A minimum evaluation protocol and stepped-wedge cluster randomized trial of ACCESS Open Minds, a large Canadian youth mental health services transformation project.

BACKGROUND: Many Canadian adolescents and young adults with mental health problems face delayed detection, long waiting lists, poorly accessible services, care of inconsistent quality and abrupt or absent inter-service transitions. To address these issues, ACCESS Open Minds, a multi-stakeholder network, is implementing and systematically evaluating a transformation of mental health services for youth aged 11 to 25 at 14 sites across Canada. The transformation plan has five key foci: early identification, rapid access, appropriate care, the elimination of age-based transitions between services, and the engagement of youth and families. METHODS: The ACCESS Open Minds Research Protocol has multiple components including a minimum evaluation protocol and a stepped-wedge cluster randomized trial, that are detailed in this paper. Additional components include qualitative methods and cost-effectiveness analyses. The services transformation is being evaluated at all sites via a minimum evaluation protocol. Six sites are participating in the stepped-wedge trial whereby the intervention (a service transformation along the key foci) was rolled out in three waves, each commencing six months apart. Two sites, one high-population and one low-population, were randomly assigned to each of the three waves, i.e., randomization was stratified by population size. Our primary hypotheses pertain to increased referral numbers, and reduced wait times to initial assessment and to the commencement of appropriate care. Secondary hypotheses pertain to simplified pathways to care; improved clinical, functional and subjective outcomes; and increased satisfaction among youth and families. Quantitative measures addressing these hypotheses are being used to determine the effectiveness of the intervention. DISCUSSION: Data from our overall research strategy will help test the effectiveness of the ACCESS Open Minds transformation, refine it further, and inform its scale-up. The process by which our research strategy was developed has implications for the practice of research itself in that it highlights the need to actively engage all stakeholder groups and address unique considerations in designing evaluations of complex healthcare interventions in multiple, diverse contexts. Our approach will generate both concrete evidence and nuanced insights, including about the challenges of conducting research in real-world settings. More such innovative approaches are needed to advance youth mental health services research. TRIAL REGISTRATION NUMBER: Clinicaltrials.gov, ISRCTN23349893 (Retrospectively registered: 16/02/2017).

Transforming child and youth mental health care: ACCESS Open Minds New Brunswick in the rural Francophone region of the Acadian Peninsula.

AIM: This paper describes how the transformation of youth mental health services in the rural Francophone region of the Acadian Peninsula in New Brunswick, Canada, is meeting the five objectives of ACCESS Open Minds. METHODS: Implementation of the ACCESS Open Minds framework of care in the Acadian Peninsula of New Brunswick began in 2016 at a well-established volunteer centre and community-based mental health organization. Through focus groups with youth aged 14 to 22 (n = 13), community mapping was used to describe the youth-related mental health service transformation, followed by thematic analysis, validation by member checking and triangulation. RESULTS: Preliminary results show a generally successful implementation of the ACCESS Open Minds model, as evidenced by the transformation of mental health service provision, the enhancement of capacity in human resources and the participation of youth. Transformation was evidenced across the five objectives of mental healthcare of ACCESS Open Minds, albeit to variable extents. Several facilitating factors and challenges are identified based on youths' accounts. CONCLUSIONS: It is possible to successfully implement the ACCESS Open Minds model among francophones living in a minority setting and despite the constraints of a rural area. Most key components of the framework were implemented with high program fidelity. The rural context presents unique challenges that require creative and effective use of resources, while offering opportunities that arise from a culture of resourcefulness and collaboration.

Canadian response to need for transformation of youth mental health services: ACCESS Open Minds (Esprits ouverts).

AIM: Youth mental health is of paramount significance to society globally. Given early onset of mental disorders and the inadequate access to appropriate services, a meaningful service transformation, based on globally recognized principles, is necessary. The aim of this paper is to describe a national Canadian project designed to achieve transformation of mental health services and to evaluate the impact of such transformation on individual and system related outcomes. METHOD: We describe a model for transformation of services for youth with mental health and substance abuse problems across 14 geographically, linguistically and culturally diverse sites, including large and small urban, rural, First Nations and Inuit communities as well as homeless youth and a post-secondary educational setting. The principles guiding service transformation and objectives are identical across all sites but the method to achieve them varies depending on prevailing resources, culture, geography and the population to be served and how each community can best utilize the extra resources for transformation. RESULTS: Each site is engaged in community mapping of services followed by training, active stakeholder engagement with youth and families, early case identification initiatives, providing rapid access (within 72 hours) to an assessment of the presenting problems, facilitating connection to an appropriate service within 30 days (if required) with no transition based on age within the 11 to 25 age group and a structured evaluation to track outcomes over the period of the study. CONCLUSIONS: Service transformation that is likely to achieve substantial change involves very detailed and carefully orchestrated processes guided by a set of values, principles, clear objectives, training and evaluation. The evidence gathered from this project can form the basis for scaling up youth mental health services in Canada across a variety of environments.

The psychological disengagement model among women in science, engineering, and technology.

Psychological responses to personal relative deprivation based on self/outgroup comparisons (named self/outgroup PRD) were explored among women in science, engineering, and technology according to the Psychological Disengagement Model. Three studies revealed that the experience of self/outgroup PRD increased women's likelihood of discounting the feedback they received at work. In turn, discounting led them to devalue their profession. Each study further documented the damaging effect of both psychological disengagement mechanisms. Study 1 (N = 93) revealed that discounting and devaluing were associated with decreased self-esteem. These results were replicated in Studies 2 and 3. Study 2 (N = 163) demonstrated that discounting and devaluing were also associated with reduced self-esteem stability. Study 3 (N = 187) further showed that psychological disengagement was also associated with women's occupational commitment. Theoretical and practical implications of these results are considered.

Profile of lipid and protein autacoids in diabetic vitreous correlates with the progression of diabetic retinopathy.

OBJECTIVE: This study was aimed at obtaining a profile of lipids and proteins with a paracrine function in normal and diabetic vitreous and exploring whether the profile correlates with retinal pathology. RESEARCH DESIGN AND METHODS: Vitreous was recovered from 47 individuals undergoing vitreoretinal surgery: 16 had nonproliferative diabetic retinopathy (NPDR), 15 had proliferative diabetic retinopathy, 7 had retinal detachments, and 9 had epiretinal membranes. Protein and lipid autacoid profiles were determined by protein arrays and mass spectrometry-based lipidomics. RESULTS: Vitreous lipids included lipoxygenase (LO)- and cytochrome P450 epoxygenase (CYP)-derived eicosanoids. The most prominent LO-derived eicosanoid was 5-hydroxyeicosate traenoic acid (HETE), which demonstrated a diabetes-specific increase (P = 0.027) with the highest increase in NPDR vitreous. Vitreous also contained CYP-derived epoxyeicosatrienoic acids; their levels were higher in nondiabetic than diabetic vitreous (P < 0.05). Among inflammatory, angiogenic, and angiostatic cytokines and chemokines, only vascular endothelial growth factor (VEGF) showed a significant diabetes-specific profile (P < 0.05), although a similar trend was noted for tumor necrosis factor (TNF)-alpha. Soluble VEGF receptors R1 and R2 were detected in all samples with lowest VEGF-R2 levels (P < 0.05) and higher ratio of VEGF to its receptors in NPDR and PDR vitreous. CONCLUSIONS: This study is the first to demonstrate diabetes-specific changes in vitreous lipid autacoids including arachidonate and docosahexanoate-derived metabolites indicating an increase in inflammatory versus anti-inflammatory lipid mediators that correlated with increased levels of inflammatory and angiogenic proteins, further supporting the notion that inflammation plays a role the pathogenesis of this disease.

Protein array characterization of bioactive proteins secreted by immortalized human corneal epithelium in response to pseudomonas constituents.

PURPOSE: To use protein arrays to delineate the spectrum of angiogenic bioactive protein modulators that might be secreted and up-regulated by the corneal epithelium in response to killed bacterial products. METHODS: Immortalized human corneal epithelial cells were grown in culture, serum starved, and exposed to heat-killed Pseudomonas aeruginosa in a dose-dependent manner. The resultant culture medium was screened by antibody arrays for 43 proteins that can modulate angiogenesis and immune and inflammatory processes. Parallel analysis was carried out on tears recovered in the open and closed eye phases (OTF and CTF) of the diurnal cycle. RESULTS: Array analysis reveals that the immortalized cells constitutively secrete several proteins and up-regulate the secretion of IL-6, IL-8, and GRO in response to killed bacteria. Also evident was the emergence of a strong signal for GM-CSF and moderate/weak signals for MCP-1, MMP-9, Leptin, and INF gamma in a dose-dependent manner. Several of these proteins, including IL-6, IL-8, GRO, MMP-9, TIMP-1, and MCP-1, accumulate in the CTF. Other proteins are unique to tear fluid. CONCLUSIONS: Nine proteins were identified that are secreted by epithelium in response to killed bacteria that contribute to the innate and adaptive defense system through potentiating PMN and macrophage recruitment, activation, and opsonization in a cooperative manner. The vast majority of these proteins are angiogenic modulators, perhaps contributing to the imbalance between angiogenic and angiostatic processes and risk of corneal vascularization.

Antibody protein array analysis of the tear film cytokines.

PURPOSE: Many bioactive proteins including cytokines are reported to increase in dry eye disease although the specific profile and concentration of inflammatory mediators varies considerably from study to study. In part, this variability results from inherent difficulties in quantifying low abundance proteins in a limited sample volume using relatively low sensitivity dot ELISA methods. Additional complexity comes with the use of pooled samples collected using a variety of techniques and intrinsic variation in the diurnal pattern of individual tear proteins. The current study describes a recent advance in the area of proteomics that has allowed the identification of dozens of low abundance proteins in human tear samples. METHODS: Commercially available stationary phase antibody protein arrays were adapted to improve suitability for use in small volume biological fluid analysis with particular emphasis on tear film proteomics. Arrays were adapted to allow simultaneous screening for a panel of inflammatory cytokines in low volume tear samples collected from individual eyes. RESULTS: A preliminary study comparing tear array results in a small population of Sjögren's syndrome patients was conducted. The multiplex microplate array assays of cytokines in tear fluid present an unanticipated challenge due to the unique nature of tear fluid. The presence of factors that exhibit an affinity for plastic, capture antibodies and IgG and create a complex series of matrix effects profoundly impacting the reliability of dot ELISA, including with elevated levels of background reactivity and reduction in capacity to bind targeted protein. CONCLUSIONS: Preliminary results using tears collected from patients with Sjögren's syndrome reveal methodological advantages of protein array technology and support the concept that autoimmune-mediated dry eye disease has an inflammatory component. They also emphasize the inherent difficulties one can face when interpreting the results of micro-well arrays that result from blooming effects, matrix effects, image saturation and cross-talk between capture and probe antibodies that can greatly reduce signal-to-noise and limit the ability to obtain meaningful results.

Antibody array characterization of inflammatory mediators in allergic and normal tears in the open and closed eye environments.

To evaluate the use of stationary phase protein array technology for tear analysis and to characterize the distribution of inflammatory mediators in normal and allergic tears in the open and closed eye states. Microcapillary tube collected Open (OTF) and closed eye tear fluid (CTF) samples from normals (N), from individuals with various active chronic ocular and other allergies (CA), as well as from an individual subsequent to unilateral induction of an acute allergic conjunctivitis were assayed using membrane arrays that were optimized to allow the detection of GM-CSF, ILs-1 alpha, 1 beta, 2-10, 12-13, INF gamma, MCP-1 and TNFalpha in clinical size samples. The protocol of a micro-well plate array specific for ILs-2, 4, 5, 8, 10, 12, 13, TNFalpha and INF gamma was modified to minimize the impact of tear matrix effects. This was used to carry out parallel analysis on selected samples. By optimizing the protocol as well as the composition of a membrane array it proved possible to significantly increase the signal-to-noise ratio and sensitivity of assay allowing for the detection of some inflammatory mediators into the sub-picogram range. This provided sufficient sensitivity to allow the assay of clinically obtainable size samples. Analysis revealed that OTF from most Ns contained a high level of IL-8 and faint signals if any for the other probed proteins. In contrast, OTF samples from most CA individuals with and without ocular symptoms exhibited to varying degrees detectable levels of most of the other probed entities. The difference between normal and pathological tears and the levels of signals became far more pronounced in the CTF compared to the OTF samples. Use of the micro-well plate assay kit without modification revealed two tear matrix effects that profoundly impact the ability to obtain meaningful ELISA data. Modifying the assay protocol reduces but does not eliminate these artifacts making it possible to approximate the concentration of many of the probed entities. The obtained data is consistent using both methodologies revealing elevated levels of IL-8 and other cytokines in approximately 60% of the OTF samples from the CA population. Other than a modest increase in IL-8, no change could be observed in the profile of OTF after induction of an acute allergic reaction.

Policewomen acting in self-defense: can psychological disengagement protect self-esteem from the negative outcomes of relative deprivation?

The role of 2 components of psychological disengagement (discounting and devaluing) in the relation between personal relative deprivation and self-esteem was explored in 3 samples of policewomen. Path analyses conducted with the 3 samples revealed that stronger feelings of personal relative deprivation resulted in stronger discounting of work evaluations, which in turn led to devaluing the importance of police work. A negative relation between discounting and self-esteem was observed in all samples. Other related outcomes of disengagement, professional withdrawal and stress, were also evaluated.

Membrane array characterization of 80 chemokines, cytokines, and growth factors in open- and closed-eye tears: angiogenin and other defense system constituents.

PURPOSE: To adapt membrane-bound antibody array (MA) technology to characterize the distribution of a wide range of bioactive trace proteins in reflex (RTF) and open-eye (OTF) and closed-eye (CTF) tear samples. METHODS: Tears were collected by capillary tube and centrifuged. A commercially available standard MA and a custom array were modified to maximize the sensitivity of detection and the signal-to-noise ratio, to assay RTF and individually pooled CTF and OTF samples for 80 chemokines, growth factors, cytokines, and angiogenic modulators. The reliability of data was assessed by Western blot and other methods. RESULTS: Coupling an ultrasensitive chemiluminescence substrate system to an MA and optimizing conditions enhanced the sensitivity several hundredfold, allowing the detection of approximately 40 of the 79 probed proteins on the standard array, most of which were shown to be elevated in CTF. Identified entities include the known constituents epidermal growth factor (EGF), monocyte chemoattractant protein (MCP)-1, IL-8, tissue inhibitor of metalloproteinase (TIMP)-1 and -2, and numerous previously undetected tear components, such as angiogenin (ANG), growth factors, and the CXC and CC chemokines IFN-gamma inducible protein (IP)-10, growth-related oncogene (GRO), epithelial neutrophil-activating protein (ENA)-78, and macrophage inflammatory protein (MIP)-3alpha. Identification of other proteins was hindered by high background on the negative control array. Using a less complex custom array dramatically reduced background and allowed the visualization in CTF of proteins, such as VEGF, that were not detected with the standard array. CONCLUSIONS: MAs are powerful tools for differential screening of tears for large numbers of trace proteins. Analysis allowed the identification of previously undetected proteins that may participate in the host defense system as well as demonstrated the profound change in tear composition associated with prolonged eye closure in a manner reflective of physiological function.

Is the cystatin-like domain of TSL functionally active in external ocular infections and during the normal diurnal cycle?

PURPOSE: To test whether the cystatin-like functional domain in tear specific lipocalin (TSL) is functionally active in tears during the normal diurnal cycle and during external ocular infections. METHODS: Capillary tube collected reflex (RTF), open (OTF) and closed (CTF) eye tear samples were recovered from six normals and semi-quantitatively western blot assayed for cystatin C and TSL. CTF samples were immunoprecipitated with antibodies raised against TSL, cystatin C and other antiproteases and screened for the co-precipitation of proteases by casein and gelatin zymography. OTF samples recovered from individuals with viral, fungal and bacterial keratitis were similarly screened for TSL-bound proteases. Human tissue was subjected to immunohistochemical study. RESULTS: Western blot analysis reveals a progressive increase in cystatin C in going from RTF to OTF to CTF samples (approximately 3, 7 and 30 ng microl(-1), respectively). In contrast, the concentration of TSL remains constant (approximately 1500 ng microl(-1)). Immunocytochemistry data show staining of the apical surface of the human conjunctiva and some intra-cellular staining for cystatin C, but not for cystatin A. Zymography confirms earlier data that CTF contains exceptionally high levels of proteases bound to a wide range of specific inhibitors. However, only trace amounts of proteases are complexed with cystatin C and no protease can be detected bound to TSL in either the pathological or CTF samples. CONCLUSION: Although TSL contains a functional cystatin-like domain, it is not physiologically active during the normal diurnal cycle or during external ocular infections. Reactive proteases in CTF are most likely controlled by the presence of excess levels of more reactive cystatins, especially cystatin C, which accumulates during prolonged eye closure. Immunohistochemical data suggest that the apical conjunctiva may be a contributing source for the accumulating cystatin C.