Application of the Key Characteristics of Carcinogens to Bisphenol A.

The ten key characteristics (KCs) of carcinogens are based on characteristics of known human carcinogens and encompass many types of endpoints. We propose that an objective review of the large amount of cancer mechanistic evidence for the chemical bisphenol A (BPA) can be achieved through use of these KCs. A search on metabolic and mechanistic data relevant to the carcinogenicity of BPA was conducted and web-based software tools were used to screen and organize the results. We applied the KCs to systematically identify, organize, and summarize mechanistic information for BPA, and to bring relevant carcinogenic mechanisms into focus. For some KCs with very large data sets, we utilized reviews focused on specific endpoints. Over 3000 studies for BPA from various data streams (exposed humans, animals, in vitro and cell-free systems) were identified. Mechanistic data relevant to each of the ten KCs were identified, with receptor-mediated effects, epigenetic alterations, oxidative stress, and cell proliferation being especially data rich. Reactive and bioactive metabolites are also associated with a number of KCs. This review demonstrates how the KCs can be applied to evaluate mechanistic data, especially for data-rich chemicals. While individual entities may have different approaches for the incorporation of mechanistic data in cancer hazard identification, the KCs provide a practical framework for conducting an objective examination of the available mechanistic data without a priori assumptions on mode of action. This analysis of the mechanistic data available for BPA suggests multiple and inter-connected mechanisms through which this chemical can act.

Halogenated bisphenol a analogues induce PPARγ-independent toxicity within human hepatocellular carcinoma cells.

Tetrabromobisphenol A (TBBPA) and tetrachlorobisphenol A (TCBPA) - both halogenated bisphenol (BPA) analogues - are suspected ligands of peroxisome proliferator-activated receptor gamma (PPARγ). While previous studies have shown that TBBPA and TCBPA activate PPARγ within cell-free assays, the downstream effects of TBBPA- and TCBPA-induced PPARγ activation on cellular transcription and physiology have not been thoroughly investigated. Therefore, the objective of this study was to determine whether exposure to TBBPA or TCBPA (either alone or in combination) alters levels of neutral lipids and fatty acid synthase (FASN) - an enzyme that catalyzes synthesis of long-chain saturated fatty acids - within intact cells in a PPARγ-dependent manner. For this study, we relied on human hepatocellular carcinoma (HepG2) cells as a model since these liver cells express basal levels of PPARγ and have been used to study lipoprotein metabolism and regulation of drug metabolizing enzymes. Although exposure to TBBPA and TCBPA alone did not affect cell viability nor neutral lipid and FASN levels in a concentration-dependent manner, exposure to binary mixtures of TBBPA and TCBPA resulted in a concentration-dependent decrease in cell viability in the absence of concentration-dependent effects on neutral lipid and FASN levels. Interestingly, exposure to TBBPA or TCBPA alone or as a mixture enhanced the effects of a reference PPARγ agonist (ciglitazone) and antagonist (GW 9662) on cell viability (but not neutral lipid levels), suggesting that these two halogenated BPA analogues may interact synergistically with ciglitazone and GW 9662 to induce cytotoxicity. However, overexpression of PPARγ did not mitigate nor enhance the effects of TBBPA - a potent PPARγ ligand predicted by ToxCast's cell-free competitive binding assays - on cell viability, neutral lipid levels, nor the cellular transcriptome. Overall, our findings suggest that halogenated BPA analogues such as TCBPA and TBBPA induce toxicity within HepG2 cells in a PPARγ-independent manner.

Tris(1,3-dichloro-2-propyl) phosphate disrupts the trajectory of cytosine methylation within developing zebrafish embryos.

Tris (1,3-dichloro-2-propyl) phosphate (TDCIPP) is an organophosphate ester-based flame retardant widely used within the United States. Within zebrafish, initiation of TDCIPP exposure at 0.75 h post-fertilization (hpf) reliably disrupts cytosine methylation from cleavage (2 hpf) through early-gastrulation (6 hpf). Therefore, the objective of this study was to determine whether TDCIPP-induced effects on cytosine methylation persist beyond 6 hpf. First, we exposed embryos to vehicle or TDCIPP from 0.75 hpf to 6, 24, or 48 hpf, and then conducted bisulfite amplicon sequencing of a target locus (lmo7b) using genomic DNA derived from whole embryos. Within both vehicle- and TDCIPP-treated embryos, CpG methylation was similar at 6 hpf and CHG/CHH methylation were similar at 24 and 48 hpf (relative to 6 hpf). However, relative to 6 hpf within the same treatment, CpG methylation was lower within vehicle-treated embryos at 48 hpf and TDCIPP-treated embryos at 24 and 48 hpf - an effect that was driven by acceleration of CpG hypomethylation. Similar to our previous findings with DNA methyltransferase, we found that, even at high µM concentrations, TDCIPP had no effect on zebrafish and human thymine DNA glycosylase activity (a key enzyme that decreases CpG methylation), suggesting that TDCIPP-induced effects on CpG methylation are not driven by direct interaction with thymine DNA glycosylase. Finally, using 5-methylcytosine (5-mC)-specific whole-mount immunochemistry and automated imaging, we found that exposure to TDCIPP increased 5-mC abundance within the yolk of blastula-stage embryos, suggesting that TDCIPP may impact cytosine methylation of maternally loaded mRNAs during the maternal-to-zygotic transition. Overall, our findings suggest that TDCIPP disrupts the trajectory of cytosine methylation during zebrafish embryogenesis, effects which do not appear to be driven by direct interaction of TDCIPP with key enzymes that regulate cytosine methylation.

Relationship between miR-203a inhibition and oil-induced toxicity in early life stage zebrafish (Danio rerio).

Dysregulation of microRNA (miRNA, miR) by environmental stressors influences the transcription of mRNA which may impair organism development and/or lead to adverse physiological outcomes. Early studies evaluating the effects of oil on developmental toxicity in early life stages of fish showed that reductions in expression of miR-203a were associated with enhanced expression of downstream mRNAs that predicted altered eye development, cardiovascular disease, and improper fin development. To better understand the effects of miR-203a inhibition as an outcome of oil-induced toxicity in early life stage (ELS) fish, embryonic zebrafish were injected with an miR-203a inhibitor or treated with 3.5 µM phenanthrene (Phe) as a positive control for morphological alterations of cardiovascular and eye development caused by oil. Embryos treated with Phe had diminished levels of miR-203a at 7 and 72 h after injection. Embryos treated with the miR-203a inhibitor and Phe exhibited a reduced heart rate by 48 h post fertilization (hpf), with an increased incidence of developmental deformities (including pericardial edema, altered eye development, and spinal deformities) and reduced caudal fin length by 72 hpf. There were significant reductions in lens and eye diameters in 120 hpf miR-203a-inhibitor and Phe-treated fish, as well as a significantly reduced number of eye saccades, determined by an optokinetic response (OKR) behavioral assay. The expression of vegfa, which is an important activator during neovascularization, was significantly upregulated in embryos receiving miR-203a inhibitor injections by 7 and 72 hpf with increased trends in vegfa expression in 72 hpf larvae treated with Phe. There were decreasing trends in crx, neurod1, and pde6h expression by 72 hpf in miR-203a inhibitor and Phe treatments, which are involved in photoreceptor function in developing eyes and regulated by miR-203a. These results suggest that an inhibition of miR-203a in ELS fish exhibits an oil-induced toxic response that is consistent with Phe treatment and specifically impacts retinal, cardiac, and fin development in ELS fish.

Informing the Future of Integrated Digital and Clinical Mental Health Care: Synthesis of the Outcomes From Project Synergy.

BACKGROUND: Globally, there are fundamental shortcomings in mental health care systems, including restricted access, siloed services, interventions that are poorly matched to service users' needs, underuse of personal outcome monitoring to track progress, exclusion of family and carers, and suboptimal experiences of care. Health information technologies (HITs) hold great potential to improve these aspects that underpin the enhanced quality of mental health care. OBJECTIVE: Project Synergy aimed to co-design, implement, and evaluate novel HITs, as exemplified by the InnoWell Platform, to work with standard health care organizations. The goals were to deliver improved outcomes for specific populations under focus and support organizations to enact significant system-level reforms. METHODS: Participating health care organizations included the following: Open Arms-Veterans & Families Counselling (in Sydney and Lismore, New South Wales [NSW]); NSW North Coast headspace centers for youth (Port Macquarie, Coffs Harbour, Grafton, Lismore, and Tweed Heads); the Butterfly Foundation's National Helpline for eating disorders; Kildare Road Medical Centre for enhanced primary care; and Connect to Wellbeing North Coast NSW (administered by Neami National), for population-based intake and assessment. Service users, families and carers, health professionals, and administrators of services across Australia were actively engaged in the configuration of the InnoWell Platform to meet service needs, identify barriers to and facilitators of quality mental health care, and highlight potentially the best points in the service pathway to integrate the InnoWell Platform. The locally configured InnoWell Platform was then implemented within the respective services. A mixed methods approach, including surveys, semistructured interviews, and workshops, was used to evaluate the impact of the InnoWell Platform. A participatory systems modeling approach involving co-design with local stakeholders was also undertaken to simulate the likely impact of the platform in combination with other services being considered for implementation within the North Coast Primary Health Network to explore resulting impacts on mental health outcomes, including suicide prevention. RESULTS: Despite overwhelming support for integrating digital health solutions into mental health service settings and promising impacts of the platform simulated under idealized implementation conditions, our results emphasized that successful implementation is dependent on health professional and service readiness for change, leadership at the local service level, the appropriateness and responsiveness of the technology for the target end users, and, critically, funding models being available to support implementation. The key places of interoperability of digital solutions and a willingness to use technology to coordinate health care system use were also highlighted. CONCLUSIONS: Although the COVID-19 pandemic has resulted in the widespread acceptance of very basic digital health solutions, Project Synergy highlights the critical need to support equity of access to HITs, provide funding for digital infrastructure and digital mental health care, and actively promote the use of technology-enabled, coordinated systems of care.

Triphenyl phosphate-induced pericardial edema is associated with elevated epidermal ionocytes within zebrafish embryos.

Triphenyl phosphate (TPHP) is an organophosphate ester-based plasticizer and flame retardant. The objective of this study was to identify the potential role of epidermal ionocytes in mediating TPHP-induced pericardial edema within zebrafish embryos. Exposure to TPHP from 24 to 72 h post fertilization (hpf) resulted in a significant increase in pericardial edema and the number of ionocytes at 72 hpf relative to time-matched embryos treated with vehicle. In addition, co-exposure of embryos to mannitol (an osmotic diuretic) blocked TPHP-induced pericardial edema and effects on ionocyte abundance. However, knockdown of ATPase1a1.4 - an abundant Na+/K+-ATPase localized to epidermal ionocytes - mitigated TPHP-induced effects on ionocyte abundance but not pericardial edema, whereas co-exposure of embryos to ouabain - a Na+/K+-ATPase inhibitor - enhanced TPHP-induced pericardial edema but not ionocyte abundance. Overall, our findings suggest that TPHP may have multiple mechanisms of toxicity leading to an increase in ionocyte abundance and pericardial edema within developing zebrafish embryos.

Right Care, First Time: Developing a Theory-Based Automated Protocol to Help Clinically Stage Young People Based on Severity and Persistence of Mental Illness.

Most mental disorders emerge before the age of 25 years and, if left untreated, have the potential to lead to considerable lifetime burden of disease. Many services struggle to manage high demand and have difficulty matching individuals to timely interventions due to the heterogeneity of disorders. The technological implementation of clinical staging for youth mental health may assist the early detection and treatment of mental disorders. We describe the development of a theory-based automated protocol to facilitate the initial clinical staging process, its intended use, and strategies for protocol validation and refinement. The automated clinical staging protocol leverages the clinical validation and evidence base of the staging model to improve its standardization, scalability, and utility by deploying it using Health Information Technologies (HIT). Its use has the potential to enhance clinical decision-making and transform existing care pathways, but further validation and evaluation of the tool in real-world settings is needed.

Utilizing systems biology to reveal cellular responses to peroxisome proliferator-activated receptor γ ligand exposure.

Peroxisome proliferator-activated receptor γ (PPARγ) is a nuclear receptor that, upon activation by ligands, heterodimerizes with retinoid X receptor (RXR), binds to PPAR response elements (PPREs), and activates transcription of downstream genes. As PPARγ plays a central role in adipogenesis, fatty acid storage, and glucose metabolism, PPARγ-specific pharmaceuticals (e.g., thiazolidinediones) have been developed to treat Type II diabetes and obesity within human populations. However, to our knowledge, no prior studies have concurrently assessed the effects of PPARγ ligand exposure on genome-wide PPARγ binding as well as effects on the transcriptome and lipidome within human cells at biologically active, non-cytotoxic concentrations. In addition to quantifying concentration-dependent effects of ciglitazone (a reference PPARγ agonist) and GW 9662 (a reference PPARγ antagonist) on human hepatocarcinoma (HepG2) cell viability, PPARγ abundance in situ, and neutral lipids, HepG2 cells were exposed to either vehicle (0.1% DMSO), ciglitazone, or GW 9662 for up to 24 h, and then harvested for 1) chromatin immunoprecipitation-sequencing (ChIP-seq) to identify PPARγ-bound regions across the entire genome, 2) mRNA-sequencing (mRNA-seq) to identify potential impacts on the transcriptome, and 3) lipidomics to identify potential alterations in lipid profiles. Following exposure to ciglitazone and GW 9662, we found that PPARγ levels were not significantly different after 2-8 h of exposure. While ciglitazone and GW 9662 resulted in a concentration-dependent increase in neutral lipids, the magnitude and localization of PPARγ-bound regions across the genome (as identified by ChIP-seq) did not vary by treatment. However, mRNA-seq and lipidomics revealed that exposure of HepG2 cells to ciglitazone and GW 9662 resulted in significant, treatment-specific effects on the transcriptome and lipidome. Overall, our findings suggest that exposure of human cells to PPARγ ligands at biologically active, non-cytotoxic concentrations results in toxicity that may be driven by a combination of both PPARγ-dependent and PPARγ-independent mechanisms.

Utilizing Zebrafish Embryos to Reveal Disruptions in Dorsoventral Patterning.

Dorsoventral (DV) patterning is a key landmark of embryonic development that is primarily regulated by bone morphogenetic protein (BMP) signaling. Disruption of DV patterning can result in downstream effects on cell specification and organogenesis. Zebrafish embryos have been extensively used to understand signaling pathways that regulate DV patterning because zebrafish embryos develop ex utero and, in contrast to mammalian embryos, which develop in utero, can be observed in real time using brightfield and fluorescence microscopy. Embryos with disrupted DV patterning are either dorsalized or ventralized, with lack of development of head or trunk/tail structures, respectively. Although these phenotypes are typically accompanied by effects on BMP signaling, exceptions exist where some drugs or environmental chemicals can disrupt DV patterning in the absence of effects on BMP signaling. Therefore, assessments of DV patterning should be accompanied by BMP signaling-specific readouts to confirm the role of BMP disruption. Here, we describe an exposure paradigm and steps for phenotyping zebrafish embryos for two types of DV defects, dorsalization and ventralization, with a range of severities. In addition, we describe a strategy for whole-mount immunohistochemistry of zebrafish embryos with an antibody specific for phospho-SMAD 1/5/9 (pSMAD 1/5/9), as disruption in pSMAD 1/5/9 localization is indicative of an effect on BMP signaling. Taken together, these protocols describe an initial strategy for evaluating DV patterning defects under various experimental conditions and confirming BMP-mediated DV patterning disruptions, which can be followed by additional studies that aim to uncover mechanisms leading to these adverse phenotypes. © 2021 Wiley Periodicals LLC. Basic Protocol 1: Phenotyping for dorsalization and ventralization Basic Protocol 2: Whole-mount immunohistochemistry with antibody to phospho-SMAD 1/5/9.

Innovative preclinic triage system to guide Australians to the right mental health care first time.

This paper presents a case study of an innovative direct-to-consumer preclinic triage system designed to reduce predicted peak demand for Australian mental health services as a result of COVID-19 and its associated socioeconomic consequences by guiding Australians to the right mental health care first time. Our innovative, digital health solution comprises two components: (1) a highly personalised and measurement-based model of care (Brain and Mind Centre model of care) that considers both the heterogeneity of mental disorders and other underlying comorbidities, as well as clinical staging; and (2) a health information technology (i.e. the InnoWell Platform). This digital health solution has been embedded as part of standard service delivery into a community-based intake service, thus resulting in a redesigned service model. The service model is currently being implemented as part of a pilot feasibility study, the marker of acceptability at the health professional and service level, and is now under active evaluation to determine its effect on outcomes for consumers, health professionals and the service. For the purposes of this paper, this model served as a prototype for the preclinic triage system that was conceptualised for national scalability at the primary health network level. When implemented at a national level, our direct-to-consumer preclinic triage system is expected to be an effective population health demand management strategy to address the rapidly emerging mental health demand crisis in Australia, and is aligned with the recent recommendation from the Productivity Commission to develop a sustainable national digital platform to facilitate the assessment and referral process to ensure access to mental health care matched to an individual's level of need.What is known about the topic?Although there is increased recognition of the mental health demand crisis in Australia as a result of the COVID-19 pandemic, little has been done to 'flatten' the curve. The Australian Government committed additional funding to support the Better Access Pandemic Support measure; however, this approach to care fails to appreciate both the disparities in service availability across Australia and the gap fees that are prohibitive to some of those seeking help. Furthermore, the expansion of this program may only result in those in care remaining in care, thus further delaying access to those in need.What does this paper add?This paper describes a digital health solution, comprised of a highly personalised and measurement-based model of care coupled with a health information technology, that has been embedded as part of standard service delivery. Consumers seeking mental health care complete a multidimensional self-report assessment via the technology, the results of which are available in real-time and used to facilitate triage to pathways of care as indicated by the severity of the consumer's illness and level of need to more effectively and efficiently allocate consumers to care. The redesigned service model is now under active evaluation to determine its effects on outcomes at consumer, health professional and service levels.What are the implications for practitioners?The redesigned local service model served as a prototype for our innovative direct-to-consumer preclinic triage system specifically designed to allocate consumers to self-management, ambulatory care or acute care based on clinical stage and level of need. It is our hypothesis that the preclinic triage system will be an effective population health demand management strategy. Importantly, the proposed preclinic triage system aligns with the recent recommendation from the Productivity Commission for the Australian Government to fund the development and sustained implementation of a digital platform to facilitate assessment and referral to evidence-based interventions matched to a consumer's level of need.

Implementing a digital health model of care in Australian youth mental health services: protocol for impact evaluation.

BACKGROUND: The World Economic Forum has recently highlighted substantial problems in mental health service provision and called for the rapid deployment of smarter, digitally-enhanced health services as a means to facilitate effective care coordination and address issues of demand. In mental health, the biggest enabler of digital solutions is the implementation of an effective model of care that is facilitated by integrated health information technologies (HITs); the latter ensuring the solution is easily accessible, scalable and sustainable. The University of Sydney's Brain and Mind Centre (BMC) has developed an innovative digital health solution - delivered through the Youth Mental Health and Technology Program - which incorporates two components: 1) a highly personalised and measurement-based (data-driven) model of youth mental health care; and 2) an industrial grade HIT registered on the Australian Register of Therapeutic Goods. This paper describes a research protocol to evaluate the impact of implementing the BMC's digital health solution into youth mental health services (i.e. headspace - a highly accessible, youth-friendly integrated service that responds to the mental health, physical health, alcohol or other substance use, and vocational concerns of young people aged 12 to 25 years) within urban and regional areas of Australia. METHODS: The digital health solution will be implemented into participating headspace centres using a naturalistic research design. Quantitative and qualitative data will be collected from headspace health professionals, service managers and administrators, as well as from lead agency and local Primary Health Network (PHN) staff, via service audits, Implementation Officer logs, online surveys, and semi-structured interviews, at baseline and then three-monthly intervals over the course of 12 months. DISCUSSION: At the time of publication, six headspace centres had been recruited to this study and had commenced implementation and impact evaluation. The first results are expected to be submitted for publication in 2021. This study will focus on the impact of implementing a digital health solution at both a service and staff level, and will evaluate digital readiness of service and staff adoption; quality, usability and acceptability of the solution by staff; staff self-reported clinical competency; overall impact on headspace centres as well as their lead agencies and local PHNs; and social return on investment.

Stage-dependent and regioselective toxicity of 2- and 6-hydroxychrysene during Japanese medaka embryogenesis.

Exposure to oxygenated polycyclic aromatic hydrocarbons (oxy-PAHs) at critical developmental time-points in fish models impairs red blood cell concentrations in a regioselective manner, with 2-hydroxychrysene being more potent than 6-hydroxychrysene. To better characterize this phenomenon, embryos of Japanese medaka (Oryzias latipes) were exposed to 2- or 6-hydroxychrysene (0.5, 2, or 5 µM) from 4 h-post-fertilization (hpf) to 7 d-post-fertilization. Following exposure, hemoglobin concentrations were quantified by staining fixed embryos with o-dianisidine (a hemoglobin-specific dye) and stained embryos were imaged using brightfield microscopy. Exposure to 2-hydroxychrysene resulted in a concentration-dependent decrease in hemoglobin relative to vehicle-exposed embryos, while only the highest concentration of 6-hydroxychrysene resulted in a significant decrease in hemoglobin. All tested concentrations of 2-hydroxychrysene also caused significant mortality (12.2 % ± 2.94, 38.9 % ± 14.4, 85.6 % ± 11.3), whereas mortality was not observed following exposure to 6-hydroxychrysene. Therefore, treatment of embryos with 2-hydroxychrysene at various developmental stages and durations was subsequently conducted to identify key developmental landmarks that may be targeted by 2-hydroxychrysene. A sensitive window of developmental toxicity to 2-hydroxychrysene was found between 52-100 hpf, with a 24 h exposure to 10 µM 2-hydroxychrysene resulting in significant anemia and mortality. Since exposure to 2-hydroxychrysene from 52 to 100 hpf, a window that includes liver morphogenesis in medaka, resulted in the highest magnitude of toxicity, liver development and function may have a role in 2-hydroxychrysene developmental toxicity.

Recommendations for Designing Health Information Technologies for Mental Health Drawn From Self-Determination Theory and Co-design With Culturally Diverse Populations: Template Analysis.

BACKGROUND: Culturally diverse populations (including Aboriginal and Torres Strait Islander people, people of diverse genders and sexualities, and culturally and linguistically diverse people) in nonurban areas face compounded barriers to accessing mental health care. Health information technologies (HITs) show promising potential to overcome these barriers. OBJECTIVE: This study aims to identify how best to improve a mental health and well-being HIT for culturally diverse Australians in nonurban areas. METHODS: We conducted 10 co-design workshops (N=105 participants) in primary youth mental health services across predominantly nonurban areas of Australia and conducted template analysis on the workshop outputs. Owing to local (including service) demographics, the workshop participants naturalistically reflected culturally diverse groups. RESULTS: We identified 4 main themes: control, usability, affirmation, and health service delivery factors. The first 3 themes overlap with the 3 basic needs postulated by self-determination theory (autonomy, competence, and relatedness) and describe participant recommendations on how to design an HIT. The final theme includes barriers to adopting HITs for mental health care and how HITs can be used to support care coordination and delivery. Hence, it describes participant recommendations on how to use an HIT. CONCLUSIONS: Although culturally diverse groups have specific concerns, their expressed needs fall broadly within the relatively universal design principles identified in this study. The findings of this study provide further support for applying self-determination theory to the design of HITs and reflect the tension in designing technologies for complex problems that overlap multiple medical, regulatory, and social domains, such as mental health care. Finally, we synthesize the identified themes into general recommendations for designing HITs for mental health and provide concrete examples of design features recommended by participants.

Recommendations for Implementing Gamification for Mental Health and Wellbeing.

Gamification is increasingly being proposed as a strategy to increase engagement for mental health and wellbeing technologies. However, its implementation has been criticized as atheoretical, particularly in relation to behavior change theory and game studies theories. Definitions of the term "gamification" vary, sometimes widely, between and within academic fields and the effectiveness of gamification is yet to be empirically established. Despite this, enthusiasm for developing gamified mental health technologies, such as interventions, continues to grow. There is a need to examine how best to implement gamification in mental health and wellbeing technologies in a way that takes quick production cycles into account while still emphasizing empirical investigation and building a rigorous evidence base. With reference to game studies and the medical (eHealth/mHealth) literature, this article interrogates gamification for mental health and wellbeing by examining core properties of the game form. It then explores how gamification can best be conceptualized and implemented for mental health and wellbeing goals from conceptualization through to iterative co-development and evaluation that accommodates software development schedules. Finally, it summarizes its conceptual analysis into recommendations for researchers and designers looking to do so. These recommendations are: (1) assess suitability, (2) implement to support, (3) assess acceptability, (4) evaluate impact, and (5) document comprehensively. These recommendations aim to encourage clear language, unified terminology, the application and evaluation of theory, comprehensive and constant documentation, and transparent evaluation of outcomes.

Flip the Clinic: A Digital Health Approach to Youth Mental Health Service Delivery During the COVID-19 Pandemic and Beyond.

The demand for mental health services is projected to rapidly increase as a direct and indirect result of the COVID-19 pandemic. Given that young people are disproportionately disadvantaged by mental illness and will face further challenges related to the COVID-19 pandemic, it is crucial to deliver appropriate mental health care to young people as early as possible. Integrating digital health solutions into mental health service delivery pathways has the potential to greatly increase efficiencies, enabling the provision of "right care, first time." We propose an innovative digital health solution for demand management intended for use by primary youth mental health services, comprised of (1) a youth mental health model of care (ie, the Brain and Mind Centre Youth Model) and (2) a health information technology specifically designed to deliver this model of care (eg, the InnoWell Platform). We also propose an operational protocol of how this solution could be applied to primary youth mental health service delivery processes. By "flipping" the conventional service delivery models of majority in-clinic and minority web-delivered care to a model where web-delivered care is the default, this digital health solution offers a scalable way of delivering quality youth mental health care both in response to public health crises (such as the COVID-19 pandemic) and on an ongoing basis in the future.

Naturalistic evaluation of a sport-themed mental health and wellbeing app aimed at men (MindMax), that incorporates applied video games and gamification.

INTRODUCTION: While men display lower help-seeking rates than women, there is a lack of mental health interventions targeting men. To address this issue, we developed a smartphone app named MindMax, an Australian Football League (AFL)-themed app containing psychoeducational modules teaching strategies derived from positive psychology and acceptance and commitment therapy. MindMax also incorporates gamification, casual video games, and social connection and is intended to appeal to male Australians interested in AFL. This study reports results from a naturalistic trial intended to investigate whether using MindMax was associated with improved wellbeing, resilience, and help-seeking intentions. METHODS: We conducted a naturalistic trial from July 2017 to May 2018, where participants were given access to MindMax to use as they wished, and asked to answer wellbeing surveys at multiple time points. As we employed a customised version of the General Help-Seeking Questionnaire (GHSQ), we conducted an exploratory factor analysis and extracted two factors that we interpreted as 'personal help-seeking' and 'impersonal help-seeking'. Mixed design MANOVAs were conducted with flourishing, resilience, personal help-seeking, impersonal help-seeking, relatedness, and sense of connection (self-group overlap) to the MindMax community to assess change between Day 1-30 and Day 1-60. RESULTS: 313 participants (174/313, 55.6% female; 131/313, 41.9% male) completed the survey at baseline and at least one follow-up survey. We observed significant 30-day and 60-day increases in impersonal help-seeking intentions and sense of connection to the MindMax community, and 60-day increases in flourishing. 30-day increases in sense of connection were highest in our male participants with high base wellbeing, present in our female participants, and not present in our male participants with low base wellbeing. 60-day increases in sense of connection were higher in high-wellbeing participants than in low-wellbeing participants. DISCUSSION/CONCLUSION: Our findings are encouraging as they could be attributed to participants' exposure to MindMax. However, they could also be attributed to other factors that may also have motivated trial participation. Future research can consider investigating more explicitly the role of conformity to masculine norms and how that may affect uptake of mHealth technologies and help-seeking behaviour.

Involving End Users in Adapting a Spanish Version of a Web-Based Mental Health Clinic for Young People in Colombia: Exploratory Study Using Participatory Design Methodologies.

BACKGROUND: Health information technologies (HITs) hold enormous promise for improving access to and providing better quality of mental health care. However, despite the spread of such technologies in high-income countries, these technologies have not yet been commonly adopted in low- and middle-income countries. People living in these parts of the world are at risk of experiencing physical, technological, and social health inequalities. A possible solution is to utilize the currently available HITs developed in other counties. OBJECTIVE: Using participatory design methodologies with Colombian end users (young people, their supportive others, and health professionals), this study aimed to conduct co-design workshops to culturally adapt a Web-based Mental Health eClinic (MHeC) for young people, perform one-on-one user-testing sessions to evaluate an alpha prototype of a Spanish version of the MHeC and adapt it to the Colombian context, and inform the development of a skeletal framework and alpha prototype for a Colombian version of the MHeC (MHeC-C). METHODS: This study involved the utilization of a research and development (R&D) cycle including 4 iterative phases: co-design workshops; knowledge translation; tailoring to language, culture, and place (or context); and one-on-one user-testing sessions. RESULTS: A total of 2 co-design workshops were held with 18 users-young people (n=7) and health professionals (n=11). Moreover, 10 users participated in one-on-one user-testing sessions-young people (n=5), supportive others (n=2), and health professionals (n=3). A total of 204 source documents were collected and 605 annotations were coded. A thematic analysis resulted in 6 themes (ie, opinions about the MHeC-C, Colombian context, functionality, content, user interface, and technology platforms). Participants liked the idea of having an MHeC designed and adapted for Colombian young people, and its 5 key elements were acceptable in this context (home page and triage system, self-report assessment, dashboard of results, booking and video-visit system, and personalized well-being plan). However, to be relevant in Colombia, participants stressed the need to develop additional functionality (eg, phone network backup; chat; geolocation; and integration with electronic medical records, apps, or electronic tools) as well as an adaptation of the self-report assessment. Importantly, the latter not only included language but also culture and context. CONCLUSIONS: The application of an R&D cycle that also included processes for adaptation to Colombia (language, culture, and context) resulted in the development of an evidence-based, language-appropriate, culturally sensitive, and context-adapted HIT that is relevant, applicable, engaging, and usable in both the short and long term. The resultant R&D cycle allowed for the adaptation of an already available HIT (ie, MHeC) to the MHeC-C-a low-cost and scalable technology solution for low- and middle-income countries like Colombia, which has the potential to provide young people with accessible, available, affordable, and integrated mental health care at the right time.

Ciglitazone-a human PPARγ agonist-disrupts dorsoventral patterning in zebrafish.

Peroxisome proliferator-activated receptor γ (PPARγ) is a ligand-activated transcription factor that regulates lipid/glucose homeostasis and adipocyte differentiation. While the role of PPARγ in adipogenesis and diabetes has been extensively studied, little is known about PPARγ function during early embryonic development. Within zebrafish, maternally-loaded pparγ transcripts are present within the first 6 h post-fertilization (hpf), and de novo transcription of zygotic pparγ commences at ~48 hpf. Since maternal pparγ transcripts are elevated during a critical window of cell fate specification, the objective of this study was to test the hypothesis that PPARγ regulates gastrulation and dorsoventral patterning during zebrafish embryogenesis. To accomplish this objective, we relied on (1) ciglitazone as a potent PPARγ agonist and (2) a splice-blocking, pparγ-specific morpholino to knockdown pparγ. We found that initiation of ciglitazone-a potent human PPARγ agonist-exposure by 4 hpf resulted in concentration-dependent effects on dorsoventral patterning in the absence of epiboly defects during gastrulation, leading to ventralized embryos by 24 hpf. Interestingly, ciglitazone-induced ventralization was reversed by co-exposure with dorsomorphin, a bone morphogenetic protein signaling inhibitor that induces strong dorsalization within zebrafish embryos. Moreover, mRNA-sequencing revealed that lipid- and cholesterol-related processes were affected by exposure to ciglitazone. However, pparγ knockdown did not block ciglitazone-induced ventralization, suggesting that PPARγ is not required for dorsoventral patterning nor involved in ciglitazone-induced toxicity within zebrafish embryos. Our findings point to a novel, PPARγ-independent mechanism of action and phenotype following ciglitazone exposure during early embryonic development.

Complex Interplay Among Nuclear Receptor Ligands, Cytosine Methylation, and the Metabolome in Driving Tris(1,3-dichloro-2-propyl)phosphate-Induced Epiboly Defects in Zebrafish.

Tris(1,3-dichloro-2-propyl)phosphate (TDCIPP) is a high-production-volume organophosphate flame retardant (OPFR) that induces epiboly defects during zebrafish embryogenesis, leading to the disruption of dorsoventral patterning. Therefore, the objectives of this study were to (1) identify the potential mechanisms involved in TDCIPP-induced epiboly defects and (2) determine whether coexposure to triphenyl phosphate (TPHP)-an OPFR commonly detected with TDCIPP-enhances or mitigates epiboly defects. Although TDCIPP-induced epiboly defects were not associated with adverse impacts on cytoskeletal protein abundance in situ, the coexposure of embryos to TPHP partially blocked TDCIPP-induced epiboly defects. As nuclear receptors are targets for both TPHP and TDCIPP, we exposed the embryos to TDCIPP in the presence or absence of 69 nuclear receptor ligands and, similar to TPHP, found that ciglitazone (a peroxisome proliferator-activated receptor γ agonist) and 17ß-estradiol (E2; an estrogen receptor α agonist) nearly abolished TDCIPP-induced epiboly defects. Moreover, E2 and ciglitazone mitigated TDCIPP-induced effects on CpG hypomethylation within the target loci prior to epiboly, and ciglitazone altered TDCIPP-induced effects on the abundance of two polar metabolites (acetylcarnitine and cytidine-5-diphosphocholine) during epiboly. Overall, our results point to a complex interplay among nuclear receptor ligands, cytosine methylation, and the metabolome in both the induction and mitigation of epiboly defects induced by TDCIPP.

Gamification in Apps and Technologies for Improving Mental Health and Well-Being: Systematic Review.

BACKGROUND: There is little research on the application of gamification to mental health and well-being. Furthermore, usage of gamification-related terminology is inconsistent. Current applications of gamification for health and well-being have also been critiqued for adopting a behaviorist approach that relies on positive reinforcement and extrinsic motivators. OBJECTIVE: This study aimed to analyze current applications of gamification for mental health and well-being by answering 3 research questions (RQs). RQ1: which gamification elements are most commonly applied to apps and technologies for improving mental health and well-being? RQ2: which mental health and well-being domains are most commonly targeted by these gamified apps and technologies? RQ3: what reasons do researchers give for applying gamification to these apps and technologies? A systematic review of the literature was conducted to answer these questions. METHODS: We searched ACM Digital Library, CINAHL, Cochrane Library, EMBASE, IEEE Explore, JMIR, MEDLINE, PsycINFO, PubMed, ScienceDirect, Scopus, and Web of Science for qualifying papers published between the years 2013 and 2018. To answer RQ1 and RQ2, papers were coded for gamification elements and mental health and well-being domains according to existing taxonomies in the game studies and medical literature. During the coding process, it was necessary to adapt our coding frame and revise these taxonomies. Thematic analysis was conducted to answer RQ3. RESULTS: The search and screening process identified 70 qualifying papers that collectively reported on 50 apps and technologies. The most commonly observed gamification elements were levels or progress feedback, points or scoring, rewards or prizes, narrative or theme, personalization, and customization; the least commonly observed elements were artificial assistance, unlockable content, social cooperation, exploratory or open-world approach, artificial challenge, and randomness. The most commonly observed mental health and well-being domains were anxiety disorders and well-being, whereas the least commonly observed domains were conduct disorder and bipolar disorders. Researchers' justification for applying gamification to improving mental health and well-being was coded in 59% (41/70) of the papers and was broadly divided into 2 themes: (1) promoting engagement and (2) enhancing an intervention's intended effects. CONCLUSIONS: Our findings suggest that the current application of gamification to apps and technologies for improving mental health and well-being does not align with the trend of positive reinforcement critiqued in the greater health and well-being literature. We also observed overlap between the most commonly used gamification techniques and existing behavior change frameworks. Results also suggest that the application of gamification is not driven by health behavior change theory, and that many researchers may treat gamification as a black box without consideration for its underlying mechanisms. We call for the inclusion of more comprehensive and explicit descriptions of how gamification is applied and the standardization of applied games terminology within and across fields.