Background Sexual violence is a major public health issue worldwide, with a high prevalence and extensive human and financial costs. Implementing prevention programs is complex, requiring not only evidence-based practices and high ethical standards, but also close collaboration with local governments and non-governmental organizations. In order to guide and support all stakeholders necessary to achieve large-scale prevention (e.g., politicians, decision-makers, in-field professionals), it is essential to establish international benchmarks for the prevention of sexual violence. Objective The main goal of this collaborative study was to conduct a systematic review of the frameworks adopted by WHO, UN Women, UNESCO, and UNICEF to help prevent sexual violence worldwide, according to the PRISMA methodology. A secondary objective was to highlight the levels of prevention and determinants of health targeted by these organizations. Results Overall, 1008 references were identified, of which 50 met the inclusion criteria. All international guidelines were limited to primary or tertiary prevention, and they were not specifically dedicated to sexual violence. In addition, each organization had developed idiosyncratic prevention strategies. Common primary prevention determinants of health were still found across organizations, including education, socio-economic inequalities, and life skills training. Tertiary prevention was poorly developed and polarized between victims and perpetrators. Secondary prevention was never addressed, however, despite the effectiveness of approaches such as helplines for people sexually attracted to children. Discussion Given these results, an international French-speaking consortium of professional teams, all involved in the secondary prevention of sexual violence, was recently formed with a ratified charter presented here.
Introduction Cannabis legalisation was enacted on 17 October 2018 in Canada. Accordingly, the effects of cannabis legalisation on patterns of cannabis consumption were examined among adolescents, including on cannabis initiation, any cannabis use, daily cannabis use and cannabis dependence. Methods Data from a biennial population‐based, cross‐sectional survey of students in Ontario were pooled in a pre‐post design (2001‐2019; N = 89,238). Participants provided self‐reports of cannabis initiation, any cannabis use, daily cannabis use and cannabis dependence. Long‐term trends in these patterns of cannabis consumption over two decades of observation were characterised to provide a broader context of usage. The effects of cannabis legalisation on patterns of cannabis consumption were quantified using logistic regression analyses. Results Long‐term trends over the two decades of observation indicated that cannabis initiation decreased and then increased ( p = 0.0220), any cannabis use decreased and daily cannabis use decreased ( p < 0.0001 and p = 0.0001, respectively) and cannabis dependence remained unchanged ( p = 0.1187). However, in comparisons between the pre‐cannabis legalisation period (2001–2017) and the post‐cannabis legalisation period (2019), cannabis legalisation was not associated with cannabis initiation (odds ratio; 95% confidence interval 1.00; 0.79–1.27), but it was associated with an increased likelihood of any cannabis use (1.31; 1.12–1.53), daily cannabis use (1.40; 1.09–1.80) and cannabis dependence (1.98; 1.29–3.04). Discussion and Conclusions Cannabis legalisation was not associated with cannabis initiation, but it was associated with an increased likelihood of any cannabis use, daily cannabis use and cannabis dependence.
Methadone and buprenorphine/naloxone are opioid agonist therapies for opioid use disorder treatment. Genetic factors contribute to individual differences in opioid response; however, little is known regarding genetic associations with clinical outcomes in people receiving opioid agonist therapies. Participants diagnosed with opioid use disorder, principally consisting of prescription opioids (licit or illicit), were randomized to methadone or buprenorphine/naloxone for 24 weeks of daily treatment (NCT03033732). Urine was collected at 12 biweekly study visits and analyzed for non‐treatment opioids. Variants in genes involved in methadone metabolism ( CYP2B6 , CYP2C19, and CYP3A4 ) , buprenorphine metabolism ( CYP3A4 and UGT2B7 ), and μ‐opioid receptor function ( OPRM1 ) were genotyped and analyzed for their association with the number of non‐treatment opioid‐free urine screens. Primary analyses focused on the last 12 weeks (6 study visits, post‐titration) of treatment among those reporting White ethnicity. Additional sensitivity and exploratory analyses were performed. Among methadone‐treated participants (n=52), the OPRM1 rs1799971 AA genotype (vs. G‐genotypes, i.e., having one or two G alleles ) was associated with greater opioid‐free urine screens (Incidence Rate Ratio=5.24, 95%CI=2.43, 11.26, p=0.000023); longitudinal analyses showed a significant genotype‐by‐time interaction over the full 24 weeks (12 study visits, β=‐0.28, 95% CI=‐0.45, ‐0.11, p=0.0015). Exploratory analyses suggest an OPRM1 rs1799971 genotype effect on retention. No evidence of association was found between other genetic variants, including in metabolic variants, and non‐treatment opioid‐free urine screens in the methadone or buprenorphine/naloxone arms. Those with the OPRM1 rs1799971 G‐genotypes may have a poorer response to methadone maintenance treatment, an effect that persisted through 24 weeks of treatment.
This protocol describes the application of cyclotron-generated [11C]CO2 fixation reactions for direct 11C-carboxylation reactions and [11C]CO for 11C-carbonylations. Herein we describe one-pot methods wherein the radioactive gas is first trapped in a reaction mixture at room temperature and atmospheric pressure prior to the radiolabeling reactions. Such procedures are widely applicable to numerous small molecules to form 11C-labeled carboxylic acids, amides, esters, ketones, oxazolidinones, carbamates, and ureas. The steps for 11C-fixation techniques described herein are tailored for a commercial automated synthesis unit and are readily adapted for routine radiopharmaceutical production.
Separation anxiety is ubiquitous in mammals, has a clear adaptive function, and is a source of individual differences. We adopt a reductionist approach, taking advantage of the interspecies, adversive nature of hypercapnia, and of the exaggerated response to CO2 stimulation proper of people with panic and separation anxiety disorders. We argue that the human developmental continuum from childhood separation anxiety disorder into adult panic disorder-agoraphobia can be modelled in murine studies of early maternal separation, with variance in respiratory parameters during CO2 stimulation as a key, non-inferential biomarker of anxiety. We show how such preclinical models of early maternal separation led to identify differentially-expressed genes that correspond to differentially-methylated genes in human responders to CO2 stimulation. Specifically, we argue that: (a) brain acid-sensing ion channels (ASICs) are important to understand how mammals orchestrate enhanced homeostatic reactions in response to early adversities, and: (b) inhaled ASIC antagonist amiloride can be a viable treatment for some human anxiety disorders.
Background Recent findings suggest that brief dialectical behavior therapy (DBT) for borderline personality disorder is effective for reducing self-harm, but it remains unknown which patients are likely to improve in brief v. 12 months of DBT. Research is needed to identify patient characteristics that moderate outcomes. Here, we characterized changes in cognition across brief DBT (DBT-6) v. a standard 12-month course (DBT-12) and examined whether cognition predicted self-harm outcomes in each arm. Methods In this secondary analysis of 240 participants in the FASTER study (NCT02387736), cognitive measures were administered at pre-treatment, after 6 months, and at 12 months. Self-harm was assessed from pre-treatment to 2-year follow-up. Multilevel models characterized changes in cognition across treatment. Generalized estimating equations examined whether pre-treatment cognitive performance predicted self-harm outcomes in each arm. Results Cognitive performance improved in both arms after 6 months of treatment, with no between-arm differences at 12-months. Pre-treatment inhibitory control was associated with different self-harm outcomes in DBT-6 v. DBT-12. For participants with average inhibitory control, self-harm outcomes were significantly better when assigned to DBT-12, relative to DBT-6, at 9–18 months after initiating treatment. In contrast, participants with poor inhibitory control showed better self-harm outcomes when assigned to brief DBT-6 v. DBT-12, at 12–24 months after initiating treatment. Conclusions This work represents an initial step toward an improved understanding of patient profiles that are best suited to briefer v. standard 12 months of DBT, but observed effects should be replicated in a waitlist-controlled study to confirm that they were treatment-specific.
Introduction: People who metabolize nicotine more quickly are generally less successful at quitting smoking. However, the mechanisms that link individual differences in the nicotine metabolite ratio (NMR), a phenotypic biomarker of the rate of nicotine clearance, to smoking outcomes are unclear. We tested the hypotheses that higher NMR is associated with greater smoking reinforcement, general craving, and cue-induced cigarette craving in a treatment-seeking sample. Methods: Participants were 252 adults who smoke cigarettes enrolled in a randomized controlled smoking cessation trial (NCT03262662) conducted in Buffalo, New York, USA. Participants completed the Choice Behavior Under Cued Conditions (CBUCC) paradigm, a laboratory choice procedure, ~1 week before the first cessation treatment visit, at which time a saliva sample was collected for NMR assessment. On each CBUCC trial, participants reported cigarette craving during cue presentation (cigarette, water) and spent $0.01-0.25 for a chance (5%-95%) to sample the cue (1 puff, sip), providing measures of smoking reinforcement (spending for cigarettes vs. water), general cigarette craving (averaged across cigarette and water cues), and cue-specific craving (cigarette craving during cigarette vs. water cues). Results: As observed in prior work, the NMR was significantly higher among white and female participants. As expected, both spending and cigarette craving were significantly greater on cigarette compared to water trials. However, contrary to our hypotheses, higher NMR was not associated with greater smoking reinforcement, general craving, or cue-specific craving. Conclusions: The present data do not support that smoking reinforcement or craving are related to nicotine metabolism among individuals seeking to quit smoking. Implications: Though greater smoking reinforcement, general craving, and cue-specific craving are hypothesized to be linked to faster nicotine metabolism, there was no evidence of such relationships in the present sample of adults seeking to quit smoking. Further research, including replication and consideration of alternate hypotheses, is warranted to elucidate the mechanisms by which the NMR is related to smoking cessation.
Aim Healthy lifestyle and appropriate diet are of critical importance after liver transplant (LT). We provided an analysis of the main patterns of physical activity and found factors associated with physical activity itself. Methods Clinically stable LT recipients were enrolled between June and September 2021. Patients completed a composite questionnaire about physical activity, adherence to Mediterranean Diet (MD), quality of life (QoL), and employment. Correlations were analysed using the Pearson coefficients while different subgroups were compared by t -test for independent samples or ANOVAs. Multivariable logistic regression analysis was conducted to find predictors of inactivity. Results We enrolled 511 subjects (71% males, mean age 63 ± 10.8 years). One hundred and ninety-three patients reported high level of physical activity, 197 a minimal activity and 121 declared insufficient activity. Among these latter, 29 subjects were totally inactive. Considering the 482 LT recipients performing some kind of physical activity, almost all reported a low-quality, non-structured activity. At multivariate analysis, time from LT (odds ratio 0.94, 95% CI 0.89–0.99, p = 0.017), sedentary lifestyle (odds ratio 0.99, 95% CI 0.19–0.81, p = 0.012), low adherence to MD (odds ratio 1.22, 95% CI 1.01–1.48, p = 0.049), and low level of QoL (physical dimension) (odds ratio 1.13, 95% CI 1.08–1.17, p < 0.001), were independently associated with total inactivity. Conclusion A large portion of LT recipients report an insufficient level of physical activity or are wholly inactive. Inactivity increases with time from LT and was strongly associated with suboptimal diet and low QoL.
Background The COVID‐19 pandemic has had a negative impact on the mental health of people with intellectual and developmental disabilities. Numerous pandemic‐related stressors experienced by people with intellectual and developmental disabilities may have impacted their ability to thrive, which has been linked to mental health outcomes. The current study examined the associations among COVID‐19 stressors, thriving, and mental health problems among youth and adults with intellectual and developmental disabilities. Method Caregivers of 159 people with intellectual and developmental disabilities between 12 and 35 years of age from Canada completed an online questionnaire. Results A mediation analysis revealed that COVID‐19 stressors were positively associated with mental health problems, and that thriving partially mediated this association. Conclusion Our findings suggest that experiences of thriving may be an important target for mental health support for people with intellectual and developmental disabilities.
Patched domain-containing 1 (PTCHD1) is a well-established susceptibility gene for autism spectrum disorder (ASD) and intellectual disability (ID). Previous studies have suggested that alterations in the dosage of PTCHD1 may contribute to the etiology of both ASD and ID. However, there has not yet been a thorough investigation regarding mechanisms that regulate PTCHD1 expression. We sought to characterize the Ptchd1 promoter in a mouse neuronal model, as well as to identify and validate cis regulatory elements. We defined specific regions of the Ptchd1 promoter essential for robust expression in P19-induced neurons. Evolutionarily-conserved putative transcription factor binding sites within these regions were subsequently identified. Using a pairwise comparison of chromatin accessibility between mouse forebrain and liver tissues, a candidate regulatory region, ~ 9.1 kbp downstream of the Ptchd1 stop codon was defined. This region harbours two ENCODE-predicted enhancer cis-regulatory elements. Further, using DNase footprint analysis, a putative YY1-binding motif was also identified. Genomic deletion of the entire 8 kbp downstream open chromatin region attenuated Ptchd1 transcription by over 60% in our neuronal model, corroborating its predicted regulatory function. This study provides mechanistic insights related to the expression of PTCHD1, and provides important context to interpret genetic and genomic variation at this locus which may influence neurodevelopment.
Establishing quantifiable biological markers associated with anxiety will increase the objectivity of phenotyping and enhance genetic research of anxiety disorders. Heart rate variability (HRV) is a physiological measure reflecting the dynamic relationship between the sympathetic and parasympathetic nervous systems, and is a promising target for further investigation. This review summarizes evidence evaluating HRV as a potential physiological biomarker of anxiety disorders by highlighting literature related to anxiety and HRV combined with investigations of endophenotypes, neuroimaging, treatment response, and genetics. Deficient HRV shows promise as an endophenotype of pathological anxiety and may serve as a noninvasive index of prefrontal cortical control over the amygdala, and potentially aid with treatment outcome prediction. We propose that the genetics of HRV can be used to enhance the understanding of the genetics of pathological anxiety for etiological investigations and treatment prediction. Given the anxiety–HRV link, strategies are offered to advance genetic analytical approaches, including the use of polygenic methods, wearable devices, and pharmacogenetic study designs. Overall, HRV shows promising support as a physiological biomarker of pathological anxiety, potentially in a transdiagnostic manner, with the heart–brain entwinement providing a novel approach to advance anxiety treatment development.
Background Substance use in pregnancy raises concern given its potential teratogenic effects. Given the unique needs of parenting people and the potential impact for developing children, specialized substance use treatment programs are increasingly being implemented for this population. Substance use treatment is associated with more positive neonatal outcomes compared with no treatment, however treatment models vary limiting our understanding of key treatment components/modelsFew studies have explored the influence of treatment model type (i.e., integrated treatments designed for pregnant clients compared with standard treatment models) and no studies have examined the influence of treatment model on neonatal outcomes using Canadian data. Method We conducted a population‐based cohort study of clients who were pregnant when initiating integrated (n = 564) and standard (n = 320) substance use treatment programs in Ontario, Canada. Results Neonatal outcomes did not significantly differ by treatment type (integrated or standard), with rates of adverse neonatal outcomes higher than published rates for the general population, despite receipt of adequate levels of prenatal care. While this suggests no significant impact of treatment, it is notable that as a group, clients engaged in integrated treatment presented with more risk factors for adverse neonatal outcomes than those in standard treatment. While we controlled for these risks in our analyses, this may have obscured their influence in relation to treatment type. Conclusion Findings underscore the need for more nuanced research that considers the influence of client factors in interaction with treatment type. Pregnant clients engaged in any form of substance use treatment are at higher risk of having children who experience adverse neonatal outcomes. This underscores the urgent need for further investment in services and research to support maternal and neonatal health before and during pregnancy, as well as long‐term service models that support women and children beyond the perinatal and early childhood periods.
Aim Deep brain stimulation (DBS) is a safe and effective treatment option for people with refractory obsessive‐compulsive disorder (OCD). Yet our understanding of predictors of response and prognostic factors remains rudimentary, and long‐term comprehensive follow‐ups are lacking. We aim to investigate the efficacy of DBS therapy for OCD patients, and predictors of clinical response. Methods Eight OCD participants underwent DBS stimulation of the nucleus accumbens (Nac) in an open‐label longitudinal trial, duration of follow‐up varied between nine months and seven years. Post‐operative care involved comprehensive fine tuning of stimulation parameters and adjunct multidisciplinary therapy. Results Six participants achieved clinical response (35% improvement in obsessions and compulsions on the Yale Brown Obsessive Compulsive Scale (YBOCS)) within 6‐9 weeks, response was maintained at last follow up. On average, the YBOCS improved by 45% at last follow up. Mixed linear modelling elucidated directionality of symptom changes: insight into symptoms strongly predicted (p=.008) changes in symptom severity during DBS therapy, likely driven by initial changes in depression and anxiety. Precise localization of DBS leads demonstrated that responders most often had their leads (and active contacts) placed dorsal compared to non‐responders, relative to the Nac. Conclusion The symptom improvements within this cohort should be seen within the context of the adjunct psychological and biopsychosocial care that implemented a shared decision‐making approach, with flexible iterative DBS programming. Further research should explore the utility of insight as a clinical correlate of response. The trial was prospectively registered with the ANZCTR (ACTRN12612001142820). This article is protected by copyright. All rights reserved.
Background We examined the acute effects of moderate alcohol administration on neurometabolites in human brains. Methods Healthy Japanese participants aged 20‐30 years who were heterozygous for an inactive allele of acetaldehyde dehydrogenase‐2 ( ALDH/*1/*2 ) were included. Participants underwent an intravenous alcohol infusion using the clamp method at a target blood alcohol concentration (BAC) of 0.50 mg/mL for 90 minutes within a range of ±0.05 mg/mL. We examined glutamate+glutamine (Glx) and N‐acetylaspartate+N‐acetylaspartylglutamate (NAA) levels in the midcingulate cortex (MCC) using 3T ¹ H‐MRS PRESS at baseline, 90 minutes, and 180 minutes (i.e., 90 minutes after alcohol infusion was finished). A two‐way repeated‐measures analysis of variance was conducted to assess longitudinal changes in Glx and NAA levels, with time and sex as within‐ and between‐subject factors, respectively. Pearson's correlation coefficients were calculated among neurometabolite levels and BAC or blood acetaldehyde concentration (BAAC). Results Eighteen participants (males/females, 7/11) completed the study. Both Glx ( F (2,32)=8.15, p =0.004, η ² =0.15) and NAA ( F (2,32)=5.01, p =0.04, η ² =0.07) levels were increased after alcohol injection. Sex effects or time ✕ sex interactions were not observed. NAA levels were positively correlated with BAAC at 90 minutes ( r (13)=0.77, p =0.01). There were no associations between neurometabolite levels and BAC. Conclusions Both Glx and NAA levels in the MCC increased in response to the administration of moderate concentrations of alcohol. Given positive associations between NAA levels and BAAC and the hypothetical glutamate release via dopamine pathways, the effects of drinking on the MCC in the acute phase might be ascribed to acetaldehyde metabolised from alcohol.
Medical assistance in dying (MAiD) is an evolving practice in Canada, with requests and outcomes increasing each year, and yet controversy is present—with a vast spectrum of ethical positions on its permissibility. International research indicates that family members who experience disagreement over their loved one’s decision to have MAiD are less likely to be actively involved in supporting patients through the practical aspects of the dying process. Family members with passive involvement in the assisted dying process may also experience more significant moral dilemmas and challenging grief experiences than those who supported the decision. Given these previous findings, we designed this study to explore the factors complicating family members’ experiences with MAiD in Canada and to understand how these complicating factors impact family members’ bereavement in the months and years following MAiD. We conducted narrative interviews with 12 MAiD-bereaved family members who experienced disagreements, family conflicts, or differences in understanding about MAiD. Documenting and analyzing participants’ experiences through storytelling allowed us to appreciate the complexity of family members’ experiences and understand their values. The analysis generated five factors that can complicate the MAiD process and bereavement for family members: family discordance, internal conflict, legislative and eligibility concerns, logistical challenges, and managing disclosure and negative reactions. To our knowledge, this is the first Canadian study that explores how family discordance can impact bereavement following MAiD. Future bereavement services and resources should consider how these complicating factors may impact bereavement and ensure that Canadians with diverse MAiD experiences can access appropriate support.
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