TLR3(-/-) mice fed an HFD developed obesity, although they exhibited improved glucose tolerance and lipid profiles compared with WT obese mice. In addition, the increase in liver weight and lipid content normally observed in WT mice on an HFD was significantly ameliorated in TLR3(-/-) mice. These changes were accompanied by up-regulation of genes involved in cholesterol efflux such as PPARδ, LXRα, and LXRα-targeting genes and down-regulation of pro-inflammatory cytokine and chemokine genes in obese TLR3(-/-) mice. Furthermore, global gene expression profiling in liver demonstrated TLR3-specific changes in both lipid biosynthesis and innate immune response pathways. CONCLUSIONS: TLR3 affects glucose and lipid metabolism as well as inflammatory mediators, and findings in this study reveal a new role for TLR3 in metabolic homeostasis. This suggests antagonizing TLR3 may be a beneficial therapeutic approach for the treatment of metabolic diseases.