The Effects of NT-1044, a Novel AMPK Activator, on Endometrial Cancer Cell Proliferation, Apoptosis, Cell Stress and In Vivo Tumor Growth.

OBJECTIVES: Anti-diabetic biguanide drugs such as metformin may have anti-tumorigenic effects by behaving as AMPK activators and mTOR inhibitors. Metformin requires organic cation transporters (OCTs) for entry into cells, and NT-1044 is an AMPK activator designed to have greater affinity for two of these transporters, OCT1 and OCT3. We sought to compare the effects of NT-1044 on cell proliferation in human endometrial cancer (EC) cell lines and on tumor growth in an endometrioid EC mouse model. METHODS: Cell proliferation was assessed in two EC cell lines, ECC-1 and Ishikawa, by MTT assay after exposure to NT-1044 for 72 hours of treatment. Apoptosis was analyzed by Annexin V-FITC and cleaved caspase 3 assays. Cell cycle progression was evaluated by Cellometer. Reactive oxygen species (ROS) were measured using DCFH-DA and JC-1 assays. For the in vivo studies, we utilized the LKB1fl/flp53fl/fl mouse model of endometrioid endometrial cancer. The mice were treated with placebo or NT-1044 or metformin following tumor onset for 4 weeks. RESULTS: NT-1044 and metformin significantly inhibited cell proliferation in a dose-dependent manner in both EC cell lines after 72 hours of exposure (IC50 218 µM for Ishikawa; 87 µM for ECC-1 cells). Treatment with NT-1044 resulted in G1 cell cycle arrest, induced apoptosis and increased ROS production in both cell lines. NT-1044 increased phosphorylation of AMPK and decreased phosphorylation of S6, a key downstream target of the mTOR pathway. Expression of the cell cycle proteins CDK4, CDK6 and cyclin D1 decreased in a dose-dependent fashion while cellular stress protein expression was induced in both cell lines. As compared to placebo, NT-1044 and metformin inhibited endometrial tumor growth in obese and lean LKB1fl/flp53fl/fl mice. CONCLUSIONS: NT-1044 suppressed EC cell growth through G1 cell cycle arrest, induction of apoptosis and cellular stress, activation of AMPK and inhibition of the mTOR pathway. In addition, NT-1044 inhibited EC tumor growth in vivo under obese and lean conditions. More work is needed to determine if this novel biguanide will be beneficial in the treatment of women with EC, a disease strongly impacted by obesity and diabetes.

Supervised consumption sites and crime: scrutinizing the methodological weaknesses and aberrant results of a government report in Alberta, Canada.

To date, peer-reviewed research has found no evidence linking supervised consumptions sites (SCSs) to increased crime. Yet, in March 2020, a government Report released in the province of Alberta, Canada, presented the results of a review that reached a different conclusion. This commentary highlights the Report's major methodological limitations with respect to its criminological components, including that crime was poorly operationalized and measured, change in crime was inadequately assessed, and the effect of SCSs on crime was not ascertained. It is argued that the magnitude of methodological flaws in the Report undermine the validity of its criminological claims and raise significant issues with the soundness of its conclusions.

Stigma associated with mental illness among Asian men in Vancouver, Canada.

BACKGROUND:: Due to racism, xenophobic nationalism, acculturation pressures and patriarchal social relations, Asian men in Western societies may be particularly susceptible to negative experiences and beliefs regarding mental illness and treatment services. AIMS:: We examine factors associated with stigma toward mental illness among Asian men in Canada. METHODS:: Between 2013 and 2017, 428 self-identified Asian men living in proximity to Vancouver, Canada, were recruited and completed self-administered questionnaires assessing social stigma and self-stigma. The degree to which these variables were associated with the men's sociodemographic characteristics was analyzed. RESULTS:: Multivariable regression revealed that social stigma was significantly predicted by age, immigration, employment status and experience with mental illness. Together, these variables accounted for 12.36% of variance in social stigma. Interaction terms were added to the regression models to examine whether the effects of immigration on social stigma varied by age and experience with mental illness, but none of the interaction terms were statistically significant. Among the 94 Asian men identified as living with mental illness, self-stigma was predicted by age, immigration and employment status, which together accounted for 14.97% of variance in self-stigma. CONCLUSION:: These results offer new knowledge about the factors predicting stigma toward mental illness among Asian men in Western societies.

Mapping of biguanide transporters in human fat cells and their impact on lipolysis.

AIM: To examine the cell membrane transporters involved in mediating the antilipolytic effect of biguanides in human fat cells. MATERIALS AND METHODS: Gene expression of biguanide transporters was mapped in human subcutaneous adipose tissue and in adipocytes before and after differentiation. Those expressed in mature fat cells were knocked down by RNA interference (RNAi) and the antilipolytic effects of metformin and two novel, highly potent biguanides, NT1014 and NT1044, were examined. RESULTS: Analysis of the transporter affinity of biguanides in HEK293 cells overexpressing individual transporters showed that NT1014 and NT1044 had >10 times higher affinity than metformin. Animal studies showed that NT1014 was >5 times more potent than metformin in lowering plasma glucose in mice. In human fat cells, the novel biguanides displayed higher AMP-activated protein kinase activation and antilipolytic efficacy than metformin. Five transporters, organic cation transporter (OCT)1 (SLC22A1), organic cation transporter novel type 1 (OCTN1; SLC22A4), OCT3 (SLC22A3), plasma membrane monoamine transporter (PMAT; SLC29A4) and multidrug and toxin extrusion transporter (MATE1; SLC47A1), were detectable in fat cells but only OCT3, PMAT and MATE1 increased during adipogenesis in vitro and were enriched in fat cells compared with other adipose cell types. Gene knockdown by RNAi showed that MATE1 and PMAT reduction attenuated the antilipolytic effect of metformin but only PMAT knockdown decreased the effect of all three biguanides. CONCLUSIONS: While human fat cells primarily express three biguanide transporters, our data suggest that PMAT is the primary target for development of fat cell-specific antilipolytic biguanides with high sensitivity and potency.

What Does Success Look Like in the Forensic Mental Health System? Perspectives of Service Users and Service Providers.

Outcomes research in forensic mental health (FMH) has concentrated on reoffending as the principal indicator of success. Defining success in one-dimensional, negative terms can create a distorted view of the diverse objectives of the FMH system. This qualitative study examined the complexity of success from the perspectives of people in the FMH system. Interviews were conducted with 18 forensic service users and 10 forensic service providers. Data were analyzed inductively using thematic analysis to identify predominant themes. The participants conceptualized success as a dynamic process materializing across six different domains in the context of the FMH system: (a) normal life, (b) independent life, (c) compliant life, (d) healthy life, (e) meaningful life, and (f) progressing life. The results indicate that people who provide or use FMH services emphasize a broad range of processes and outcomes, apart from public safety, when they think about success.

Primary Care Physicians' Views about Prescribing Methadone to Treat Opioid Use Disorder.

BACKGROUND: Methadone maintenance treatment is an effective way to reduce harms associated with opioid use disorder and, in several countries, is delivered in community-based primary care settings. Expanding methadone into primary care depends, in part, on physicians' willingness and readiness to integrate it into their practices. OBJECTIVES: This qualitative study explores factors that primary care physicians consider important when contemplating prescribing methadone to treat opioid use disorder. METHODS: In-depth interviews were conducted during 2015 with 20 primary care physicians in various sized communities throughout Nova Scotia, Canada. Participants shared their views and experiences related to prescribing methadone to treat opioid use disorder. Data were analyzed inductively using thematic analysis to identify predominant themes. RESULTS: Participants discussed an interplay of factors as they contemplated prescribing methadone to treat opioid use disorder in primary care. Physician-related factors included access to methadone expertise, support from allied professionals, suitability of skills, and personal experiences. Patient-related factors involved perceptions about methadone users as a difficult patient group with highly complex needs. Practice-related factors encompassed concerns about threats to physicians' careers, surveillance duties, unfair remuneration, safety risks, and practice disruptions. Contextual factors included knowledge deficits about substance use disorders, the generalist nature of primary care, methadone's socio-political context, and opioid prescribing patterns in primary care. CONCLUSIONS: Understanding the perspectives of physicians is vital to expanding methadone into primary care. This study identifies factors that should be addressed to attract, support, and retain primary care physicians in prescribing methadone to treat opioid use disorder.

Contact Between Police and People With Mental Disorders: A Review of Rates.

OBJECTIVE: There is widespread belief that people with mental disorders are overrepresented in police encounters. The prevalence of such interactions is used as evidence of extensive problems in our health care and social support systems. The goal of this study was to estimate the rates of police arrests among people with mental disorders, police involvement in pathways to mental health care, and police calls for service involving persons with mental disorders. METHODS: A systematic review was performed with seven multidisciplinary databases. Additional studies were identified by reviewing the reference lists of all included records and by using the "related articles" and "cited articles" tools in the Web of Science database. Studies were included if they were published in peer-reviewed journals, reported primary research findings, and were written in English. RESULTS: Eighty-five unique studies covering 329,461 cases met inclusion criteria. Data reported in 21 studies indicated that one in four people with mental disorders have histories of police arrest. Data from 48 studies indicated that about one in ten individuals have police involved in their pathway to mental health care. Data reported in 13 studies indicated that one in 100 police dispatches and encounters involve people with mental disorders. CONCLUSIONS: These estimates illuminate the magnitude of the issue and supply an empirically based reference point to scholars and practitioners in this area. The findings are useful for understanding how local trends regarding police involvement in the lives of people with mental disorders compare with rates in the broader research literature.

Using social bonding theory to examine 'recovery' in a forensic mental health hospital: A qualitative study.

BACKGROUND: For people living with mental illness, recovery involves learning to overcome and manage their symptoms and striving to live fulfilling lives. The literature on achieving recovery emphasises the importance of social connections and positive role models. Hirschi's social bonding theory posits that an individual's attachment to others, belief in social norms, and their commitment and involvement in conventional activities are the major contributors to normalising social behaviour. AIMS: The aim of this study is to understand the qualities of service identified by patients in a forensic hospital as being important and meaningful to recovery. METHODS: Semi-structured interviews with 30 inpatients in a forensic mental health hospital in British Columbia, Canada, were audio recorded, and the transcriptions were analysed using thematic analysis. RESULTS: Five themes emerged: involvement in programmes, belief in rules and social norms, attachment to supportive individuals, commitment to work-related activities and concern about indeterminacy of stay. CONCLUSIONS: The first four themes map closely onto Hirschi's criminologically derived social bonding theory; however, indeterminacy of stay also arose as a common theme. In addition, the theory was too simple in its separation of elements; our data suggested the complex integration of themes. Our findings may be useful for informing evaluation of forensic mental health services.

Using theatre to address mental illness stigma: a knowledge translation study in bipolar disorder.

BACKGROUND: Reduction of the stigma of mental illness is an international priority; arts- and contact-based approaches represent a promising mode of intervention. This project was designed to explore the impact of a one-woman theatrical performance on attitudes towards bipolar disorder (BD) on people with BD and healthcare providers. METHODS: A playwright and actress who lives with BD developed a stage performance - 'That's Just Crazy Talk' - targeting stigmatizing attitudes towards BD. Prospective, longitudinal and sequential mixed methods were used to assess the impact of the performance on people with BD (n = 80) and healthcare providers (n = 84). Qualitative interviews were conducted with 33 participants (14 people with BD and 19 healthcare providers). RESULTS AND DISCUSSION: Quantitatively, healthcare providers showed significantly improved attitudes immediately post-performance, but this change was not maintained over time; people with BD showed little quantitative change. Qualitatively, both people with BD and BD healthcare providers showed enduring and broadly positive changes. A theatrical presentation designed to reduce stigma produced immediate impact on healthcare providers quantitatively and significant qualitative impact on people with BD and healthcare providers. Additionally, the utility of using mixed-method approaches in mental health research was demonstrated.

Perceptions and experiences of people with mental illness regarding their interactions with police.

This study examined the perceptions and lived experiences of people with mental illness in relation to their interactions with the police. A community-based participatory research approach was used and a procedural justice theoretical perspective guided the study. In-depth, semi-structured interviews were conducted by peer researchers with 60 people with mental illness who had interacted with the police and were living in Metro Vancouver, Canada. Among the study participants, contact with the police was frequent and occurred under a diverse range of circumstances. The majority of participants perceived being treated in a procedurally just manner by the police officer(s) who were involved in their most recent interaction. Almost three-quarters (n=43, 72%) of participants were generally satisfied with how the police officer(s) had handled their most recent interaction. The slight majority of participants (n=30, 51%) rated their previous contacts with the police as a positive experience overall, with 32% (n=19) indicating that their previous interactions with the police were negative life experiences. The findings paint a more balanced picture than that which is often portrayed by the media. Emphasizing a procedural justice framework for police handling of situations involving people with mental illness is a vital step toward improving how these interactions are experienced and perceived.

Another time point, a different story: one year effects of a social media intervention on the attitudes of young people towards mental health issues.

PURPOSE: This study extends an evaluation of a brief, social media intervention, called In One Voice, for raising mental health awareness and improving attitudes of youth and young adults towards mental health issues. METHODS: A successive independent samples design assessed market penetration and attitudinal changes among the young people who completed an online questionnaire 1 year after (T3: n = 438) the intervention. This is compared with two samples that completed a survey either immediately before (T1: n = 403) or 2 months after (T2: n = 403) the campaign launch. RESULTS: The proportion of respondents who remembered the campaign grew from 24.8 % at T2 to 48.6 % at T3. Elevated website activity on mindcheck.ca was sustained 1 year after In One Voice had ended. Small but significant reductions in personal stigma and social distance were detected from T1 and T3, which were not observed at T2. Respondents' self-rated ability to help others with mental health issues and to engage in positive behaviors relating to mental health issues (e.g., seeking information) did not improve significantly from T1 to T3. CONCLUSIONS: Improved attitudes towards mental health issues were observed among young people 1 year following a brief social media campaign. The campaign was less effective at providing the tools young people need to feel capable of helping someone who may be experiencing mental health issues, and motivating them to engage in constructive behaviors related to mental health.

What influences perceptions of procedural justice among people with mental illness regarding their interactions with the police?

According to procedural justice theory, a central factor shaping perceptions about authority figures and dispute resolution processes is whether an individual believes they were treated justly and fairly during personal encounters with agents of authority. This paper describes findings from a community-based participatory research study examining perceptions of procedural justice among sixty people with mental illness regarding their interactions with police. The degree to which these perceptions were associated with selected individual (e.g., socio-demographic characteristics), contextual (e.g., neighborhood, past experiences), and interactional (e.g., actions of the officer) factors was explored. The results of regression analyses indicate that the behavior of police officers during the interactions appears to be the key to whether or not these interactions are perceived by people with mental illness as being procedurally just. Implications of these findings for improving interactions between the police and people with mental illness are discussed.

Supporting recovery by improving patient engagement in a forensic mental health hospital: results from a demonstration project.

BACKGROUND: Mental health services are shifting toward approaches that promote patients' choices and acknowledge the value of their lived experiences. OBJECTIVE: To support patients' recovery and improve their experiences of care in a Canadian forensic mental health hospital, an intervention was launched to increase patient engagement by establishing a peer support program, strengthening a patient advisory committee, and creating a patient-led research team. DESIGN: The effect of the intervention on patient- and system-level outcomes was studied using a naturalistic, prospective, longitudinal approach. Quantitative and qualitative data were gathered from inpatients and service providers twice during the 19-month intervention. RESULTS: Despite succeeding in supporting patients' participation, the intervention had minimal impacts on internalized stigma, personal recovery, personal empowerment, service engagement, therapeutic milieu, and the recovery orientation of services. Peer support demonstrated positive effects on internalized stigma and personal recovery. CONCLUSIONS: Strengthening patient engagement contributes toward improving experiences of care in a forensic hospital, but it may have limited effects on outcomes.

Evaluation of a campaign to improve awareness and attitudes of young people towards mental health issues.

PURPOSE: This study evaluated the effectiveness of the In One Voice campaign for raising mental health awareness and improving attitudes of youth and young adults towards mental health issues. The campaign featured a prominent male sports figure talking about mental health issues and used online social media. METHODS: A successive independent samples design assessed market penetration and attitudinal changes among the young people. Two samples completed an online questionnaire either immediately before (T1: n = 403) or 2 months after (T2: n = 403) the campaign launch. Website analytics determined changes in activity levels of a youth-focused mental health website (mindcheck.ca). RESULTS: One-quarter (24.8 %, n = 100) of the respondents remembered the campaign. The proportion of respondents who were aware of the website increased significantly from 6.0 % at T1 to 15.6 % at T2. Average overall scores on standardized measures of personal stigma and social distance were not significantly different between T1 and T2 respondents. Attitudes towards mental health issues were statistically similar between respondents who were or were not exposed to the campaign. Those who were exposed to the campaign were significantly more likely to talk about and seek information relating to mental health issues. CONCLUSIONS: The proximal outcomes of the campaign to increase awareness and use of the website were achieved. The distal outcome of the campaign to improve attitudes towards mental health issues was not successfully achieved. The brief social media campaign improved mental health literacy outcomes, but had limited effect on personal stigma and social distance.

Improving care and wellness in bipolar disorder: origins, evolution and future directions of a collaborative knowledge exchange network.

The Collaborative RESearch team to study psychosocial factors in bipolar disorder (CREST.BD) is a multidisciplinary, cross-sectoral network dedicated to both fundamental research and knowledge exchange on bipolar disorder (BD). The core mission of the network is to advance the science and understanding of psychological and social issues associated with BD, improve the care and wellness of people living with BD, and strengthen services and supports for these individuals. CREST.BD bridges traditional and newer research approaches, particularly embracing community-based participatory research (CBPR) methods. Membership of CREST is broad, including academic researchers, people with BD, their family members and supports, and a variety of health care providers. Here, we describe the origins, evolution, approach to planning and evaluation and future vision for our network within the landscape of CBPR and integrated knowledge translation (KT), and explore the keys and challenges to success we have encountered working within this framework.

A tale of two cultures: examining patient-centered care in a forensic mental health hospital.

Several questions remain unanswered regarding the extent to which the principles and practices of patient-centered care are achievable in the context of a forensic mental health hospital. This study examined patient-centered care from the perspectives of patients and providers in a forensic mental health hospital. Patient-centered care was assessed using several measures of complementary constructs. Interviews were conducted with 30 patients and surveys were completed by 28 service providers in a forensic mental health hospital. Patients and providers shared similar views of the therapeutic milieu and recovery orientation of services; however, providers were more likely to perceive the hospital as being potentially unsafe. Overall, the findings indicated that characteristics of patient-centered care may be found within a forensic mental health hospital. The principles of patient-centered care can be integrated into service delivery in forensic mental health hospitals, though special attention to providers' perceptions of safety is needed.

Stressors and barriers to using mental health services among diverse groups of first-generation immigrants to the United States.

This study examined stressors and barriers to using mental health services among first-generation immigrants in San Jose, California. Focus groups for 30 immigrants from Cambodia, Eastern Europe, Iran, Iraq, Africa, and Vietnam were audio-recorded, translated and transcribed. Two researchers coded the data and identified themes pertaining to mental health stressors and barriers. Six primary stressors were identified: economic, discrimination, acculturation due to language differences, enculturation, parenting differences, and finding suitable employment. Primary barriers included: stigma, lack of a perceived norm in country of origin for using mental health services, competing cultural practices, lack of information, language barriers, and cost. A conceptual model is presented that may be used to inform the design and implementation of mental health services for this population.

The effectiveness of interventions for reducing stigma related to substance use disorders: a systematic review.

AIMS: This study provides a systematic review of existing research that has empirically evaluated interventions designed to reduce stigma related to substance use disorders. METHODS: A comprehensive review of electronic databases was conducted to identify evaluations of substance use disorder related stigma interventions. Studies that met inclusion criteria were synthesized and assessed using systematic review methods. RESULTS: Thirteen studies met the inclusion criteria. The methodological quality of the studies was moderately strong. Interventions of three studies (23%) focused on people with substance use disorders (self-stigma), three studies (23%) targeted the general public (social stigma) and seven studies (54%) focused on medical students and other professional groups (structural stigma). Nine interventions (69%) used approaches that included education and/or direct contact with people who have substance use disorders. All but one study indicated their interventions produced positive effects on at least one stigma outcome measure. None of the interventions have been evaluated across different settings or populations. CONCLUSIONS: A range of interventions demonstrate promise for achieving meaningful improvements in stigma related to substance use disorders. The limited evidence indicates that self-stigma can be reduced through therapeutic interventions such as group-based acceptance and commitment therapy. Effective strategies for addressing social stigma include motivational interviewing and communicating positive stories of people with substance use disorders. For changing stigma at a structural level, contact-based training and education programs targeting medical students and professionals (e.g. police, counsellors) are effective.

Use of Medicare claims to rank hospitals by surgical site infection risk following coronary artery bypass graft surgery.

OBJECTIVE: To evaluate whether longitudinal insurer claims data allow reliable identification of elevated hospital surgical site infection (SSI) rates. DESIGN: We conducted a retrospective cohort study of Medicare beneficiaries who underwent coronary artery bypass grafting (CABG) in US hospitals performing at least 80 procedures in 2005. Hospitals were assigned to deciles by using case mix-adjusted probabilities of having an SSI-related inpatient or outpatient claim code within 60 days of surgery. We then reviewed medical records of randomly selected patients to assess whether chart-confirmed SSI risk was higher in hospitals in the worst deciles compared with the best deciles. PARTICIPANTS: Fee-for-service Medicare beneficiaries who underwent CABG in these hospitals in 2005. RESULTS: We evaluated 114,673 patients who underwent CABG in 671 hospitals. In the best decile, 7.8% (958/12,307) of patients had an SSI-related code, compared with 24.8% (2,747/11,068) in the worst decile ([Formula: see text]). Medical record review confirmed SSI in 40% (388/980) of those with SSI-related codes. In the best decile, the chart-confirmed annual SSI rate was 3.2%, compared with 9.4% in the worst decile, with an adjusted odds ratio of SSI of 2.7 (confidence interval, 2.2-3.3; [Formula: see text]) for CABG performed in a worst-decile hospital compared with a best-decile hospital. CONCLUSIONS: Claims data can identify groups of hospitals with unusually high or low post-CABG SSI rates. Assessment of claims is more reproducible and efficient than current surveillance methods. This example of secondary use of routinely recorded electronic health information to assess quality of care can identify hospitals that may benefit from prevention programs.