Cannabis and Psychosis.

Psychosis and cannabis use may overlap in multiple ways in young people. Research suggests that cannabis use increases risk for having psychotic symptoms, both attenuated (subthreshold) and acute. Cannabis use may also exacerbate psychosis symptoms among young people with underlying psychosis risk and psychotic disorders. Although there are suggestions for treating co-occurring psychosis and cannabis use in young people (e.g., incorporating cannabis use assessment and treatment strategies into specialized early psychosis care), there are many gaps in clinical trial research to support evidence-based treatment of these overlapping concerns.

Simplified Liquid Chromatography-Mass Spectrometry Methods for Gestagen Analysis in Animal Fat and Liver.

Gestagens, a class of veterinary drugs also called progestogens, are synthetic hormones used to increase feed efficiency and rate of gain in heifers. The Canadian Food Inspection Agency analyzes progestogens melengestrol acetate (MGA), megestrol acetate, and chlormadinone acetate using liquid chromatography-mass spectrometry (LC-MS). Our conventional gestagen method for kidney fat has many time-consuming steps, including solid-phase extraction. A sample preparation procedure having fewer clean-up steps was developed for routine diagnostic analysis of kidney fat and provided similar results faster, and at lower cost. A confirmatory liver method for gestagens, developed using salt-assisted extraction, employed minimal clean-up steps that resulted in high chemical background at the desired lower limit of quantification (LLOQ). Differential ion mobility spectrometry, specifically high-field asymmetric waveform ion mobility spectrometry (FAIMS), was used to filter chemical background in the gas phase. The effect of the ionization probe position on FAIMS parameters, including sensitivity, is described. With LC-FAIMS-MS, chemical background for each gestagen was virtually eliminated, resulting in a quantitative liver method having the desired 0.6 ng/g LLOQ and estimated limits of detection (LODs) up to 140 times lower than LC-MS. Incurred MGA samples, analyzed using kidney fat and liver methods from the same animal, show levels within the quantitative ranges of both methods.

Rationale and design of a pilot randomized controlled trial to increase moderate-to-vigorous physical activity in preadolescent Latina girls and their mothers.

Background: Hispanic/Latina girls have a low prevalence of moderate-intensity physical activity (PA) compared to their male counterparts and non-Hispanic White girls. Mothers influence their children's activity levels by creating and supporting PA opportunities, modeling PA, and reinforcing children's efforts to be physically active. The Conmigo trial will evaluate a mother-daughter intervention to promote PA and examine potential mechanisms of change including mothers' PA, parenting regarding PA, and mother-daughter communication. Method: This randomized controlled trial examines the feasibility, acceptability, and impact of a 12-week intervention promoting PA in preadolescent Latina girls in San Diego County, CA. Participants (n = 90 dyads) are randomized to the Conmigo PA intervention or to a control group that receive an abbreviated version of the intervention. The intervention was informed by Social Cognitive Theory and Family Systems Theory and emphasize family-level factors to promote PA using an actor-partner model. Mothers and daughters attend weekly 90-min sessions in English or in Spanish via Zoom video conferencing, supported by facilitator follow-ups and WhatsApp supportive chat group for mothers. Objective (accelerometer) and self-report measures at baseline, 3 months, and 6 months capture the frequency and intensity of PA and correlates and predictors of PA. We also examine the impact of the intervention on the bidirectional influence of mother-daughter PA. Implications: The findings from the Conmigo trial will form the basis of a randomized controlled community trial and will move the field forward in identifying targets of change in preventing chronic disease risk in Hispanic/Latino communities.

The association between mental health stigma and face emotion recognition in individuals at risk for psychosis.

Self-stigma has been associated with reduced accuracy of face emotion recognition in individuals at clinical high risk for psychosis (CHR). Stigma may also relate to slowing of performance during cognitive tasks for which a negative stereotype is relevant. This study aimed to investigate the association of mental illness stigma with face emotion recognition among CHR individuals. Participants were 143 CHR individuals identified using the Structured Interview for Psychosis-Risk Syndromes (SIPS). Face emotion recognition was assessed using the Penn Emotion Recognition Task (ER-40). Stigma was assessed using discrimination, stereotype awareness, and stereotype agreement subscales of the Mental Health Attitudes Interview for CHR. We tested associations of ER-40 accuracy and response times with these stigma variables, including the role of clinical and demographic factors. Racial/ethnic minoritized participants had higher attenuated positive symptoms than non-minoritized participants. Longer ER-40 response times were correlated with greater stereotype agreement (r=.17, p=.045) and discrimination (r=.22, p=.012). A regression model predicting ER-40 response times revealed an interaction of stereotype agreement with minoritized status (p=.008), with slower response times for minoritized participants as stereotype agreement increased. Greater disorganized symptoms and male gender also predicted longer response times. ER-40 accuracy was not associated with stigma. Overall, minoritized CHR individuals with greater internalized stigma took longer to identify face emotions. Future research is needed to assess whether slower response times are specific to social cues, and if internalized stigma interferes with performance in real-world social situations. Reducing stigma may be an important target for interventions that aim to improve social skills.

Cannabis and Psychosis.

Psychosis and cannabis use may overlap in multiple ways in young people. Research suggests that cannabis use increases risk for having psychotic symptoms, both attenuated (subthreshold) and acute. Cannabis use may also exacerbate psychosis symptoms among young people with underlying psychosis risk and psychotic disorders. Although there are suggestions for treating co-occurring psychosis and cannabis use in young people (e.g., incorporating cannabis use assessment and treatment strategies into specialized early psychosis care), there are many gaps in clinical trial research to support evidence-based treatment of these overlapping concerns.

Borderline personality features among individuals at clinical high risk for psychosis (CHR-P): A brief report.

AIM: This exploratory study reports on borderline symptomatology within a sample of individuals at clinical high risk for psychosis (CHR-P) through a validated, self-report instrument, the short version of the Borderline Symptom List (BSL-23). METHODS: The sample consisted of 44 help-seeking CHR-P youth (ages 14-29 years) who completed an initial evaluation at a specialized clinic for psychosis-risk. RESULTS: The mean BSL-23 score was 1.5 (SD = 1.0, range 0.1-4.0). Higher scores were strongly associated with greater reported depressive symptoms (r = 0.84, p < 0.001). Additionally, borderline symptoms associated with attenuated positive symptoms (r = 0.32, p = 0.034) and social anxiety (r = 0.34, p = 0.027). Borderline symptomatology was not associated with role or social functioning. CONCLUSIONS: This study is one of the first examinations of borderline symptomatology within a CHR-P sample through a validated self-report measure. Future research replicating these results is required to determine their robustness.

Regulation of B cell receptor signalling by Epstein-Barr virus nuclear antigens.

The cancer-associated Epstein-Barr virus (EBV) latently infects and immortalises B lymphocytes. EBV latent membrane protein 2A and EBV-encoded microRNAs are known to manipulate B cell receptor signalling to control cell growth and survival and suppress lytic replication. Here, we show that the EBV transcription factors EBNA2, 3A, 3B and 3C bind to genomic sites around multiple B cell receptor (BCR) pathway genes, regulate their expression and affect BCR signalling. EBNA2 regulates the majority of BCR pathway genes associated with binding sites, where EBNA3 proteins regulate only 42% of targets predicted by binding. Both EBNA2 and 3 proteins predominantly repress BCR pathway gene expression and target some common genes. EBNA2 and at least one EBNA3 protein repress the central BCR components CD79A and CD79B and the downstream genes BLNK, CD22, CD72, NFATC1, PIK3CG and RASGRP3. Studying repression of CD79B, we show that EBNA2 decreases transcription by disrupting binding of Early B cell Factor-1 to the CD79B promoter. Consistent with repression of BCR signalling, we demonstrate that EBNA2 and EBNA3 proteins suppress the basal or active BCR signalling that culminates in NFAT activation. Additionally, we show that EBNA2, EBNA3A and EBNA3C expression can result in reductions in the active serine 473 phosphorylated form of Akt in certain cell contexts, consistent with transcriptional repression of the PI3K-Akt BCR signalling arm. Overall, we identify EBNA2, EBNA3A and EBNA3C-mediated transcription control of BCR signalling as an additional strategy through which EBV may control the growth and survival of infected B cells and maintain viral latency.

Dissecting the impact of bromodomain inhibitors on the Interferon Regulatory Factor 4-MYC oncogenic axis in multiple myeloma.

B-cell progenitor fate determinant interferon regulatory factor 4 (IRF4) exerts key roles in the pathogenesis and progression of multiple myeloma (MM), a currently incurable plasma cell malignancy. Aberrant expression of IRF4 and the establishment of a positive auto-regulatory loop with oncogene MYC, drives a MM specific gene-expression program leading to the abnormal expansion of malignant immature plasma cells. Targeting the IRF4-MYC oncogenic loop has the potential to provide a selective and effective therapy for MM. Here we evaluate the use of bromodomain inhibitors to target the IRF4-MYC axis through combined inhibition of their known epigenetic regulators, BRD4 and CBP/EP300. Although all inhibitors induced cell death, we found no synergistic effect of targeting both of these regulators on the viability of MM cell-lines. Importantly, for all inhibitors over a time period up to 72 h, we detected reduced IRF4 mRNA, but a limited decrease in IRF4 protein expression or mRNA levels of downstream target genes. This indicates that inhibitor-induced loss of cell viability is not mediated through reduced IRF4 protein expression, as previously proposed. Further analysis revealed a long half-life of IRF4 protein in MM cells. In support of our experimental observations, gene network modeling of MM suggests that bromodomain inhibition is exerted primarily through MYC and not IRF4. These findings suggest that despite the autofeedback positive regulatory loop between IRF4 and MYC, bromodomain inhibitors are not effective at targeting IRF4 in MM and that novel therapeutic strategies should focus on the direct inhibition or degradation of IRF4.

Probing the Mechanism of Action of Cry41Aa on HepG2 through the Establishment of a Resistant Subline.

Cry41Aa, also called parasporin-3, belongs to a group of toxins from the entomopathogenic bacterium Bacillus thuringiensis that show activity against human cancer cells. Cry41Aa exhibits preferential cytocidal activity towards HL-60 (human promyelocytic leukaemia cells) and HepG2 (human liver cancer cells) cell lines after being proteolytically activated. To better understand the mechanism of action of Cry41Aa, we evolved resistance in HepG2 cells through repeated exposure to increasing doses of the toxin. Concentrations of Cry41Aa that killed over 50% of the parental HepG2 cells had no significant effect on the viability of the resistant cells and did not induce either pore formation or p38 phosphorylation (both characteristic features of pore-forming toxins). Preliminary RNA sequencing data identified AQP9 as a potential mediator of resistance, but extensive investigations failed to show a causal link and did not support an enhanced cell repair process as the resistance mechanism.

Improved Thyreostatic Drug Detection in Animal Tissues Using Liquid Chromatography-High-Field Asymmetric Waveform Ion Mobility Spectrometry-Mass Spectrometry.

Thyreostatic drugs (thyreostats) interfere with thyroid function and have been used illegally in animals slaughtered for food. Thyreostat use leads to poorer quality meat, and the drug residues can cause adverse effects in humans. These drugs, with the exception of thiouracil, do not occur naturally and require sensitive methodologies for their detection in animal tissues. Because thyreostats are low-molecular-weight polar analytes, liquid chromatography-mass spectrometry (LC-MS) is typically used for detection and, in particular, triple quadrupole mass spectrometry with selective reaction monitoring (i.e., LC-SRM). However, LC-SRM thyreostat methods suffer from chemical background noise and endogenous interferences arising from the complex tissue matrix. An improved high-field asymmetric waveform ion mobility spectrometry interface (FAIMS Pro), which separates ions based on differential ion mobility, was combined with LC-SRM to minimize these interferences. Using the same samples and conditions, LC-FAIMS-SRM showed improvements in the signal-to-noise ratio (S/N) of up to 50 times compared with our validated LC-SRM method. In addition, wider linear ranges, including substantial improvements in the lower limit of quantification (approximately an order of magnitude for tapazole and methylthiouracil), were observed with LC-FAIMS-SRM.

Changes in community providers' screening behaviours, referral practices, and clinical confidence following participation in an early psychosis educational campaign.

AIM: Successful delivery of care to individuals with early psychosis depends on the ability of community providers to identify and refer appropriate candidates for services. Although specialty centres commonly rely upon education and outreach campaigns to building bridges with community providers, few studies have examined the effectiveness of these campaigns or the mechanisms by which they may achieve their intended effects. METHODS: We surveyed community clinicians (N = 39) about their screening behaviours, referral practices, and confidence in managing early psychosis just before and 3-6 months after attending an educational event designed to promote recognition and quality treatment of early psychosis. RESULTS: Three to six months following attendance, providers reported screening a greater proportion of clients for early psychosis, referring a greater number of clients to specialty services, and feeling more confident in their ability to respond to clients with early psychosis. Increases in confidence following attendance were associated with corresponding increases in screening behaviour. CONCLUSIONS: The results suggest that outreach campaigns designed to enhance community providers' knowledge about early psychosis assessment and resources may be effective in promoting screening, referrals, and confidence in managing psychosis. Gains in provider confidence may contribute to increases in screening. Given the lack of control group and relatively short follow-up period, more research is needed to determine the effects of early psychosis educational events and the mechanisms by which they may promote successful treatment delivery for young people in need.

Individualized vocational and educational support and training for youth at clinical high risk for psychosis.

AIM: Early intervention for psychosis has been of high interest in the past two decades. Research demonstrates that clinical high risk for psychosis (CHR-p) populations experience impairments in role functioning. Although several vocational and cognitive interventions exist for people living with psychosis, there are no known evidence-based treatments for role functioning difficulties during the CHR-p stage. There is clear evidence for a need for interventions that directly target role functioning. METHODS: This paper describes the theoretical development and implementation of a novel intervention targeting role functioning impairments: Individualized Vocational and Educational Support and Training (InVEST). The CEDAR Clinic, a specialized CHR-p coordinated specialty care (CSC) team, has worked to develop InVEST to target core aspects of role functioning, namely executive functioning, stress sensitivity, and task initiation. The intervention is cost-efficient, as bachelor level clinicians provide the service under supervision of licensed clinicians. This summary describes InVEST, provides a disguised case example, and presents initial exploratory data (N = 135) focused on the intervention's feasibility in this CSC program. RESULTS: Although these preliminary data are limited, available information suggests that InVEST may provide a core treatment modality within CHR-p treatment programs. CONCLUSIONS: More research formally investigating InVEST with a larger sample would provide further evidence of the intervention's efficacy.

Treatment outcomes for young people at clinical high risk for psychosis: Data from a specialized clinic.

AIM: Treatment for youth exhibiting signs of clinical high risk for psychosis (CHR-P) has been emphasized in recent years, but there is need for a greater understanding of the course of symptoms and functioning across treatment. The aim of this study is to describe 10 years of naturalistic treatment outcomes in a real-world, specialized CHR-P outpatient clinic, the Center for Early Detection, Assessment, and Response to Risk (CEDAR) Clinic. METHODS: The CEDAR Clinic routinely collects client outcomes data for the purposes of program development, monitoring treatment effectiveness, and characterizing the clinic population. Clients are assessed at baseline, every 6 months (for up to 2 years depending on duration of treatment), and at the end of treatment. A series of mixed-effects models were performed to analyse change over time in outcomes (symptoms and functioning) between baseline and follow-up time points. RESULTS: Over time, clients' (N = 123) positive (F = 11.8, p < .001) and negative (F = 4.91, p = .002) symptoms declined relative to their baseline. Social functioning improved over time (F = 2.50, p = .049), as did depression (F = 8.60, p < .001) and hopelessness (F = 4.21, p = .004). Clients' total CEDAR treatment hours ranged across type of treatment service, but the amount of treatment clients received was not associated with any clinical outcomes. CONCLUSIONS: Over the course of treatment at this real-world, specialized CHR-P program, clients exhibited significant improvement in clinical outcomes and did not significantly decline in any measured outcomes. We discuss this study in the context of current understanding and guidelines for specialized coordinated specialty care treatment for CHR-P.

Emotional and stigma-related experiences relative to being told one is at risk for psychosis.

OBJECTIVE: Despite the appeal of early intervention in psychosis, there is concern that identifying youth as having high psychosis risk (PR) may trigger stigma. This study employed a pre-post design to measure change in PR participants' emotions about PR upon being told of their PR status and according to whether this was the first time receiving this information. METHODS: Participants (n = 54) identified as at PR via structured interview rated their emotions about PR before and after being told they were at PR. Qualitative analyses explored the valence of participant reflections on being given this information. RESULTS: Participants reported significantly less negative emotion after being told of their PR status (p < .001), regardless of whether they were hearing this for the first time (p = .72). There was no change in positive emotions or the predominant belief that they should keep their PR status private. Most participants commented positively about the process of feedback but negatively about its impact on their self-perceptions and/or expectations of others' perceptions of them. CONCLUSION: This is the first study to collect pre-post data related to being told one is at PR and to examine quantitative and qualitative responses across and within individuals. For a majority of participants, clinical feedback stimulated negative stereotypes even as it relieved some distress. To actively address internalized stigma, clinicians providing feedback to PR youth must attend to the positive and negative impacts on how youth think about themselves as well as how they feel.

Comorbid early psychosis and borderline personality disorder: Conceptualizing clinical overlap, etiology, and treatment.

Despite substantial efforts aimed at the detection and intervention for early symptoms of mental illness, there is relatively limited research on the clinical overlap between borderline personality disorder (BPD) and early psychosis, for example, clinical high risk (CHR) for psychosis, in young people. We present a narrative review of the clinical overlap between BPD and psychosis spectrum symptoms. Both conditions have unstable temporal course, and both are marked by functional impairment, increased suicide risk, and higher rates of psychiatric inpatient services. We then review evidence-based treatments for psychosis and BPD, emphasizing treatments for early presentations of these symptoms and initial research considering treatments for the overlap. Psychotherapies with the strongest empirical support include cognitive behavioral models, with BPD showing limited response to adjunctive pharmacotherapy. We end by discussing specific recommendations for future research, including longitudinal studies to determine the predictors of the course of illness and the development of treatments to target comorbid BPD and CHR symptoms.

Population Management Approach to Kidney Stone Care Improves Patient Compliance to Preventive Measures and Reduces Resource Utilization in Patients at High Risk for Stone Recurrence.

INTRODUCTION: Nephrolithiasis is a chronic condition with 5 to 10-year recurrence rates as high as 50%. Stone recurrence can be reduced by implementing American Urological Association kidney stone medical management guidelines, which recommend additional metabolic testing for high risk, recurrent and interested first-time stone formers. However, clinician adherence to guidelines is variable, and patient compliance with preventive evaluations is low. We evaluated our kidney stone population management program's role in patient compliance with completing American Urological Association metabolic studies. We assessed the program's impact on office encounters, operating room procedures and emergency department visits for known high risk kidney stone patients. METHODS: A retrospective review of electronic medical records between 2009 and 2017 identified 4,029 kidney stone patients. A total of 873 patients were at high risk for kidney stone recurrence. In 2013, we established a population management program in which high risk patients were referred and followed by a nurse case manager. Patients were contacted by email or telephone if metabolic serum and urine collections were incomplete. Office, operating room and emergency department visits were compared before and after the program's implementation. RESULTS: Metabolic evaluation orders increased from 17% to 35% in our institution's urology department. Patient compliance with recommended studies improved from <10% to 82%, and reductions in office visits by 48%, surgical procedures by 38% and emergency department encounters by 40% were observed. CONCLUSIONS: Our program improved patient compliance with American Urological Association recommended studies for high risk kidney stone patients. Reductions in stone events may have been due to our program but require further study in the future.

Gender and dementia national strategy policymaking: Working toward health equity in Canada through gender-based analysis plus.

This article discusses the results of a content and critical discourse analysis of Canadian federal policy documentation relating to the development of a national Canadian dementia strategy. These documents span from 2013 and focus upon Canadian federal policy directives and directions up to the release, and including the release, of a national strategy in June 2019. The analyses, supplemented by a subtextual examination of these documents guided by Bacchi's (2012) "What's the Problem Represented to be?" framework, focuses upon the treatment of gender in policy documentation and the specific gender related policy framework, known as GBA+ (gender-based analysis and intersectionality), which is intended to bring about health equity to disadvantaged groups. As women, particularly, working class women and their carers, as well as women with additional intersecting factors, such as being lesbian or bisexual, are less likely to receive the dementia related care and services they need, precipitating a premature move to residential care, GBA+ is an essential policy framework in the attempt to address these inequities. However, findings point to a superficial treatment of gender, GBA and GBA+ in federal policy documents and lack a meaningful invocation of women's gendered and intersectional lived experiences of dementia. Additionally, the Canadian federal government's Dementia Strategy for Canada: Together We Aspire (2019) is grounded in a rendition of citizenship that do not work to unearth the complex relationships between citizenship, old age, gender and intersectional factors. As a result, the Dementia Strategy for Canada: Together We Aspire (2019) presents a version of citizenship that homogenizes older adults and prevents representations of older adults as diverse, complex and continually changing groupings. Therefore, inspired by Bartlett et al. (2018), I advocate for the application of a feminist and intersectional citizenship lens in Canadian federal dementia-related policymaking documentation going forward.

Active and Protected: Developing a "Safer Sex" Handout for Adolescents and Young Adults with Cancer.

There is a critical need to engage adolescents and young adults (AYAs) with cancer in conversations regarding "safer" sexual activity during treatment. Many providers, however, report lacking the knowledge and/or tools to engage in these discussions. This article describes the experience of one pediatric institution in assessing and addressing provider barriers to safer sexual activity discussions among AYAs with cancer. Feedback from patients and providers resulted in an educational handout detailing recommendations regarding safer sex practices for AYAs with cancer. Handout adoption, acceptability, appropriateness, and feasibility are described alongside barriers to assist other institutions seeking to develop similar interventions.

Are you really doing 'codesign'? Critical reflections when working with vulnerable populations.

'Codesign' and associated terms such as 'coproduction' or 'patient engagement', are increasingly common in the health research literature, due to an increased emphasis on the importance of ensuring that research related to service/systems development is meaningful to end-users.  However, there continues to be a lack of clarity regarding the key principles and practices of codesign, and wide variation in the extent to which service users are meaningfully engaged in the process. These issues are particularly acute when end-users include populations who have significant health and healthcare disparities that are linked to a range of intersecting vulnerabilities (eg, poverty, language barriers, age, disability, minority status, stigmatised conditions).  The purpose of this paper is to prompt critical reflection on the nature of codesign research with vulnerable populations, including key issues to consider in the initial planning phases, the implementation process, and final outputs.  Risks and tensions will be identified in each phase of the process, followed by a tool to foster reflexivity in codesign processes to address these issues.