The N1 domain of the peroxisomal AAA-ATPase Pex6 is required for Pex15 binding and proper assembly with Pex1.

The heterohexameric ATPases associated with diverse cellular activities (AAA)-ATPase Pex1/Pex6 is essential for the formation and maintenance of peroxisomes. Pex1/Pex6, similar to other AAA-ATPases, uses the energy from ATP hydrolysis to mechanically thread substrate proteins through its central pore, thereby unfolding them. In related AAA-ATPase motors, substrates are recruited through binding to the motor's N-terminal domains or N terminally bound cofactors. Here, we use structural and biochemical techniques to characterize the function of the N1 domain in Pex6 from budding yeast, Saccharomyces cerevisiae. We found that although Pex1/ΔN1-Pex6 is an active ATPase in vitro, it does not support Pex1/Pex6 function at the peroxisome in vivo. An X-ray crystal structure of the isolated Pex6 N1 domain shows that the Pex6 N1 domain shares the same fold as the N-terminal domains of PEX1, CDC48, and NSF, despite poor sequence conservation. Integrating this structure with a cryo-EM reconstruction of Pex1/Pex6, AlphaFold2 predictions, and biochemical assays shows that Pex6 N1 mediates binding to both the peroxisomal membrane tether Pex15 and an extended loop from the D2 ATPase domain of Pex1 that influences Pex1/Pex6 heterohexamer stability. Given the direct interactions with both Pex15 and the D2 ATPase domains, the Pex6 N1 domain is poised to coordinate binding of cofactors and substrates with Pex1/Pex6 ATPase activity.

Effectiveness of the Minder Mobile Mental Health and Substance Use Intervention for University Students: Randomized Controlled Trial.

BACKGROUND: University attendance represents a transition period for students that often coincides with the emergence of mental health and substance use challenges. Digital interventions have been identified as a promising means of supporting students due to their scalability, adaptability, and acceptability. Minder is a mental health and substance use mobile app that was codeveloped with university students. OBJECTIVE: This study aims to examine the effectiveness of the Minder mobile app in improving mental health and substance use outcomes in a general population of university students. METHODS: A 2-arm, parallel-assignment, single-blinded, 30-day randomized controlled trial was used to evaluate Minder using intention-to-treat analysis. In total, 1489 participants were recruited and randomly assigned to the intervention (n=743, 49.9%) or waitlist control (n=746, 50.1%) condition. The Minder app delivers evidence-based content through an automated chatbot and connects participants with services and university social groups. Participants are also assigned a trained peer coach to support them. The primary outcomes were measured through in-app self-assessments and included changes in general anxiety symptomology, depressive symptomology, and alcohol consumption risk measured using the 7-item General Anxiety Disorder scale, 9-item Patient Health Questionnaire, and US Alcohol Use Disorders Identification Test-Consumption Scale, respectively, from baseline to 30-day follow-up. Secondary outcomes included measures related to changes in the frequency of substance use (cannabis, alcohol, opioids, and nonmedical stimulants) and mental well-being. Generalized linear mixed-effects models were used to examine each outcome. RESULTS: In total, 79.3% (589/743) of participants in the intervention group and 83% (619/746) of participants in the control group completed the follow-up survey. The intervention group had significantly greater average reductions in anxiety symptoms measured using the 7-item General Anxiety Disorder scale (adjusted group mean difference=-0.85, 95% CI -1.27 to -0.42; P<.001; Cohen d=-0.17) and depressive symptoms measured using the 9-item Patient Health Questionnaire (adjusted group mean difference=-0.63, 95% CI -1.08 to -0.17; P=.007; Cohen d=-0.11). A reduction in the US Alcohol Use Disorders Identification Test-Consumption Scale score among intervention participants was also observed, but it was not significant (P=.23). Statistically significant differences in favor of the intervention group were found for mental well-being and reductions in the frequency of cannabis use and typical number of drinks consumed. A total of 77.1% (573/743) of participants in the intervention group accessed at least 1 app component during the study period. CONCLUSIONS: In a general population sample of university students, the Minder app was effective in reducing symptoms of anxiety and depression, with provisional support for increasing mental well-being and reducing the frequency of cannabis and alcohol use. These findings highlight the potential ability of e-tools focused on prevention and early intervention to be integrated into existing university systems to support students' needs. TRIAL REGISTRATION: ClinicalTrials.gov NCT05606601; https://clinicaltrials.gov/ct2/show/NCT05606601. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR2-10.2196/49364.

Suicidal Ideation Amongst University Students During the COVID-19 Pandemic: Time Trends and Risk Factors.

OBJECTIVE: Examine time trends in suicidal ideation in post-secondary students over the first three waves of the COVID-19 pandemic in Canada and identify subpopulations of students with increased risk. METHOD: We analysed 14 months of data collected through repeated cross-sectional deployment of the World Health Organization (WHO) World Mental Health-International College Student (WMH-ICS) survey at the University of British Columbia. Estimated log odds weekly trends of 30-day suicidal ideation (yes/no) were plotted against time with adjustments for demographics using binary logistic generalized additive model (GAM). Risk factors for 30-day suicidal ideation frequency (four categories) were examined using the ordered logistic GAM, with a cubic smoothing spline for modelling time trend in obervation weeks and accounting for demographics. RESULTS: Nearly one-fifth (18.9%) of students experienced suicidal ideation in the previous 30 days. While the estimated log odds suggested that binary suicidal ideation was relatively stable across the course of the pandemic, an initial drop followed by an increasing trend was observed. Risk factors for suicidal ideation frequency during the pandemic included identifying as Chinese or as another non-Indigenous ethnic minority; experiencing current symptoms of depression or anxiety; having a history of suicidal planning or attempts; and feeling overwhelmed but unable to get help as a result of COVID-19. Older age was identified as a protective factor. CONCLUSIONS: The general university student population in our study was relatively resilient with respect to suicidal ideation during the first three waves of the pandemic, but trends indicate the possibility of delayed impact. Specific sub-populations were found to be at increased risk and should be considered for targeted support. Further analyses should be undertaken to continue monitoring suicidality trends throughout the remainder of the pandemic and beyond.

Emotional response patterns, mental health, and structural vulnerability during the COVID-19 pandemic in Canada: a latent class analysis.

BACKGROUND: The COVID-19 pandemic has contributed to increases in negative emotions such as fear, worry, and loneliness, as well as changes in positive emotions, including calmness and hopefulness. Alongside these complex emotional changes has been an inequitable worsening of population mental health, with many people experiencing suicidal ideation and using substances to cope. This study examines how patterns of co-occurring positive and negative emotions relate to structural vulnerability and mental health amid the pandemic. METHODS: Data are drawn from a cross-sectional monitoring survey (January 22-28, 2021) on the mental health of adults in Canada during the pandemic. Latent class analysis was used to group participants (N = 3009) by emotional response pattern types. Descriptive statistics, bivariate cross-tabulations, and multivariable logistic regression were used to characterize each class while quantifying associations with suicidal ideation and increased use of substances to cope. RESULTS: A four-class model was identified as the best fit in this latent class analysis. This included the most at-risk Class 1 (15.6%; high negative emotions, low positive emotions), the mixed-risk Class 2 (7.1%; high negative emotions, high positive emotions), the norm/reference Class 3 (50.5%; moderate negative emotions, low positive emotions), and the most protected Class 4 (26.8% low negative emotions, high positive emotions). The most at-risk class disproportionately included people who were younger, with lower incomes, and with pre-existing mental health conditions. They were most likely to report not coping well (48.5%), deteriorated mental health (84.2%), suicidal ideation (21.5%), and increased use of substances to cope (27.2%). Compared to the norm/reference class, being in the most at-risk class was associated with suicidal ideation (OR = 2.84; 95% CI = 2.12, 3.80) and increased use of substances to cope (OR = 4.64; 95% CI = 3.19, 6.75). CONCLUSIONS: This study identified that adults experiencing structural vulnerabilities were disproportionately represented in a latent class characterized by high negative emotions and low positive emotions amid the COVID-19 pandemic in Canada. Membership in this class was associated with higher risk for adverse mental health outcomes, including suicidal ideation and increased use of substances to cope. Tailored population-level responses are needed to promote positive coping and redress mental health inequities throughout the pandemic and beyond.

A portrait of the early and differential mental health impacts of the COVID-19 pandemic in Canada: Findings from the first wave of a nationally representative cross-sectional survey.

Evidence on the population-level mental health impacts of COVID-19 are beginning to amass; however, to date, there are significant gaps in our understandings of whose mental health is most impacted, how the pandemic is contributing to widening mental health inequities, and the coping strategies being used to sustain mental health. The first wave of a repeated cross-sectional monitoring survey was conducted between May 14-29, 2020 to assess the mental health impacts of the pandemic and to identify the disproportionate impacts on populations or groups identified as experiencing increased risks due to structural vulnerability and pre-existing health and social inequities. Respondents included a nationally representative probability sample (n = 3000) of Canadian adults 18 years and older. Overall, Canadian populations are experiencing a deterioration in mental health and coping due to the pandemic. Those who experience health, social, and/or structural vulnerabilities due to pre-existing mental health conditions, disability, income, ethnicity, sexuality, and/or gender are more likely to endorse mental health deterioration, challenging emotions, and difficulties coping. This monitoring study highlights the differential mental health impacts of the pandemic for those who experience health, social, and structural inequities. These data are critical to informing responsive, equity-oriented public health, and policy responses in real-time to protect and promote the mental health of those most at risk during the pandemic and beyond.

[Association of COVID-19 dissemination with symptoms of anxiety and depression among university students]. / Asociación de la diseminación del COVID-19 con síntomas de ansiedad y depresión en estudiantes universitarios.

BACKGROUND: Evidence about the impact of the COVID-19 pandemic on the mental health of specific subpopulations- such as university students-is needed as communities prepare for future waves. AIMS: To study the association of proximity of COVID-19 with symptoms of anxiety and depression in university students. METHODS: This trend study analyzed weekly cross-sectional surveys of probabilistic samples of students from the University of British Columbia for 13 weeks through the first wave of COVID-19. The main variable assessed was propinquity of COVID-19, defined as "knowing someone who tested positive for COVID-19", which was specified at different levels: knowing someone anywhere globally, in Canada, in Vancouver, in their course, or at home. Proximity was included in multivariable linear regressions to assess its association with primary outcomes, including 30-day symptoms of anxiety and/or depression. RESULTS: Of 1,388 respondents (adjusted response rate=50%), 5.6% knew someone with COVID-19 in Vancouver, 0.8% in their course, and 0.3% at home. Ten percent were overwhelmed and unable to access help. Knowing someone in Vancouver was associated with an 11 percentage-point increase in the probability of 30-day anxiety symptoms (SE=0,05; p≤0,05), moderated by gender, with a significant interaction of the exposure and being female (coefficient= 20(SE=0,09), p≤0,05). No association was found with depressive symptoms. CONCLUSION: Propinquity of COVID-19 cases may increase the likelihood of anxiety symptoms in students, particularly amongst men. Most students report coping well, but additional supports are needed for an emotionally overwhelmed minority who report being unable to access help.

Use of Asynchronous Virtual Mental Health Resources for COVID-19 Pandemic-Related Stress Among the General Population in Canada: Cross-Sectional Survey Study.

BACKGROUND: The COVID-19 pandemic has resulted in profound mental health impacts among the general population worldwide. As many in-person mental health support services have been suspended or transitioned online to facilitate physical distancing, there have been numerous calls for the rapid expansion of asynchronous virtual mental health (AVMH) resources. These AVMH resources have great potential to provide support for people coping with negative mental health impacts associated with the pandemic; however, literature examining use prior to COVID-19 illustrates that the uptake of these resources is consistently low. OBJECTIVE: The aim of this paper is to examine the use of AVMH resources in Canada during the COVID-19 pandemic among the general population and among a participant subgroup classified as experiencing an adverse mental health impact related to the pandemic. METHODS: Data from this study were drawn from the first wave of a large multiwave cross-sectional monitoring survey, distributed from May 14 to 29, 2020. Participants (N=3000) were adults living in Canada. Descriptive statistics were used to characterize the sample, and bivariate cross-tabulations were used to examine the relationships between the use of AVMH resources and self-reported indicators of mental health that included a range of emotional and coping-related responses to the pandemic. Univariate and fully adjusted multivariate logistic regression models were used to examine associations between sociodemographic and health-related characteristics and use of AVMH resources in the subgroup of participants who reported experiencing one or more adverse mental health impacts identified in the set of self-reported mental health indicators. RESULTS: Among the total sample, 2.0% (n=59) of participants reported accessing AVMH resources in the prior 2 weeks to cope with stress related to the COVID-19 pandemic, with the highest rates of use among individuals who reported self-harm (n=5, 10.4%) and those who reported coping "not well" with COVID-19-related stress (n=22, 5.5%). Within the subgroup of 1954 participants (65.1% of the total sample) who reported an adverse mental health impact related to COVID-19, 54 (2.8%) reported use of AVMH resources. Individuals were more likely to have used AVMH resources if they had reported receiving in-person mental health supports, were connecting virtually with a mental health worker or counselor, or belonged to a visible minority group. CONCLUSIONS: Despite substantial government investment into AVMH resources, uptake is low among both the general population and individuals who may benefit from the use of these resources as a means of coping with the adverse mental health impacts of the COVID-19 pandemic. Further research is needed to improve our understanding of the barriers to use.

Examining patterns of cognitive impairment among homeless and precariously housed urban youth.

INTRODUCTION: Homeless and precariously housed young people are a complex, vulnerable population frequently perceived as being difficult to engage in health and social services. Although unrecognized deficits in cognitive functioning may adversely affect their ability to access assistance and meaningfully participate in programming, few researchers have examined these deficits. The purpose of this study was to examine the extent of global and domain-specific cognitive impairment of street involved young people. METHODS: A retrospective chart review was conducted using intake data from 494 clients (64% male; average age of 21 years) enrolled in a community-based inner city mental health program in Vancouver, Canada. Descriptive statistics were used to examine performance on six cognitive domains for a subsample (N = 44) referred for neuropsychological evaluation and bivariate statistics were used to compare youth who were and were not referred. RESULTS: Cognitive impairment was evident in 80% of referred clients, with the most frequent difficulties involving attention and processing speed. Approximately 51% of clients referred for testing did not have more than a grade ten education and only 5% received government support for those with significant disabilities. Apart from alcohol use disorder, no significant differences were identified on sociodemographic and mental health variables between groups of referred and non-referred clients. CONCLUSIONS: Significant cognitive impairment was found in 80% of the young people referred for neuropsychological evaluation. This level of impairment combined with high levels of early school exiting and low levels of government support highlight the need for targeted screening to facilitate early identification and intervention.

Evaluating a Web-Based Social Anxiety Intervention Among University Students: Randomized Controlled Trial.

BACKGROUND: Treatment rates for social anxiety, a prevalent and potentially debilitating condition, remain among the lowest of all major mental disorders today. Although computer-delivered interventions are well poised to surmount key barriers to the treatment of social anxiety, most are only marginally effective when delivered as stand-alone treatments. A new, Web-based cognitive behavioral therapy (CBT) intervention called Overcome Social Anxiety was recently created to address the limitations of prior computer-delivered interventions. Users of Overcome Social Anxiety are self-directed through various CBT modules incorporating cognitive restructuring and behavioral experiments. The intervention is personalized to each user's symptoms, and automatic email reminders and time limits are used to encourage adherence. OBJECTIVE: The purpose of this study was to conduct a randomized controlled trial to investigate the effectiveness of Overcome Social Anxiety in reducing social anxiety symptoms in a nonclinical sample of university students. As a secondary aim, we also investigated whether Overcome Social Anxiety would increase life satisfaction in this sample. METHODS: Following eligibility screening, participants were randomly assigned to a treatment condition or a wait-list control condition. Only those assigned to the treatment condition were given access to Overcome Social Anxiety; they were asked to complete the program within 4 months. The social interaction anxiety scale (SIAS), the fear of negative evaluation scale (FNE), and the quality of life enjoyment and satisfaction questionnaire-short form (Q-LES-Q-SF) were administered to participants from both conditions during baseline and 4-month follow-up lab visits. RESULTS: Over the course of the study, participants assigned to the treatment condition experienced a significant reduction in social anxiety (SIAS: P<.001, Cohen d=0.72; FNE: P<.001, Cohen d=0.82), whereas those assigned to the control condition did not (SIAS: P=.13, Cohen d=0.26; FNE: P=.40, Cohen d=0.14). Additionally, a direct comparison of the average change in social anxiety in the 2 conditions over the course of the study showed that those assigned to the treatment condition experienced significantly more improvement than those assigned to the control condition (SIAS: P=.03, Cohen d=0.56; FNE: P=.001, Cohen d=0.97). Although participants assigned to the treatment condition experienced a slight increase in life satisfaction, as measured by Q-LES-Q-SF scores, and those assigned to the control condition experienced a slight decrease, these changes were not statistically significant (treatment: P=.35, Cohen d=-0.18; control: P=.30, Cohen d=0.18). CONCLUSIONS: Our findings indicate that Overcome Social Anxiety is an effective intervention for treating symptoms of social anxiety and that it may have further utility in serving as a model for the development of new interventions. Additionally, our findings provide evidence that contemporary Web-based interventions can be sophisticated enough to benefit users even when delivered as stand-alone treatments, suggesting that further opportunities likely exist for the development of other Web-based mental health interventions. TRIAL REGISTRATION: ClinicalTrials.gov NCT02792127; https://clinicaltrials.gov/ct2/show/record/NCT02792127 (Archived by WebCite at http://www.webcitation.org/6xGSRh7MG).

Naloxone and the Inner City Youth Experience (NICYE): a community-based participatory research study examining young people's perceptions of the BC take home naloxone program.

BACKGROUND: Take home naloxone (THN) programs reduce mortality by training bystanders to respond to opioid overdoses. Clinical observation by the health care team at the Inner City Youth (ICY) program indicated that young adults appeared to enthusiastically participate in the THN program and developed improved relationships with staff after THN training. However, we found a dearth of literature exploring the experiences of young adults with THN programs. This study set out to address this gap and identify suggestions from the young adults for program improvement. The primary research question was "How do street-involved young people experience the THN Program in Vancouver, BC?" METHODS: The study was undertaken at the ICY Program. Two peer researchers with lived experience of THN were recruited from ICY and were involved in all phases of the study. The peer researchers and a graduate student facilitated two focus groups and five individual interviews with ICY program participants using a semi-structured interview guide. Audio recordings were transcribed verbatim. The cut-up-and-put-in-folders approach was used to identify emerging themes. RESULTS: The themes that emerged were perceptions of risk, altruism, strengthening relationship with staff, access to training, empowerment, and confidence in ability to respond, and suggestions for youth-friendly training. These themes were then situated within the framework of the health belief model to provide additional context. Participants viewed themselves as vulnerable to overdose and spoke of the importance of expanding access to THN training. Following training, participants reported an increase in internal locus of control, an improved sense of safety among the community of people who use drugs, improved self-esteem, and strengthened relationships with ICY staff. Overall, participants found THN training engaging, which appeared to enhance participation in other ICY programming. CONCLUSIONS: Young people perceived THN training as a positive experience that improved relationships with staff. Participant recommendations for quality improvement were implemented within the provincial program.

Application of a Brief Measure of Delay Discounting to Examine the Relationship Between Delay Discounting and the Initiation of Substance Use Among Adolescents.

BACKGROUND: Higher rate of Delay Discounting (DD) is associated with increased risk for the initiation and development of substance use disorders in adolescents. OBJECTIVES: This study aimed to provide a preliminary assessment of the validity of a brief self-report measure of DD by examining discounting rates across 3 periods of increasing delay and subsequently examining the extent to which overall DD scores are associated with having initiated tobacco, alcohol and cannabis use. METHODS: Data were collected in the 2012 fall cycle of the British Columbia Adolescent Substance Use Survey. The sample consisted of 1,143 adolescents (61% female) in grades 10 and 11. A brief self-report measure of DD was developed to assess the tendency of adolescents to discount a delayed monetary reward of $100 over a period of 1-year, 1-month, and 1-week. The area under the curve was calculated for each participant's DD responses and coded into quartiles. RESULTS: The amount of discounting increased as reward delay increased from 1-week to 1-month to 1-year. Compared to participants in the lowest DD quartile, being in the second, third, or fourth quartile was associated with significantly greater odds of having initiated tobacco use, binge drinking, and cannabis use after controlling for sex, age, maternal education, and ethnicity. CONCLUSIONS: These results provide preliminary support for the validity of the brief measure of DD presented in this study and support the emerging body of evidence suggesting that DD is an important indicator of increased risk for the initiation of substance use among adolescents.

Development of a brief substance use sensation seeking scale: validation and prediction of injection-related behaviors.

Sensation seeking, a personality trait, has been shown to predict engagement in high-risk behaviors. However, little is known regarding the impact of sensation seeking on substance use among street youth. We therefore sought to modify a sensation seeking scale (SSS) for use among this population. Street youth from the Vancouver-based At-Risk Youth Study (n = 226) completed the modified SSS. Exploratory and confirmatory factor analysis (EFA/CFA) were undertaken to establish the scale's dimensionality and internal validity. The association between SSS score and injection-related behaviors was tested using generalized estimating equation analysis. EFA results indicated scale unidimensionality. The comparative fit index (CFI) suggested acceptable fit (CFI = 0.914). In multivariate analysis, sensation seeking was independently associated with injection drug use, crystal methamphetamine use, polysubstance use, and binge drug use (all p < 0.05). Our findings provide preliminary support for the use of the modified SSS among street youth.

The Cedar Project: resilience in the face of HIV vulnerability within a cohort study involving young Indigenous people who use drugs in three Canadian cities.

BACKGROUND: Indigenous scholars have long argued that it is critical for researchers to identify factors related to cultural connectedness that may protect against HIV and hepatitis C infection and buffer the effects of historical and lifetime trauma among young Indigenous peoples. To our knowledge, no previous epidemiological studies have explored the effect of historical and lifetime traumas, cultural connectedness, and risk factors on resilience among young, urban Indigenous people who use drugs. METHODS: This study explored risk and protective factors associated with resilience among participants of the Cedar Project, a cohort study involving young Indigenous peoples who use illicit drugs in three cities in British Columbia, Canada. We utilized the Connor-Davidson Resilience Scale to measure resilience, the Childhood Trauma Questionnaire to measure childhood maltreatment, and the Symptom-Checklist 90-Revised to measure psychological distress among study participants. Multivariate linear mixed effects models (LME) estimated the effect of study variables on mean change in resilience scores between 2011-2012. RESULTS: Among 191 participants, 92 % had experienced any form of childhood maltreatment, 48 % had a parent who attended residential school, and 71 % had been in foster care. The overall mean resilience score was 62.04, with no differences between the young men and women (p = 0.871). Adjusted factors associated with higher mean resilience scores included having grown up in a family that often/always lived by traditional culture (B = 7.70, p = 0.004) and had often/always spoken their traditional language at home (B = 10.52, p < 0.001). Currently knowing how to speak a traditional language (B = 13.06, p = 0.001), currently often or always living by traditional culture (B = 6.50, p = 0.025), and having recently sought drug/alcohol treatment (B = 4.84, p = 0.036) were also significantly associated with higher mean resilience scores. Adjusted factors associated with diminished mean resilience scores included severe childhood emotional neglect (B = -13.34, p = 0.001), smoking crack daily (B = -5.42, p = 0.044), having been sexual assaulted (B = 14.42, p = 0.041), and blackout drinking (B = -6.19, p = 0.027). CONCLUSIONS: Young people in this study have faced multiple complex challenges to their strength. However, cultural foundations continue to function as buffers that protect young Indigenous people from severe health outcomes, including vulnerability to HIV and HCV infection.

An examination of exposure and avoidance behavior related to second-hand cigarette smoke among adolescent girls in Canada.

BACKGROUND: Although rates of tobacco use and exposure to second-hand smoke (SHS) are declining in Canada, SHS exposure among non-smoking adolescents remains high. This study aimed to describe frequency, locations, and avoidance behavior related to SHS exposure among adolescent girls in British Columbia, Canada. METHODS: Data were analyzed from 841 adolescent girls aged 13 to 15 years old who completed an internet-delivered survey as part of a cohort study examining SHS exposure and substance use. Measures assessed demographics, smoking behavior and intentions, frequency and locations of SHS exposure, and avoidance behavior related to SHS. RESULTS: Excluding their own smoking, 27% of girls reported exposure at least once a week and an additional 17% reported daily or almost daily exposure over the past month. Among girls who reported daily or almost daily exposure, the locations of most frequent levels of high exposure were in the home, at or near school, inside a vehicle, and outdoor public places. Avoidance behavior related to SHS exposure significantly differed by overall SHS exposure in the past month. CONCLUSIONS: Despite historically low smoking rates, many adolescent girls continue to report regular SHS exposure in multiple locations in British Columbia. Girls with the most frequent exposure were significantly less likely to report habitual avoidance behavior related to SHS compared to those less frequently exposed. This study elucidates settings of high SHS exposure among adolescent girls that could be targeted in future policy interventions. Additionally, future interventions could target adolescent girls who are frequently exposed to SHS and report infrequent avoidance behavior around their SHS exposure.

Designing Tailored Messages about Smoking and Breast Cancer: A Focus Group Study with Youth.

The purpose of this study was to design an approach to supporting the development of gender- and Aboriginal-specific messages regarding the link between tobacco exposure and breast cancer, drawing on youth perspectives. Focus groups were held with 18 girls (8 First Nations and Métis) and 25 boys (12 First Nations and Métis) to solicit advice in the design of messages. Transcribed data were analyzed for themes. Girls preferred messages that included the use of novel images, a personal story of breast cancer, and ways to avoid secondhand smoke. Boys endorsed messages that were "catchy" but not "cheesy" and had masculine themes. First Nations and Métis participants confirmed the use of Aboriginal symbols in messages as signalling their relevance to youth in their communities. The results can be used as a guide in developing tailored health promotion messages. Challenges in developing gender-appropriate messages for youth are described.

Notre étude visait à mettre au point une approche propice à la création de messages axés sur le lien entre l'exposition au tabac et le cancer du sein, qui s'adresseraient aux jeunes Autochtones de chaque sexe et s'inspireraient de leurs perspectives. Nous avons tenu des groupes de discussion formés de 18 filles (issues de huit Premières nations et du peuple métis) et de 25 garçons (issus de 12 Premières nations et du peuple métis), dans le but d'obtenir leur avis sur cette question. Les données transcrites ont été analysées pour en dégager les thèmes principaux. Chez les filles, on préfère des messages qui proposent des images originales, une histoire personnelle sur le cancer du sein et des conseils sur les façons d'éviter de s'exposer à la fumée secondaire. Les garçons préfèrent quant à eux des messages « accrocheurs ¼, qui ne sont pas « de mauvais goût ¼ et comportent des thèmes masculins. Tous et toutes ont jugé que le recours à des symboles autochtones dans les messages était pertinent pour les jeunes de leurs communautés. Ces résultats pourront servir de guide en vue de créer des messages ciblés axés sur la promotion de la santé. On explique les difficultés que présente la formulation de messages adaptés en fonction du sexe des jeunes.

A social media approach to inform youth about breast cancer and smoking: an exploratory descriptive study.

Tobacco exposure during periods of breast development has been shown to increase risk of premenopausal breast cancer. An urgent need exists, therefore, to raise awareness among adolescent girls about this new evidence, and for adolescent girls and boys who smoke to understand how their smoking puts their female peers at risk for breast cancer. The purpose of this study was to develop two youth-informed, gender specific YouTube-style videos designed to raise awareness among adolescent girls and boys about tobacco exposure as a modifiable risk factor for breast cancer and to assess youths' responses to the videos and their potential for inclusion on social media platforms. Both videos consisted of a combination of moving text, novel images, animations, and youth-friendly music. A brief questionnaire was used to gather feedback on two videos using a convenience sample of 135 youth in British Columbia, Canada. The overall positive responses by girls and boys to their respective videos and their reported interest in sharing these videos via social networking suggests that this approach holds potential for other types of health promotion messaging targeting youth. The videos offer a promising messaging strategy for raising awareness about tobacco exposure as a modifiable risk factor for breast cancer. Tailored, gender-specific messages for use on social media hold the potential for cost-effective, health promotion and cancer prevention initiatives targeting youth.

A genome-wide screen links peroxisome regulation with Wnt signaling through RNF146 and tankyrase.

Peroxisomes are membrane-bound organelles harboring metabolic enzymes. In humans, peroxisomes are required for normal development, yet the genes regulating peroxisome function remain unclear. We performed a genome-wide CRISPRi screen to identify novel factors involved in peroxisomal homeostasis. We found that inhibition of RNF146, an E3 ligase activated by poly(ADP-ribose), reduced the import of proteins into peroxisomes. RNF146-mediated loss of peroxisome import depended on the stabilization and activity of the poly(ADP-ribose) polymerase tankyrase, which binds the peroxisomal membrane protein PEX14. We propose that RNF146 and tankyrase regulate peroxisome import efficiency by PARsylation of proteins at the peroxisome membrane. Interestingly, we found that the loss of peroxisomes increased tankyrase and RNF146-dependent degradation of non-peroxisomal substrates, including the beta-catenin destruction complex component AXIN1, which was sufficient to alter the amplitude of beta-catenin transcription. Together, these observations not only suggest previously undescribed roles for RNF146 in peroxisomal regulation, but also a novel role in bridging peroxisome function with Wnt/beta-catenin signaling during development.

A genome-wide screen links peroxisome regulation with Wnt signaling through RNF146 and TNKS/2.

Peroxisomes are membrane-bound organelles harboring metabolic enzymes. In humans, peroxisomes are required for normal development, yet the genes regulating peroxisome function remain unclear. We performed a genome-wide CRISPRi screen to identify novel factors involved in peroxisomal homeostasis. We found that inhibition of RNF146, an E3 ligase activated by poly(ADP-ribose), reduced the import of proteins into peroxisomes. RNF146-mediated loss of peroxisome import depended on the stabilization and activity of the poly(ADP-ribose) polymerases TNKS and TNKS2, which bind the peroxisomal membrane protein PEX14. We propose that RNF146 and TNKS/2 regulate peroxisome import efficiency by PARsylation of proteins at the peroxisome membrane. Interestingly, we found that the loss of peroxisomes increased TNKS/2 and RNF146-dependent degradation of non-peroxisomal substrates, including the ß-catenin destruction complex component AXIN1, which was sufficient to alter the amplitude of ß-catenin transcription. Together, these observations not only suggest previously undescribed roles for RNF146 in peroxisomal regulation but also a novel role in bridging peroxisome function with Wnt/ß-catenin signaling during development.

Engineering water exchange is a safe and effective method for magnetic resonance imaging in diverse cell types.

Aquaporin-1 (Aqp1), a water channel, has garnered significant interest for cell-based medicine and in vivo synthetic biology due to its ability to be genetically encoded to produce magnetic resonance signals by increasing the rate of water diffusion in cells. However, concerns regarding the effects of Aqp1 overexpression and increased membrane diffusivity on cell physiology have limited its widespread use as a deep-tissue reporter. In this study, we present evidence that Aqp1 generates strong diffusion-based magnetic resonance signals without adversely affecting cell viability or morphology in diverse cell lines derived from mice and humans. Our findings indicate that Aqp1 overexpression does not induce ER stress, which is frequently associated with heterologous expression of membrane proteins. Furthermore, we observed that Aqp1 expression had no detrimental effects on native biological activities, such as phagocytosis, immune response, insulin secretion, and tumor cell migration in the analyzed cell lines. These findings should serve to alleviate any lingering safety concerns regarding the utilization of Aqp1 as a genetic reporter and should foster its broader application as a noninvasive reporter for in vivo studies.

Crystal methamphetamine and initiation of injection drug use among street-involved youth in a Canadian setting.

BACKGROUND: Although injection drug use is known to result in a range of health-related harms, including transmission of HIV and fatal overdose, little is known about the possible role of synthetic drugs in injection initiation. We sought to determine the effect of crystal methamphetamine use on risk of injection initiation among street-involved youth in a Canadian setting. METHODS: We used Cox regression analyses to identify predictors of injection initiation among injection-naive street-involved youth enrolled in the At-Risk Youth Study, a prospective cohort study of street-involved youth in Vancouver, British Columbia. Data on circumstances of first injection were also obtained. RESULTS: Between October 2005 and November 2010, a total of 395 drug injection-naive, street-involved youth provided 1434 observations, with 64 (16.2%) participants initiating injection drug use during the follow-up period, for a cumulative incidence of 21.7 (95% confidence interval [CI] 1.7-41.7) per 100 person-years. In multivariable analysis, recent noninjection use of crystal methamphetamine was positively associated with subsequent injection initiation (adjusted hazard ratio 1.93, 95% CI 1.31-2.85). The drug of first injection was most commonly reported as crystal methamphetamine (14/31 [45%]). INTERPRETATION: Noninjection use of crystal methamphetamine predicted subsequent injection initiation, and crystal methamphetamine was the most commonly used drug at the time of first injection. Evidence-based strategies to prevent transition to injection drug use among crystal methamphetamine users are urgently needed.