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Background: Substance use disorder is characterized by long-lasting changes in reward-related brain regions, such as the nucleus accumbens. Previous work has shown that cocaine exposure induces plasticity in broad, genetically defined cell types in the nucleus accumbens; however, in response to a stimulus, only a small percentage of neurons are transcriptionally active-termed an ensemble. Here, we identify an Arc-expressing neuronal ensemble that has a unique trajectory of recruitment and causally controls drug self-administration after repeated, but not acute, cocaine exposure., Methods: Using Arc-CreER T2 transgenic mice, we expressed transgenes in Arc+ ensembles activated by cocaine exposure (either acute [1 × 10 mg/kg intraperitoneally] or repeated [10 × 10 mg/kg intraperitoneally]). Using genetic, optical, and physiological recording and manipulation strategies, we assessed the contribution of these ensembles to behaviors associated with substance use disorder., Results: Repeated cocaine exposure reduced the size of the ensemble while simultaneously increasing its control over behavior. Neurons within the repeated cocaine ensemble were hyperexcitable, and their optogenetic excitation was sufficient for reinforcement. Finally, lesioning the repeated cocaine, but not the acute cocaine, ensemble blunted cocaine self-administration. Thus, repeated cocaine exposure reduced the size of the ensemble while simultaneously increasing its contributions to drug reinforcement., Conclusions: We showed that repeated, but not acute, cocaine exposure induced a physiologically distinct ensemble characterized by the expression of the immediate early gene Arc, which was uniquely capable of modulating reinforcement behavior., (Copyright © 2024 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Purpose: To measure trends in the rates and costs of hospitalizations over a 15-year period among young adults with physical and/or psychiatric disorders., Methods: This population-based, repeated cross-sectional study identified all 18- to 26- year-olds hospitalized in Ontario, Canada from April 1, 2003 and March 31, 2018 (fiscal years 2003-2017). Using discharge diagnoses, we assigned hospitalizations to one of four categories: 1) psychiatric disorder only; 2) primary psychiatric disorder with comorbid physical illness; 3) primary physical with comorbid psychiatric disorder; and 4) physical illness only. We compared health service utilization and changes in rates of hospitalizations over time using restricted cubic spline regression. Secondary outcome measures included change in hospital costs for each hospitalization category over the study period., Results: Of 1,076,951 hospitalizations in young adults (73.7% female), 195,726 (18.2%) had a psychiatric disorder (either primary or comorbid). There were 129,676 hospitalizations (12.0%) with psychiatric disorders only, 36,287 (3.4%) with primary psychiatric and comorbid physical disorders, 29,763 (2.8%) with primary physical and comorbid psychiatric disorders, and 881,225 (81.8%) with physical disorders only. Rates of hospitalization for psychiatric disorders only increased 81% from 4.32 to 7.84/1,000 population, and those with physical health disorders with comorbid psychiatric disorders increased 172% from 0.47 to 1.28/1,000 population. Substance-related disorders were the most common comorbid psychiatric disorders among youth hospitalized for physical illness and increased 260% from 0.9 to 3.3/1,000 population., Discussion: Hospitalizations among young adults with primary and comorbid psychiatric disorders have increased significantly over the past 15 years. Health system resources should be adequately directed to meet the shifting and complex needs of hospitalized young adults., (Copyright © 2023 Society for Adolescent Health and Medicine. Published by Elsevier Inc. All rights reserved.)

Introduction: Case-finding algorithms can be applied to administrative healthcare records to identify people with diseases, including people with HIV (PWH). When supplementing an existing registry of a low prevalence disease, near-perfect specificity helps minimize impacts of adding in algorithm-identified false positive cases. We evaluated the performance of algorithms applied to healthcare records to supplement an HIV registry in British Columbia (BC), Canada., Methods: We applied algorithms based on HIV-related diagnostic codes to healthcare practitioner and hospitalization records. We evaluated 28 algorithms in a validation sub-sample of 7,124 persons with positive HIV tests (2,817 with a prior negative test) from the STOP HIV/AIDS data linkage-a linkage of healthcare, clinical, and HIV test records for PWH in BC, resembling a disease registry (1996-2020). Algorithms were primarily assessed based on their specificity-derived from this validation sub-sample-and their impact on the estimate of the total number of PWH in BC as of 2020., Results: In the validation sub-sample, median age at positive HIV test was 37 years (Q1: 30, Q3: 46), 80.1% were men, and 48.9% resided in the Vancouver Coastal Health Authority. For all algorithms, specificity exceeded 97% and sensitivity ranged from 81% to 95%. To supplement the HIV registry, we selected an algorithm with 99.89% (95% CI: 99.76% - 100.00%) specificity and 82.21% (95% CI: 81.26% - 83.16%) sensitivity, requiring five HIV-related healthcare practitioner encounters or two HIV-related hospitalizations within a 12-month window, or one hospitalization with HIV as the most responsible diagnosis. Upon adding PWH identified by this highly-specific algorithm to the registry, 8,774 PWH were present in BC as of March 2020, of whom 333 (3.8%) were algorithm-identified., Discussion: In the context of an existing low prevalence disease registry, the results of our validation study demonstrate the value of highly-specific case-finding algorithms applied to administrative healthcare records to enhance our ability to estimate the number of PWH living in BC., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: JSGM is the Executive Director and Physician-in-Chief of the BC Centre for Excellence in HIV/AIDS, a provincial program serving all BC health authorities, and based at St. Paul’s Hospital-Providence Health Care. JM’s Treatment as Prevention® (TasP®) research, paid to his institution, has received support from the BC Ministry of Health, Health Canada, Public Health Agency of Canada, Genome BC, Vancouver Coastal Health and VGH Foundation. Institutional grants have been provided by Gilead, Merck and ViiV Healthcare. JSGM received no specific funding for this work and has no competing interests. VDL is funded by a grant from the Canadian Institutes of Health Research, the Canadian Foundation for AIDS Research (CANFAR Innovation Grant – 30-101), and has received honoraria for the CROI Ambassador Program from ViiV Healthcare. KK is funded by a Michael Smith Health Research BC Research Trainee Fellowship (grant number: #RT-2022-2559), a CTN Postdoctoral Fellowship (no grant number), and a Canadian Institutes of Health Research Postdoctoral Fellowship (grant number: HIV 181935). The other authors declare that they have no competing interests. This does not alter our adherence to PLOS ONE policies on sharing data and materials., (Copyright: © 2023 Emerson et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Accidental overdoses are now the leading cause of death among people with HIV (PWH) in British Columbia (BC). We examined the utilization and retention of opioid agonist therapy (OAT). Adult PWH (≥19 years) with ≥ 1 OAT dispensation in BC between 2008 and 2020 were included (n = 1,515). OAT treatment episodes were formed based on specific criteria for slow-release oral morphine (SROM), methadone, injectable OAT (iOAT), and buprenorphine/naloxone. Retention in treatment was defined as any episode lasting ≥ 12 months. Logistic regression with generalized estimating equations modeled retention-associated factors. There was a 56.6% decline in OAT retention over time. Buprenorphine treatment exhibited significantly lower odds of retention (OR: 0.58; 95% CI: 0.36-0.92) compared to methadone. Conversely, no significant change in retention odds was observed for SROM (0.72; 0.33-1.54) and iOAT (0.81; 0.31-2.12). Factors associated with increased odds of retention included a 10-year increase in age (1.69; 1.46-1.95), previous retention history (1.96; 1.40-2.73), achieving OAT therapeutic dose (8.22; 6.67-10.14), and suppressed HIV viral load (1.35; 1.10-1.67). Individuals with a lifetime HCV diagnosis receiving iOAT were more likely to retain (3.61; 1.20-10.83). Each additional year on OAT during the study period was associated with a 4% increase in the odds of retention. A significant proportion of PWH had a history of OAT prescribing but experienced low retention rates. Retention outcomes were more positive for SROM and iOAT. The association between OAT medication type and retention odds may be particularly influenced by HCV diagnosis. Optimal management of opioid use disorder among PWH, with an emphasis on attaining the therapeutic dose is crucial., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Dr. Julio S. G. Montaner is the Executive Director and Physician-in-Chief of the BC Centre for Excellence in HIV/AIDS, a provincial program serving all BC health authorities, and based at St. Paul’s Hospital-Providence Health Care. JM’s Treatment as Prevention® (TasP®) research, paid to his institution, has received support from the BC Ministry of Health, Health Canada, Public Health Agency of Canada, Genome BC, Vancouver Coastal Health and VGH Foundation. Institutional grants have been provided by Gilead, Merck and ViiV Healthcare., (© 2023 The Authors.)

A large body of work has demonstrated that cocaine-induced changes in transcriptional regulation play a central role in the onset and maintenance of cocaine use disorder. An underappreciated aspect of this area of research, however, is that the pharmacodynamic properties of cocaine can change depending on an organism's previous drug-exposure history. In this study, we utilized RNA sequencing to characterize how the transcriptome-wide effects of acute cocaine exposure were altered by a history of cocaine self-administration and long-term withdrawal (30 days) in the ventral tegmental area (VTA), nucleus accumbens (NAc), and prefrontal cortex (PFC) in male mice. First, we found that the gene expression patterns induced by a single cocaine injection (10 mg/kg) were discordant between cocaine-naïve mice and mice in withdrawal from cocaine self-administration. Specifically, the same genes that were upregulated by acute cocaine in cocaine-naïve mice were downregulated by the same dose of cocaine in mice undergoing long-term withdrawal; the same pattern of opposite regulation was observed for the genes downregulated by initial acute cocaine exposure. When we analyzed this dataset further, we found that the gene expression patterns that were induced by long-term withdrawal from cocaine self-administration showed a high degree of overlap with the gene expression patterns of acute cocaine exposure - even though animals had not consumed cocaine in 30 days. Interestingly, cocaine re-exposure at this withdrawal time point reversed this expression pattern. Finally, we found that this pattern was similar across the VTA, PFC, NAc, and within each brain region the same genes were induced by acute cocaine, re-induced during long-term withdrawal, and reversed by cocaine re-exposure. Together, we identified a longitudinal pattern of gene regulation that is conserved across the VTA, PFC, and NAc, and characterized the genes constituting this pattern in each brain region., Competing Interests: Declaration of competing interest The authors have no competing interests., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Purpose: Evidence from systematic reviews suggests that adult immigrants living in areas of higher immigrant density (areas with a higher proportion of foreign-born residents) tend to experience fewer mental health problems-likely through less discrimination, greater access to culturally/linguistically appropriate services, and greater social support. Less is known about how such contexts are associated with mental health during childhood-a key period in the onset and development of many mental health challenges. This study examined associations between neighbourhood immigrant density and youth mental health conditions in British Columbia (BC; Canada)., Methods: Census-derived neighbourhood characteristics were linked to medical records for youth present in ten of BC's largest school districts from age 5 through 19 over the study period (1995-2016; n = 138,090). Occurrence of physician assessed diagnoses of mood and/or anxiety disorders, attention deficit hyperactivity disorder (ADHD), and conduct disorder was inferred through International Classification of Diseases (ICD) diagnostic codes in universal public health insurance records. Multi-level logistic regression was used to model associations between neighbourhood characteristics and odds of diagnoses for each condition; models were stratified by generation status (first-generation: foreign-born; second-generation: Canadian-born to a foreign-born parent; non-immigrant)., Results: Higher neighbourhood immigrant density was associated with lower odds of disorders among first-generation immigrant youth (e.g., adjusted odds of mood-anxiety disorders for those in neighbourhoods with the highest immigrant density were 0.67 times lower (95% CI: 0.49, 0.92) than those in neighbourhoods with the lowest immigrant density). Such protective associations generally extended to second-generation and non-immigrant youth, but were-for some disorders-stronger for first-generation than second-generation or non-immigrant youth., Conclusions: Findings suggest there may be protective mechanisms associated with higher neighbourhood immigrant density for mental health conditions in immigrant and non-immigrant youth. It is important that future work examines potential pathways by which contextual factors impact immigrant and non-immigrant youth mental health., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

Background: Refugee children face numerous challenges associated with pre-migration trauma and post-migration adaptation. Much research pertaining to refugee children's well-being focuses on psychiatric symptoms. Relatively few studies have examined how social context factors-such as perceptions of peer belonging, and support from adults at home and at school-contribute to the emotional health of refugee children. Informed by social-ecological theories emphasizing dynamic interactions between the contexts in which children develop, we examined associations between social context factors and emotional health in refugee children., Methods: Data were drawn from a population-based data linkage in British Columbia, Canada. The analytic sample included 682 grade 4 students (M age 9.2 years; 46.3% female) with a refugee background who responded to the Middle Years Development Instrument (MDI) during the 2010/2011-2016/2017 school years. The MDI is a self-report survey of children's social and emotional competencies and social context factors completed at school. Regression analyses were used to examine associations of social context factors (school climate, supportive adults at school and at home, and peer belonging) with indicators of emotional health (life satisfaction, self-concept, optimism, and sadness). Refugee generation status (first/second) was considered through stratification and testing of interactions with social context factors., Results: Perceived supportive school climate, support from adults in school and at home, and peer belonging were each independently associated with better emotional health. Results were similar for first- and second-generation children., Conclusion: Taken together, results suggest a unique role of the school context to refugee children's emotional health. School-based programming that promotes positive school climate can be considered as an important approach to support newcomer refugee children and their families., (© 2021. Springer-Verlag GmbH Germany, part of Springer Nature.)

Objective: Routinely collected health administrative data can be used to efficiently assess disease burden in large populations, but it is important to evaluate the validity of these data. The objective of this study was to develop and validate International Classification of Disease 10th revision (ICD -10) algorithms that identify laboratory-confirmed influenza or laboratory-confirmed respiratory syncytial virus (RSV) hospitalizations using population-based health administrative data from Ontario, Canada., Study Design and Setting: Influenza and RSV laboratory data from the 2014-15, 2015-16, 2016-17 and 2017-18 respiratory virus seasons were obtained from the Ontario Laboratories Information System (OLIS) and were linked to hospital discharge abstract data to generate influenza and RSV reference cohorts. These reference cohorts were used to assess the sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of the ICD-10 algorithms. To minimize misclassification in future studies, we prioritized specificity and PPV in selecting top-performing algorithms., Results: 83,638 and 61,117 hospitalized patients were included in the influenza and RSV reference cohorts, respectively. The best influenza algorithm had a sensitivity of 73% (95% CI 72% to 74%), specificity of 99% (95% CI 99% to 99%), PPV of 94% (95% CI 94% to 95%), and NPV of 94% (95% CI 94% to 95%). The best RSV algorithm had a sensitivity of 69% (95% CI 68% to 70%), specificity of 99% (95% CI 99% to 99%), PPV of 91% (95% CI 90% to 91%) and NPV of 97% (95% CI 97% to 97%)., Conclusion: We identified two highly specific algorithms that best ascertain patients hospitalized with influenza or RSV. These algorithms may be applied to hospitalized patients if data on laboratory tests are not available, and will thereby improve the power of future epidemiologic studies of influenza, RSV, and potentially other severe acute respiratory infections., Competing Interests: The authors have declared that no competing interests exist.

By dehydrating actinide salts with an ionic liquid containing a common anion and subsequent reaction with N-heterocyclic ligands, we challenge the concept that actinides prefer O- over N-donors; rather the acidic hydrogen atoms of protic solvents hinder the formation of more elusive f-element N-donor coordination complexes.

The present study examined the association of residential instability with hospitalizations among homeless and vulnerably housed individuals over a 4-year time period. Survey data were linked to administrative records on hospitalizations. Specifically, we used data from the Health and Housing in Transition study, a prospective cohort study that tracked the health and housing status of homeless and vulnerably housed individuals in Canada. Responses from Vancouver-based participants (n = 378) from baseline and 3 follow-ups were linked to their administrative health records on hospitalizations (Discharge Abstract Database - Hospital Separation Files; 2008-2012). A generalized estimating equations model was used to examine associations between the number of residential moves and any hospitalizations during each year (none versus ≥ 1 hospitalizations). Analyses included demographic and health variables. Survey data were collected via structured interviews. Hospitalizations were derived from provincial administrative health records. A higher number of residential moves were associated with hospitalization over the study period (adjusted odds ratio: 1.14; 95% confidence interval: 1.01, 1.28). Transgender, female gender, perceived social support, better self-reported mental health, and having ≥ 3 chronic health conditions also predicted having been hospitalized over the study period, whereas high school/higher education was negatively associated with hospitalizations. Our results indicate that residential instability is associated with increased risk of hospitalization, illustrating the importance of addressing housing as a social determinant of health.

Using a linked population-based database established on healthcare, socio-economic, and survey datasets in British Columbia, Canada, we examined how biological, socio-demographic, and socio-economic status (SES) factors at birth related to children's emotional development and mental health. One analysis examined teacher-rated anxiety, hyperactivity, and aggression for kindergarten children (M age  = 5.7; n = 134,094). Another analysis examined administrative healthcare records comprising of physician-assigned diagnostic codes for mental health conditions (conduct disorder, attention deficit hyperactivity disorder, anxiety disorder and depression) from ages 5 through 15 (n = 89,404). Various factors at birth, including gestational age, birthweight, and maternal demographics, were related to emotional development and mental health in childhood. Across outcomes, low SES indicated detrimental associations with various aspects of children's emotional development and mental health (e.g., adjusted odds of mental health conditions were 25-39% higher for children of low income families versus others). Findings reinforce evidence that poverty (reduction) is a primary public health issue.

Purpose: Mental illness represents a major public health burden among Canada's large immigrant population. A burgeoning cross-sectional, longitudinal, and experimental evidence base implicates nutrition in mental health. Healthier diets (e.g., those rich in certain micro-nutrients) may benefit cognitive, social, and emotional functioning through attenuated inflammation and other bio-psychological pathways. The present study examined associations between nutrition and three markers of mental health among immigrants to Canada., Methods: Employing cross-sectional data from immigrant respondents (n = 37,071) to a nationally representative population-based survey (the Canadian Community Health Survey: CCHS 2011-2014), we modelled associations of daily fruit and vegetable consumption with three mental health outcomes: anxiety and/or mood disorder diagnosis, being distressed (assessed via the 6-item Kessler Psychological Distress Scale), and having good self-rated overall mental health. Multivariable logistic regression analyses were employed, adjusting for various socio-demographic and lifestyle-related variables., Results: Higher consumption of fruit and vegetables demonstrated significant, protective associations with odds of having a mood and/or anxiety disorder, being distressed, and self-rated good mental health. Such patterns of association were similar regardless of ethno-cultural minority status and recency of immigration. Moreover, the protective associations of nutrition and mental health were independent of socio-demographic, health, and lifestyle factors., Conclusions: Results suggested evidence of protective associations between healthy nutritional intake and mental illness among a large-scale sample of immigrants in Canada. Importantly, the protective associations of healthier diets with immigrants' mental health were independent of various markers of healthy lifestyles (e.g., general health status, physical activity, alcohol use). Healthy dietary intake may, therefore, be worth consideration in efforts to prevent mental illness among immigrants.

Importance: More than 50% of lifetime mental health disorders develop by early adolescence, and yet it is not well understood how early childhood social-emotional functioning varies in populations or how differences in functioning may be associated with emerging mental health conditions., Objectives: To identify profiles of social-emotional functioning at kindergarten school entry (age 5 years) and to examine to what extent profiles are related to early-onset mental health conditions (ages 6-14 years)., Design, Setting, and Participants: This prospective cohort study followed up a population cohort of 34 552 children in British Columbia, Canada, from birth (born 1996-1998) to age 14 years (last follow-up, December 31, 2011). Data were analyzed from the Developmental Trajectories cohort that links British Columbia child development data from the Early Development Instrument (EDI) to British Columbia Ministry of Health and Ministry of Education records. Data were analyzed between May and September 2017., Exposures: Early childhood social-emotional functioning (defined as social competence, internalizing, and externalizing symptoms) rated by the children's kindergarten teachers., Main Outcomes and Measures: Occurrences of physician-assessed mental health conditions throughout childhood and early adolescence, including depression, anxiety, conduct disorder, and attention-deficit/hyperactivity disorder (ADHD), calculated from billing codes from the International Classification of Diseases, Ninth Revision recorded in provincial health insurance data., Results: Data from 34 323 children (mean [SD] age, 5.7 [0.3] years; 17 538 [51.1%] were boys) were analyzed at kindergarten and followed up to age 14 years (15 204 completed follow-up). Latent profile analysis identified 6 unique social-emotional functioning profiles at school entry, with 41.6% of children (n = 14 262) exhibiting comparative vulnerabilities in internalizing or externalizing behaviors. Prevalence of mental health conditions from ages 6 to 14 years was 4.0% for depression, 7.0% for anxiety, 5.5% for conduct disorder, 7.1% for ADHD, and 5.4% for multiple conditions. Zero-inflated Poisson analyses showed an association between social-emotional functioning profiles at kindergarten school entry and physician-assessed mental health conditions by age 14 years (range of adjusted odds ratios: depression, 1.10 [95% CI, 0.76-1.60] to 2.93 [95% CI, 1.93-4.44]; anxiety, 1.00 [95% CI, 0.74-1.36] to 1.73 [95% CI, 1.11-2.70]; conduct disorder, 2.17 [95% CI, 1.41-3.34] to 6.91 [95% CI, 4.90-9.74]; ADHD, 1.46 [95% CI, 1.11-1.93] to 8.72 [95% CI, 6.46-11.78]; and multiple conditions, 1.20 [95% CI, 0.88-1.63] to 6.81 [95% CI, 4.91-9.44]). Children with higher teacher ratings of aggression and hyperactivity had more frequent consultations for conduct disorder, ADHD, and multiple conditions., Conclusions and Relevance: This study's findings suggest that more than 40% of children enter the school system with relative vulnerabilities in social-emotional functioning that are associated with early-onset mental health conditions. The results raise important questions for using population-level early childhood development monitoring in the context of universal and proactive mental health strategies.

Canada has an increasingly large immigrant population. Areas of higher immigrant density, may relate to immigrants' health through reduced acculturation to Western foods, greater access to cultural foods, and/or promotion of salubrious values/practices. It is unclear, however, whether an association exists between Canada-wide regional immigrant density and obesity among immigrants. Thus, we examined whether regional immigrant density was related to obesity, among immigrants. Adult immigrant respondents (n = 15,595) to a national population-level health survey were merged with region-level immigrant density data. Multi-level logistic regression was used to model the odds of obesity associated with increased immigrant density. The prevalence of obesity among the analytic sample was 16%. Increasing regional immigrant density was associated with lower odds of obesity among minority immigrants and long-term white immigrants. Immigrant density at the region-level in Canada may be an important contextual factor to consider when examining obesity among immigrants.

Purpose: The Satisfaction With Life Scale adapted for Children (SWLS-C) is a self-report measure of children's quality of life and has exhibited sound psychometric properties. In light of increasing ethno-cultural diversity, it is important to understand child life satisfaction across diverse subgroups. Employing children's language background as a proxy for cultural background among children in British Columbia, Canada, we examined (a) the cross-cultural measurement equivalence of the SWLS-C; and (b) cross-cultural relations of peer support and adult support with SWLS-C., Methods: Participants were 20,119 children (M age 9.2; 50.2% boys) who provided data as part of a self-report child health survey (the Middle-years Development Instrument). Measurement equivalence across eight language/cultural background groups was tested via multi-group confirmatory factor analysis. Multi-level analyses were used to compare: a) SWLS-C means; and b) associations of peer support and adult support with SWLS-C scores, by language/cultural background., Results: Findings supported strict measurement equivalence between the English language/cultural background group and all other language/cultural background groups for the SWLS-C. Relative to the English language background group, SWLS-C means differed for several language/cultural background groups. Within every language/cultural background group, however, peer and adult support scale scores were significant positive correlates of SWLS-C scores., Conclusions: This study provided evidence for measurement equivalence of a life satisfaction measure across children from diverse language/cultural backgrounds and identified between-group differences in the level of child life satisfaction that were generally consistent with prior theory and findings. Moreover, results provided evidence of promotive associations of adult support and peer support with life satisfaction among diverse groups of children.

This paper examined measurement invariance (MI), both across gender and over time, of the Satisfaction With Life Scale adapted for Children (SWLS-C). Adapted from the adult SWLS, the SWLS-C is a self-report measure for children and adolescents to assess their life satisfaction. The sample comprised elementary school students in British Columbia, Canada (n = 4,026) who responded to the SWLS-C in Grade 4 (M(age) = 9.3, SD = 0.6; 48.9% girls) and approximately 3 years later in Grade 7. We examined MI regarding gender, time, and both gender and time (i.e., interactional invariance) using Clustered Repeated Measures Multi-Group Confirmatory Factor Analysis with a mean- and variance-adjusted weighted least squares (WLSMV) estimation. Residual invariance by gender was supported at Grades 4 and 7; scalar invariance was supported longitudinally for each gender and overall. In the "interactional" model, including gender and time, analyses indicated scalar MI, but not residual MI. Analyses of latent factor means indicated that SWLS-C scores significantly decreased for both girls and boys from Grade 4 to Grade 7. The decrease was more pronounced for girls, but gender differences at either age were not significant. The pattern of observed mean scores differed, as it indicated no significant decrease for boys' SWLS-C scores, but significant gender differences at both time points. However, given the lack of residual invariance, comparisons of observed SWLS-C mean scores across gender and over time may be compromised. The different results for latent and observed mean SWLS-C scores highlight the importance of routinely conducting MI analyses for group comparisons. (PsycINFO Database Record, ((c) 2018 APA, all rights reserved).)

Background: Ethnic minorities form an increasingly large proportion of Canada's population. Living in areas of greater ethnic density may help protect mental health among ethnic minorities through psychosocial pathways such as accessibility to culturally appropriate provision of mental health care, less discrimination and a greater sense of belonging. Mood and anxiety disorders are common psychiatric disorders., Aim: This study examined whether ethnic density of regions was related to mood and anxiety disorders among ethnic minorities in Canada., Method: Responses by ethnic minority individuals to the 2011-2014 administrations of the Canadian Community Health Survey ( n =  33,201) were linked to health region ethnic density data. Multilevel logistic regression was employed to model the odds of having mood and/or anxiety disorders associated with increasing region-level ethnic density and to examine whether sense of community belonging helped explain variance in such associations. Analyses were adjusted for individual-level demographic factors as well as region-level socio-economic factors., Results: Higher ethnic density related to lower odds of mood and/or anxiety disorders for Canadian-born (but not foreign-born) ethnic minorities. Sense of community belonging did not help explain such associations, but independently related to lower odds of mood and/or anxiety disorders. These findings remained after adjusting for regional population density and after excluding (rural/remote) regions of very low ethnic density., Conclusion: Ethnic density of regions in Canada may be an important protective factor against mental illness among Canadian-born ethnic minorities. It is important to better understand how, and for which specific ethno-cultural groups, ethnic density may influence mental health.

Purpose: The Satisfaction with Life Scale (SWLS) is a widely used measure of life satisfaction, a key aspect in quality of life. The SWLS has been used across many socio-demographic groups. Comparison of life satisfaction across different subgroups (e.g., cultures) is meaningful to researchers; such cross-group comparison presupposes that validity of the inferences from SWLS scores holds across various subgroups (measurement invariance: MI). The aim of the present review was to identify, summarize, and evaluate research testing measurement invariance of the SWLS., Methods: A targeted literature search identified articles (published 1985-2016) that examined MI of the SWLS using multi-group confirmatory factor analysis., Results: The search retrieved 27 articles, representing 66,380 respondents across 24 nations. Gender, age, and culture were the most common types of MI assessed. Most articles used translated (non-English) versions of the SWLS. The highest level of MI tested in each article (i.e., configural, metric, scalar, strict) varied. Findings generally supported a unidimensional structure (configural MI), but less commonly supported were equivalent factor loadings (metric MI). Over half of the gender invariance analyses supported scalar or strict MI, whereas scalar or strict MI was supported in only 1 of the 11 culture MI analyses and 1 of the 9 age MI analyses., Conclusions: Findings suggest meaningful comparisons of SWLS means across gender may be valid in some situations, but most likely not across culture or age groups. Participants mostly ascribe similar meaning to like items on the SWLS regardless of their gender, but age and especially culture seem to influence this process.

The ionic liquid (IL) 1-ethyl-3-methylimidazolium acetate was utilized as a liquid-state crystallization agent to form ionic co-crystals using amphoteric azoles selected as model compounds for active pharmaceutical ingredients. Weakly acidic azoles crystallize the IL relatively quickly, while stronger acidic azoles undergo slower ion exchange with the IL to form salts.

Renin is an aspartyl protease involved in the production of angiotensin II, a potent vasoconstrictor. Renin inhibitors can prevent blood vessel constriction and therefore could be useful for the treatment of hypertension. High-throughput screening efforts identified a small molecule renin inhibitor with a core substituted diaminopyrimidine ring. Parallel medicinal chemistry efforts based on this lead resulted in compound 1. A complex of 1 bound to renin was crystallized, and structural data were obtained by X-ray diffraction. The structure indicated that there were adjacent unoccupied binding pockets. Synthetic efforts were initiated to extend functionality into these pockets so as to improve affinity and adjust pharmacokinetic parameters. Thermodynamics data for inhibitor binding to renin were also collected using isothermal titration calorimetry. These data were used to help guide inhibitor optimization by suggesting molecular alterations to improve binding affinity from both thermodynamic and structural perspectives. The addition of a methoxypropyl group extending into the S3 subpocket improved inhibitor affinity and resulted in greater binding enthalpy. Initial additions to the pyrimidine ring template that extended into the large hydrophobic S2 pocket did not improve affinity and dramatically altered the thermodynamic driving force for the binding interaction. Binding of the core template was enthalpically driven, whereas binding of initial inhibitors with S2 extensions was both enthalpically and entropically driven but lost significant binding enthalpy. Additional electrostatic interactions were then incorporated into the S2 extension to improve binding enthalpy while taking advantage of the favorable entropy.

MDM2 is a regulator of cell growth processes that acts by binding to the tumor suppressor protein p53 and ultimately restraining its activity. While inactivation of p53 by mutation is commonly observed in human cancers, a substantial percentage of tumors express wild type p53. In many of these cases, MDM2 is overexpressed, and it is believed that suppression of MDM2 activity could yield therapeutic benefits. Therefore, we have been focusing on the p53-MDM2 interaction as the basis of a drug discovery program and have been able to develop a series of small molecule inhibitors. We herein report a high resolution NMR structure of a complex between the p53-binding domain of MDM2 and one of these inhibitors. The form of MDM2 utilized was an engineered hybrid between the human and Xenopus sequences, which provided a favorable combination of relevancy and stability. The inhibitor is found to bind in the same site as does a highly potent peptide fragment of p53. The inhibitor is able to successfully mimic the peptide by duplicating interactions in three subpockets normally made by amino acid sidechains, and by utilizing a scaffold that presents substituents with rigidity and spatial orientation comparable to that provided by the alpha helical backbone of the peptide. The structure also suggests opportunities for modifying the inhibitor to increase its potency.

This paper examines security issues from the unique perspective of our nation's coastlines and associated infrastructure. It surveys ongoing efforts to secure offshore shipping lanes, as well as the transportation systems and huge capital investments on the narrow strip of land intersecting with coastal waters. The paper recounts the extraordinary demands recently placed on the Coast Guard, port authorities and other agencies charged with offshore security. New federal requirements such as port assessments continue to be mandated, while solutions to finding are still unfolding. An up-to-date summary of maritime security functions is provided. Those requirements are compared and contrasted with security guidelines and regulatory demands placed upon mobile and fixed assets of the Chemical Process Industry (CPI) in coastal environs. These span the gamut from recommendations by industry groups and professional organizations, to federal and state requirements, to insurance demands, to general duty obligations.

Nuclear magnetic resonance (NMR) methods were employed to study the interaction of the cytokine Interleukin-2 (IL-2) with the alpha-subunit of its receptor (IL-2Ralpha), and to help understand the behavior of small molecule inhibitors of this interaction. Heteronuclear (1)H-(15)N HSQC experiments were used to identify the interaction surface of (15)N-enriched Interleukin-2 ((15)N-IL-2) in complex with human IL-2Ralpha. In these experiments, chemical shift and line width changes in the heteronuclear single-quantum coherence (HSQC) spectra upon binding of (15)N-IL-2 enabled classification of NH atoms as either near to, or far from, the IL-2Ralpha interaction surface. These data were complemented by hydrogen/deuterium (H/D) exchange measurements, which illustrated enhanced protection of slowly-exchanging IL-2 NH protons near the site of interaction with IL-2Ralpha. The interaction surface defined by NMR compared well with the IL-2Ralpha binding site identified previously using mutagenesis of human and murine IL-2. Two low molecular weight inhibitors of the IL-2/IL-2Ralpha interaction were studied: one (a cyclic peptide derivative) was found to mimic a part of the cytokine and bind to IL-2Ralpha; the other (an acylphenylalanine derivative) was found to bind to IL-2. For the interaction between IL-2 and the acylphenylalanine, chemical shift perturbations of (15)N and (15)NH backbone resonances were tracked as a function of ligand concentration. The perturbation pattern observed for this complex revealed that the acylphenylalanine is a competitive inhibitor-it binds to the same site on IL-2 that interacts with IL-2Ralpha.

The structure of the Ras-binding domain of human c-Raf-1 (residues 55 to 132) as determined in solution by NMR spectroscopy is presented. It consists of a five-stranded beta-sheet, a twelve residue alpha-helix, and an additional one-turn helix. The fold belongs to a known family whose members include ubiquitin and protein G. The surface of Raf55-132 that interacts with Ras has been identified by resonance perturbation mapping. The binding site is a spatially contiguous patch comprised of the two-N-terminal beta-strands, the loop between them, and the C-terminal end of the alpha-helix. A model of the Raf-Ras complex is presented, which was derived by analogy to the complex between protein G and a Fab fragment of IgG. In the model, edge beta-strands of each protein align in an antiparallel orientation, forming a unified beta-sheet, and side chains from both proteins are able to participate in ionic and hydrophobic interactions at the interface.

The structure of the Ras-binding domain of human c-Raf-1 (residues 55-132) has been determined in solution by nuclear magnetic resonance (NMR) spectroscopy. Following complete assignment of the backbone and side-chain 1H, 15N, and 13C resonances, the structure was calculated using the program CHARMM. Over 1300 NOE-derived constraints were applied, resulting in a detailed structure. The fold of Raf55-132 consists of a five-stranded beta-sheet, a 12-residue alpha-helix, and an additional one-turn helix. It is similar to those of ubiquitin and the IgG-binding domain of protein G, although the three proteins share very little sequence identity. The surface of Raf55-132 that interacts with Ras has been identified by monitoring perturbation of line widths and chemical shifts of 15N-labeled Raf55-132 resonances during titration with unlabeled Ras-GMPPNP. The Ras-binding site is contained within a spatially contiguous patch comprised of the N-terminal beta-hairpin and the C-terminal end of the alpha-helix.

Four overlapping peptide fragments of human c-Raf-1 (residues 55-132, 55-117, 77-132, and 77-117) were expressed in Escherichia coli as carboxyl-terminal extensions of maltose binding protein (MBP). The MBP-Raf fusions were purified by affinity chromatography on amylose resin and tested for binding to Ras.GTP indirectly by measuring their ability to inhibit the stimulation of Ras GTPase activity by GTPase activating protein (GAP120) in vitro. MBP-Raf(55-132) was a potent inhibitor in this assay (50% inhibition at 100 nM concentration), but the other fusion proteins had no measurable effect. The fusion partners were cleaved with Factor Xa protease and separated by gel filtration. The 8960-dalton Raf(55-132) fragment retained full activity as a competitive inhibitor of GAP120. It also blocked Ras-stimulated germinal vesicle breakdown in frog oocytes. Raf(55-132) was further characterized by circular dichroism and nuclear magnetic resonance spectroscopy. The results indicate that this fragment of c-Raf-1 adopts a highly structured, monomeric conformation in solution.

Raf-1 is a 74-kDa serine-threonine kinase which serves as the immediate downstream target of Ras in the cell growth signal transduction pathway. Recent genetic and biochemical experiments have demonstrated that (1) Ras interacts directly with the amino-terminal domain of Raf and (2) residues 51-131 of the Raf sequence are sufficient to mediate this interaction [Vojtek, A. B., Hollenberg, S. M., & Cooper, J. A. (1993) Cell 74, 205-214]. We have expressed a corresponding segment of the human Raf sequence (Raf55-132) in Escherichia coli as a fusion with maltose binding protein. The fusion protein was purified by affinity chromatography and cleaved at a pre-engineered site with factor Xa protease to liberate the 78-residue fragment of Raf. Raf55-132 bound to Ras with high affinity in a competition assay with GAP. An unlabeled version of Raf55-132 was studied by 2D homonuclear NMR, and uniformly 15N- and 13C/15N-labeled versions of Raf55-132 were studied by 2D and 3D heteronuclear NMR. Nearly complete sequence-specific assignments were made for the backbone HN, H alpha, 15N, and 13C alpha resonances. NOEs were used to determine regions of secondary structure and the overall folding topology. Raf55-132 is an independently folded domain composed of a five-stranded beta-sheet, a three-turn alpha-helix, and possibly an additional one-turn helix. Its structure resembles that of ubiquitin, even though there is no more than 11% sequence homology between the two proteins.

Sequence-specific 1H and 15N resonance assignments have been determined for the major cold shock protein (CspA) from Escherichia coli with recently developed three-dimensional triple-resonance NMR experiments. By use of these assignments, five antiparallel beta-strands were identified from analysis of NMR data. Strands 1-4 have a classical 3-2-1-4 Greek key beta-sheet topology and there are two beta-bulges, at positions Lys10-Trp11 and Gly65-Asn66. Three-dimensional structures of CspA were generated from NMR data by using simulated annealing with molecular dynamics. The overall chain fold of CspA is a beta-barrel structure, with a tightly packed hydrophobic core. Two-dimensional isotope-edited pulsed-field gradient 15N-1H heteronuclear single-quantum coherence spectroscopy was used to characterize the 15N-1H fingerprint spectrum with and without a 24-base oligodeoxyribonucleotide, 5'-AACGGTTTGACGTACAGACCATTA-3'. Protein-DNA complex formation perturbs a subset of the amide resonances that are located mostly on one face of the CspA molecule. This portion of the CspA molecular surface includes two putative RNA-binding sequence motifs which contribute to an unusual cluster of eight surface aromatic side chains: Trp11, Phe12, Phe18, Phe20, Phe31, His33, Phe34, and Tyr42. These surface aromatic groups, and also residues Lys16, Ser44, and Lys60 located on this same face of CspA, are highly conserved in the family of CspA homologues. These isotope-edited pulsed-field gradient NMR data provide a low-resolution mapping of a DNA-binding epitope on CspA.

CS7.4 is the major cold-shock protein specifically expressed to a level as high as 13% of the total cellular protein within the first hour when Escherichia coli cell culture is shifted from 37 to 15 degrees C [Goldstein et al. (1990) Proc. Natl. Acad. Sci. USA 87, 283-287]. It consists of 70 amino acid residues with a very high content of aromatic residues. CS7.4 was overproduced and purified to homogeneity. Its secondary structure was analyzed by examining circular dichroism at both the far and near-UV regions; the results suggest that the protein is largely beta-sheet in conformation. The predominance of beta-sheet structure in the protein was confirmed by using Fourier-transform infrared spectroscopy. A folded compact conformation was also verified by fluorescence emission spectroscopy. We evaluated Tm, delta H, and delta S from the thermal denaturation profile of the protein. Unusual spectral features observed in the far-UV region are attributed to the high content of aromatic residues. The protein is relatively small and contains no disulfide bonds. However, it is surprisingly stable to heat denaturation.

A combination of one- and two-dimensional NMR experiments has been used to identify and spatially locate the heme pocket residues in the paramagnetic, low spin, met-cyano complex of elephant myoglobin. In addition to assigning resonances of the conserved residues, we have also assigned Gln64 (E7) and an aromatic ring designated PheA whose side chain is inserted into the heme pocket, as found earlier for elephant carbonmonoxy-myoglobin and oxy-myoglobin (Yu, L. P., La Mar, G. N., and Mizukami, H. (1990) Biochemistry 29, 2578-2585). The assigned conserved proximal side residues (Leu89(F4), Ala90(F5), His93(F8), His97(FG3), Ile99(FG5), Leu104(G5), Phe138(H15), and Tyr146(H23)) and conserved distal side residues (Phe43(CD1), Thr67(E10), Val68(E11), and Ala71(E14)) in elephant met-cyano-myoglobin are found to have orientations similar to those in sperm whale met-cyano-myoglobin. The observed dipolar connectivities and dipolar shift pattern for the substituted Gln64(E7) place the Gln in the heme pocket oriented toward the iron, as found for His64(E7). The conserved structural elements demand that the inserted PheA originate from the B-helix (i.e. Phe27 or Phe33). Dipolar contacts between the inserted PheA and the conserved residues Phe43(CD1), Val68(E11), Ile107(G8), and Gln64(E7), place PheA in the position occupied by the B10 residue in sperm whale myoglobin (Mb), with the larger size of the PheA side chain as compared to the replaced Leu being accommodated by the vacancy that occurs in sperm whale Mb. The paramagnetic induced relaxation places PheA in van der Waals contact with the bound ligand. Hence we conclude that the B10 position of elephant Mb is occupied by a Phe, and this substitution relative to sperm whale Mb is responsible for the low autoxidation rate and low reduction potential of elephant Mb. A reduced autoxidation rate has been reported for a sperm whale synthetic point mutant Leu29(B10) --> Phe (Carver, T. E., Brantley, R. E., Jr., Singleton, E. W., Arduini, R. M., Quillin, M. L., Phillips, G. N., and Olson, J. S. (1992) J. Biol. Chem. 267, 14443-14450). The published sequence of elephant Mb places B-helix Phe residues at position 27(B8) and 33(B14), but a Phe at neither of these positions can account for the observed NMR properties. Since a large proportion of the substitutions in elephant relative to sperm whale Mb, and some of the least conservative, occur in the B-helix, neither a structurally perturbed B-helix nor an error in the sequence can be discounted.

A general approach is described for measuring homo- and heteronuclear spin coupling constants in polypeptides and small proteins. This method uses selective magnetization transfer to generate cross peaks similar to exclusive correlated spectroscopy (E.COSY) and a large direct spin coupling (1J) in one dimension to "pull apart" cross-peak components by frequencies much larger than the resonance line width. A general description of this method is presented, along with a brief discussion of spin topology and relaxation effects that must be considered in designing multidimensional nmr pulse sequences for measuring vicinal coupling constants. The principles are demonstrated in designs of several two-dimensional nmr experiments for determining coupling constants in polypeptides and proteins. These include experiments for measuring 3J(HN-H alpha), 3J(H alpha i-1-15Ni), 3J(15N-H beta), and 3J(H alpha-H beta) coupling constants, which depend on the polypeptide dihedral angles phi, psi, and chi 1. Multidimensional nmr experiments developed with this approach will allow measurements of many vicinal coupling constants in peptides, proteins, and other molecules. Coupling constants measured in these spectra can be used to determine backbone and side-chain conformations, to obtain stereospecific resonance assignments of prochiral atoms, and to characterize conformational distributions of dihedral angles. Combined with information obtained from nuclear Overhauser effect measurements, these data will provide more precise determinations of protein solution structures by nmr spectroscopy.

Steady-state nuclear Overhauser effects (NOE), two-dimensional (2D) nuclear Overhauser effect spectroscopy (NOESY), and 2D spin correlation spectroscopy (COSY) have been applied to the fully paramagnetic low-spin, cyanide-ligated complex of sperm whale ferric myoglobin to assign the majority of the heme pocket side-chain proton signals and the remainder of the heme signals. It is shown that the 2D NOESY map reveals essentially all dipolar connectivities observed in ordinary 1D NOE experiments and expected on the basis of crystal coordinates, albeit often more weakly than in a diamagnetic analogue. For extremely broad (approximately 600-Hz) and rapidly relaxing (Tf1 approximately 3 ms) signals which show no NEOSY peaks, we demonstrate that conventional steady-state NOEs obtained under very rapid pulsing conditions still allow detection of the critical dipoar connectivities that allow unambiguous assignments. The COSY map was found to be generally less useful for the hyperfine-shifted residues, with cross peaks detected only for protons greater than 6 A from the iron. Nevertheless, numerous critical COSY cross peaks between strongly hyperfine-shifted peaks were resolved and assigned. In all, 95% (53 of 56 signals) of the total proton sets within approximately 7.5 A of the iron, the region experiencing the strongest hyperfine shifts and paramagnetic relaxation, are now unambiguously assigned. Hence it is clear that the 2D methods can be profitably applied to paramagnetic proteins. The scope and limitations of such application are discussed. The resulting hyperfine shift pattern for the heme confirmed expectations based on model compounds. In contrast, while exhibiting fortuitous 1H NMR spectral similarities, a major discrepancy was uncovered between the hyperfine shift pattern of the axially bound (F8 histidyl) imidazole in the protein and that of the imidazole in a relevant model compound [Chacko, V.P., & La Mar, G. N. (1982) J. Am. Chem. Soc. 104, 7002-7007], providing direct evidence for a protein-based deformation of axial bonding in the protein.

The experimentally determined paramagnetic dipolar shifts for noncoordinated amino acid side-chain protons in the heme pocket of sperm whale cyanometmyoglobin [Emerson, S. d., & La Mar, G. N. (1990) Biochemistry (preceding paper in this issue]) were used to determine in solution the orientation of the principal axes for the paramagnetic susceptibility tensor relative to the heme iron molecular coordinates. The determination was made by a least-squares search for the unique Euler rotation angles which convert the geometric factors in the molecular (crystal) coordinates to ones that correctly predict each of 41 known dipolar shifts by using the magnetic anisotropies computed previously [Horrocks, W. D., Jr., & Greenberg, E. S. (973) Biochim. Biophys. Acta 322, 38-44]. An excellent fit to experimental shifts was obtained, which also provided predictions that allowed subsequent new assignments to be made. The magnetic axes are oriented so that the z axis is tipped approximately 15 degrees from the heme normal toward the hem delta-meso-H and coincides approximately with the characterized FeCO tilt axis in the isostructural MbCO complex [Kuriyan, J., Wilz, S., Karplus, M., & Petsko, G. A. (1986) J. Mol. Biol. 192, 133-154]. Since the FeCO and FeCN units are isostructural, we propose that the dominant protein constraints that tips the magnetic z axis from the heme normal is the tilt of the FeCN by steric interactions with the distal residues. The rhombic magnetic axes were found to align closely with the projection of the proximal His imidazole plane on the heme, confirming that the His-Fe bonding provides the protein constraints that orients the in-plane anisotrophy. The tipped magnetic z axis is shown to account quantitatively for the previously noted major discrepancy between the hyperfine shift patterns for the bound imidazole side chain in models and protein. Moreover, it is shown that the proximal His ring nolabile proton hyperfine shifts provide direct and exquisitely sensitive indicators of the degree of the z axis tilt that may serve as a valuable probe for characterizing variable steric interactions in the distal pocket of both point mutants and natural genetic variants of myoglobin.