The genetics of Graves' disease.

Graves' disease (GD) is the commonest cause of hyperthyroidism and has a strong female preponderance. Everyday clinical practice suggests strong aggregation within families and twin studies demonstrate that genetic factors account for 60-80% of risk of developing GD. In this review, we collate numerous genetic studies and outline the discoveries over the years, starting with historic candidate gene studies and then exploring more recent genome-wide linkage and association studies, which have involved substantial cohorts of East Asian patients as well as those of European descent. Variants in genes including HLA, CTLA4, and PTPN22 have been shown to have substantial individual effects on disease susceptibility. In addition, we examine emerging evidence concerning the possibility that genetic variants may correlate with relevant clinical phenotypes including age of onset of GD, severity of thyrotoxicosis, goitre size and relapse of hyperthyroidism following antithyroid drug therapy, as well as thyroid eye disease. This review supports the inheritance of GD as a complex genetic trait, with a growing number of more than 80 susceptibility loci identified so far. Future implementation of more targeted clinical therapies requires larger studies investigating the influence of these genetic variants on the various phenotypes and different outcomes of conventional treatments.

Glycosaminoglycan modifications of betaglycan regulate ectodomain shedding to fine-tune TGF-ß signaling responses in ovarian cancer.

In pathologies including cancer, aberrant Transforming Growth Factor-ß (TGF-ß) signaling exerts profound tumor intrinsic and extrinsic consequences. Intense clinical endeavors are underway to target this pathway. Central to the success of these interventions is pinpointing factors that decisively modulate the TGF-ß responses. Betaglycan/type III TGF-ß receptor (TßRIII), is an established co-receptor for the TGF-ß superfamily known to bind directly to TGF-ßs 1-3 and inhibin A/B. Betaglycan can be membrane-bound and also undergo ectodomain cleavage to produce soluble-betaglycan that can sequester its ligands. Its extracellular domain undergoes heparan sulfate and chondroitin sulfate glycosaminoglycan modifications, transforming betaglycan into a proteoglycan. We report the unexpected discovery that the heparan sulfate glycosaminoglycan chains on betaglycan are critical for the ectodomain shedding. In the absence of such glycosaminoglycan chains betaglycan is not shed, a feature indispensable for the ability of betaglycan to suppress TGF-ß signaling and the cells' responses to exogenous TGF-ß ligands. Using unbiased transcriptomics, we identified TIMP3 as a key inhibitor of betaglycan shedding thereby influencing TGF-ß signaling. Our results bear significant clinical relevance as modified betaglycan is present in the ascites of patients with ovarian cancer and can serve as a marker for predicting patient outcomes and TGF-ß signaling responses. These studies are the first to demonstrate a unique reliance on the glycosaminoglycan chains of betaglycan for shedding and influence on TGF-ß signaling responses. Dysregulated shedding of TGF-ß receptors plays a vital role in determining the response and availability of TGF-ßs', which is crucial for prognostic predictions and understanding of TGF-ß signaling dynamics.

Implementing One-at-a-Time Therapy in community addiction and mental health centres: a retrospective exploration of the implementation process and initial outcomes.

BACKGROUND: The Department of Health of the Government of New Brunswick and Regional Health Authorities elected to implement Stepped Care 2.0 (SC2.0) in 2021, and began with One-at-a-Time (OAAT) therapy in Community Addiction and Mental Health Centres (CAMHCs) to facilitate rapid access to addiction and mental healthcare. This study: 1) explicated the process of implementing OAAT therapy as it aligned to evidence-based implementation frameworks and strategies; 2) assessed readiness for change among providers during the implementation; and 3) evaluated initial client and system outcomes. METHODS: The process of implementing OAAT therapy within CAMHCs was documented and retrospectively aligned with the Active Implementation Frameworks-Stages of Implementation, Consolidated Framework for Implementation Research, and incorporated strategies endorsed by the Expert Recommendations for Implementing Change. Providers working in CAMHCs completed online asynchronous courses in OAAT therapy and SC2.0, and were recruited to participate in research on perceptions of organizational readiness. Initial outcomes of the implementation were evaluated through client satisfaction surveys administered in CAMHCs and system performance indicators. RESULTS: Aligning with implementation stages, key strategies included: 1) continuously monitoring readiness and soliciting stakeholder feedback for iterative improvement; 2) building a representative implementation team with engaged leaders; 3) creating a comprehensive implementation plan on staff training, communication, and system changes; and 4) supporting sustainability. Providers who participated in research (N = 170, ~ 50% response rate) agreed that their organization was ready for implementation, and that OAAT therapy delivered within a SC2.0 framework was acceptable, appropriate, and feasible. More than 3,600 OAAT therapy sessions were delivered during the initial implementation stage, and waitlists were reduced by 64.1%. The majority of clients who completed surveys (N = 1240, ~ 35% response rate) reported that their OAAT therapy session was helpful, with a minority reporting that additional intervention was needed. CONCLUSIONS: Thoughtful planning and execution, aligned with evidence-based implementation frameworks and strategies, played an important role in this provincial change initiative. Implementation steps outlined can help inform others looking to enact large-scale change.

Emerging adult perceptions of higher-risk cannabis consumption behaviours.

BACKGROUND: Emerging adults have the highest cannabis consumption rates in Canada and are among the most vulnerable to cannabis-related harms. Since certain cannabis consumption behaviours carry greater risks of harm, the Lower-Risk Cannabis Use Guidelines (LRCUG) provide harm reduction strategies. To address a critical gap in the literature, the current study examined emerging adults' awareness of the guidelines and perceptions of higher-risk cannabis consumption behaviours identified within the LRCUG. METHODS: Emerging adults (N = 653) between the ages of 18-25 years were recruited from across Canada. Participants were presented with five vignettes depicting a character's cannabis consumption behaviours. Each vignette focused on a unique aspect of the character's consumption (frequency, polysubstance use, family history of mental illness, method of consumption, and potency). Participants were randomly assigned to one of three conditions within each of the five vignettes that were altered to capture varying levels of risk (e.g. weekly, almost daily, or daily consumption). Following each vignette, participants were asked to respond to four items relating to overall risk of harm, cognitive health, physical health, and mental health. RESULTS: Participants perceived: (1) frequent consumption to be associated with greater risks than less frequent consumption; (2) simultaneous consumption of cannabis and tobacco as being associated with higher risk of harm, yet no difference between simultaneous consumption of cannabis and alcohol or cannabis consumption alone; (3) consuming cannabis with a family history of psychosis or substance use disorder as being associated with greater overall risk than consumption with no family history; (4) smoking and vaping cannabis as associated with more risk than ingesting edibles; and (5) higher-potency THC-dominant strains as being associated with more risk than lower-potency CBD-dominant strains, yet no difference between the two higher-potency THC-dominant strains. CONCLUSIONS: While emerging adults seemed to appreciate the risks associated with some cannabis consumption behaviours, they had difficulty identifying appropriate levels of harm of other higher-risk behaviours. Through an improved understanding of emerging adult perceptions, effective education campaigns should be designed to improve the awareness of cannabis risks and encourage the uptake of harm reduction awareness and strategies.

A survey of the young person's experience of Graves' disease and its management.

OBJECTIVE: A suboptimal quality of life (QoL) has been reported in patients with Graves' disease treated in adult life, but long-term QoL in those treated in childhood and adolescence is unclear. We wanted to understand how Graves' disease and its management impact on the physical, psychological and social well-being of young people and their longer-term QoL. DESIGN, PATIENTS AND MEASUREMENTS: Two questionnaires were used to assess QoL and patient experience of Graves' disease; PedsQL™ Generic Core Scales and a Graves' disease questionnaire devised for this project. The anonymized questionnaires were sent to young people (<30 years) diagnosed with Graves' disease in childhood and adolescence and managed at a tertiary paediatric endocrine unit in the North of England. Respondent QoL scores were compared with a healthy UK cohort. RESULTS: Questionnaires were sent to 51 young people, and 26 responded (51%). Graves' patients reported a lower total QoL score compared with the healthy cohort (p = .003). This was particularly apparent in the psychosocial domain (p = .0016). No patient regretted having definitive treatment (surgery/radioiodine), and all said they would recommend it to others. Half of those who had received definitive treatment still did not feel recovered. There was no difference in the long-term QoL in those who did/did not receive definitive treatment (p = .40). CONCLUSIONS: This study highlights short- and long-term impacts on the QoL and general well-being of young people with Graves' disease. There were no regrets regarding the choice of definitive treatment. This information will help inform the counselling of patients and their families.

Fifteen-minute consultation: An approach to the child receiving glucocorticoids.

Glucocorticoids (GC) are used in paediatric practice for a broad range of conditions and all paediatricians will prescribe GC, in some form, during their career. A wide variety of GC formulations, doses and administration routes are used for periods of time ranging from days to years. Exposure to exogenous GC can result in hypothalamic-pituitary-adrenal axis suppression-otherwise known as adrenal suppression (AS). Patients with AS may be well most of the time but if GC therapy is reduced or stopped or if additional endogenous GC cannot be generated during illness, then an absolute or relative lack of GC can result in severe illness or death. Here, we highlight the relevance of AS to all paediatricians by providing an overview of the background and discussing the presentation and approaches to the management of this clinical entity.

Analysis of BAFF gene polymorphisms in UK Graves' disease patients.

OBJECTIVE: B lymphocyte activating factor (BAFF), a member of the tumour necrosis factor superfamily, is essential for B cell activation, differentiation and survival. Elevated circulating BAFF levels have been found in patients with several autoimmune conditions, including Graves' disease. In addition, BAFF gene variants have been associated with Graves' disease in a Taiwanese cohort, and with several other autoimmune conditions in non-Taiwanese populations. DESIGN AND METHODS: We performed a case-control association study to investigate two BAFF polymorphisms (rs9514828 and rs4000607) in a UK cohort of 444 patients with Graves' disease. Genotype frequencies were compared to those from 447 local controls and more than 5000 healthy controls from the Wellcome Trust case-control consortium (WTCCC2). RESULTS: There was a significant difference in the frequency of the AA genotype at rs4000607 between the Graves' disease cohort and both the local controls (P = 0.045) and the WTCCC2 controls (P = 4.56 × 10-6 ). Furthermore, the frequency of the A allele was found to be increased in the Graves' disease group compared to WTCCC2 controls (P = 0.02, OR 1.20 (95% CI 1.03-1.41). No association was observed at the rs9514828 locus. CONCLUSION: Dysfunction of the humoral immune system is an obligatory pathophysiological component of Graves' disease, hence BAFF is an excellent functional candidate gene. We have demonstrated, for the first time, a significant association of the BAFF polymorphism rs4000607 with Graves' disease in a UK cohort. Further work to elucidate the role of BAFF in the pathogenesis of Graves' disease is now warranted.

Screening for psychosocial distress in pediatric cancer patients: An examination of feasibility in a single institution.

Despite the availability of tools to assess psychosocial screening in pediatric oncology, little is known about the feasibility and acceptability of systematic screening. We aimed to assess the feasibility of implementing a tool, or set of tools, capable of screening for psychosocial distress in pediatric cancer patients across the cancer continuum (on treatment, off treatment). Psychometric criteria were also evaluated. Patients 8-18 years were recruited from a pediatric oncology program. Patients completed self-report measures of the Distress Thermometer (DT) and Pediatric Quality of Life Inventory (PedsQL). One parent of each patient completed three screening tools: DT (proxy-report); PedsQL (proxy-report), and the Psychosocial Assessment Tool adapted for the Canadian context (PATrev), as well as a measure of patient psychological functioning (Behavioral Assessment System for Children-2), and an assessment of screening tool acceptability. Recruitment rates and acceptability informed feasibility of implementation. Ninety-five patients (58 men) with a mean age of 11.47 participated in the study (on treatment, n = 43; off treatment, n = 52). Recruitment rates were on treatment: 56.6% and off treatment: 47.3%. Mean acceptability scores of tools ranged from 3.41 to 4.97 out of 7. Screening tools were comparable with respect to their psychometric properties. The DT took the least amount of time to complete, while the PATrev offered the most robust data with respect to psychometrics. Feasibility of screening for psychosocial distress with our tool was moderate and may be enhanced when administered by a known health-care provider. Future research exploring how to further enhance feasibility of implementation for pediatric cancer patients is warranted.

Mass spectrometry reveals differences in stability and subunit interactions between activated and nonactivated conformers of the (αßγδ)4 phosphorylase kinase complex.

Phosphorylase kinase (PhK), a 1.3 MDa enzyme complex that regulates glycogenolysis, is composed of four copies each of four distinct subunits (α, ß, γ, and δ). The catalytic protein kinase subunit within this complex is γ, and its activity is regulated by the three remaining subunits, which are targeted by allosteric activators from neuronal, metabolic, and hormonal signaling pathways. The regulation of activity of the PhK complex from skeletal muscle has been studied extensively; however, considerably less is known about the interactions among its subunits, particularly within the non-activated versus activated forms of the complex. Here, nanoelectrospray mass spectrometry and partial denaturation were used to disrupt PhK, and subunit dissociation patterns of non-activated and phospho-activated (autophosphorylation) conformers were compared. In so doing, we have established a network of subunit contacts that complements and extends prior evidence of subunit interactions obtained from chemical crosslinking, and these subunit interactions have been modeled for both conformers within the context of a known three-dimensional structure of PhK solved by cryoelectron microscopy. Our analyses show that the network of contacts among subunits differs significantly between the nonactivated and phospho-activated conformers of PhK, with the latter revealing new interprotomeric contact patterns for the ß subunit, the predominant subunit responsible for PhK's activation by phosphorylation. Partial disruption of the phosphorylated conformer yields several novel subcomplexes containing multiple ß subunits, arguing for their self-association within the activated complex. Evidence for the theoretical αßγδ protomeric subcomplex, which has been sought but not previously observed, was also derived from the phospho-activated complex. In addition to changes in subunit interaction patterns upon phospho-activation, mass spectrometry revealed a large change in the overall stability of the complex, with the phospho-activated conformer being more labile, in concordance with previous hypotheses on the mechanism of allosteric activation of PhK through perturbation of its inhibitory quaternary structure.

Structure and location of the regulatory ß subunits in the (αßγδ)4 phosphorylase kinase complex.

Phosphorylase kinase (PhK) is a hexadecameric (αßγδ)(4) complex that regulates glycogenolysis in skeletal muscle. Activity of the catalytic γ subunit is regulated by allosteric activators targeting the regulatory α, ß, and δ subunits. Three-dimensional EM reconstructions of PhK show it to be two large (αßγδ)(2) lobes joined with D(2) symmetry through interconnecting bridges. The subunit composition of these bridges was unknown, although indirect evidence suggested the ß subunits may be involved in their formation. We have used biochemical, biophysical, and computational approaches to not only address the quaternary structure of the ß subunits within the PhK complex, i.e. whether they compose the bridges, but also their secondary and tertiary structures. The secondary structure of ß was determined to be predominantly helical by comparing the CD spectrum of an αγδ subcomplex with that of the native (αßγδ)(4) complex. An atomic model displaying tertiary structure for the entire ß subunit was constructed using chemical cross-linking, MS, threading, and ab initio approaches. Nearly all this model is covered by two templates corresponding to glycosyl hydrolase 15 family members and the A subunit of protein phosphatase 2A. Regarding the quaternary structure of the ß subunits, they were directly determined to compose the four interconnecting bridges in the (αßγδ)(4) kinase core, because a ß(4) subcomplex was observed through both chemical cross-linking and top-down MS of PhK. The predicted model of the ß subunit was docked within the bridges of a cryoelectron microscopic density envelope of PhK utilizing known surface features of the subunit.

Graves' disease: moving forwards.

Graves' disease is a rare disorder that continues to present clinicians and families with a series of challenges. There are no new established treatments for children or adolescents, but the outcomes of recent clinical trials and meta-analyses have helped clinicians to prepare families for the road ahead. We have a more refined understanding of how to administer antithyroid drugs, which one to use and how long to treat the young person. We also have a greater insight into how best to reduce any risks associated with surgery and radioiodine. We understand more about long-term outcomes and their determinants and have greater awareness about the impact of the disease and its treatment on quality of life. A holistic approach to management is key to supporting and counselling young people and their families about the diagnosis and management options. In this review, we will discuss the recent literature and reflect on how this should be translated into clinical practice.

Expansion of the immature B lymphocyte compartment in Graves' disease.

OBJECTIVE: The specific mechanisms driving autoimmunity in Graves' disease (GD) remain largely unknown. Kappa-deleting recombination excision circles (KRECs) are circular DNA molecules generated during B cell maturation in the bone marrow which provide a measure of B cell production and proliferation. We aimed to investigate the association between KRECs and B cell subpopulations, with thyroid status and clinical outcome in GD patients. METHODS: Kappa-deleting recombination excision circles were measured by quantitative real-time PCR using a triple-insert plasmid control in 132 GD patients and 140 healthy controls. In addition, KRECs in GD patients on withdrawal of antithyroid drug (ATD) and 6-10 weeks later were analysed according to a clinical outcome at 1 year. Flow cytometry was performed on isolated CD19+ B cells to quantitate 7 B lymphocyte subpopulations in 65 GD patients. RESULTS: Circulating KRECs were higher in GD vs. controls (P = 1.5 × 10-9) and demonstrated a positive correlation to thyroid hormones and autoantibodies (free thyroxine: P = 2.14 × 10-5, rho = .30; free triiodothyronine: P = 1.99 × 10-7, rho = .37; thyroid stimulating hormone receptor autoantibodies: P = 1.36 × 10-5, rho = .23). Higher KRECs in GD patients 6-10 weeks after ATD withdrawal were associated with relapse of hyperthyroidism at 1 year (P = .04). The KRECs were positively correlated to the total CD19+ B cell count (P = 3.2 × 10-7). CONCLUSIONS: This study reports a robust association between KRECs and GD, highlighting the importance of B cells in the pathogenesis of GD and the influence of thyroid status on B cell activity. The findings indicate a potential role for KRECs as a marker of disease activity and outcome in GD.

STEP IN: Supporting Together Exercise and Play and Improving Nutrition; a Feasibility Study of Parent-Led Group Sessions and Fitness Trackers to Improve Family Healthy Lifestyle Behaviors in a Low-Income, Predominantly Black Population.

BACKGROUND: Pediatric obesity is prevalent and challenging to treat. Although family-centered behavioral management is the gold standard, many families face structural inequities to its access and efficacy. Identifying ways to manage pediatric obesity within primary care is needed. METHODS: This feasibility study included three sequential trials of peer-led group sessions occurring biweekly or monthly between 3/2016 and 2/2017. Parent-child dyads were recruited from a large academic primary care clinic via mailed invitations, prioritizing patients living in local zip codes of historical disinvestment. Eligible patients were 6 to 12 years with a body mass index ≥85th percentile, with parent and child interest in making healthy lifestyle changes, and English speaking. RESULTS: 27 dyads participated, 77% were non-Hispanic Black. Retention and attendance rates were highest in the initial four-session biweekly pilot (100%, 0 dropouts), high in the full six-session biweekly cohort (83%, 1 dropout), and moderate in the monthly cohort (62.7%, 4 dropouts). Families reported high satisfaction with the sessions (4.75/5). Qualitative comments suggested social connections had motivated behavior change in some families. CONCLUSION: Parent-led group sessions for pediatric weight management show promise in engaging families. A future large trial is needed to assess behavior change and anthropometric outcomes.

Emerging Adult Perceptions of Cannabis Consumption Post-Legalization: Considering Age and Sex Differences.

PURPOSE: Increased access to legalized non-medical cannabis has led to growing concern over the potential adverse health impacts of cannabis consumption among youth and emerging adults. This study explored emerging adult perceptions of cannabis consumption and if perceptions changed based on the age and sex of the cannabis consumer. METHODS: Canadian emerging adults between the ages of 18 and 25 years (N = 1,424, Mean = 21.23) were randomly assigned to one of six vignettes that varied by age (14 years, 21 years, and 28 years) or sex (male, female) of the cannabis consumer. Participants were asked to rate seven single-item measures on perceived dangerousness, problematic consumption, negative impacts, and level of disapproval related to the vignette character's almost daily cannabis consumption. RESULTS: The results of seven 2 × 3 factorial analyses of variance revealed a main effect of age on six of seven items, no main effects of sex, and no interactions. Except for social life, participants noted significant differences in harms of cannabis consumption by 14-year-olds, compared to 21-year-olds and 28-year-olds. There were no significant differences in overall perceived dangerousness, problematic consumption, or impact on mental or cognitive health between 21-year-olds and 28-year-olds. Participants perceived cannabis consumption by a 21-year-old to be more harmful to brain development and reported greater disapproval than consumption by a 28-year-old. DISCUSSION: Emerging adults may appreciate the impacts of cannabis consumption within their age cohort on brain development and perceive greater risks for youth. Further education should focus on the potential cognitive and mental health impacts of cannabis in emerging adults.

Evaluation of a Community Suicide Prevention Project (Roots of Hope): Protocol for an Implementation Science Study.

BACKGROUND: Roots of Hope (RoH) is a multisite Canadian community-based suicide prevention initiative developed by the Mental Health Commission of Canada (MHCC), which is based on evidence for intervention effectiveness and World Health Organization recommendations. Seven communities developed local activities in the following 5 pillars: specialized supports, training and networks, public awareness, means safety, and evaluation research. OBJECTIVE: We aim to use an implementation research approach to understand the RoH model for reducing suicidal behaviors and their impacts in communities, and the lessons learned for the equitable development and implementation of RoH in different contexts. Moreover, we want to understand how the program is implemented in relation to the context, the causal pathways, and the factors influencing successful implementation. The evaluation includes assessments of short-term and intermediate effects at each site and overall. METHODS: The principal investigator (PI) developed a consensus among local research coordinators on common approaches and indicators through ongoing participation in an online community of practice, and regular virtual and in-person meetings. At the completion of the pilot phase, the PI will summarize evaluation results across sites and conduct pooled analyses. The RoH theory of change and evaluation model shows how evaluation activities from the planning phase through the implementation of activities in each of the pillars can help clarify the viability of the RoH model and identify factors that facilitate and inhibit effective and equitable implementation in different contexts. Beginning with a situational analysis to identify resources in each community and local specificities, we will examine the implementation characteristics of conformity, dosage, coverage, quality, utility, equity, appreciation, facilitators, and impediments. Evaluation of short-term effects will focus on changes in knowledge, attitudes, behaviors, help-seeking, service use, stigma, media reports, empowerment, and care experiences. Intermediate effects, long-term effects, and impact will include assessments of the changes in suicides, suicide attempt rates, and suicide risk indicators. A variety of data sources, both quantitative and qualitative, will be used. RESULTS: The quantitative and qualitative data from all sites will be summarized by the PI in March 2023 to draw conclusions to help the MHCC in its improvements to the RoH model, and to inform communities about how to better implement RoH. Since the COVID-19 pandemic occurred at the beginning of program implementation, its impact and influence will be documented. The validity of RoH in contributing to the prevention of suicides and suicidal behaviors will be clarified in a variety of contexts. The final evaluation report will be available in September 2023. CONCLUSIONS: The evaluation results, including the identification of factors that facilitate and inhibit the implementation of RoH and the adaptations to challenges, will be useful to the MHCC, current RoH communities, and those considering adopting the RoH model. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/39978.

Provider perceptions of the anticipated benefits, barriers, and facilitators associated with implementing a stepped care model for the delivery of addiction and mental health services in New Brunswick: a mixed-methods observational implementation study.

BACKGROUND: Providers who work within addiction and mental health (A&MH) services in New Brunswick (NB), Canada completed training in Stepped Care 2.0 and One-at-a-Time (OAAT) therapy as part of a provincial practice change initiative to implement a provincial stepped care model. The present study aimed to identify: (1) the perceived acceptability and feasibility of the SC2.0 model; (2) the perceived benefits, barriers, and facilitators to implement SC2.0 in practice; and (3) perceived impacts on clinical practice. METHODS: This is a mixed-methods observational implementation study. Quantitative surveys were completed after training courses. Open-ended responses were collected after completion of SC2.0 training. A subset of providers who completed surveys were asked to participate in semi-structured interviews. Descriptive statistics were used to describe results from surveys. Open-ended responses and semi-structured interviews were compiled and thematically synthesized in an iterative process using a grounded theory framework. Quantitative and qualitative data were triangulated to build an in-depth understanding of provider perceptions. RESULTS: 316 providers completed surveys and responded to open-ended prompts. Interviews were completed with 28 of those providers. SC2.0 was deemed to be acceptable, a suitable fit, and feasible to implement. Perceived benefits included: (1) timely access to services; (2) increased practice efficiency; and (3) increased availability of services. Perceived barriers included: (1) insufficient availability of resources to populate a SC2.0 continuum of care; (2) provider complacency with their current practice; and (3) difficulty for clients to accept and adjust to change. CONCLUSIONS: Identifying the perceived benefits, facilitators, and barriers to adopting stepped care in practice can lead to targeted implementation strategies and the collection of data that can inform continuous improvement cycles.

Emerging adult perceptions of cannabis consumption: Examining changes in perceptions from pre-legalization to post-legalization.

BACKGROUND: Emerging adults (EAs) have the highest rates of cannabis consumption in Canada and are vulnerable to the potential impacts of frequent cannabis consumption. This study assessed EAs' perceived risk of cannabis consumption across multiple domains of potential harm based on the age (14-year-old, 21-year-old, or 28-year-old) and sex (male or female) of the vignette character, time-point (pre- or post-legalization), and participant's gender. METHODS: Secondary analyses were conducted on data from a pre-legalization study and post-legalization replication. Participants included EAs between 18 and 25 years of age and living in Newfoundland and Labrador. Participants from the pre- and post-legalization studies were matched based on demographic variables and the assigned vignette character. Participants responded to seven items of perceived risk based on their assigned vignette character's (varied by age or sex) almost daily cannabis consumption. RESULTS: Participants (N = 689) viewed cannabis consumption to have greater risks for a 14-year-old compared to a 21- or 28-year-old in all domains except for social life. Prior to legalization, participants who identified as a woman felt that cannabis had more detrimental impacts on social life than participants who identified as a man. Findings also suggested that pre-legalization cannabis consumption by a female was perceived as more detrimental to their social life than pre-legalization consumption by a male and post-legalization consumption by a female. CONCLUSION: EAs do not fully appreciate the risks of cannabis consumption, suggesting that it is imperative for public health strategies to promote increased awareness of the risks of frequent cannabis consumption, and improve cannabis health literacy in this population.

Heparan sulfate modifications of betaglycan promote TIMP3-dependent ectodomain shedding to fine-tune TGF-ß signaling.

In pathologies such as cancer, aberrant Transforming Growth Factor-ß (TGF-ß) signaling exerts profound tumor intrinsic and extrinsic consequences. Intense clinical endeavors are underway to target this pivotal pathway. Central to the success of these interventions is pinpointing factors that decisively modulate the TGF-ß responses. Betaglycan/type III TGF-ß receptor (TßRIII), is an established co-receptor for the TGF-ß superfamily known to bind directly to TGF-ßs 1-3 and inhibin A/B. While betaglycan can be membrane-bound, it can also undergo ectodomain cleavage to produce soluble-betaglycan that can sequester its ligands. The extracellular domain of betaglycan undergoes heparan sulfate and chondroitin sulfate glycosaminoglycan modifications, transforming betaglycan into a proteoglycan. Here we report the unexpected discovery that the heparan sulfate modifications are critical for the ectodomain shedding of betaglycan. In the absence of such modifications, betaglycan is not shed. Such shedding is indispensable for the ability of betaglycan to suppress TGF-ß signaling and the cells' responses to exogenous TGF-ß ligands. Using unbiased transcriptomics, we identified TIMP3 as a key regulator of betaglycan shedding and thereby TGF-ß signaling. Our results bear significant clinical relevance as modified betaglycan is present in the ascites of patients with ovarian cancer and can serve as a marker for predicting patient outcomes and TGF-ß signaling responses. These studies are the first to demonstrate a unique reliance on the glycosaminoglycan modifications of betaglycan for shedding and influence on TGF-ß signaling responses. Dysregulated shedding of TGF-ß receptors plays a vital role in determining the response and availability of TGF-ßs', which is crucial for prognostic predictions and understanding of TGF-ß signaling dynamics.

Whom are we comforting? An analysis of comfort medications delivered to dying neonates.

OBJECTIVES: To clarify the use of end-of-life comfort medications or neuromuscular blockers (NMBs) in culturally different neonatal intensive care units (NICUs). STUDY DESIGN: Review of medical files of newborns > 22 weeks gestation who died in the delivery room or the NICU during 12 months in four NICUs (Chicago, Milwaukee, Montreal, and Groningen). We compared use of end-of-life comfort medications and NMBs. RESULTS: None of the babies who died in the delivery room received comfort medications. The use of opiods (77%) or benzodiazepines (41%) around death was similar in all NICUs. Increasing this medication around extubation occurred most often in Montreal, rarely in Milwaukee and Groningen, and never in Chicago. Comfort medications use had no significant impact on the time between extubation and death. NMBs were never used around death in Chicago, once in Montreal, and more frequently in Milwaukee and Groningen. Initiation of NMB after extubation occurred only in Groningen. CONCLUSION: Comfort medications were administered to almost all dying infants in each NICU. Some, but not all, centers were comfortable increasing these medications around or after extubation. In three centers, NMBs were at times present at the time of death. However, only in Holland were NMBs initiated after extubation.

The NFKB1 (g.-24519delATTG) variant is associated with necrotizing enterocolitis (NEC) in premature infants.

OBJECTIVE: While it is known that gene-environment interactions contribute to necrotizing enterocolitis (NEC) pathogenesis, characterization of genetic risk-factors that can predict NEC in preterm infants remains nascent. We hypothesized that altered intestinal immune responses arising from sequence variation in the toll-like receptor (TLR) pathway genes contribute to NEC susceptibility. MATERIALS AND METHODS: Very low birth weight (VLBW) infants were recruited prospectively in a multi-center, cohort study involving collection of blood samples along with collation of clinical information. DNA obtained from blood samples was used to genotype nine single nucleotide polymorphisms (SNPs) in eight TLR pathway genes by single-base extension. Prevalence of the variant allele was compared between cases and controls using Fisher's exact test. RESULTS: In our cohort of 271 infants, 15 infants (5.6%) developed NEC, and five died from it. Infants with NEC were less mature (P < 0.001), and were more likely to be African-American (P = 0.007). SNPs in the TLR2, TLR4, TLR5, TLR9, IRAK1, and TIRAP genes were not associated with NEC. The NFKB1 (g.-24519delATTG) variant was present in all infants with NEC but only in 65% of infants without NEC (P = 0.003), while the NFKBIA (g.-1004A>G) variant was present in 13.3% of infants with NEC but in 49% of infants without NEC (P = 0.007). After correcting for multiple comparisons, the NFKB1 and NFKBIA variants remained associated with NEC (P < 0.05). CONCLUSIONS: These data suggest that TLR genetic variants can alter susceptibility to NEC in VLBW infants and support the hypothesis that genetically programmed differences in the innate immune response contribute to NEC pathogenesis.